Complete Study Guide

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Library of Congress Cataloging-in-Publication Data Names: Dlugasch, Lucie, author | Story, Lachel, author. | Based on (Work): Story, Lachel. Pathophysiology. Title: Applied pathophysiology for the advanced practice nurse / Lucie Dlugasch & Lachel Story. Description: Burlington, Massachusetts : Jones & Bartlett Learning, [2020] | Includes bibliographical references. Identifiers: LCCN 2019014108 | ISBN 9781284150452 Subjects: | MESH: Pathology | Physiology | Advanced Practice Nursing | Nurses Instruction Classification: LCC RB113 | NLM QZ 140 | DDC 616.07--dc23 LC record available at https://lccn.loc.gov/2019014108

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Contents

Preface Acknowledgments Contributors

Chapter 1 Cellular Function Basic Cell Function and Structure Cellular Components Exchanging Material Energy Production Chromosomes, DNA, and Genes Replication and Differentiation Cellular Organization Types of Tissue Cellular Adaptation and Damage Cellular Adaptation Cellular Injury and Death Neoplasms Benign and Malignant Neoplasms Genetic and Congenital Disorders Patterns of Inheritance Single-Gene Disorders Chromosomal Disorders—Number or Structural Autosomal Aneuploidy X-Linked Aneuploidy Chromosomal Structural Disorders Multifactorial Disorders Chapter Summary References and Resources

Chapter 2 Immunity Innate Immunity Barriers Inflammatory Response Adaptive Immunity Cellular Immunity Humoral Immunity Vaccines Altered Immune Response Hypersensitivity Hypersensitivity by Mechanism Hypersensitivity by Antigen Immunodeficiency Developing a Strong Immune System Chapter Summary References and Resources

Chapter 3 Hematopoietic Function Hematopoietic System Hematopoiesis Hemostasis Lymphoid System Diseases of the White Blood Cells Neutrophils Eosinophils and Basophils Lymphocytes and Monocytes Lymphomas Myelodysplastic Syndrome Leukemias Diseases of the Red Blood Cells Anemia Polycythemia Iron Overload Diseases of the Platelets Thrombocytopenia

Thrombocythemia Diseases of Coagulation or Hemostasis Hemophilia Von Willebrand Disease Disseminated Intravascular Coagulation Thrombophilia Chapter Summary References and Resources

Chapter 4 Cardiovascular Function Anatomy and Physiology Heart Cardiac Cycle Conduction System Blood Vessels Blood Pressure and Cardiac Output Lymphatic System Understanding Conditions That Affect the Cardiovascular System Impaired Cardiac Output: Heart Disease Pericarditis Infective Endocarditis Myocarditis Valvular Disorders Cardiomyopathy Electrical Alterations Heart Failure Congenital Heart Defects Impaired Tissue Perfusion: Vascular Disorders Arterial Disorders Arterial and Venous Disorders Venous Disorders Lymphedema Conditions Resulting in Decreased Cardiac Output and Altered Perfusion Hypertension Shock

Chapter Summary References and Resources

Chapter 5 Pulmonary Function Anatomy and Physiology Understanding Conditions That Affect the Pulmonary System Infectious Disorders Upper Respiratory Tract Infections Lower Respiratory Tract Infections Alterations in Ventilation Asthma—Obstructive Chronic Obstructive Pulmonary Disease Sleep Apnea—Obstructive Cystic Fibrosis—Obstructive Lung Cancer Pleural Effusion Pneumothorax Acute Respiratory Distress Syndrome—Restrictive Alterations in Ventilation and Perfusion Atelectasis—Restrictive Acute Respiratory Failure Chapter Summary References and Resources

Chapter 6 Fluid, Electrolyte, and Acid–Base Homeostasis Fluid and Electrolyte Balance Distribution Fluid Movement Fluid Regulation Electrolytes Fluid and Electrolyte Imbalances Water, Sodium, and Chloride Relationship Fluid Excess Fluid Deficit Sodium Chloride

Potassium Calcium Phosphorus Magnesium Acid–Base Balance pH Regulation Buffers Respiratory Regulation Renal Regulation Compensation Metabolic Acidosis Metabolic Alkalosis Respiratory Acidosis Respiratory Alkalosis Mixed Disorders Arterial Blood Gas Interpretation Chapter Summary References and Resources

Chapter 7 Urinary Function Anatomy and Physiology Structure and Function Urine Formation and Elimination Understanding Conditions That Affect the Urinary System Conditions Resulting in Altered Urinary Elimination Incontinence Neurogenic Bladder Painful Bladder Syndrome/Interstitial Cystitis Congenital Disorders Urinary Tract Infections—Cystitis and Pyelonephritis Urinary Tract Obstructions Tumors and Cysts Benign Prostatic Hyperplasia Conditions Resulting in Impaired Renal Function Polycystic Kidney Disease

Glomerular Disorders Kidney Injury and Disease Chapter Summary References and Resources

Chapter 8 Reproductive Function Anatomy and Physiology Normal Male Reproductive System Normal Female Reproductive System Congenital Disorders Epispadias Hypospadias Cryptorchidism Infertility Issues Disorders of the Penis Erectile Dysfunction Phimosis and Paraphimosis Priapism Disorders of the Testes and Scrotum Hydrocele Varicocele Testicular Torsion Disorders of Pelvic Support Clinical Manifestations Diagnosis and Treatment Menstrual Disorders Abnormal Uterine Bleeding Amenorrhea Heavy and Intermenstrual Bleeding Dysmenorrhea Premenstrual Syndrome Disorders of the Uterus Endometriosis Leiomyomas Disorders of the Ovaries

Ovarian Cysts Polycystic Ovary Syndrome Disorders of the Breasts Benign Breast Masses Mastitis Reproductive Tract Infections Prostatitis Epididymitis Candidiasis Sexually Transmitted Infections Bacterial STIs Viral STIs Protozoan STIs Trichomoniasis Cancers Penile Cancer Prostate Cancer Testicular Cancer Breast Cancer Cervical Cancer Endometrial Cancer and Uterine Sarcoma Ovarian Cancer Chapter Summary References and Resources

Chapter 9 Gastrointestinal Function Anatomy and Physiology Upper Gastrointestinal Tract Lower Gastrointestinal Tract Liver Pancreas Gastrointestinal Changes Associated With Aging Understanding Conditions That Affect the Gastrointestinal System Disorders of the Upper Gastrointestinal Tract and Accessory Organs Congenital Defects

Cleft Lip and Cleft Palate Esophageal Atresia Pyloric Stenosis Dysphagia Vomiting Hiatal Hernia Gastroesophageal Reflux Disease Gastritis Peptic Ulcers Cholelithiasis Disorders of the Liver Hepatitis Cirrhosis Disorders of the Pancreas Pancreatitis Disorders of the Lower Gastrointestinal Tract Diarrhea Constipation Intestinal Obstruction Appendicitis Peritonitis Celiac Disease Inflammatory Bowel Disease Crohn Disease Ulcerative Colitis Irritable Bowel Syndrome Diverticular Disease Cancers Oral Cancer Esophageal Cancer Gastric Cancer Liver Cancer Pancreatic Cancer Colorectal Cancer Chapter Summary

References and Resources

Chapter 10 Endocrine Function Anatomy and Physiology Hormonal Regulation Pituitary Gland and Hypothalamus Pancreas Thyroid Gland Parathyroid Glands Adrenal Glands Understanding Conditions That Affect the Endocrine System Disorders of the Pituitary Gland Hyperpituitarism Hypopituitarism Prolactin Disorders: Prolactinemia Growth Hormone Disorders Antidiuretic Hormone (Vasopressin) Disorders Diabetes Mellitus Type 1 Diabetes Type 2 Diabetes Gestational Diabetes Metabolic Syndrome Clinical Manifestations and Complications Diagnosis and Treatment Obesity Clinical Manifestations Diagnosis and Treatment Disorders of the Thyroid Goiter and Thyroid Nodules Hypothyroidism Hyperthyroidism Disorders of the Parathyroid Glands Hypoparathyroidism Hyperparathyroidism Disorders of the Adrenal Gland

Pheochromocytoma Cushing Syndrome Addison Disease Chapter Summary References and Resources

Chapter 11 Neural Function Anatomy and Physiology Central Nervous System Peripheral Nervous System Autonomic Nervous System Blood Supply to the CNS Understanding Conditions That Affect the Nervous System Congenital Neurologic Disorders Hydrocephalus Spina Bifida Cerebral Palsy Infectious Neurologic Disorders Meningitis Encephalitis Zika Virus Disease Traumatic Neurologic Disorders Brain Injuries Increased Intracranial Pressure Hematomas Diagnosis and Treatment Spinal Cord Injuries Vascular Neurologic Disorders Cerebrovascular Accident Cerebral Aneurysm Arteriovenous Malformations Headache Disorders Migraine Headaches Tension-Type Headaches Cluster Headaches

Seizure Disorders Clinical Manifestations Diagnosis and Treatment Chronic Degenerative Disorders Multiple Sclerosis Parkinson Disease Amyotrophic Lateral Sclerosis Clinical Manifestations Diagnosis and Treatment Myasthenia Gravis Huntington Disease Dementia Alzheimer Disease Vascular Dementia Dementia With Lewy Bodies Frontotemporal Dementia Creutzfeldt-Jakob Disease AIDS Dementia Complex Cancers of the Nervous System Brain Tumors Mental Health Disorders Depressive Disorders Bipolar Disorders Schizophrenia Anxiety Disorders Obsessive-Compulsive Disorders Chapter Summary References and Resources

Chapter 12 Musculoskeletal Function Anatomy and Physiology Bones Bone Remodelling Joints Muscles

Understanding Conditions That Affect the Musculoskeletal System Congenital and Developmental Musculoskeletal Disorders Developmental Hip Dysplasia Osteogenesis Imperfecta Spinal Deviations Traumatic Musculoskeletal Disorders Fractures Dislocations Sprains Strains Child Abuse Bursitis Anatomic-Specific Injuries Low Back Pain Metabolic Bone Disorders Osteoporosis Rickets and Osteomalacia Paget Disease Inflammatory Joint Disorders Osteoarthritis Rheumatoid Arthritis Juvenile Idiopathic Arthritis Gout Ankylosing Spondylitis Chronic Muscle Disorders Muscular Dystrophy Fibromyalgia Bone and Muscle Neoplasms Chapter Summary References and Resources

Chapter 13 Integumentary Function Anatomy and Physiology Epidermis Dermis and Appendages

Subcutaneous Tissue Nails Understanding Conditions That Affect the Integumentary System Congenital Integumentary Disorders Birthmarks Disorders of Melanin Integumentary Changes Associated With Aging Inflammatory Integumentary Disorders Contact Dermatitis Atopic Dermatitis Urticaria Psoriasis Infectious Integumentary Disorders Bacterial Infections Viral Infections Parasitic Infections Traumatic Integumentary Disorders Burns Pressure Injuries Clinical Manifestations Diagnosis and Treatment Chronic Integumentary Disorders Acne Vulgaris Rosacea Integumentary Cancers Manifestations Hair Disorders Nail Disorders Chapter Summary References and Resources

Chapter 14 Sensory Function Anatomy and Physiology Pain Mechanisms Pain Transmission

Types of Pain Eyes Ears Understanding Conditions That Affect the Senses Congenital Sensory Disorders Sensory Conditions Associated With Aging Infectious and Inflammatory Sensory Disorders Traumatic Sensory Disorders Chronic Sensory Disorders Sensory Organ Cancers Miscellaneous Sensory Organ Conditions Chapter Summary References and Resources

Glossary

Index

Preface

Pathophysiology is a critical foundational course for all nurses. Advanced pathophysiology is a core course that must be included in all graduate nursing curriculums preparing nurses in direct care roles. These roles are varied and include nurse practitioners, nurse anesthetists, nurse midwives, clinical nurse specialists, and nurse educators. This text includes content across the life span and content to meet the needs of advanced practice population areas including pediatrics, psychiatric mental health, and gerontology and incorporates information from an acute and primary care focus.

Many pathophysiology books are geared toward undergraduate nursing students and often lack the requisite content and focus to prepare advanced practice nurses. Educators teaching this course often have to create supplementary materials to ensure their students are better prepared for their advanced practice roles. Some of these books are also unwieldly and contain too much information, and educators must often edit texts’ content to make it manageable and understandable. Without a dedicated pathophysiology text available for advanced practice nursing, students are often overwhelmed, and educators are frustrated when teaching this course. This text was developed with these issues in mind and takes a comprehensive yet concise approach to presenting the content.

The text was also developed with the awareness that graduate students have a foundation in pathophysiology yet have different experiences. Students enter advanced pathophysiology with varying numbers of years since they took basic sciences and nursing courses. Therefore, this text serves as a bridge between their basic education and clinical experience and the advanced knowledge necessary for their new advanced roles. Concepts in pathophysiology can be difficult to understand and remember. In this text, concept descriptions are repeated several times within a chapter and between different chapters. As an example, there is an extensive discussion pertaining to osmosis in the cellular function chapter. The concept of osmosis is then briefly described again when discussing the process in the vascular and renal systems. This repetition serves as a prompt for students to remember and see concepts in different contexts, disorders, and practice situations.

Advanced pathophysiology is usually one of the courses students must take in the beginning of their academic programs. This text was written in a format so that students can start to transition into their new roles and think like an advanced

practice nurse. Advanced practice nurses must have the ability to understand and compare and contrast presenting signs and symptoms and then discern between one diagnosis and another. Choices must then be made pertaining to necessary diagnostic tests, and treatment plans need to be developed. The text contains information and examples in a way that helps students to begin mastering these competencies. In each chapter, there are several Application to Practice activities. Within these application activities are case studies that I have developed from real- life scenarios accumulated from 35 years as a practicing nurse (24 of those as an advanced practice registered nurse) and educator. These cases represent common encounters an advanced practice nurse may face in practice. Some of the cases were developed by other faculty who are also expert practicing clinicians and educators. The content in the cases is concise, mimicking typical clinical encounters. These shorter cases allow students to practice what they just read and help them gain understanding and confidence. Several of the application activities have multiple cases that have common features, yet the diagnosis or clinical manifestations may be different. These activities allow the students to develop knowledge necessary to differentiate between clinical presentations, pathogenesis, diagnosis, and treatment.

The chapters are written in a format providing students with information pertaining to the most common scenario and likely underlying disorder. Chapters are organized with overarching concepts and disorders organized by underlying pathophysiologic processes. Disorders that have a common presentation are discussed in a common section as patients come in with concerns and clinical manifestations, not diagnoses. The grouping of common presentations with varying diagnoses is another technique to help students think like an advanced practice nurse and develop critical thinking skills. As an example, when a patient is complaining of a sore throat the various possible diagnoses can include viral pharyngitis, streptococcal pharyngitis, and infectious mononucleosis. Infectious mononucleosis in other texts is often discussed in hematology chapters, and in this text, it is discussed with other common pharyngitis causes. Providing information in this format sets the stage for future courses and clinical encounters where students need to establish a diagnosis based on a patient’s presentation. Tables are also provided to help students understand differentiation between disorders.

Diagnostic links are another tool found throughout each chapter. These diagnostic links provide the student with a background for commonly used diagnostic tests in practice. The links are strategically placed in the chapter where content pertaining to the diagnostic test was just discussed to maximize understanding. As examples, a reticulocyte count is discussed with a description of hematopoiesis or clotting studies are discussed with hemostasis.

The strength of this text is that the content is written in a format linking together multiple concepts from an applied pathophysiologic perspective; a style that is often

lacking in other pathophysiology texts. This text is written to answer the how, when, and why to how things can go wrong, along with guidelines for diagnosis and treatment. With this practical approach to discussing the complex topic of pathophysiology, the student will gain confidence and be prepared to make sound decisions.

Sources APRN Consensus Work Group & National Council of State Boards of Nursing APRN Advisory Committee. (2008). The Consensus Model for APRN Regulation: Licensure, Accreditation, Certification, Education. Retrieved Dec. 9, 2019 from https://www.ncsbn.org/Consensus_Model_for_APRN_Regulation_July_2008.pdf

AACN. (2011). The essentials of master’s education in nursing. Retrieved from http://www.aacn.nche.edu/education-(2011). The essentials of master education in nursing. American Association of Colleges of Nursing.

American Association of Colleges of Nursing and National Organization of Nurse Practitioner Faculties. (2016). Criteria for evaluation of nurse practitioner programs: A report of the National Task Force on quality nurse practitioner education.

Acknowledgments

I would like to thank my husband, Philip, for supporting me during all my career endeavors such as writing this book. You are not only my husband but are also my best friend and are one of the most passionate fellow nurse practitioners I know. Thank you for reviewing many sections in my book. The personal sacrifices you have made for me are immeasurable and have been noticed, and for this I am so grateful. To my daughters, Nicole and Lauren, I thank you for your words and gestures of encouragement and pushing me along the way when I was tired and doubted myself. To Analise, my daughter in heaven who now lives as an eternal part of my soul, I was able to find inspiration in my memories of how passionately you lived your life. I was also fueled by the drive and dedication you displayed in all your pursuits. To my friends and colleagues, thank you for listening and instilling confidence in my abilities. To my mom and stepdad, thanks for picking up the pieces, bringing me food, helping me with the house and just always being there for me; I am lucky to be the recipient of your tireless generosity. I love you both so much. To all my students, I am happiest when I am with you in the classroom. Our discussions, even the contentious ones, energize me and remind me how in health care, information is always evolving and learning is lifelong. Although we may become weary, we must never rest, as we are charged and entrusted with caring for the most important thing in life and that is the health of others.

A big thank you to Lachel Story, my coauthor, who enabled me to embark on this journey, provided much encouragement, and guided me along the way. I am also thankful to the team at Jones & Bartlett Learning: Anna Maria Forger, Tina Chen, and Alex Schab, and many behind-the-scenes people who were supportive and flexible with me throughout this process.

Lucie Dlugasch

First, I would like to thank my husband, Tom, and children, Clayton and Mason, for their never-ending love and encouragement. I would also like to express my deepest gratitude to my mom, Carolyn, and dad, Tommy, because I would not be who I am today without them. I would also like to acknowledge all my students past, present, and future for constantly teaching me more than I could ever teach them and for all their feedback—I heard it and I hope this is more what you had in mind. Finally, I

would like to convey my appreciation to my colleagues for their gracious mentoring and support.

Lachel Story

Contributors

Philip Dlugasch, MSN, APRN, ACNP-BC Intensive Care Unit APRN Jackson Memorial Hospital Adjunct Nursing Instructor University of Miami School of Nursing Lt. Colonel, Retired Chief Nurse United States Air Force

Derrick C. Glymph, CNAP, CRNA, APRN, COL., USAR Nicole Wertheim College of Nursing and Health Sciences Florida International University Miami, Florida

Deana Goldin, PhD, DNP, MSN, APRN, FNP-BC Assistant Clinical Professor and Family Nurse Practitioner Program Leader Nicole Wertheim College of Nursing and Health Sciences Florida International University Miami, Florida

Dana Sherman, DNP, MSN, APRN, ANP-BC, FNP-BC Assistant Clinical Professor Nicole Wertheim College of Nursing and Health Sciences Florida International University Miami, Florida

Reviewers Nicole R. Clark, DNP, FNP-BC Oakland University Rochester, Michigan

Angie M. Fetsko, BSN, RN-BC

Greater Waco Advanced Health Care Academy Waco, Texas

Julian L. Gallegos, PhD, RN, FNP-BC, CNL Touro University Vallejo, California

Mary Knowlton, DNP, RN, CNE Western Carolina University Cullowhee, North Carolina

Leanna R. Miller, DNP, CCRN-CMC, PCCN-CSC, CEN, CNRN, CMSRN, NP Western Kentucky University Bowling Green, Kentucky

Katie Morales, PhD, RN, CNE Berry College Mount Berry, Georgia

Tonya Sawyer-McGee, DNP, MBA, MSN, RN, ACNP Abilene Christian University Abilene, Texas

Crystal Slaughter, DNP, APRN, CNS Saint Francis Medical Center College of Nursing Peoria, Illinois

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C H A P T E R 1

Cellular Function

L E A R N I N G O B J E C T I V E S

Analyze the purpose and function of cellular structures. Analyze how various substances cross the cell membrane. Explain cellular energy sources and production. Discuss the process of protein synthesis. Summarize how cells are organized. Analyze mechanisms of cellular proliferation, differentiation, and adaptation as they relate to disease development. Describe the correlation between genetics, epigenetics, and environment in disease development. Evaluate patterns of inheritance and compare how various disorders are inherited. Differentiate genetic and congenital disorders.

athophysiology inquiry begins with exploring the basic building blocks of living organisms. Cells give organisms their immense diversity. Organisms can be made up of a single cell, such as with bacteria or viruses, or billions of cells,

such as with humans. In humans, these building blocks work together to form tissues, organs, and organ systems. Alterations and maladaptation in these basic units of life are also the foundation for the development of disease.

The impact of disease is evident from the cellular level up to the system level. Knowledge of cellular-level mechanisms, genetics, genomics, and epigenetics have led to scientific breakthrough in the understanding of disease and treatment strategies. Therefore, understanding basic cellular function and dysfunction are core and essential to understanding pathophysiology.

Basic Cell Function and Structure Cells are complex miniorganisms resulting from millions of years of evolution. Individual cells are part of a network of other cells that are grouped together to serve a function and purpose. These groupings of cells are organized into tissues. Groups of tissues then form organs, and groups of organs are organized into systems. Survival of an organism is dependent on these groupings and not just on individual cells. Cells, therefore, must coexist and communicate with each other to proliferate and survive. When this communal environment does not exist, then adaptation or disease occurs. Cells can arise only from a preexisting cell, and through the process of differentiation, cells become specialized to perform certain functions. Cells will vary greatly in size and shape in order to perform certain functions. Despite having varying functions and features, cells have several commonalities such as a nucleus, cytoplasm, and organelles. Cells also have the remarkable ability to exchange materials with their immediate surroundings, obtain energy from organic nutrients, synthesize complex molecules, and replicate themselves.

Cellular Components The basic components of cells include the cytoplasm, organelles (including the nucleus), and cell membrane. The cytoplasm, or protoplasm, is a colorless, viscous liquid containing water, nutrients, ions, dissolved gases, and waste products; this liquid is where the cellular work takes place. The cytoplasm supports all the internal cellular structures called organelles (FIGURE 1-1), which are little organs that perform the work that maintains the cell’s life (TABLE 1-1). The cytoplasm also surrounds the nucleus. The nucleus is usually the largest and most prominent cellular compartment and is the control center of the cell. The nucleus contains all the genetic information (deoxyribonucleic acid, or DNA) and is surrounded by a double membrane. The nucleus regulates cell growth, metabolism, and reproduction. The cell membrane, also called the plasma membrane, is the semipermeable boundary containing the cell and its components (FIGURE 1-2). A lipid bilayer, or fatty double covering, makes up the membrane. The interior surface of the bilayer is uncharged and primarily made up of lipids. The exterior surface of the bilayer is charged and is less fatty than the interior surface. This fatty cover protects the cell from the aqueous environment in which it exists, while allowing it to be permeable to some molecules but not others.

FIGURE 1-1 The cytoplasm contains several organelles.

FIGURE 1-2 A selectively permeable membrane maintains homeostasis by allowing some molecules to pass through, while others may not. (A, B, D) Simple diffusion. (C) Facilitated diffusion.

TABLE 1-1 Overview of Cell Organelles

Organelle Structure Function

Nucleus Round or oval body. Surrounded by nuclear envelope. Largest organelle. Has membrane with pores to allow communication with the cytoplasm.

Contains the genetic information (DNA and histones). Histones (proteins) bind DNA into tight, threadlike packages called chromosomes. Necessary for control of cell structure, function, and replication. Genes are sections of DNA that contain hereditary information.

Nucleolus Round or oval body in the nucleus. Produces ribosomal ribonucleic acid (RNA) subunits (rRNA) and transcribes, processes, and assembles these subunits

which are then sent out to the cell to form into ribosomes.

Endoplasmic reticulum (ER)

Network of membranous tubules in the cytoplasm of the cell. Continuous with nuclear and cell membrane. Smooth endoplasmic reticulum (SER) contains no ribosomes. Rough endoplasmic reticulum (RER) is studded with ribosomes.

SER is involved in the production of phospholipids and has many different functions depending on the cells. RER is the site of the synthesis of lysosomal enzymes and proteins for intracellular and extracellular use.

Ribosomes Small particles found in the cytoplasm. Made of rRNA and ribosomal proteins.

Aid in protein production on the RER and polysomes (messenger RNA and ribosomes). The ribosome along with transfer RNA (tRNA) interpret messenger RNA (mRNA), which carries the genetic material from the DNA.

Golgi complex Series of flattened sacs usually located near the nucleus.

Sorts, chemically modifies, and packages proteins produced on the RER.

Secretory vesicles Membrane-bound vesicles containing proteins produced by the RER and repackaged by the Golgi complex. Contain protein hormones or enzymes.

Store protein hormones or enzymes in the cytoplasm awaiting a signal for release to the outside of the cell.

Food vacuole Membrane-bound vesicle containing material engulfed by the cell.

Stores ingested material and combines with lysosomes. Site of digestion and degradation of engulfed materials (i.e., autophagy).

Lysosome Round, membrane-bound structure containing digestive enzymes (i.e., hydrolases).

Combines with food vacuoles and digests materials engulfed by cells. Lysosome membrane separates digestive enzymes from cytoplasm.

Peroxisomes Small structures containing enzymes. Break down various potentially toxic intracellular molecules and involved in nerve cell myelin sheath development.

Mitochondria Round, oval, or elongated structures with a double membrane. The inner membrane is shaped into folds.

Contains enzymes to convert food into energy. Complete the breakdown of glucose, producing nicotine adenine dinucleotide and adenosine triphosphate (ATP), which is the cell’s fuel source.

Cytoskeleton Network of microtubules and microfilaments in the cell.

Gives the cell internal support, helps transport molecules and some organelles inside the cell, and binds to enzymes of metabolic pathways.

Cilia Small projections of the cell membrane containing microtubules; found on a limited number of cells.

Propel materials along the surface of certain cells.

Flagella Large projections of the cell membrane containing microtubules. In humans, found only on sperm cells.

Provide motile force for sperm cells.

Centrioles Small cylindrical bodies composed of microtubules arranged in nine sets of triplets. Found in animal cells, not plants.

Help organize spindle apparatus necessary for cell division.

Modified from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Exchanging Material Cellular permeability is the ability of the cell to allow passage of some substances through the membrane, while not permitting others to enter or exit (Figure 1-2). To accomplish this process, cells have gates that may be opened or closed by proteins, chemical signals, or electrical charges. Being selectively permeable allows the cell to maintain a state of internal balance, or homeostasis. Some substances have free passage in and out of the cells, including enzymes, glucose, and electrolytes. Enzymes are proteins that facilitate chemical reactions in cells, while glucose is a sugar molecule that provides energy. Electrolytes are chemicals that are charged conductors when they are dissolved in water. Passage across the cell membrane is accomplished through several mechanisms, including diffusion, osmosis, active transport, endocytosis, and exocytosis. Failure of these exchange mechanisms can lead to the development of disease.

Diffusion is the movement of solutes—that is, particles dissolved in a solvent— from an area of higher concentration to an area of lower concentration (FIGURE 1- 3). Simple diffusion will occur until the concentration gradient, which is the difference in concentrations of substances on either side of the membrane, is equal on each side. How fast diffusion will occur depends on the size and polarity of particles and on lipid solubility. Particles that are smaller, such as water, and particles that are lipid soluble, such as steroids, will diffuse faster. The outer charged cell membrane (mainly Ca++) repels polar particles; therefore, diffusion is slower with ions and polarized molecules, such as Na+ and K+, and faster for nonpolarized particles like oxygen. Diffusion is a passive process and cell energy is not expended. Facilitated diffusion is also the movement of substances from an area of higher concentration to an area of lower concentration, but as opposed to simple diffusion, it occurs with the assistance of a carrier molecule (FIGURE 1-4). Energy is not required for this process, and the number of molecules that can be transported in this way is directly equivalent to the concentration of the carrier molecule. Insulin transports glucose into the cells using this method.

FIGURE 1-3 Lipid-soluble substances pass through the membrane directly via simple diffusion from high to low concentration and without a transport protein or ATP.

FIGURE 1-4 Facilitated diffusion and active transport use a transport protein. (A) Water-soluble molecules can also diffuse through membranes with the assistance of proteins but without ATP in facilitated diffusion. (B) Other proteins use energy from ATP to move against concentration gradients in a process called active transport.

Learning Points

Diffusion solution is made of a solvent and solutes. Solvents dissolve solutes. In the human body, the solvent is usually

A water, and the solutes are particles such as sodium, potassium, glucose, urea, and oxygen.

Water is an important solvent—a substance that dissolves solutes (i.e., dissolved particles)—and intracellular amounts must be balanced to maintain cellular health. Water amount across various body compartments is mediated by the process of osmosis (FIGURE 1-5). Osmosis is the movement of water or any other solvent across the cellular membrane from an area of low solute concentration or high water to an area of high solute concentration or low water. The membrane is permeable to the solvent (e.g., water) but not to the solute (e.g., Na+, Cl−). The movement of the solvent (water) usually continues until concentrations of the solute equalize on both sides of the membrane. The solute concentration is the determinant of the ability to attract water, which is termed osmotic pressure. The higher the solute concentration, the higher the osmotic pressure, and more water is drawn into the cell. Osmotic pressure can be used to describe the concentration of a solution. A solution consists of solvent, such as water, and solute, such as Na+, Cl−. Cellular balance of water is critical to cell health because the cell will swell and burst (lysis) if too much water enters the cell membrane. If too much water moves out of the cell, the cell will shrink (crenation). Like simple and facilitated diffusion, osmosis is passive. Osmolality and osmolarity are units of measure of osmotic activity/pressure, and both measures reflect water and electrolyte balance. Osmotic pressure decreases with too much water (e.g., excess hydration, inappropriate antidiuretic hormone—too much causes a person to retain water) and increases with less water or more solutes (e.g., dehydration, hypernatremia).

FIGURE 1-5 (A) When a bag of sugar water is immersed in a solution of pure water, (B) water will diffuse into the bag toward the lower concentrations of water, causing the bag to swell.

In addition to osmotic pressure, hydrostatic pressure, and colloid osmotic pressures (i.e., oncotic pressure) are also factors that affect filtration (movement out) and reabsorption (movement in). Hydrostatic pressure is created by water pushing against the cellular membrane, forcing the water out, which is the opposite of osmotic pressure, which, when higher, draws water in. Osmotic and hydrostatic pressure help regulate fluid balance in the body; an example can be found in the functioning of the kidneys. Oncotic pressure is created by plasma proteins— particularly albumin—and is similar to osmotic pressure as higher pressure draws water in. Like osmotic pressure, oncotic pressure is in opposition to hydrostatic pressure. Patients with low albumin levels (e.g., liver failure) therefore, have a low oncotic pressure and have an inability to draw water into the cell, so the water stays in the interstitial space, resulting in edema.

Diagnostic Link

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Osmolality and Osmolarity and Osmolar Gap smolality and osmolarity are units of measure of osmotic activity/pressure. The results reflect body water and electrolyte balance (sodium in particular) and, therefore, can be used as a reflection of hydration status.

Clinically, the terms are used interchangeably, but there are differences. Osmolality is expressed as milliosmoles of solute/1 kilogram of solvent. The numerator is a reflection of solutes (intracellular and extracellular), mainly sodium and other ions (e.g., bicarbonate, chloride), glucose, and urea. The denominator is the solvent, which is water in urine or water in plasma (serum). The osmolality can be measured with an osmometer or calculated. Normal serum range is 270–300 mosm/kg (mmol/kg). Sodium, glucose, and blood urea nitrogen are used in the calculation. Osmolality is the preferred term when referring to fluids inside the body. Osmolarity is expressed as milliosmoles of solute/1 liter of solution. The denominator is a solution, which is different than the osmolality denominator. The osmolarity is a calculation. Normal serum range is 282–295 mosm/kg (mmol/kg). Osmolarity is best used to describe fluids outside the body. The osmolal gap is a difference between the measured osmolality and the calculated osmolality. Normal gap is about 6 mosmol/L. A high (> 10 mosmol/L) osmolal gap usually occurs with the ingestion of ethanol or toxic alcohols such as methanol (e.g., in windshield wiper fluid) or ethylene glycol (e.g., in anti-freeze products).

Active transport is the movement of a substance from an area of lower concentration to an area of higher concentration, against a concentration gradient (Figure 1-4). This movement involves a carrier molecule, like facilitated diffusion, but energy, usually in the form of adenosine triphosphate (ATP), is required because of the effort necessary to go against the gradient. The sodium-potassium (Na+-K+) pump is an example of active transport (see chapter 4).

Learning Points

Diffusion o illustrate diffusion, consider an elevator filled beyond capacity with people. When the door opens, the people near the door naturally fall out—moving from an area of high concentration to an area with less

concentration with no effort, or energy. In the body, gases are exchanged in the lungs by diffusion. Unoxygenated blood enters the pulmonary capillaries (low concentration of oxygen; high concentration of carbon dioxide), where it picks up oxygen from the inhaled air of the alveoli (high concentration of oxygen; low concentration of carbon dioxide), while dropping off carbon dioxide to the alveoli to be exhaled.

Reproduced from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Learning Points

Osmosis o understand osmosis, envision a plastic bag filled with sugar water (solute) and with holes punched in it that allow only water to pass through them. If this bag is submerged in distilled water (contains no

impurities), the bag will begin to swell because the water is attracted to the sugar. The water shifts to the areas with higher concentrations of sugar (i.e., high solute) in an attempt to dilute the sugar concentrations (Figure 1- 5). So, the high sugar area with low water has a high osmotic pressure attracting water. Osmotic pressure is determined by the solute concentration, not the water amount. In our bodies, osmosis allows the cells to remain hydrated.

Modified from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones &

Bartlett Learning.

Endocytosis is the process of bringing a substance into the cell that is too large to go by other mechanisms (FIGURE 1-6). The cell membrane surrounds the particles, engulfing them. Phagocytosis, or cell eating, occurs when this process involves solid particles. Pinocytosis, or cell drinking, takes place when this process involves a liquid. Components of the immune system use endocytosis, particularly phagocytosis, to consume and destroy bacteria and other foreign material. Exocytosis is the release of materials (typically large particles) from the cell onto the cell membrane, usually with the assistance of a vesicle (a membrane-bound sac) (Figure 1-6). The materials that are deposited onto the cell membrane will either function to replace the part of the membrane that was used during endocytosis or is released. Often glands secrete hormones using exocytosis.

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FIGURE 1-6 (A–C) Cells can engulf large particles, cell fragments, liquids, and even entire cells. (D) Cells can also get rid of large particles.

Learning Points

Active Transport o understand active transport, consider the overfilled elevator again. If the door opens and someone from outside the elevator attempts to get in, it will require a great deal of effort (energy) to enter the full elevator.

The sodium-potassium pump is an example of active transport in the body. Energy is required to move sodium out of the cell where the concentrations are high and move potassium into the cell where the concentrations are high.

Reproduced from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

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Energy Production Energy is needed to fuel cellular activity. Cells can obtain energy from two main sources—the breakdown of glucose (a type of carbohydrate) and the breakdown of triglycerides (a type of fat). Food enters the gastrointestinal tract, where it is broken down into sugars, amino acids, and fatty acids. These substances then are either converted to larger molecules (e.g., glucose to glycogen, amino acids to proteins, and fatty acids to triglycerides and fats), stored until needed, or metabolized to make ATP. When used to make ATP, all three sources of energy (amino acids, sugars, fatty acids) must first be converted. Sugars, through the process of glycolysis (splitting), becomes pyruvate in the cytoplasm. If oxygen is present (i.e., through an aerobic process), pyruvate then becomes acetyl coenzyme A (acetyl CoA). Acetyl CoA is also derived from amino acids and fatty acids. The acetyl CoA then enters the Krebs cycle (i.e., citric acid cycle or tricarboxylic cycle), which is a high-electron-producing process that occurs in the mitochondria. During the Krebs cycle, these molecules go through a complex series of reactions that result in the production of large amounts of ATP. If there is no oxygen present (i.e., anaerobic process), the process of glycolysis will result in a less efficient pathway to create ATP, and the pyruvate becomes lactic acid rather than acetyl CoA. Lactic dehydrogenase (LDH) is the enzyme that catalyzes the conversion of pyruvate to lactic acid. Lactate is produced from lactic acid and can be used as a measure of disease severity.The inefficient anaerobic pathway provides energy to cells with no mitochondria (e.g., red blood cells) or is used during times when oxygen delivery is inadequate, such as during exercise or with tissue hypoxia from disease.

Diagnostic Link

Lactate Levels actate forms predominantly from muscle cells and is cleared by the liver. Lactate levels can rise and can eventually lead to lactic acidosis. Lactate levels are used as a measure of disease severity and outcome or

as a measure of response to therapy. Elevated levels occur when there is an increased production or decreased excretion. Common causes of increased production of lactate include hypoxia from inadequate oxygen uptake from lungs (e.g., respiratory failure), decreased perfusion of oxygen to tissues (e.g., shock), or a combination of both. Lactate levels can also rise even when uptake and perfusion are adequate but demand for oxygen is increased (e.g., exercise). Liver and renal dysfunction can result in decreased metabolism and excretion. Lactate levels are measured in serum or cerebrospinal fluid.

Chromosomes, DNA, and Genes When the cells are replicating, information is being produced and transmitted. That information is packaged in chromosomes, which are in the nucleus of the cell (FIGURE 1-7). A chromosome consists of deoxyribonucleic acid (DNA) and histone and nonhistone proteins. Chromosomes have a well-defined structure. The centromere is an area where the chromosomes are attached. The centromere gives

a chromosome its shape, and because of the shape, genes can be more easily located. DNA consists of a nucleotide where genetic codes are stored. The nucleotide is a double helix strand (it looks like a twisted rope ladder) made of a sugar molecule and phosphate (forms the ladder sides) attached to a nitrogen containing base (forms the ladder steps). If you were to stretch out DNA, it would be up to six feet long. However, DNA is tightly coiled and wound around proteins (like a spool), and it all fits into every cell nucleus. The DNA that is combined and wrapped around the histone proteins is called chromatin. About 99% of DNA is in the nucleus (i.e., nuclear DNA), while less than 1% of DNA is in the mitochondria.

FIGURE 1-7 Diagram of a cell demonstrating that genetic material in the form of DNA is organized into chromosomes. Each chromosome contains thousands of genes in tightly coiled strands of DNA.

The nitrogen bases (steps) of the nucleotide are either purine (adenine and guanine) or pyrimidine (thymine and cytosine). These four nitrogen bases act as letters in an alphabet. These letters come together to form words and sentences (i.e., a person). The bases are in pairs and packaged into the 46 chromosomes of each cell. Adenine pairs only with thymine, and guanine pairs only with cytosine for DNA replication; however, RNA bases are different for transcription (a step to protein building) (FIGURE 1-8 and FIGURE 1-9). Each of these pairings (e.g., adenine/thymine) is called a base pair. There are 3 billion nucleotide base pair sequences available inside the 46 chromosomes (i.e., 23 pairs) located in each cell nucleus. On the DNA are small parts or sections on the double helix known as genes (like tags hanging from the rope ladder). Genes are made of DNA, and multiple genes are on DNA; hence, multiple genes are on a chromosome. Genes are the physical and functional units passed on to offspring and, therefore, form the basis of inheritance. This transmitted gene information forms the genotype or blueprint (karyotype) of a person. The complete set of DNA and genes (i.e., genetic instructions) is called a genome.

FIGURE 1-8 Termination of protein synthesis.

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FIGURE 1-9 Protein synthesis.

Gene function and expression is influenced by many factors, such as the environment. The detectable outward expression of the genotype is termed phenotype. About 20,000–25,000 genes have been identified in nuclear DNA and about 37 genes in mitochondrial DNA. Approximately 1% of nuclear DNA genes serve as instructions (code) to make the body’s basic building blocks and proteins, and the remaining 99% of DNA are noncoding proteins. It is not clear what all these noncoding proteins do, but they are thought to control gene activity such as enhancing or repressing transcription. In other words, only about 1% of DNA has genes that make up a person.

Learning Points

Chromatin Versus Chromosome Versus Chromatid hromatin is used to refer to the DNA coiled up in histone proteins. Chromatin is also loose inside the nucleus waiting for transcription (protein formation). The term chromatin is also used to refer to the

structure inside a chromosome. The coiled-up chromatin loops that are structured are what make up a chromosome. When the chromosome replicates, it creates an identical version of itself, and the pairs attach to each other through a centromere. Each of those separate individual copies is called a chromatid (they are also known as sister chromatids), and the two copies together are called a chromosome.

Learning Points

Genetic Engineering enetic engineering (i.e., genetic modification or manipulation) is the process of genetic or genome alteration with the intent of creating a new genotype and phenotype. The alteration may involve changing

a base pair and adding or deleting whole genes. DNA can be taken from one organism and combined with another organism, which is termed recombinant DNA. Genetic engineering has been used in many areas including developing resilient crop varieties that have a high nutritional value or to allow sheep to produce a protein in their milk that patients with cystic fibrosis can consume. Genetically engineered organisms are called transgenic organisms or more commonly, genetically modified organisms (GMO). The use of GMO for food sources is an area of significant bioethical discussion. While the intent of genetically modifying food is to

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produce a better food product; the potential long-term clinical consequences are an area of concern. Pharmacologic agents are produced through recombinant DNA approaches and a common example is insulin. A piece of human insulin gene is inserted into a loop (plasmid) of bacteria DNA, this combined piece is returned to the bacteria (now a recombinant bacterium), and insulin is produced. Some examples of insulin produced in this manner include insulin glargine and regular insulin. Genetic engineering is a broad term associated with several other concepts such as gene cloning, which is making identical copies of DNA. Polymerase chain reaction (PCR) is a technique to make many copies of a specific DNA segment. PCR is used in laboratory diagnostic tests to identify pathogens or forensic DNA analysis.

Learning Points

Genetic/Genomic Editing; Clustered, Regularly Interspaced Short Palindromic Repeats, and Other Techniques

enetic engineering techniques that were originally used for functions such as locating and creating mutations, were imprecise, time consuming, and costly. In the early 2000s, new techniques to edit genes

and genomes were developed, revolutionizing genetic engineering. These new techniques include clustered, regularly interspaced short palindromic repeats (CRISPR), meganucleases, zinc finger, and transcription activator-like effector-based nucleases. The way these newer techniques can edit genes is by using engineered nucleases, which break DNA strands in desired locations. The CRISPR-Cas9 system is considered the most reliable, fastest, and least expensive of the techniques. With CRISPR, an enzyme called Cas9 is guided by a piece of predesigned guide RNA to cut a specific genome location. At the cut area, the damage is noticed and repaired.

Replication and Differentiation A cell’s basic requirement for life is ensuring that it can reproduce. Many cells divide numerous times throughout the life span, whereas others die and are replaced with new cells. Proliferation is the regulated process by which cells divide and reproduce. The process of growth and division is regulated by protein growth factors known as cytokines and genetic material. Cells do not decide to divide on their own but rather wait for a stimulus from growth factors that comes from neighboring cells. Genes such as proto-oncogenes within the cell direct production of growth factor receptor sites on the cell membrane. Tumor suppressor genes and some growth factors inhibit cell division and differentiation. Replication control and balance is important to prevent abnormal proliferation, termed neoplasms, which can become cancer. While most mature cells can replicate and divide, some are incapable of division and replication, and these cells are found in nerves, muscles, and eye lenses. Cells have a finite number of times in which they can divide, and then they die.

The most common form of cell division, in which the cell divides into two separate cells, is mitosis (FIGURE 1-10). Mitosis is the way somatic (nongamete) cells divide. Meiosis, the second type of cell division, is the way sperm and ova cells (gametes) divide.

FIGURE 1-10 Mitosis and meiosis.

The cell cycle is divided into two key stages: interphase and mitosis (FIGURE 1- 11). Interphase is the phase prior to mitosis and is the time when the cell grows and

prepares for division by producing many substances such as RNA and DNA. Interphase is a crucial phase in the cell cycle and can last anywhere from 18 to 23 hours. Some cells divide quickly, but others divide slowly and can remain in the beginning of interphase from days to years. During interphase, various checkpoints serve as a cell quality control mechanism. Progression through the cell cycle does not occur until the genome is checked and found ready to move into mitosis. As an example, at one of these checkpoints, a tumor suppressor protein (known as p53) ensures that damaged DNA is fixed before proceeding. In several cancers, p53 is mutated and, therefore, damaged DNA is replicated. A focus in tumor biology is the identification of these regulatory proteins so that therapies can be developed to stop abnormal proliferation.

FIGURE 1-11 Cell cycle. © ellepigrafica/Shutterstock.

After interphase, the cell enters mitosis. This process, which lasts about 1 hour, occurs in four steps—prophase, metaphase, anaphase, and telophase. In prophase,

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the chromosomes condense, and the nuclear membrane disintegrates. In metaphase, the spindle fibers attach to centromeres, and the chromosomes align. The chromosomes separate and move to opposite poles in anaphase. Finally, the chromosomes arrive at each pole, and new membranes are formed in telophase. The result in mitosis is the division of one cell, which results in two genetically identical (homologous) and equal diploid daughter cells. Cytokinesis is cytoplasm division.

Meiosis is a form of cell division that occurs only in mature sperm and ova (Figure 1-10). Meiosis also has two key stages—interphase and meiosis (prophase, metaphase, anaphase, telophase). The processes of ova development (oogenesis) and sperm development (spermatogenesis), while similar, have some key differences. Sperm are continually produced, while the ova are not. All the ova in the ovaries remain in a state of prophase for as long as 45 years. Meiosis completion in egg cells occurs during fertilization. As a woman gets older, the ova released are also older. There is a greater risk for abnormal meiosis in these older ova resulting in chromosomal abnormalities and congenital diseases.

After meiosis, an ovum produces 1 daughter cell, sperm produces 4 daughter cells, and each contains 23 chromosomes, which are called haploid cells. The haploid cells are not yet paired with other chromosomes. When the sperm and ova join, a single-cell zygote is formed and becomes diploid during sexual reproduction. The zygote is a mixture of traits with 23 chromosomes transmitted from the mother and 23 from the father. The result is a total of 23 chromosomes pairs (46 total chromosomes). Of the 23 pairs, one pair are sex chromosomes. A homologous XX chromosome will be present if female, and a nonhomologous XY chromosome will be present if male. The other 22 pairs of autosome (somatic) cells are homologous. In summary, each body cell has 23 pairs of chromosomes (46 total), and in each cell are 22 autosome pairs (total 44) and 1 sex chromosome pair (total 2).

Learning Points

Mitochondrial DNA Inheritance uclear DNA is inherited from both parents. However, the small 1% DNA in the mitochondria is only inherited from the maternal lineage as the paternal mitochondrial DNA gets destroyed during fertilization.

Mitochondrial DNA mutations can cause rare diseases such as Leber hereditary optic neuropathy. Mitochondrial DNA diseases can also affect nuclear DNA.

Differentiation (cell maturation) is a process by which cells become specialized in terms of cell type, function, structure, and cell cycle. After fertilization, the zygote starts to divide by mitosis into a blastocyst. Inside this blastocyst is an inner cell mass (embryonic stem cells). Embryonic stem cells go on to become the embryo. The primitive, undifferentiated embryonic stem cells are called pluripotent, as they develop into any kind of cells and ultimately will develop into the over 200

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specialized cells (e.g., cardiac cells, nerve cells) of the adult human. During this early development after fertilization, the embryo is the most susceptible to damage from environmental influences. While embryonic stem cells were used to essentially build a human, the adult stem cells are important in the maintenance and repair of tissue such as skin regeneration or hematopoiesis. Adult stem cells are called multipotent because they can only make cells from their same germ layer. Therefore, multipotent adult stem cells from blood (a mesoderm tissue) can only make other blood cells and not liver cells, which is endodermal tissue. Some adult stem cells are called unipotent as they can only make a single cell type such as precursors to egg or sperm cells. All stem cells, whether embryonic or adult stem cells, can self- produce into more undifferentiated stem cells and can differentiate. Clinically, embryonic cells have been used for therapeutic uses such as retinal disease, spinal cord injury, and diabetes mellitus type 1 because they can make any cells. Cord and placental blood stem cells have been used to treat leukemias. A mature cell that was differentiated can be genetically manipulated to reverts to a pluripotent embryonic type stem cell. These cells are termed induced pluripotent stem (iPS) cells. The iPS cells have been used in Huntington disease and are being evaluated for use in other diseases.

Learning Points

Germ Layers uring ovum development, cells branch out into two groups—a peripheral and inner group. The peripheral group forms tissue that maintains the embryo (e.g., placenta), while the inner group divides into three

levels (ectoderm, mesoderm, endoderm), called germ layers. Each of these layers form different organs and tissues. The ectoderm is the outer, the middle is the mesoderm, and the inner is the endoderm. For example, the brain and spinal cord arise from the ectoderm, while the endoderm forms the digestive system epithelial lining.

Learning Points

Stem Cell Sources mbryonic stem cells are derived from embryos in vitro and not from a pregnant woman. These pluripotent cells are taken from the blastocyst at about 4–5 days after fertilization. Cord blood cells are not from

embryos but, rather, from cord and placental blood after birth. These cells are adult multipotent hematopoietic stem cells.

Cellular Organization Types of Tissue Individual cells do not function in isolation. Each cell is part of a complex community that performs specific functions. Tissues are a group of cells with a common structure and function. There are four major types of tissue—epithelial, connective, muscle, and neural. Groups of tissue form organs such as the liver and kidneys, which have a specific function. A system is a grouping of organs that work together to perform similar and complementary functions, such as the cardiovascular or endocrine system. In order for tissues and organs to form, the cells must recognize, adhere, and migrate toward each other and retain their distinct identity from other cells.

Epithelial Tissue Epithelial tissue lines the outside and all interior areas of the body. Epithelial tissue structure varies depending on the location and function. A single layer of cells is termed simple epithelium, and multiple layers are referred to as stratified epithelium. The epithelial cells can also have different shapes, and there are three types— squamous, cuboidal, and columnar. Epithelial cells have a protective function, such as the stratified squamous epithelia of the skin and other orifices that open to the outside, such as the mouth, esophagus, and vagina. The outer layer of the skin has a fibrous protein called keratin, and through keratinization, these cells shed and are replenished rapidly. Irritants, chemicals, pressure, and other factors can lead to the overproduction of keratin (hyperkeratosis), which is manifested in conditions such as calluses, warts, and eczema. Other functions of the epithelia include absorption, secretion, and excretion.

Connective Tissue Connective tissue is made up of a large extracellular matrix and fibroblast cells that produce several types of fibers. These fibers are in various parts of the body and serve different functions. Connective tissue most commonly functions to support, attach, and store. The three types of fiber are collagen, elastic, and reticular.

Muscle Tissue Muscle tissue is made of fibers, termed myocytes, that consists of the contractile proteins actin and myosin. These proteins bind to each other causing a shortening and lengthening action. At a neuromuscular junction, the neurotransmitter acetylcholine stimulates the muscle fiber.

The fiber stimulation leads to an action potential, which causes depolarization

and the release of calcium. The calcium binds to troponin, and this binding uncovers the actin-binding sites and allows for myosin strands (myosin heads) to pull the actin, leading to contraction. Binding requires energy in the form of ATP. Relaxation occurs when there is no longer a signal or no ATP, calcium is pumped back in, and tropomyosin covers the actin-binding sites.

Muscle fibers are either smooth, cardiac, or skeletal and can be under voluntary (e.g., skeletal movement) or involuntary control (e.g., heart contraction or blood vessels diameter). In general, muscle cells are incapable of replication.

Neural Tissue Neural tissue is composed of neural (nerve) cells called neurons (FIGURE 1-12) whose chief function is to process and transmit information. Neurons have specialized characteristics in comparison to other cells. Neurons have a cell body (i.e., soma), an axon that conduct impulses away from the cell body, and dendrites, which tend to conduct impulses toward the cell body. In addition to neurons, the second type of neural cells are neuroglial (glial) cells. These cells are more numerous than neurons and function in a supporting role. Neuroglial cells consist of astrocytes, oligodendrocytes, Schwann cells, microglia, and ependymal cells. Astrocytes form the framework of the brain and spinal cord and form the blood–brain barrier. Ependymal cells form the epithelial lining of the central nervous system and produce cerebrospinal fluid. The oligodendrocytes are responsible for the development of myelin in the central nervous system. Myelin covers and protects nerves and speeds transmission of impulses. Schwann cells produce myelin, but in the peripheral nervous system. Microglia have phagocytic activities. Nerve cells, like muscle cells, are incapable of division and replication.

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FIGURE 1-12 A motor neuron structure. © Ducu59us/Shutterstock.

BOX 1-1 Application to Practice Understanding the cellular organization is important in understanding diseases and therapies. Read the following scenarios and identify the tissue level discussed.

Scenario 1: A 40-year-old woman has a cervical cytology report with the following findings: Atypical squamous cells of undetermined significance. Choose the tissue level the findings refer to:

Epithelial Connective Muscle Neural

Scenario 2: A 55-year-old woman would like to get hyaluronic injection fillers for her “laugh lines.” Choose the tissue level the injections are administered in:

Epithelial Connective Muscle Neural

Scenario 3: A 40-year-old man is diagnosed with a glioblastoma. Choose the tissue level the disease is affecting:

Epithelial Connective Muscle Neural

Scenario 4: A 72-year-old woman has a cystoscopy/biopsy report with the following findings: transitional cell carcinoma of the bladder. Choose the tissue level the disease is affecting:

Epithelial Connective Muscle Neural

Cellular Adaptation and Damage Cellular Adaptation Cells are constantly exposed to a variety of environmental factors that can cause damage. Cells attempt to prevent their own death from environmental changes through adaptation. They may modify their size, numbers, or types in an attempt to manage these changes and maintain homeostasis. Adaptation may involve one or a combination of these modifications. These modifications may be normal or abnormal depending on whether they were mediated through standard pathways. They may also be permanent or reversible. Nevertheless, adaptation ceases once the stimulus is removed. Specific types of adaptive changes include atrophy, hypertrophy, hyperplasia, metaplasia, and dysplasia (FIGURE 1-13).

FIGURE 1-13 Cellular adaptation: abnormal cellular growth patterns.

Atrophy occurs because of decreased work demands on the cell. The body attempts to work as efficiently as possible to conserve energy and resources. When cellular work demands decrease, the cells decrease in size and number. These

atrophied cells utilize less oxygen, and their organelles decrease in size and number. Causes of atrophy include disuse, denervation, endocrine hypofunction, inadequate nutrition, and ischemia. An example of disuse atrophy can be seen when a muscle shrinks in an extremity that has been in an immobilizing cast for an extended period. Denervation atrophy is closely associated with disuse; it can be seen when a muscle shrinks in a paralyzed extremity. Atrophy because of a loss of endocrine function (e.g., reduced estrogen) can be seen when the reproductive organs (e.g., ovaries) of postmenopausal women shrink. When these organs are not supplied with adequate nutrition and blood flow, cells shrink due to a lack of substances necessary for their survival—much like when water and fertilizer are withheld from a plant.

The opposite of atrophy is hypertrophy. Hypertrophy occurs when cells increase in size (not number), leading to an increase in the affected organ size. Hypertrophy occurs in an attempt to meet increased work demand. This size increase may result from either normal or abnormal changes. Such changes are commonly seen in cardiac and skeletal muscle. For example, consider what happens when a body builder diligently performs biceps curls with weights—the biceps gets larger. This type of hypertrophy is a normal change. An abnormal hypertrophic change can be seen with hypertension. Just as the biceps muscle grows larger from increased work, the cardiac muscle will thicken and enlarge when an increased workload is placed on it because of hypertension. The biceps muscle increases in strength and function when its workload is increased; however, over time the heart loses the flexibility to fill with blood and pump the blood when the cardiac muscle increases in size. This abnormal hypertrophic change can lead to complications such as cardiomyopathy and heart failure (see chapter 4).

Hyperplasia refers to an increase in the number of cells (not size of cell) leading to an increase in the affected organ/tissue size. This increase occurs only in cells that can perform mitotic division, such as epithelial cells. The hyperplasia process can be the result of normal or abnormal stimuli. Examples of normal or beneficial hyperplasia include menstruation, liver regeneration, wound healing, and skin callouses. Hyperplasia can also be pathologic, and under these circumstances is usually the result of abnormal hormonal stimulation. Some examples include endometrial (inner uterine lining) hyperplasia, which can be the result of oversecretion of estrogen leading to an imbalance with progesterone. The endometrial hyperplastic cells can become malignant. While hyperplasia is different from hypertrophy, these processes often occur together because they have similar triggers.

The process in which one adult cell is replaced by another cell type that is less mature is called metaplasia. This change is usually initiated by chronic irritation and inflammation, such that a more virulent cell line emerges. The cell types do not cross over the overarching cell type. For instance, epithelial cells may be converted into another type of epithelial cell, but they will not be replaced with nerve cells.

Metaplastic changes can occur in the airway when the protective columnar cells that usually secrete mucus and have cilia change to stratified squamous epithelium, which does not have the same protective function. In the airway, this metaplasia usually occurs due to chronic smoking or vitamin A deficiency. Metaplasia, just like hyperplasia, does not necessarily lead to cancerous changes; however, if the stimulus is not removed, cancerous changes will likely occur.

The final cellular adaption is dysplasia, which is also called atypical hyperplasia. In dysplasia, cells mutate into cells of a different size, shape, and appearance. Although dysplasia is abnormal, it is potentially reversible by removing the trigger. Dysplastic changes are often implicated as precancerous cells. Areas in the reproductive tract such as the cervix or respiratory tract are common sites for this type of adaptation because of their increased exposure to carcinogens (e.g., human papillomavirus and cigarette smoke).

Cellular Injury and Death Death is a normal part of the human existence, and it is no different at the cellular level. Cellular death can occur due to injury or a programmed cell death, termed apoptosis. Cellular injury can occur in many ways and is usually reversible up to a point. Whether the injury is reversible or irreversible usually depends on the severity of the injury and intrinsic factors (e.g., blood supply, nutritional status). The vulnerability and tolerance of the cell in adverse conditions can influence survival. Brain and cardiac cells can only last a few minutes without oxygen, while connective tissue can last longer. Cell injury can occur for multiple reasons and can include 1) physical agents such as mechanical forces and extreme temperature; 2) chemical injury such as pollution, lead, and drugs; 3) radiation; 4) biologic agents such as viruses, bacteria, and parasites; 5) nutritional imbalances; 6) hypoxia; 7) genetics; and 8) free radicals. In general, ATP is depleted when cells are injured and a whole cascade of events leads to cell membrane dysfunction. Free radicals (unstable atoms in the body) also cause membrane and cellular destruction. The membrane dysfunction causes imbalances in intracellular calcium, further damaging the membrane. Normal substances such as water, carbohydrates, lipids, and proteins are no longer in a homeostatic state. Metabolic internal substances or external toxins (e.g., infectious organisms, lead) accumulate. As a result of this cellular dysfunction, the cells either produce abnormal substances or phagocytic cells engulf the abnormal substance and store them throughout the body or in certain organs. A clinical example of the consequence of the storage problem is proliferation of macrophages that can cause enlargement of the spleen.

BOX 1-2 Application to Practice Review and interpret the following endometrial biopsy reports that were done for two women with postmenopausal bleeding.

Report 1: Atrophic endometrium

Report 2: Atypical adenomatous hyperplasia

Review and interpret the following esophagus biopsy reports that were done for two people with history of persistent gastroesophageal reflux disease despite therapy.

Report 1: Low-grade dysplasia

Report 2: Intestinal metaplasia

Hypoxia is a common cause of cellular injury and is often the result of ischemia, which refers to inadequate blood flow to tissue or an organ. This lack of blood flow essentially strangles the tissue or organ by limiting the supply of necessary nutrients and oxygen. Ischemia can leave cells damaged to the extent that they cannot survive, a condition called infarction. Myocardial infarction and cerebrovascular accidents (cerebral infarction) are life-threatening diseases as a result of ischemia. Another type of cellular death that can occur from ischemia is called necrosis (FIGURE 1-14). Infarction is tissue death from lack of blood supply, and necrosis is tissue death from injury, disease, or lack of blood supply. (See chapter 4 and chapter 11.)

FIGURE 1-14 Cellular damage can result in necrosis, which has a different appearance than apoptosis, as organelles swell and the plasma membrane ruptures.

Necrosis can take one of several pathways (FIGURE 1-15, FIGURE 1-16, and FIGURE 1-17). Liquefaction necrosis occurs when caustic enzymes dissolve and liquefy necrotic cells. The most common site of this type of necrosis is the brain, which contains a plentiful supply of these enzymes. Caseous necrosis (Figure 1-15) occurs when the necrotic cells disintegrate, but the cellular debris remains in the area for months or years. This type of necrosis has a cottage cheese–like appearance, and it is most commonly noted with pulmonary tuberculosis. Fat necrosis occurs when lipase enzymes break down intracellular triglycerides into free fatty acids. These fatty acids then combine with magnesium, sodium, and calcium, forming soaps. These soaps give fat necrosis an opaque, chalky appearance. Fat necrosis can occur with injury to breast from trauma or radiation or with acute pancreatitis. Coagulative necrosis usually results from an interruption in blood flow. In such a case, the pH drops (acidosis), denaturing the cell’s enzymes. This type of necrosis most often occurs in the kidneys, heart, and adrenal glands.

FIGURE 1-15 Caseous necrosis. Reproduced from Gibson, M. S., Pucket, M. L., & Shelly, M. E. (2004). Renal tuberculosis. Radiographics, 24(1),

251–256.

FIGURE 1-16 Dry gangrene.

FIGURE 1-17 Wet gangrene. © Krit_manavid/Shutterstock.

Gangrene is a form of coagulative necrosis that represents a combination of impaired blood flow and a bacterial invasion. Gangrene usually occurs in the legs because of arteriosclerosis (hardening of the arteries) or in the gastrointestinal tract. Gangrene can take any of three forms—dry, wet, and gas. Dry gangrene (Figure 1- 16) occurs when bacterial presence is minimal, and the skin has a dry, dark brown, or black appearance. Wet gangrene (Figure 1-17) occurs with liquefaction necrosis. In this condition, extensive damage from bacteria and white blood cells produces a

A

liquid wound. Wet gangrene can occur in extremities and internal organs. Gas gangrene develops because of the presence of Clostridium, an anaerobic bacterium. This type of gangrene is the most serious and has the greatest potential to be fatal. The bacterium releases toxins that destroy surrounding cells, so the infection spreads rapidly. The gas released from this process bubbles from the tissue, often underneath the skin.

Another important mechanism of cellular injury is reactive oxygen species (ROS), which are types of free radicals. Free radicals are injurious, unstable agents that can cause cell death. A single unbalanced atom initiates this pathway, which can rapidly produce a wide range of damage. Such an atom has an unpaired electron, making it unstable (electrons are stable in pairs). In an attempt to stabilize itself, the atom borrows an electron from a nearby atom, usually rendering it unstable. This newly unstable atom will then borrow an electron from its neighbor, creating a domino effect that continues until the atom giving the electron is stable without it. The free radicals that are most concerning are those derived from oxygen and, therefore, called ROS. These ROS are formed through oxidation, which is a process of losing electrons, and oxygen is one of the key oxidizers. The body can generally handle a certain number of ROS; however, excesses from stress, pollution, smoking, and poor diet can lead to disease. Protective antioxidant systems (e.g., vitamins C and E, transferrin, and enzymes) are unable to overcome the deleterious effects of ROS leading to oxidative stress. ROS are a cause or contributor to many deleterious effects in the inflammatory and vascular systems. ROS are a major influence in the development and correlation of hypertension, diabetes, and heart disease. ROS have also been linked to cancer, aging, and a variety of other conditions.

Learning Points

Antioxidants ntioxidant is a general term for molecules that can protect against oxidation, which is how free radicals/ROS can develop. Oxidative processes, however, can be normal, such as when glucose oxidizes

to carbon dioxide and oxygen to water. Additionally, not all free radicals generated are dangerous such as when phagocytes release free radicals to fight off infections. Regardless, many free radicals/ROS are deleterious and associated with disease. Many types of antioxidants are marketed as preventing and/or fighting disease and preventing aging. Antioxidants are in food, or in supplements whether in pill form or topical agents. There are over 100 antioxidants, and examples of common ones include vitamin A, C, E, and beta carotene. While antioxidants are beneficial, they can cause disease in excess. An example is the excess use of vitamin E has been associated with an increased prostate cancer risk.

In addition to injury, cell death occurs due to apoptosis. Apoptosis is a programmed cell death and is the process by which unwanted cells (damaged or stressed) are eliminated (Figure 1-14). Programmed cell death is genetically controlled and occurs at a specific point in development. Apoptosis occurs because of morphologic (structure or form) cell changes. Apoptosis as a mechanism of cell

death is not limited to certain times in development, but may also result from environmental triggers (e.g., ultraviolet rays, chemotherapy). Apoptosis is important in tissue development, immune defense, and cancer prevention. However, apoptosis can result in inappropriate destruction of cells if it is unregulated. Inappropriate apoptosis (too much or not enough) can lead to degenerative neurologic diseases such as Alzheimer disease, ischemia, and autoimmune disorders. Several therapeutic agents (e.g., anticancer) are geared toward altering apoptotic pathways. While apoptosis and necrosis both result in cellular death, they cause different cellular morphologic changes. In apoptosis, the cells condense or shrink; in necrosis, the cells swell and burst (Figure 1-14). Necrosis and apoptosis can occur at the same time together or independently.

Neoplasms During cellular division, DNA is being copied and transmitted to the cell being reproduced. From the time of embryonic development forward, cellular division is a constantly occurring process, and while errors occur, they are usually corrected. Cellular repair mechanisms, however, can fail and lead to a DNA nucleotide sequence mutation (variation). Many different types of mutations can occur. Mutations can occur in multiple nucleotides (copy number variants) or in a single nucleotide (single nucleotide variants). Sometimes mutations have no health effects, but, at times, mutations can lead to the development of disease or predispose a person to the development of disease. Chromosomal numbers and structure can be altered and lead to disease such as in Down syndrome, when there is an extra copy (trisomy) or as in cri du chat syndrome where there is a chromosomal deletion. Pieces of one chromosome can translocate to another chromosome such as in leukemia.

Mutations alone are usually insufficient to cause disease. Epigenetic and environmental factors contribute to mutational alterations. Epigenetics involves determining gene expression (how the genes are read) as opposed to genetics, which involves the actual DNA sequence. Epigenetics changes, in other simple terms, can determine whether a gene is “on or off.” Many chemical compounds attach or are on (i.e., epi) the genome, and therefore these compounds are termed epigenomic or epigenetic. Environmental factors include infections, smoking, and eating patterns, can cause genetic mutations or these factors can alter the epigenome

Gene mutations or variations can be hereditary or acquired. If mutations occur in the germline cells (ovum and sperm), the mutation will be inherited from either parent or both, and the mutation will occur in every body cell of the offspring. Acquired mutations occur in somatic cells and do not affect all the cells in the body. Somatic mutations are not inherited. As the understanding of the human genome increases, evidence emerges that most diseases, whether inherited or acquired, have a genetic component.

Cancer is one of the 10 leading causes of death and is discussed in the next section as an example of how a combination of genetic, epigenetic, and many other factors culminate into disease. Congenital disorders, or birth defects, and patterns of inheritance with select inherited disorders all originate from genetic insult and are also discussed. More in-depth information on cancer and congenital disorders will be discussed in respective system chapters, such as leukemia in chapter 3 and congenital urologic disorders in chapter 8.

Benign and Malignant Neoplasms When the process of cellular proliferation or differentiation goes wrong, neoplasms

(abnormal cells) can develop. A neoplasm, or tumor, is a cellular growth that is no longer responding to normal regulator processes, usually because of a mutation. The loss of differentiation that occurs with cells is referred to as anaplasia. Anaplasia occurs in varying degrees. The less the cell resembles the original cell, the more anaplastic the cell is. Anaplastic cells may begin functioning as completely different cells, often producing hormones or hormonelike substances.

The two major types of neoplasms are benign and malignant (TABLE 1-2; FIGURE 1-18). Malignant neoplasms are called cancer. Tumors can occur anywhere in the body and are generally named based on the organ, tissue, or cell origin. Benign tumor prefixes provide information pertaining to the location (lipo- refers to fat, osteo- to bone, and chondro- to cartilage). Therefore, a benign tumor from fat tissue would be a lipoma, and a benign bone tumor would be an osteoma. Malignant tumors are categorized into three groups based on the tissue origin—carcinoma (epithelial), sarcoma (connective), and leukemia/lymphoma (hematopoietic). Other descriptors can be added to these three cancer categories. Carcinomas and sarcomas can be further identified by the origin, such as osteosarcoma (bone), adenocarcinoma (glands), or the epithelial layer such as squamous cell carcinoma.

FIGURE 1-18 Characteristics of (A) benign and (B) malignant tumors.

TABLE 1-2 Characteristics of Benign and Malignant Tumors

Benign tumors Malignant tumors

Cells Similar to normal cells Differentiated Mitosis normal

Varied in size and shape Many undifferentiated Mitosis increased and atypical

Growth Relatively slow Expanding mass Frequently encapsulated

Rapid growth Cells not adhesive, infiltrate tissue No capsule

Spread Remains localized Invades nearby tissue or metastasizes to distant sites through blood and lymph vessels

Systemic effects Rare Common

Life threatening Only in certain locations (e.g., brain) Yes, by tissue destruction and spread

Reproduced from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Benign tumors usually consist of differentiated (less anaplastic) cells that are reproducing more rapidly than normal cells. Because of their differentiation, benign tumors (e.g., lipoma, leiomyoma) are more like normal cells and cause fewer problems. Benign cells are usually encapsulated and are unable to metastasize. The tumor, however, can compress surrounding tissue as it grows. Benign tumors can cause problems due to that compression. Regardless of its size, the tumor can cause devastating problems if it arises in a sensitive area, such as the brain or spinal cord. Benign tumors are discussed in various chapters based on their location (e.g., leiomyoma in chapter 7).

Malignant Neoplasms Malignant tumors usually are undifferentiated (more anaplastic), nonfunctioning cells that are reproducing rapidly. Malignant tumors often penetrate surrounding tissue and spread to secondary sites (TABLE 1-3). Some malignant tumors become solid (e.g., sarcoma, carcinoma), while other malignancies are not solid tumors (e.g., leukemia). Cancer’s key features include rapid, uncontrolled proliferation and a loss of differentiation (FIGURE 1-19). Thus, cancer cells differ from normal cells in size, shape, number, differentiation, purpose, and function.

FIGURE 1-19 The hallmarks of cancer.

TABLE 1-3 Common Sites of Metastasis

Cancer type Main sites of metastasis*

Bladder Bone, liver, lung

Breast Bone, brain, liver, lung

Colorectal Liver, lung, peritoneum

Kidney Adrenal gland, bone, brain, liver, lung

Lung Adrenal gland, bone, brain, liver, other lung

Melanoma Bone, brain, liver, lung, skin/muscle

Ovary Liver, lung, peritoneum

Pancreas Liver, lung, peritoneum

Prostate Adrenal gland, bone, liver, lung

Stomach Liver, lung, peritoneum

Thyroid Bone, liver, lung

Uterus Bone, liver, lung, peritoneum, vagina

*In alphabetical order. Reproduced from National Cancer Institute. (2017). Metastatic cancer. Retrieved from http://www.cancer.gov/about-cancer/what-is-cancer/metastatic-fact-sheet

Cancer is the second leading cause of death in the United States and in many countries following cardiovascular disease (CDC, 2016). Cancer can affect many organs and tissues throughout the body. Over 100 diseases are classified as cancers. Some cancers (e.g., pancreatic cancer) are aggressive and/or difficult to manage and significantly shorten life span, while others (e.g., basal cell carcinoma) are not as aggressive and easier to cure. Cancer incidence increases with age, and with a continuing rise in the number of people living longer, many people will develop the disease.

Cancer development, invasion, and metastasis (spread) are caused by genetic, epigenetic, and microenvironmental factors. Cancer development, therefore, is not one single event but, rather, results due to a series of events. Carcinogenesis, the process by which cancer develops, has some common features and can be described as occurring in three phases—initiation, promotion, and progression (FIGURE 1-20).

FIGURE 1-20 Carcinogenesis: the stages leading to cancer.

Initiation involves the exposure of a normal cell to an environmental substance or event (e.g., chemicals, viruses, or radiation) that causes DNA damage or mutation. While a mutation is a change in DNA structure, DNA can also be damaged without the structure necessarily being changed. In cancer, one single cell has many genetic alterations. This cell no longer responds to normal regulatory processes and proliferates regardless of the body needs. The cancer cells are clonal (meaning they are cells derived from other identical cells), share the same genotype, and perpetuate this same abnormal genotype. Genetic mutations that can lead to cancer can be inherited or acquired. The inherited mutations are in germline cells and can come from one or both parents. Acquired mutations occur in somatic body cells and are due to DNA errors during replication or repair. These mutations can also be due to carcinogen exposure (e.g., chemicals, viruses, or radiation). Acquired cancer mutations are often sporadic and nonfamilial and are more common than inherited (i.e., familial) mutations which account for approximately 5–15% of cancers. Somatic mutations occur regularly in the body. Enzymes detect the damage or mutations and repair the cell or cause apoptosis. If the event is overlooked, the mutation can become permanent, irreversible, and passed onto that cell’s future cellular generations. The germline or somatic mutated cells are vulnerable, and further insults may lead to cancer development. Many errors and faulty repair systems occur as the body ages, which is probably one of the reasons for a higher rate of cancer with aging. With cancer, many types of DNA mutations, including frameshift, missense, and nonsense, as well as chromosomal changes such as rearrangements and deletions are possible.

M

Learning Points

Mutagens and Carcinogens utations are errors in a cell’s DNA and can lead to abnormal protein production. Chemical (e.g., poison) or physical (e.g., ultraviolet light) mutagens can cause these DNA structural changes (i.e., mutations).

Carcinogens are cancer-causing substances, and some are mutagens. Some carcinogens, however, are not mutagenic, and they damage DNA without affecting the DNA structure.

Mutations can occur on many genes, but mutations in several specific classes of genes are likely to lead to cancer. These genes are normally involved in the proliferation and differentiation process; in other words, they are involved in the cell- cycle regulatory process (i.e., interphase–telophase). These regulatory genes can be divided into two broad categories—proto-oncogenes and tumor suppressor genes.

Proto-oncogenes are involved in normal cellular growth and division. When mutation occurs, they are called oncogenes and can cause cancer. The oncogenes (i.e., mutated proto-oncogenes) act like accelerators, and the cell is said to gain function. Oncogene mutations are on somatic cells as opposed to germline cells, so they are not inherited. Over 100 oncogenes exist, and only some oncogenes are associated with cancer. Examples of proto-oncogenic proteins that are mutated and become oncogenic as well as the associated cancer include RAS—pancreatic cancer, c-sis—glioblastoma, c-Myc—oral cancer, and BCR-ABL—chronic granulocytic leukemia. The cancer-causing oncogenes affect several different areas of the cell cycle. As an example, the RAS proto-oncogene in its inactive form is bound to guanosine diphosphate (GDP) during normal cell growth and when activated, becomes guanosine triphosphate (GTP). The activated RAS triggers transcription factors that facilitates progression through the cell cycle. RAS then reverts from GTP to GDP. A mutation in RAS prevents GTP from reverting to its inactive state GDP, thereby keeping transcription turned on and causing proliferation.

Tumor suppressor genes have an opposite role of proto-oncogenes and are involved in suppressing cellular growth and division and act as the brakes on the cell cycle. Some tumor suppressor genes regulate the cell cycle and cell apoptosis while others are involved in maintenance and repair of DNA. Mutations in tumor suppressor genes cause a lost or diminished braking ability. Tumor suppressor gene mutations, therefore, lead to a loss of function. Tumor suppressor gene mutations can be on germline (inheritable) or somatic cells. Several tumor suppressor gene mutations are associated with cancer development, such as the retinoblastoma gene and the TP53 gene associated with colon, breast, and lung cancer. The TP53 gene normally produces the protein p53, which regulates whether mutated genes can be repaired or apoptosis should occur. The TP53 gene, therefore, is called the guardian of the genome. TP53 gene mutation allows mutated genes to survive and multiply. Breast carcinoma 1 and 2 (BRCA1 and BRCA2) are two other well-known tumor suppressor genes that when mutated are associated with breast, ovarian, and other

cancers. Genes become mutated (initiation), but this mutation is not usually sufficient for

carcinogenesis. The second phase of carcinogenesis, promotion, involves the mutated cells’ exposure to factors (e.g., hormones, nitrates, or nicotine) that promote growth. This phase may occur just after initiation or years later, and it can be reversible if the promoting factors are removed. Several therapeutic agents are geared at removing promoting factors.

Epigenetic abnormalities can lead to cancer development. During transcription and translation (Figures 1-8 and 1-9), many things can go wrong. With epigenetics abnormalities, DNA sequence is intact, but gene expression, which can be described as the turning on and off of genes, is altered. Epigenetic expression normally changes throughout life to activate or inactivate different genes depending on body needs. During pregnancy, for example, various processes need to change to accommodate a developing fetus, so some genes are turned on and others are turned off. Genes are passed down to children, but epigenetic factors can also be hereditary. In the last few decades, research and knowledge in the field of epigenetics has increased dramatically. The same factors that can mutate genes (DNA sequence), such as smoking and diet, can lead to abnormalities in epigenetic mechanisms. Epigenetic changes can be reversible, and how to cause this reversal is an exciting area in the development of cancer therapies.

Epigenetic mechanisms can be grouped into three categories—DNA methylation, histone modification, and microribonucleic acids. Gene expression regulation is modulated by the cell so that protein expression occurs in an efficient manner and at appropriate times. DNA methylation (FIGURE 1-21) involves the addition of a methyl group to DNA cytosine. DNA methylation causes a gene to become inactive or silent, leading to inhibition of transcription. This process is essential for normal development. Methylation is different depending on the type of cell (e.g., skin versus muscle). Demethylation is the removal of the methyl group. Some cancer cells have been found to have changes in the normal methylation/demethylation process on genes.

FIGURE 1-21 DNA methylation and histone acetylation. OpenStax, Biology. OpenStax CNX. 23 Mar 2016. Retrieved from

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https://cnx.org/contents/[email protected]:ES2pStNH@5/Eukaryotic-Epigenetic-Gene-Regulation

Histones are proteins that basically are the spools that DNA wraps itself around. These packaged repeating spools of protein and DNA are called nucleosomes. There are four different types of histones. Histones can change how tightly or loosely the DNA is coiled and bound around them. The process of histone uncoiling is called acetylation (Figure 1-21) and involves the enzyme histone acetyltransferase. The uncoiling is necessary to allow access for transcription for the expression of genes (turn on). Deacetylation is the process of binding that involves the enzyme histone deacetylase (HDAC). Deacetylation leads to less transcription (turning off). In cancer cells, some histones (e.g., H3 and H4) have modifications that affect the process of transcription. Therapeutic agents used in cancer therapy, such as HDAC inhibitors, block deacetylation and through complex processes keep normal genes active, arrest cancer cell growth, and increase apoptosis. Examples of some HDAC inhibitor agents include panobinostat, which is used in multiple myeloma and vorinostat for T- cell lymphoma. HDAC inhibitors are also used in neurologic disorders.

MicroRNA are noncoding proteins whose function is decreasing mRNA translation or stability. MicroRNA, in essence, function as regulators. There are many types of microRNA; some types have an oncogenic effect, leading to cancer. Tumor suppressive types of microRNA are not as abundant in cancer cells. An area of microRNA research is focused on determining if microRNAs can be clinically used as tumor markers to aid in diagnosis and prognosis of cancer. Development of therapeutic applications of microRNA is also under investigation.

Cancer cells live in a microenvironment (like a neighborhood) that also includes noncancer cells (like neighbors) and other components in the extracellular matrix (like sidewalks, parks, etc.). The neighboring noncancer cells and other surroundings influence cancer cell proliferation, survival, metastasis, and treatment response. The microenvironment includes all kinds of cell types (e.g., macrophages, endothelial cells). Some cells in the microenvironment, such as myofibroblasts, form an environment facilitating cancer cell growth and survival. Other cells in the microenvironment may promote angiogenesis (growth of new blood vessels) or metastasis. Further understanding of the microenvironment will lead to continued improvements in diagnosis and treatment strategies.

Learning Points

Precision Medicine recision medicine is an approach to treatment and prevention strategies that take into account the similarities and differences among individuals. The traditional approach to care is a standardized treatment

for all. In contrast, the individual’s genes, environment, and lifestyle are considered when determining treatment strategies with precision medicine. Targeted molecular drugs or therapy, also called precision drugs, are available for several diseases such as cystic fibrosis. In cancer, several types of targeted drug therapies are available, such as monoclonal antibodies (immunotherapy) and hormones. In comparison to traditional

chemotherapy, these drugs are designed to attack only the cancer cells with less effect on normal cells.

The third phase of carcinogenesis is progression, which is when the tumor invades, metastasizes, and becomes drug resistant. This final phase is permanent or irreversible. Most cancer deaths are due to metastasis, but not all tumors can metastasize. The tumor’s ability to metastasize (FIGURE 1-22 and FIGURE 1-23) depends on its ability to access and survive in the circulatory or the lymphatic system. Most commonly, the tumor metastasizes to tissue or organs near the primary site, but some tumor cells may travel to distant sites (Table 1-3). The tumor at the site of metastasis has the same cells as the primary site, so the cancer continues to be named by the primary site. As an example, if cancer cells are found in the lungs and they came from the primary breast cancer, then the diagnosis is breast cancer with metastasis to lung or metastatic breast cancer. A second primary cancer can develop but is rare.

FIGURE 1-22 How cancer metastasizes.

FIGURE 1-23 Pathogenesis of metastasis.

The mechanism of metastasis is a multistep process, and similar genetic, epigenetic, and microenvironment abnormalities induce and contribute to metastasis just like in proliferation and differentiation. Regardless of the type of tumor, several factors are essential for the tumor’s progression and survival in the new environment. The tumor must have an adequate blood supply, and sometimes it will divert the blood supply from surrounding tissue and grow new blood vessels (angiogenesis) to meet those needs. The tumor will grow only as large as the blood supply will support. Location is critical because it determines the cytology of the tumor as well as the tumor’s ability to survive and metastasize. Host factors including age, gender, health status, and immune function will also affect the tumor. Alterations in some of these host factors can create a prime environment for the tumor to grow and prosper. Metastatic cells can also remain in an inactive state and potentially reactivate or never reactivate. Therapies are limited in the treatment of metastasis since the process is not fully understood. One example of a drug targeting metastasis is the monoclonal antibody trastuzumab (Herceptin). This drug targets human epidermal growth factor receptor-2 (HER-2). In breast cancer, this growth factor receptor malfunctions and causes multiple copies of genes (gene amplification) leading to overexpression and proliferation. HER-2 is associated with an aggressive breast cancer. Trastuzumab binds to HER-2, thereby inhibiting proliferation.

Clinical Manifestations In most cases, a patient’s prognosis improves the earlier the cancer is detected and treated. Healthcare providers, patients, and family members detect many cases of cancer first through the recognition of manifestations. Heeding these warning signs is vital to initiating treatment early. Unfortunately, people often ignore or do not recognize the warning signs for a variety of reasons (e.g., denial and symptom ambiguity).

As the cancer progresses, the patient may present with manifestations of advancing disease, including anemia, cachexia, fatigue, infection, leukopenia, thrombocytopenia, and pain. Anemia can be a result of the blood-borne cancers (e.g., leukemias), chronic bleeding, malnutrition, chemotherapy, or radiation. Cachexia, a generalized wasting syndrome in which the person appears emaciated, often occurs due to malnutrition. Fatigue, or feeling of weakness, is a result of the parasitic nature of a tumor, anemia, malnutrition, stress, anxiety, and chemotherapy. Factors that can increase the risk for infection include bone marrow depression, chemotherapy, and stress. Leukopenia (low leukocyte levels) and thrombocytopenia (low platelet levels) are common side effects of chemotherapy and radiation due to bone marrow depression. Pain is often associated with cancer due to tissue pressure, obstructions, tissue invasion, visceral stretching, tissue destruction, and inflammation. Cancers have many different clinical manifestations depending on the

type, and these manifestations will be discussed in the appropriate chapter (e.g., lung cancer in chapter 4).

Diagnosis and Treatment Diagnosis of cancer is complex and is specific to the type of cancer suspected. This section provides a basic overview of cancer diagnostic procedures; more specifics are presented in other chapters as specific cancers are discussed. A set of diagnostic procedures usually follows a thorough history and physical examination. These diagnostic procedures may vary depending on the type of cancer suspected. The intention of these diagnostic tests is to identify cancer cells, establish the cytology, and determine the primary site and any secondary sites; however, all these goals are not always accomplished. The healthcare provider will gather as much information as possible to paint the clearest and most complete picture possible of the patient to develop an appropriate treatment plan.

Screening tests and procedures are used for early detection of cancer prior to the development of any symptoms (TABLE 1-4). Some of the criteria for determining whether a screening test is recommended are age, gender, behavioral risk behaviors (e.g., tobacco), family history, and ethnicity/race. Screening test recommendations vary based on the organization. As an example, the American Cancer Society recommends offering annual screening mammograms from the age of 40 while the United States Preventive Services Task Force recommends screening mammograms every 2 years starting at the age of 40. If the screening tests are abnormal, further confirmatory tests (e.g., biopsy) may be needed for diagnosis. In addition to screening tests, various other types of diagnostic tests are used in cancer diagnosis such as X-rays, radioactive isotope scanning, computed tomography scans, endoscopies, ultrasonography, magnetic resonance imaging, positron emission tomography scanning, biopsies, and blood tests. Some of the blood tests may include tumor markers—substances secreted by the cancer cells—for specific cancers (TABLE 1-5). These tumor markers not only aid in cancer detection but also assist in tracking disease progression and treatment response.

TABLE 1-4 Selected Cancer Screening Guidelines Based on Age, Gender, and Risks (Asymptomatic)*

Screening Routine

Risks—most listed; family or personal history often dictates earlier screening in asymptomatic individuals

Breast

Mammogram Clinical and self-breast exam

Yearly age 40 and older or 50–74 every 2 years can stop at 75 and over unless expect to live longer than 10 years No clear benefit but women should get to

Yearly—Age 30 if: BRCA1 or BRCA2 gene mutation (self or 1st-degree relative)

know their breasts and notify provider of change

Radiation therapy to chest ages 10–30 Lifetime risk ≥ 20% based on family history

Breast and ovarian

BRCA1 and BRCA2 genetic screen and testing

No If at risk based on a screening questionnaire then do BRCA1 and BRCA2 blood test

Cervix

Cytology (Pap) and human papillomavirus (HPV)

Cytology only every 3 years ages 21–65 Cytology if with HPV co-testing can increase to every 5 years between the ages of 30–65; HPV co-testing not recommended ages 21–29

Continue after 65 under certain circumstances (e.g., history of precancer or cancer within 20 years)

Endometrium

Endometrial biopsy or pelvic ultrasound

No Consider at 35 if history of oligomenorrhea (times of no menses or long intervals between menses) or 1st-degree relative with uterine, colon, or ovarian cancer Potential benefits vs. harm inconclusive

Prostate

Prostate-specific antigen Digital rectal exam

Consider at age 50 and older Potential benefits vs. harm inconclusive

Consider at 45 if African American, or father/brother with prostate cancer before 65

Lung

Low-dose computed tomography (CT)

No Age 55–74 with 30-pack year smoking history (current smoker or quit smoking in past 15 years)

Colorectal

Colonoscopy (gold standard); if unable, other tests (e.g., sigmoidoscopy, fecal test) may be done

Age 50–75 or 45–75 every 10 years Consider younger than 45 if family history of colorectal or personal history of colorectal cancer or polyps, inflammatory bowel disease, or abdominal/pelvic radiation

*Guidelines may vary based on recommending organization. These were based on American Cancer Society and United States Preventive Services Task Force recommendations accessed in 2018. Modified from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

TABLE 1-5 Common Tumor Cell Markers

Marker Malignant condition Nonmalignant condition

Alpha fetoprotein Liver cancer Ataxia telangiectasia

Ovarian germ cell cancer Testicular germ cell cancer

Cirrhosis Hepatitis Pregnancy

Anaplastic lymphoma kinase Lung cancer Large-cell lymphoma

Unknown

BCR-ABL Chronic myeloid leukemia Acute lymphocytic leukemia

Unknown

β2-microglobulin Multiple myeloma Chronic lymphocytic leukemia Some lymphomas

Kidney disease

Carcinoembryonic antigen Bladder cancer Breast cancer Cervical cancer Colorectal cancer Kidney cancer Liver cancer Lung cancer Lymphoma Melanoma Ovarian cancer Pancreatic cancer Stomach cancer Thyroid cancer

Inflammatory bowel disease Liver disease Pancreatitis Chronic obstructive pulmonary disease Rheumatoid arthritis Tobacco use

CA 15-3 Breast cancer Lung cancer Ovarian cancer Prostate cancer

Benign breast disease Endometriosis Hepatitis Lactation Benign ovarian disease Pelvic inflammatory disease Pregnancy

CA 19-9 Bile duct cancer Colorectal cancer Pancreatic cancer Stomach cancer

Thyroid disease Rheumatoid arthritis Cholecystitis Inflammatory bowel disease Cirrhosis Pancreatitis

CA 27-29 Breast cancer Colon cancer Kidney cancer Liver cancer Lung cancer Ovarian cancer Pancreatic cancer Stomach cancer Uterine cancer

Benign breast disease Endometriosis Kidney disease Liver disease Ovarian cysts Pregnancy (first trimester)

CA 125 Colorectal cancer Gastric cancer Ovarian cancer Pancreatic cancer

Endometriosis Liver disease Menstruation Pancreatitis Pelvic inflammatory disease Peritonitis Pregnancy

Human chorionic gonadotropin Choriocarcinoma Embryonic cell carcinoma Liver cancer Lung cancer Pancreatic cancer Stomach cancer Testicular cancer

Marijuana use Pregnancy

Lactate dehydrogenase Almost all cancers Ewing sarcoma Leukemia Non-Hodgkin lymphoma Testicular cancer

Anemia Heart failure Hypothyroidism Liver disease Lung disease

Neuron-specific enolase Kidney cancer Melanoma Neuroblastoma Pancreatic cancer Small-cell lung cancer Testicular cancer Thyroid cancer Wilms tumor

Unknown

Prostatic acid phosphatase Prostate cancer Benign prostate conditions

Prostate-specific antigen Prostate cancer Multiple myeloma Lung cancer

Benign prostatic hyperplasia Prostatitis

Reproduced from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Malignant cancer cells are classified based on the degree of differentiation (grading) and extent of disease (staging). The grading system determines the degree of differentiation on a scale of 1 to 4, in order of clinical severity. For instance, grade 1 cancers are well differentiated, meaning they are less likely to cause serious problems because they are more like the original tissue. By comparison, grade 4 cancers are undifferentiated, meaning they are highly likely to cause serious problems because they do not share any characteristics of the original tissue. The TNM staging system evaluates the tumor size, nodal involvement, and metastatic progress (FIGURE 1-24).

FIGURE 1-24 TNM staging system. The example shown is staging of colorectal cancer. © 2005 Terese Winslow, U.S. Govt. has certain rights.

Cancer treatment usually consists of a combination of chemotherapy, radiation, surgery, targeted therapy, hormone therapy, immunotherapy, hyperthermia, stem cell transplants, photodynamic therapy, and laser treatment. Additionally, other strategies may include watchful waiting and alternative therapies, including herbs, diet, and acupuncture. The goal of treatment may be either curative (eradicate the disease), palliative (treat symptoms to increase comfort), or prophylactic (prevent the disease).

When surgery is undertaken, attempts are made to remove the tumor and surrounding tissue. Chemotherapy involves the administration of a wide range of medications that destroy replicating tumor cells. Radiation includes the use of ionizing radiation to cause cancer cellular mutation and interrupt the tumor’s blood supply. Radiation may be administered by external sources or through internally implanted sources. Targeted therapy is a treatment that uses drugs to identify and attack cancer cells while sparing normal cells; this drug therapy differs from traditional chemotherapy but is often used in combination. Hormone therapy involves administering specific hormones that inhibit the growth of certain cancers. Immunotherapy involves administering specific immune agents (e.g., interferons and interleukins) to alter the host’s biologic response to the cancer. Hyperthermia precisely delivers heat to a small area of cells or part of the body to destroy tumor cells. This technique can also increase the effectiveness of radiation,

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immunotherapy, and chemotherapy. Stem cell transplants may include peripheral blood, bone marrow, or umbilical cord blood. These transplants are used to restore stem cells in bone marrow destroyed by disease or treatment. In photodynamic therapy, specific drugs are combined with light to kill cancer cells; these drugs work only when certain types of light activate them. Lasers may be used to shrink or destroy a tumor through application of heat, perform precise cuts in surgery, or activate a chemical.

Learning Points

Gene Therapy ene therapy is aimed at treating the basic cause of a disease by using DNA to treat a person’s disease- causing DNA. Gene therapy is still limited to a few diseases but is an area under investigation for several

disorders. One effective gene therapy is for melanoma called talimogene laherparepvec (T-VEC). The medication is a herpes simplex 1 virus that has been modified and is unable to cause the usual cold sores. Instead the virus causes the immune system to target the cancer cells in the tumor and elsewhere in the body.

Prognosis A cure for cancer is usually defined as a 5-year survival without recurrence after diagnosis and treatment. Prognosis refers to the patient’s likelihood for surviving the cancer. Prognosis is heavily dependent on the cancer’s ability to metastasize. The more the cancer spreads to other sites by way of the circulation or lymph system, the worse the patient’s prognosis. Early diagnosis and treatment usually improve the prognosis by treating the cancer before metastasis has occurred. Fewer treatment options are available once metastasis has occurred. Remission refers to a period when the cancer has responded to treatment and is under control. Remission may occur with some cancers, and generally the patient does not exhibit any manifestations of cancer during that time.

Many cancers are preventable, so health-promoting education (e.g., smoking cessation, proper nutrition, and weight management) is vital to decrease the incidence and prevalence of all cancers. Although the likelihood of these cancers can be diminished with these strategies, it is noteworthy that cancer can develop in people with no risk factors. This unpredictable development contributes to the mystery and challenges surrounding cancer.

Genetic and Congenital Disorders Genetic and congenital defects are important to understand because of the encompassing nature of these disorders. These diseases affect people in all age groups and can involve almost any system. These disorders can result in serious disability or death. Genetic disorders are caused by changes in DNA sequence (mutations) with cancer just discussed as an example of one of many diseases with a genetic basis. Genetic disorders may or may not be present at birth. Congenital defects, often referred to as birth defects, usually develop during the prenatal phase of life, are apparent at birth or shortly thereafter, and are often due to genetic or chromosomal abnormalities. Genetic and congenital defects can be hereditary (e.g., cystic fibrosis) or acquired (e.g., Down syndrome). Genetic disorders can be separated into three categories (TABLE 1-6)—single-gene (monogenic) disorders, chromosome disorders, and multifactorial inheritance disorders. Multifactorial inheritance disorders are the most common types of genetic disorders. Some disorders also fall into two categories such as fragile X syndrome, which is a single- gene disorder with chromosomal duplication abnormalities. Patterns of inheritance and select genetic disorders (hereditary and acquired) from each category are discussed in this chapter, while many others are discussed throughout the respective chapters (e.g., cystic fibrosis in chapter 5).

TABLE 1-6 Genetic Disorders and Inheritance

Single-gene disorders Multifactorial disorders Chromosomal disorders

Autosomal dominant Adult polycystic kidney disease Familial hypercholesterolemia Huntington disease Marfan syndrome

Anencephaly Cleft lip and palate Clubfoot Congenital heart disease Myelomeningocele Schizophrenia Alcoholism Breast cancer

Cri du chat syndrome Down syndrome Monosomy X (Turner syndrome) Polysomy X (Klinefelter syndrome) Trisomy 18 (Edwards syndrome)Autosomal recessive

Albinism Color blindness Cystic fibrosis Phenylketonuria Sickle cell anemia Tay-Sachs disease

X-linked recessive Duchenne muscular dystrophy Hemophilia A

Reproduced from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Patterns of Inheritance During reproduction, each parent contributes one set of chromosomes to the

fertilized egg. Some characteristics, or traits, and diseases be can determined by one single gene (monogenic) such as cystic fibrosis or a widow’s peak on hair. Some traits are determined by multiple genes (polygenic) such as height and skin color (FIGURE 1-25). Genes are located on a specific area of the chromosome called a locus. That locus has a function (e.g., hair color, skin color, height, protein expression). The locus function and location are the same on each chromosome transmitted from each parent. At the locus, however, the base pairs (nucleotide) vary, and this base pair variation is the allele. Traits are a pair of alleles. When looking at the gene locus for hair color, the mother’s allele on this locus may be brown hair and the father’s may be blond hair. Therefore, the gene locus function is hair color, but different versions of the hair color gene are possible, such as shades of brown (allele). A person who has identical alleles of each chromosome is homozygous for that gene; if the alleles are different, then the person is said to be heterozygous for that gene.

FIGURE 1-25 Single single gene/multiple genes

For unknown reasons, one allele on a chromosome may be more influential than the other in determining a specific trait. The more powerful, or dominant, allele is more likely to be expressed in the offspring than the less influential, or recessive, allele. The dominant allele is symbolized by a capital letter and the recessive by a lowercase letter. Offspring will express the dominant allele in both homozygous (e.g., AA) and heterozygous (e.g., Aa) allele pairs. In contrast, offspring will express the recessive allele only in homozygous pairs (aa). Alleles can be codominant, which means a heterozygote has two dominant alleles (e.g., AB) like in a blood type or sickle cell disease. Single-gene (monogenic) trait inheritance follow principles of dominance and recessiveness. Single-gene patterns are sometimes called Mendelian inheritance patterns after Gregor Mendel. Polygenic traits are more complex and do not follow usual single-gene inheritance patterns. These polygenic genes and traits are often a product of genetic and environmental factors (see Table 1-6). An example of a polygenic trait is blood pressure. The blood pressure trait is affected by environmental factors, such as diet and exercise.

If a person has a diseased allele but does not express the disease (phenotype normal), then the person is called a carrier. Carriers can transmit diseases to offspring.

The sex chromosomes (X and Y) can pass on genes when they are linked, or attached, to one of the sex chromosomes. For example, a male will transmit one copy of each X-linked gene to his daughter but none to his son, whereas a female will transmit a copy of her X-linked gene to each offspring, male or female. X-linked disorders follow the inheritance pattern of dominance and recessive.

Single-Gene Disorders An estimated 4,000 diseases are caused by single-gene alterations. Most single- gene disorders are hereditary and transmitted more commonly on autosomes in comparison to the X chromosome. Inheritance patterns for these single-gene disorders, like single-gene traits (Mendelian traits), follow the traditional dominant versus recessive allele transmission. The four types of modes of inheritance are autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. On the Y chromosome there is very little genetic material and few genes that cause disease. Diseases of the Y chromosome primarily affect male fertility. Autosomal dominant disorders and, less commonly, autosomal recessive disorders can have a genotype but features (phenotype) of the disorder may never develop. This lack of development is termed incomplete penetrance. Variable expressivity refers to having a genetic disorder, but the clinical manifestations vary widely among affected individuals. Incomplete penetrance and variations in expression are thought to occur due to epigenetics, environmental factors, or differences in the mutation.

H

Learning Points

Hereditary Versus Acquired Mutations ereditary mutations are usually on single genes (particularly autosomes), and this mutated gene is in all body cells of the mother and/or father. The mother and/or father, depending on the gene mutation (e.g.,

dominant or recessive), may be a carrier or have the disease. During reproduction, this mutation may be passed on to all cells of the child. Hereditary mutations may have also existed in other biologic family members. Hereditary mutations are also called germline mutations as they are passed on through the germline cells (from precursors, ovum, or spermatozoa cells).

Acquired mutations were not in a mother’s and/or father’s body cells, so they are not passed on. These mutations occur on somatic cells (nongametes) and occur spontaneously or due to an insult (e.g., radiation, infection), and they are called de novo mutations. These mutations can occur during embryonic development or after birth. No family history of the mutation is present. Chromosomal abnormalities are often not hereditary and often are a result of a failure of separation during meiosis (i.e., nondisjunction). If this happens during gametogenesis then during fertililzation the zygote will have a chromosomal abnormality.

Autosomal Dominant Disorders Autosomal dominant disorders are single-gene mutations that are passed from an affected parent to an offspring regardless of sex. When a child has an autosomal dominant disorder, one of the parents must have the trait. Male and female are equally capable of transmission to offspring. Autosomal dominant disorders occur with both homozygous (e.g., AA) and heterozygous (e.g., Aa) allele pairs. Depending on the disease, a homozygous-affected fetus may not survive. If the infant does survive, he or she will likely have a more severe expression of the disorder, compared to children with the heterozygous pair, because the homozygous pair provides a double dose of the gene.

Autosomal dominant disorders typically involve abnormalities with structural proteins. Recurrence risks can be evaluated with a diagram (Punnett square) to predict gene combinations of recessive and dominant traits in offspring (FIGURE 1- 26). The recurrence risks for an autosomal disorder being transmitted when one parent is heterozygous and the other is normal is 50% for each child, and the risk remains 50% for each subsequent birth. If both parents are affected (not as common of a union), the risk remains 50% even though one allele of the four possibilities will be homozygous dominant (AA). A homozygous-dominant (AA) infant is unlikely to survive. Even with two affected parents, each birth is an independent event; therefore, the recurrence risk continues to be 50%.

FIGURE 1-26 Punnett square for autosomal dominant disorder. Typical mating scenario.

If both parents do not have the trait or any family history but a child is born with an autosomal dominant disorder, then a new mutation occurred in one of the parent’s genes during reproduction. In these circumstances, all the other cells in the parents are normal, so next time there is a pregnancy, the risk is the same as the general population. Examples of autosomal dominant disorders include Marfan syndrome and neurofibromatosis.

How to Use a Punnett Square for Autosomal Dominance 1. In autosomal dominance, the capital letter (A) is the representation of the

mutated gene. Since the disease is rare, the most likely scenario is a pairing of a normal parent (does not have disease trait so homozygous (a) is the normal) and an affected heterozygous parent (most homozygous dominant people do not survive or are severely affected and not likely to reproduce).

2. By reviewing the square, you can see that there is a 50% chance of an offspring being affected (disease) and a 50% chance of being unaffected in this typical mating scenario.

Marfan Syndrome

Marfan syndrome is one of the more common inherited degenerative generalized disorders of the connective tissue with an incidence of 1 in 5,000 persons (FIGURE 1-27). Most cases of Marfan syndrome are inherited in an autosomal dominant pattern, but 25% are a result of new mutations (no family history). The condition results from a single-gene mutation (FBN1) on chromosome 15, and in less than 10% of cases, no mutations on the FBN1 are present, but, rather, other genetic abnormalities (e.g., allele deletion) occur. The FBN1 gene provides instructions for making a protein called fibrillin-1. Fibrillin-1 binds to other fibrillin-1 proteins and other molecules to form threadlike filaments called microfibrils. Microfibrils provide strength and flexibility to connective tissue as well as store and release growth factors to control growth and tissue repair. The mutation causes excess growth factors to be released, and elasticity in many tissues is decreased; together, these two processes lead to overgrowth and instability of tissues.

FIGURE 1-27 Marfan syndrome. Courtesy of Rick Guidotti/Positive Exposure/National Marfan Foundation.

Clinical Manifestations The manifestations of Marfan syndrome vary widely in their severity, timing of onset, and rate of progression. The defects in Marfan syndrome produce a variety of classic ocular, musculoskeletal, and cardiovascular disorders. The lungs, skin, and central nervous system, however, can also be affected. The classic manifestations include

1. 2.

the following:

BOX 1-3 Application to Practice Case 1: Mary and John want to have a second child. They have a 10-year-old with Down syndrome, and they have questions about the risks of having a second child with Down syndrome.

Explain the risks for the development of Down syndrome and the recurrence risk in a second pregnancy.

Case 2: A 5-year-old boy was just diagnosed with red–green color blindness. His parents are concerned and want clarification regarding how their son got this disorder as they have a daughter who does not have the disorder. Answer the following questions his parents have about the new diagnosis.

How is red–green color blindness inherited? Why doesn’t our daughter have the disorder?

Case 3: Draw a Punnett square for cystic fibrosis (both parents are carriers) and Marfan syndrome (one parent is affected and one is unaffected) and discuss the gender distribution, risks of being a carrier, or affected. Discuss risks for subsequent births.

Cardiovascular Aortic defects (coarctation, aneurysm, dissection, aortic regurgitation) (most life threatening because it can lead to aortic rupture and internal bleeding) Mitral valvular defects (e.g., redundancy of leaflets, stretching of the chordae tendineae, mitral valve regurgitation)

Ocular Ectopia lentis (lens displacement) which is an ocular hallmark Increased tendency for cataracts, glaucoma, and retinal detachment

Musculoskeletal Great height (tall and slender) Long extremities (e.g., arm span-to-height ratio is increased) Arachnodactyly (long, spiderlike fingers) Sternum defects (e.g., funnel chest [pectus excavatum] or pigeon breast [pectus carinatum] Spine deformities (e.g., scoliosis or kyphosis) Pes planus (flat feet) Acetabulum protrudes (seen on imaging such as computed tomography, magnetic resonance imaging)

Hypotonia and increased joint flexibility but some with decreased mobility (elbow and fingers), which can predispose to musculoskeletal injury Facial features (highly arched palate, crowded teeth, small lower jaw, thin, narrow face)

Manifestations in other systems include lung disorders such as emphysematous changes with bullae that predispose to pneumothorax. The skin can develop striae. The brain and spinal cord dura can enlarge and swell (i.e., dural ectasia), causing symptoms depending on location (e.g., low back pain, perineal pain, headaches).

Diagnosis and Treatment A thorough history and physical examination are vital in diagnosing Marfan syndrome. In most cases, the family history is positive for the disease or the symptoms. A physical examination would reveal the presence of the hallmark lens displacement and other symptoms of the disease. Diagnostic procedures may include a skin biopsy that would be positive for fibrillin, X-rays that would confirm the skeletal abnormalities, an echocardiogram that would reveal the cardiac abnormalities, and a DNA analysis for the gene. Marfan manifestations may mimic other disorders. To improve diagnostic accuracy, defined criteria (e.g., Ghent nosology) are established and take into consideration family history. With the Ghent nosology, numerous manifestations are possible, and each manifestation is assigned points (e.g., dural ectasia +2). The criteria and easy to use calculators can be found at www.marfan.org/dx/home.

Clinical care usually involves a comprehensive multidisciplinary team. Typical treatment focuses on relieving symptoms and may include the following measures:

Surgical repair of aneurysms and valvular defects Surgical correction of ocular deformities Steroid and sex hormone therapy to aid in closure of long bones, thereby, limiting height Beta-adrenergic blocking agent or angiotensin receptor blockers (which decrease blood pressure and heart rate) to limit complications from cardiac deformities Bracing and physical therapy for mild scoliosis and surgical correction for severe cases

Other strategies include avoiding contact sports, supportive care for the patient and family, and frequent checkups. Relatives at risk should be tested.

Neurofibromatosis Neurofibromatosis is a condition involving neurogenic (nervous system) tumors that arise from Schwann cells and other similar cells. Schwann cells are a type of

neuroglial cells that keep peripheral nerve fibers alive through functions such as forming and maintaining the myelin sheath in motor and sensory axons. Although most cases of neurofibromatosis are inherited, 30–50% occur spontaneously. There are three main types—type 1 and type 2 neurofibromatosis and schwannomatosis.

Type 1 neurofibromatosis (von Recklinghausen disease) (FIGURE 1-28) is the most common of the 3 types and occurs in 1 in 3,000–4,000 people. Type 1 neurofibromatosis results from mutations in the NFI gene on chromosome 17. This gene provides instructions for making a protein called neurofibromin present in many tissues such as the brain, kidney, and spleen. Neurofibromin acts to suppress tumor development. The defect caused by the mutations results in lesions that may include and typically appear in this order with aging—café au lait spots (brown pigmented birthmarks), freckling, iris elevated with tan nodules (Lisch nodules), and neurofibromas. Manifestations are different from person to person with some developing tumors compressing nerves leading to pain and loss of function, while others may only have café au lait spots.

FIGURE 1-28 Neurofibromatosis type 1. © Chiewr/iStock/Getty Images.

Type 2 neurofibromatosis results from mutations in the NF2 gene on

chromosome 22. This gene provides the instructions for making a protein called merlin that acts to suppress tumor development. The defect caused by the mutations results in bilateral acoustic (eighth cranial nerve) tumors, called vestibular schwannomas or acoustic neuromas, that cause hearing impairment (loss and tinnitus) and balance issues. Intracranial and spinal meningiomas can also develop, and manifestations will vary depending on the location and size. The clinical manifestations usually appear around the age of 20, and if diagnosed in children, they have a more severe presentation. Type 2 neurofibromatosis occurs in 1 in 33,000 people.

Schwannomatosis causes multiple benign tumors along the nerve sheaths with no skin or vestibular involvement. The genetic mutation is of the SMARCB1 or LZTR1 tumor suppressor gene located on chromosome 22. The manifestations are multiple tumors with nerve symptoms, such as tingling and weakness, that will vary depending on the tumor location. Chronic pain is common and may or may not be tumor related. The incidence is like type 2 and occurs in about 1–40,000 afflicted individuals. The signs appear in adulthood (25–30 years old) with an average age of diagnosis around 40 years.

People with neurofibromatosis can be affected in many ways. For example, this genetic disorder is associated with an increased incidence of learning disabilities and seizure disorders. Vision, skeletal, and cardiac issues including optic gliomas and cataracts, scoliosis, and hypertension may also be present, particularly with type 1. Cognitive impairments, seen in type 1 and schwannomatosis, are not associated with type 2. Some individuals with type 1 neurofibromatosis, but not type 2, develop cancerous tumors such as neurofibrosarcoma, and neurofibromatosis increases risk of developing other cancers (e.g., brain and leukemia). The appearance of the lesions varies between individuals, and the lesions can be disfiguring in some cases. There is no cure for neurofibromatosis, but regular tumor surveillance (e.g., annual brain magnetic resonance imaging) is important. Surgeries may be necessary to remove the lesions for palliative or safety reasons. Pain management is important. Targeted tumor therapy with drugs such as monoclonal antibodies are another area of investigation. Screening at-risk family members is recommended.

Autosomal Recessive Disorders Autosomal recessive disorders are single-gene mutations passed from an affected parent to an offspring regardless of sex, but they occur only in homozygous (aa) allele pairs. Those persons with heterozygous (Aa) pairs are only carriers and exhibit no symptoms (phenotypically normal). The usual scenario for transmission will be two carrier (heterozygous) parents, and a recessive defective gene from each will be passed down in order to result in the disease. By looking at the Punnett square (FIGURE 1-29), we see that 25% of offspring will get the disease and 50% will

become carriers. If one parent is a carrier and one is not a carrier or unaffected then no disease will be produced, but 50% will be carriers. If both parents have the disease, then all offspring will have the disease. As opposed to dominant disorders, recessive traits usually continue from generation to generation as they are hidden in normal carriers. Consanguinity, which refers to relation by blood, is often implicated in recessive disorders as both may share the recessive allele passed down from ancestors. The age of onset for these disorders is usually early in life, and they occur most commonly as deficiencies in enzymes and inborn errors in metabolism. Examples of autosomal recessive disorders include cystic fibrosis, phenylketonuria (PKU), and Tay-Sachs disease.

FIGURE 1-29 Punnett square for autosomal recessive disorder. Typical mating scenario.

How to Use a Punnett Square for Autosomal Recessiveness 1. In autosomal recessive disorders, the lowercase letter (a) represents the

recessive gene mutation. For an offspring to get the disease, both parents have to be carriers (the most common mating scenario).

2. By reviewing the square, we see that with two carriers, there is a 25% chance of an offspring being affected (disease); a 50% chance an offspring will be a carrier, and a 25% chance an offspring will be unaffected. Another mating scenario is if one parent is a carrier and one is unaffected, then the disease will not be

inherited but 50% will be carriers.

Phenylketonuria PKU is a deficiency of phenylalanine hydroxylase, the enzyme necessary for the conversion of phenylalanine to tyrosine, due to a mutation in the PAH gene on chromosome 12. Phenylalanine is a building block of proteins that is obtained in the diet (proteins and aspartame), and it plays a role in melanin production. A deficiency of phenylalanine hydroxylase leads to toxic levels of phenylalanine in the blood, causing central nervous system damage. The occurrence of PKU varies worldwide, but it is found in 1 in 10,000–15,000 newborns.

Clinical Manifestations If untreated, PKU leads to severe intellectual disability. Symptoms develop slowly and can go undetected. Because untreated cases almost always lead to intellectual disability, all newborns in the United States are screened for PKU shortly after birth by testing for high serum phenylalanine levels. If untreated, children can develop the following clinical manifestations:

Failure to meet milestones Microcephaly Progressive neurologic decline Seizures Hyperactivity Electrocardiograph abnormalities Learning disability Mousy or musty-smelling urine, skin, hair, and sweat Lighter skin and hair than unaffected family members Eczema Behavioral problems (e.g., hyperactivity disorders) Psychiatric disorders

Diagnosis and Treatment In addition to diagnosis after birth, prenatal screening through chorionic villus sampling and amniocentesis can be done for at-risk women. Treatment for PKU involves consumption of a diet low in phenylalanine. Newborns may be breastfed, but the quantity of breastmilk taken in has to be monitored. Special infant formulas are available for supplementation. Dietary restrictions include avoiding proteins and aspartame as well as minimizing starches. Oral medications are available to lower phenylalanine (e.g., sapropterin [Kuvan]). Additionally, gene and enzyme therapy have demonstrated promise in treating PKU.

Tay-Sachs Disease Tay-Sachs disease is a progressive disorder that results from a mutation in the HEXA gene on chromosome 15. This gene provides the instructions for making part of a lysosomal enzyme called beta-hexosaminidase A. The enzyme is necessary to metabolize certain lipids called gangliosides. With HEXA gene mutation, lipids accumulate in the lysosomes of nerve cells and gradually destroy and demyelinate nerve cells. This destruction of nerve cells leads to a progressive mental and motor deterioration, often causing death by 5 years of age.

Tay-Sachs disease is rare in the general population and almost exclusively affects individuals of Ashkenazi Jewish descent, of whom about 1 in every 27 is a carrier. The mutation is also more common in certain French Canadian communities in Quebec, the Old Order Amish community in Pennsylvania, and the Cajun population in Louisiana.

Clinical Manifestations Tay-Sachs disease is divided into three forms based on symptom onset—infantile (most common), juvenile, and adult (extremely rare). Clinical manifestations of Tay- Sachs disease usually appear between 3 and 10 months and include the following:

Exaggerated Moro reflex (startle reflex) at birth Apathy to loud sounds by age 3–6 months Inability to sit up, lift head, or grasp objects Difficulty turning over Progressive vision loss Deafness and blindness Seizure activity Paralysis Spasticity Pneumonia

Diagnosis and Treatment This genetic disorder is diagnosed by a thorough history and physical examination as well as evaluating for deficient serum and amniotic beta-hexosaminidase A levels. Because of the devastating nature of Tay-Sachs disease, genetic counseling is important for persons of Jewish ancestry and individuals with a positive family history. No cure for the disease exists; most treatments are supportive. Those supportive approaches include seizure control, parenteral nutrition, pulmonary hygiene including suctioning and postural drainage, skin care, laxatives, and psychological counseling.

Sex-Linked Disorders—Recessive or Dominant Genes located on the sex chromosomes cause a variety of genetic disorders. Most sex-linked disorders are X linked as the Y chromosome carries little genetic material. X-linked disorders may be either recessive or dominant, with recessive disorders being more common. In general, with X-linked disorders, males are more affected than females. Males tend to have a more severe presentation than females. In terms of inheritance, the patterns are somewhat different than autosomal disorders, and there are also differences between dominant and recessive X-linked disorders.

There are differences in the inheritance patterns between X-linked disorders (dominant vs. recessive) between males and females. In X-linked recessive disorders, a female becomes a carrier when inheriting only one copy of a defective allele from its carrier or from an affected mother or an affected father. For a female to get the disease, she needs to get two recessive alleles (one from her mother and one from her father). In dominant X-linked disorders, the female needs only one mutated X copy to get the disease. The other normal X effects are dominated by this dominant mutated allele. This mutated dominant allele can come from the mother or father.

All males who get the disease with X-linked recessive disorders do so because they only have one X chromosome and do not have a normal other X allele to counteract. Males, therefore, cannot be carriers. Fathers only give a Y chromosome to their sons, so they never transmit the disease to their sons. The disease is transmitted from their mother. X-linked dominant disorders are rare except for fragile X syndrome. This disorder has a more complicated inheritance pattern and males can be carriers. Fragile X inheritance will be discussed in the next section. Examples of X-linked recessive diseases include Duchenne muscular dystrophy and hemophilia.

Fragile X Syndrome Fragile X syndrome (FIGURE 1-30) is an X-linked dominant disorder associated with a single trinucleotide gene sequence (FMR1) on the X chromosome. The FMR1 gene provides the instructions for making a protein called familial mental retardation protein (FMRP) that regulates production of other proteins and plays a role in synapse development. Synapses are critical in relaying nerve impulses. Normally, this trinucleotide sequence is repeated about 5–40 times, but in people with fragile X syndrome, it is repeated more than 200 times. The increased repetitions lead to turning off or silencing of the FMR1 gene and FMRP production stops. The more repeats of this gene sequence, the more severe the disease.

FIGURE 1-30 Fragile X syndrome. © Courtesy of Nikki Deal.

Fragile X syndrome is considered the second most common cause of intellectual disability following Down syndrome. Fragile X syndrome is more common and usually more severe in males (it occurs in 1 in 4,000 males and 1 in 8,000 females). There are a few differences in fragile X syndrome inheritance pattern and X-linked recessive disorders. Males who are not carriers of X-linked recessive disorders can be carriers of fragile X and be phenotypically normal. Males can become carriers because there is incomplete penetrance. The FMR1 gene goes through stages as it is passed down in families. The gene can start off as normal, then premutate, and then fully mutate. Other X-linked disorders do not have a premutation stage. Sometimes, alleles have 45–54 sequence repeats and are termed gray area alleles. These alleles are a bit unstable and may result in a premutation. A premutation is defined as 55–200 sequence repeats, and a person with such a premutation is said to be a carrier. A full mutation and disease occur with over 200 trinucleotide

sequence repeats. Females with premutations are at risk of passing on the abnormal genes; the more sequence repeats, the higher the risk and the more likely the premutation will be a full mutation. Some females with premutation have health issues such as menstrual irregularities, infertility, and premature ovarian failure. Males with premutations will pass this carrier gene to all their daughters but not the full mutation. Some males with the premutations may develop tremors and ataxia with aging.

Clinical Manifestations Clinical manifestations of fragile X syndrome, particularly language and developmental delays, are usually seen by age 2. The average age of diagnosis for males is 36 months, and for females it is 42 months. The manifestations include the following:

Intellectual, behavioral, and learning disabilities Prominent jaw and forehead Long, narrow face with long or large ears Connective tissue abnormalities (e.g., flexible fingers, flat feet) Large testes Hyperactivity, inattentiveness, and anxiety Seizures Speech and language delays Tendency to avoid eye contact Autism spectrum disorders

Diagnosis and Treatment Diagnosis of fragile X syndrome involves the identification of clinical manifestations and a positive genetic test. No cure for this condition exists, so treatment focuses on controlling individual symptoms. Genetic counseling is appropriate for persons with a positive family history. Behavioral and psychological support may be indicated for both parents and the affected child. Other supportive interventions include physical, speech, and occupational therapy. The earlier the interventions, the better the outcomes.

Chromosomal Disorders—Number or Structural Chromosomal disorders are a major category of genetic disorders that result most often from alteration in chromosomal number or structure. These alterations can occur on autosomes or X chromosomes. These disorders often occur in utero because of some environmental influences (e.g., maternal age, drugs, infections). The most vulnerable time for the fetus is at 15–60 days’ gestation. This period immediately follows fertilization and implantation, when much of the cellular

differentiation is occurring. More than 60 disorders fall in this category, many of which result in first-trimester spontaneous abortions.

Chromosomal aberrations include those with an abnormal number of pairs or copies of chromosomes. Polyploidy is the term used when there is more than the normal (euploid) 23 pairs in a cell. Types of polyploidy include triploidy, which occurs when there are 3 copies of each pair, or tetraploidy, where there are 4 copies of each pair (4 × 23 = 92 pairs of chromosomes). These conditions are not compatible with life, so fetuses or newborns die. Aneuploidy is another term that has to do with chromosomal numbers. Aneuploidy occurs due to nondisjunction (FIGURE 1-31), which is an abnormal separation during cell division leading to too many or too few chromosomes.

FIGURE 1-31 Chromosome nondisjunction abnormality.

An aneuploidy, such as monosomy, occurs when there is only one copy of a chromosome inside a pair, so there are 45 chromosomes. Autosomal monosomy is not compatible with life; therefore, the fetus will not survive. Those individuals with X- linked monosomy (e.g., Turner syndrome), however, can survive. If there is no X chromosome at all, then there is no zygote survival (males cannot survive with Y only). With aneuploidy, an extra copy within a pair, such as trisomy where there are 47 chromosomes, may be present (FIGURE 1-32).

FIGURE 1-32 Karyotype with trisomy 21. © Jens Goepfert/Shutterstock.

Autosomal trisomies, as opposed to autosomal monosomy, can survive; trisomy 21 (Down syndrome) and trisomy 13 (Patau syndrome) are examples. X-linked trisomies include disorders such as Klinefelter syndrome (e.g., XXY), but there can be 3 or 4 copies of X (e.g., 45, XXXY). Females can also have too many X chromosomes (e.g., XXX) and have reproductive disorders and other manifestations.

With aneuploidy, all or part of a chromosome may be lost. Chromosomal mosaicism is when the aneuploidy only occurs in some of the body cells of the offspring, but others are normal (FIGURE 1-33). Mosaicism can occur in many disorders such as Turner, Klinefelter, and Down syndromes. Individuals with mosaicism are affected by the abnormal chromosomes.

FIGURE 1-33 Chromosomal mosaicism. Help Me Understand Genetics Mutations and Health, Genetic Home Reference, April 2 2019, U.S. National

Library of Medicine.

Since polyploidy and aneuploidy have to do with numbers, it can be easy to

confuse them. One way to remember is polyploidy has to do with pairs and aneuploidy has to do with individual chromosomes inside the pair. With aneuploidy, there are always 23 pairs, but the number of individual chromosomes goes up or down. Individuals with polyploidy and aneuploidy with fewer chromosomes (except for X-linked monosomies) usually do not survive.

Autosomal Aneuploidy Trisomy 21 Trisomy 21, or Down syndrome, is a spontaneous chromosomal mutation that results in three copies of chromosome 21 (Figure 1-32 and FIGURE 1-34). These extra copies are thought to disrupt the course of normal development. Trisomy 21 occurs in about 1 in 800 births. The risk of this mutation increases with greater parental age and environmental teratogen exposure. Up to 95% of Down syndrome cases are due to nondisjunction of the maternal egg, and most of the remaining cases are due to paternal sperm cell nondisjunction (Figure 1-31). Less commonly (about 4% of cases), the cause of the mutation is due to translocation (FIGURE 1-35), which is the exchange of genetic material between different chromosomes. In the case of Down syndrome caused by translocation, chromosome 21 fuses and exchanges material with chromosome 14. While most Down syndrome cases are not hereditary, some translocations can be passed on to offspring. Those individuals with a stable translocation can be unaffected yet they can pass down the stable abnormal translocation to an offspring. In an offspring, the once stable translocation can become unstable and cause Down syndrome.

FIGURE 1-34 Down syndrome. Courtesy of Sarah Coulter-Danner.

FIGURE 1-35 Chromosome breaks.

Clinical Manifestations Clinical manifestations can vary widely and are apparent at birth and often in utero. These manifestations typically include the following characteristics:

Hypotonia Distinctive facial features (e.g., low nasal bridge, epicanthic folds, protruding tongue, low-set ears, and small, open mouth) Congenital heart defects Single crease on the palm (simian crease) White spots on the iris Varying intellectual disability that typically worsens with age Developmental delay Behavioral issues (e.g., inattention, obsessive/compulsive behavior, stubbornness, and tantrums) Strabismus and cataracts Poorly developed genitalia and delayed puberty

Early death can occur due to cardiac and pulmonary complications (e.g., hypertension and pneumonia). Persons with trisomy 21 have increased susceptibility

to leukemia and infections. These individuals are also at increased risk for developing gastrointestinal (e.g., intestinal obstruction, gastroesophageal reflux disease, and celiac disease) and thyroid issues (e.g., hypothyroidism). Approximately half of all persons with trisomy 21 will develop Alzheimer disease, usually starting around the age of 50.

Diagnosis and Treatment Clinical manifestations can be detected using four-dimensional ultrasounds. Other prenatal testing includes amniocentesis and serum hormone levels. No cure for trisomy 21 exists. Treatment strategies focus on symptom and complication management.

X-Linked Aneuploidy Turner Syndrome Monosomy X, or Turner syndrome, is the result of a deletion of part or all of an X chromosome. This abnormality is due to nondisjunction and usually occurs spontaneously (not inherited) during the formation of reproductive cells (eggs and sperm) in the parents. When transmitted, all cells of the child are affected. At times, however, only some of the cells are affected during early fetal division, and other cells have a full two copies of the XX. This event is known as mosaic Turner syndrome. While most cases of Turner syndrome are not inherited, partial X deletions can be inherited. It is not completely understood which genes on the X chromosome are associated with the features of Turner syndrome. This condition occurs in about 1 of every 2,500 live births but is much more common among pregnancies that do not continue to term.

Clinical Manifestations Turner syndrome affects only females as males cannot live without an X chromosome. Affected females develop gonadal streaks instead of ovaries; therefore, they will not menstruate. A small percentage, however, will retain normal ovarian function. Intelligence is usually normal. Clinical presentation can vary and includes the following:

Short stature Lymphedema (swelling) of the hands and feet Broad chest with widely spaced nipples Low-set ears Small lower jaw Drooping eyelids Increased weight

Small fingernails Webbing of the neck Coarctation of the aorta Horseshoe kidney Ear infections Reduced bone mass

Complications of monosomy X include vision (e.g., cataracts), skeletal (e.g., osteoporosis, pathologic fractures, and scoliosis), hearing, metabolic (e.g., diabetes and thyroid), cardiac (e.g., hypertension and valvular defects), and renal (e.g., kidney failure) issues.

Diagnosis and Treatment Diagnosis is usually accomplished through a history, physical examination, serum hormone levels, and genetic testing (either before or after birth). Turner syndrome is treated by administering female sex hormones to promote development of secondary sex characteristics and skeletal growth. Growth hormones may also be administered to improve skeletal growth. Identification of this condition is often delayed until late childhood or early adolescence if the clinical presentation is subtle, but chromosomal analysis can confirm the diagnosis. Early treatment allows for early hormone replacement to minimize problems and detect complications.

Klinefelter Syndrome Polysomy X, or Klinefelter syndrome, is a relatively common abnormality that results from one or more extra X chromosomes and at least one Y. The karyotype would be XXY (trisomy) sex chromosome. Klinefelter syndrome is not inherited and occurs due to spontaneous mutation in reproductive cells due to nondisjunction. If this mutation is passed on, then all of the offspring’s cells will be affected. Because of the presence of a Y chromosome, persons with this syndrome are male (FIGURE 1-36). Klinefelter syndrome affects 1 in 500 to 1,000 newborn males. The syndrome usually becomes apparent at puberty when testicles fail to mature, rendering affected boys infertile. The extra copies of the X chromosome interfere with male sexual development. Health issues worsen with each additional X chromosome (e.g. 48, XXXY or 49, XXXXY).

FIGURE 1-36 Klinefelter syndrome. Courtesy of www.dermnet.com

Clinical Manifestations Clinical manifestations of Klinefelter syndrome include the following:

Small penis, prostate gland, and testicles Sparse facial and body hair Sexual dysfunction (e.g., impotence, decreased libido) Gynecomastia (femalelike breasts) Long legs with a short, obese trunk Tall stature Behavioral problems Learning disabilities Delayed speech and language development Increased incidence of pulmonary disease and varicose veins

Other problems that can develop include osteoporosis and breast cancer.

Diagnosis and Treatment Diagnostic procedures consist of a history, physical examination, hormone levels, and chromosomal testing. Treatment includes male hormone replacement to promote secondary sex characteristics. A mastectomy may be performed in cases of gynecomastia and breast cancer. Psychological counseling and support may be beneficial to the patient and the parents.

Chromosomal Structural Disorders Chromosomal structural disorders can occur during cellular division and can result in disease. These breaks occur spontaneously or due to environmental factors (e.g., radiation, infections), inherited traits or a combination. The types of breakage are deletions, duplications, translocations (Figure 1-34), inversions, substitution, and fragile sites.

Deletions result in missing a part of genetic material (e.g., multiple myeloma chromosome 13). Duplications result in extra genetic material. With translocations, part of one chromosome exchanges place with another. In chronic myeloid leukemia, a translocation on chromosome 22 and 9 called the Philadelphia chromosome (discovered in Philadelphia) is present. With inversions, the chromosome breaks off and reattaches in a different manner (e.g., cancer).

Multifactorial Disorders Single-gene and chromosomal abnormalities can be devastating but are far less prevalent than multifactorial disorders. Most multifactorial disorders are the result of an interaction between multiple genes (polygenic) and environmental factors. These

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disorders can be inherited or acquired (e.g., cancers). If inherited, these disorders do not follow a clear-cut pattern of inheritance. Risks of transmission and/or development of the disease are often based on epidemiologic data. These disorders may be present at birth (congenital), as with cleft lip or palate, or they may be expressed later in life, as with hypertension or diabetes. Environmental factors that play roles in these disorders may include any of a number of teratogens (birth defect–causing agents) such as infections, chemicals, or radiation.

Researchers are discovering that most diseases have a multifactorial component. Some diseases have a higher incidence or prevalence and seem to occur more often in some families, certain ethnicities, or geographic regions. With multifactorial disorders, the influences are multiple and may include diet, age, exercise, smoking, and many other lifestyle choices that impact health. Various principles and some common congenital and adult disorders are discussed in the upcoming sections.

When evaluating for multifactorial inherited diseases, ascertaining a history of blood relatives is important. Higher risk for inheriting a disease that is multifactorial include things such as the relationship to the relative. The closer the relationship (e.g., mother, daughter, or siblings), the higher the chance for inheriting the disorder. A high number of members in a family who have the disease can increase the inheritance risk.

Learning Points

Single Nucleotide Polymorphisms and Diseases he completion of the Human Genome Project (2003) and the International HapMap Project (2005) provided the human genome sequence and map of genetic variation. There is only 0.1% genome sequence variation

among people, or, in other words, 99.9% of the genome sequence is identical for all people. The variances in the human genome could account for disease and even more benign differences such as eye and hair color. The site where the variation occurs in a single DNA base pair is known as single nucleotide polymorphism (SNPs or snips). About once for every 1,000 base pairs a SNPs occurs. These human variance points are like genetic markers. The two major completed projects paved the way for the Genome Wide Association Studies (GWAS), which involves a comparison of large groups (e.g., thousands) of people with disease and without disease who are matched for various criteria such as age and sex. The groups’ genomes are analyzed to evaluate SNPs. GWAS have found SNPs associated with disease, increased risk of disease, and SNPs that may influence a response to a drug. Most SNPs have no effect on health.

C H A P T E R S U M M A R Y

Cells are the basic units of life, and they face many challenges in their struggle to survive. These challenges include hypoxia, nutritional changes, infection, inflammation, and chemicals. Cells adapt to the challenges in an attempt to prevent or limit damage as well as death. This adaptation may be reversible or permanent.

Neoplasms arise from abnormal cellular proliferation or differentiation. They can be either benign or malignant. Benign neoplasms are more differentiated; therefore, they are more like the parent cells. Benign tumors are less likely to cause problems in the host or metastasize except in terms of location. Malignant tumors are less differentiated; therefore, they are less like the parent cells. Malignant tumors are more likely to cause problems in the host and metastasize.

Genetic and congenital disorders can develop from factors that disrupt normal fetal development or interact with defective genes. These factors, or teratogens, can include radiation, infections, or chemicals. Genetic and congenital disorders may be present at birth or may not appear until later in life. Many diseases have a genetic basis in their development. New discoveries and information are evolving rapidly regarding the understanding of complex gene–gene interactions, epigenetics, and environmental factors. Exploring these basic cellular and genetic concepts and issues lays the foundation for understanding where disease begins.

R E F E R E N C E S A N D R E S O U R C E S

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Berry, T., & Workman, L. (2011). Genetics and genomics in nursing and health care. Philadelphia, PA: F. A. Davis.

Centers for Disease Control and Prevention (CDC). (2016). Leading cause of death. Retrieved from https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm

Chiras, D. (2015). Human biology (8th ed.). Burlington, MA: Jones & Bartlett Learning. Crowley, L. (2017). An introduction to human disease: Pathology and pathophysiology correlations (10th ed.). Burlington, MA: Jones & Bartlett Learning.

Eckschlager, T., Plch, J., Stiborova, M., & Hrabeta, J. (2017). Histone deacetylase inhibitors as anticancer drugs. International Journal of Molecular Sciences, 18(7), 1414. doi.org/10.3390/ijms18071414

Elling, B., Elling, K., & Rothenberg, M. (2004). Anatomy and physiology. Sudbury, MA: Jones and Bartlett Publishers.

Hartl, D. L. (2020). Essential genetics and genomics (7th ed.). Burlington, MA: Jones & Bartlett Learning. Jacob, M., Varghese, J., & Weil, P. (2018). Cancer: An overview. In V. W. Rodwell, D. A. Bender, K. M. Botham, P. J. Kennelly, & P. Weil (Eds.), Harper’s illustrated biochemistry (31st ed.). New York, NY: McGraw-Hill.

Lewin, B., Cassimeris, L., Lingappa, V., & Plopper, G. (Eds.). (2007). Cells. Sudbury, MA: Jones and Bartlett Publishers.

Mosby’s dictionary of medicine, nursing, and health professionals (9th ed.). (2012). St. Louis, MO: Mosby. Murphy, S. L., Xu, J., Kochanek, K. D., Curtin, S. C., Arias, E., for the Division of Vital Statistics, CDC. (2017). National vital statistics reports: Deaths, final data for 2015, 66(6), 1-75.

National Human Genome Research Institute. (n.d.). Frequently asked questions about genetic disorders. Updated November 10, 2015. Retrieved from https://www.genome.gov/19016930/faq-about-genetic-disorders/

National Institutes of Health: National Center for Complementary and Integrative Health. (2013). Antioxidants: In depth. Retrieved from https://nccih.nih.gov/health/antioxidants/introduction.htm

National Institutes of Health: U.S. National Library of Medicine. (2019). What Is DNA? Retrieved from https://www.ghr.nlm.nih.gov

Porth, C. (2014). Essentials of pathophysiology (9th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. Professional guide to pathophysiology (3rd ed.). (2010). Philadelphia, PA: Lippincott Williams & Wilkins. Schropfer, E., Rauthe, S., & Meyer, T. (2008). Diagnosis and misdiagnosis of necrotizing soft tissue infections: Three case reports. Cases Journal, 1, 252.

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C H A P T E R 2

Immunity

L E A R N I N G O B J E C T I V E S

Explain the role of the body’s normal defenses in preventing disease. Describe the similarities and differences between innate and adaptive immunity. Discuss the various types of vaccines and their use in different clinical scenarios. Compare and contrast the pathogenesis of hypersensitivity by mechanism and antigen. Apply understanding of altered immune responses when describing and discussing common disorders such as systemic lupus erythematosus and human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). Identify factors that enhance and impair the body’s defenses. Develop diagnostic and treatment considerations for various immune disorders.

he body is under constant assault by life-threatening microbes and environmental toxins. Although the vast majority of microbes and toxins are harmless, occasionally they are not. The immune system is responsible for

protecting the body against an array of microorganisms (e.g., bacteria, viruses, fungi, protozoans, and prions) as well as removing damaged cells and destroying cancer cells. The immune system provides this protection through two major actions— defending and attacking. A functioning immune system is essential for survival. Optimal immunity requires intact nonspecific defenses (e.g., skin, mucous membranes, phagocytes, complement systems), a functional lymphatic system, an efficient innate immune response, an operational inflammatory response, and an appropriate and adaptive acquired immunity. Innate immunity provides immediate protection and is nonspecific, meaning it provides protection against all invaders. Adaptive or acquired immunity can take 7–10 days to provide protection, but it is specific to the antigen. Antigens are any substances that the body recognizes as foreign and can include microorganisms, environmental substances, drugs, and transplanted tissues. Fundamental to a properly functioning immune system is the

ability to recognize and respond to a foreign agent or antigen. Some immune cells circulate constantly, always on alert for an invasion, whereas others remain passively in tissue and organs, waiting to be activated (TABLE 2-1). Additionally, some of the body’s structures serve as barriers to antigens, preventing invasion, and some components are designed to manage the degree of the immune response, as an overzealous response can also be deleterious.

TABLE 2-1 Major Components of the Immune System

Antigen A foreign agent that triggers the production of antibodies by the immune system.

Antibody (immunoglobulin) A protein used by the immune system to identify and neutralize foreign agents, such as viruses and bacteria.

Autoantibody An antibody made by the immune system that attacks an individual’s own proteins.

Thymus A gland located in the anterior superior mediastinum; develops T lymphocytes and thymosins.

Lymphatic tissue Connective tissue containing many lymphocytes; transports immune cells, antigen-presenting cells, fatty acids, and fats; filters body fluids.

Bone marrow Soft, fatty tissue found inside of bones; contains stem cells and leukocytes.

Cells

Neutrophils Infection-fighting agents; usually the first to arrive on the scene of an infection; attracted by various chemicals released by infected tissue; escape from the capillary wall; migrate to the site of infection; and phagocytize microorganisms.

Basophils White blood cells that bind immunoglobulin E (IgE) and release histamine in specific inflammatory responses (e.g., anaphylaxis).

Eosinophils White blood cells involved in allergic reactions.

Monocytes White blood cells that replenish macrophages and dendritic cells in normal states and respond to inflammation by migrating to infected tissue to become macrophages and dendritic cells; their conversion elicits an immune response.

Macrophages White blood cells within tissues, produced by differentiation of monocytes; phagocytize and stimulate lymphocytes and other immune cells to respond to pathogens.

Mast cells Connective tissue cells that contain histamine, heparin, hyaluronic acid, slow- reacting substance of anaphylaxis, and serotonin.

B cells (B lymphocytes) Cells that mature in the bone marrow, where they differentiate into memory cells or immunoglobulin-secreting (antibody) cells, eliminate bacteria, neutralize bacterial toxins, prevent viral reinfection, and produce immediate inflammatory response.

Memory B cells B cells that stimulate a quick response with subsequent exposures to an antigen; recall of the antigen as foreign leads to rapid antibody production.

Plasma cells White blood cells that develop from B cells and produce large volumes of specific antibodies.

T cells (T lymphocytes) Produced in the bone marrow and mature in the thymus, hence T cell; include two major types that work to destroy antigens—regulator cells and effector cells.

Killer T cells T cells that destroy cells infected with viruses by releasing lymphokines that degrade cell walls; also called cytotoxic cells and effector cells.

Helper T cells Regulator cells that activate, or call up, B cells to produce antibodies.

Natural killer lymphocytes Cells that destroy cancer cells, foreign cells, and virus-infected cells.

Innate Immunity Barriers The first innate or nonspecific approach relies on physical and chemical barriers that indiscriminately protect against all invaders. The most prominent barriers used in this approach are the skin and mucous membranes. The skin is a thick, impermeable layer of epidermal cells overlying a rich vascular layer known as the dermis. Newly produced skin cells push the dead ones outward while also removing bacteria. The dead cells produce a protective, waterproof layer because of the keratin contained in those dead cells. Although the skin protects the human body from microbe invasions, some passageways (respiratory, gastrointestinal, and genitourinary tracts) allow direct access to the body’s interior. These passageways are lined with a protective mucous membrane that is not as thick as skin but does provide a moderate layer of protection. The epithelial cells are constantly turning over and are thereby preventing microorganisms from residing on the surfaces of these passageways. The passageways have an ability to mechanically wash off their surfaces from microorganisms. Vomiting, as an example, can be an attempt to remove a noxious substance such as a toxin or microorganism from the gastrointestinal tract.

The physical barriers also include chemical barriers to prevent invasion. The skin, for example, produces a slightly acidic substance that inhibits bacterial growth. Hydrochloric acid in the stomach destroys many ingested bacteria. Tears and saliva contain lysozyme, an enzyme that dissolves bacterial cell walls. The epithelial layers also secrete several proteins known as cathelicidins and defensins that serve as antimicrobials and can stimulate the adaptive immune system.

Even microorganisms participate in innate immunity to benefit humans. The human microbiome consists of bacteria and some fungi (collectively referred to as normal flora) which reside on the skin, gastrointestinal, and genitourinary tracts. Normal flora do not usually cause disease unless there is an imbalance or immunocompromise. Microorganisms can contribute to immune defenses by secreting chemicals, blocking pathogenic attachment, and secreting protein molecules. Therefore, the human microbiome is involved in health and disease states. When reviewing results of samples sent for microbial evaluation, consider whether the microbe is part of the normal flora; it can lead to disease even if it is part of normal flora. Review the culture report to determine what is pathogenic and what promotes pathogenicity.

Diagnostic Link

Sample Collection for Infection

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pecimen quality to evaluate for infection is critical as improper collection can lead to difficulties in interpretating whether the results are due to contamination, normal residing organisms, or infection. There

are three ways to obtain specimens to evaluate for infection: 1) direct sampling, 2) indirect sampling, and 3) microbiota sampling. Direct sampling involves collecting a specimen from sterile tissue such as from the lung or cerebrospinal fluid and is usually done surgically or with a needle aspiration. Direct sampling specimens are the most accurate in diagnosing infection as they usually only contain the pathogen. The technique, however, is invasive and is the riskiest to obtain. The second technique is indirect sampling, which is a local sampling that is normally sterile such as from the lungs (sputum) or the bladder (urine). With indirect sampling the specimen has to go through normal flora to be obtained, so normal flora and contamination may be present and must be considered with interpretation. The third technique is microbiota sampling such as from the throat or vagina, which has normal flora (usually several different) mixed in with pathogens. Since there are usually several normal bacteria, the specimen may require handling with special media.This media is necessary do determine which organisms are nonresident (e.g., beta-hemolytic streptococci in the throat) and which are normal nonpathogenic organisms.

Learning Points

The Human Microbiome icrobes are all around us. There are 10 times more bacteria in the body than human cells, and 1,000 more genes in the microbiome than in the human genome (NIH Human Microbiome Project, 2016). Usually,

microbes have been studied as a specie and in an artificial laboratory environment. The science of metagenomics, however, has transformed the ability to study microbes and understand genomes collected from microbial communities in their natural environment as opposed to in a culture dish. This knowledge has contributed to understanding the critical role of microbes in disease and health leading to exciting information about diagnosis, prevention, and treatment. Key points about the human microbiome include:

The composition of the microbiome starts prenatally and changes over the years with growth, development, and aging. The microbiome each person has is influenced by many other factors, such as genetics, environment, and physiology. Alterations in the microbiota have been linked to many diseases of the gastrointestinal system and metabolic functioning as well as neuropsychiatric disorders. Most diseases demonstrate some evidence of microbiota changes, although the meaning of these changes is still unclear. Several areas of research continue to explore the causal link, ratio of microbiota (between flora and host) in terms of disease and health, and the implications of a lack of diversity in flora.

The physical and chemical barriers are not completely impenetrable. Tiny breaks in the skin or in the lining of the respiratory, gastrointestinal, or genitourinary tract may permit an antigen invasion. When the barriers are penetrated, blood-borne innate defenses are in place to respond to those antigens through the activation of the inflammatory response.

Inflammatory Response When cells and body tissues are injured, regardless of the cause (e.g., microorganisms, chemical irritants, immune/genetic defects, hypoxia), a series of reactions referred to as the inflammatory response is triggered. As part of the innate immune response, the inflammatory reaction is nondiscriminatory. The same sequence of response occurs no matter the type of injury or prior exposure as there

is no memory involved. The acute phase of the inflammatory response starts immediately after the injury and continues until the threat is eliminated (usually hours to days), or a chronic inflammatory response takes over until healing and repair are complete (usually weeks or months). Acute or chronic inflammation leads to local or systemic effects—a common vascular response and the release of a series of cellular and plasma mediators that create and regulate the inflammatory response.

Vascular Response and Cellular Mediators The acute inflammatory response consists mainly of a vascular response that creates the cardinal signs of erythema, edema, heat, and pain at the site of injury (FIGURE 2-1). These clinical manifestations are the result of the release of preformed mediators and the synthesis of new biochemical mediators from mast cell degranulation (TABLE 2-2). Mast cells are white blood cells (granulocytes) that are abundantly found in areas exposed to the environment such as the skin, gastrointestinal tract, and respiratory tract and are central to the inflammatory process. The mast cells release several preformed mediators such as histamine, which stimulates vasodilation causing erythema, edema, and heat. Mast cells also cause synthesis of other mediators such as prostaglandins, which stimulate pain receptors in the area. Prostaglandin and another mediator, leukotriene, causes vasodilation and increased vascular permeability. Platelet-activating factor acts similarly to leukotrienes and also activates platelets. While the preformed mediators are released immediately, the newly synthesized mediators start 15 minutes to hours after activation. Several other mediators that continue to contribute to the inflammatory process are released and/or synthesized.

FIGURE 2-1 Inflammatory response.

TABLE 2-2 Mediators From Mast Cell Degranulation

Mediator/category* Key effect**

Histamine/preformed H1 receptors—increased vascular permeability, vasodilation, bronchial and smooth muscle contraction H2 receptors—increased vascular permeability, increased gastric secretion

Proteoglycans (heparin and chondroitin sulfate)/preformed

Heparin—anticoagulant, promotes new blood vessel growth (angiogenesis) Chondrotin sulfate—affects kinin pathway. Bradykinin is key component produced and causes vasodilation and works with prostaglandin

Tryptase/preformed Inactivates fibrinogen and inhibits fibrinogenesis (leads to bleeding); recruits eisonophils; increases interleukin 8 response (i.e., neutrophil chemotactic factor)—attraction of neutrophils, stimulate phagocytosis, promotes angiogenesis

Cytokines and chemokines (e.g., interleukins, tumor necrosis factor-alpha,

Involved in multiple processes such as B cell proliferation, antibody development, white blood cell recruitment

tumor growth factor-beta)/both

Leukotrienes/newly synthesized Bronchoconstriction, increased vascular permeability, and pain in conjunction with prostaglandins

Platelet activating factor/newly synthesized Attract white blood cells (eosinophils, neutrophils, monocytes, macrophages); bronchoconstriction, increased vascular permeability

Prostaglandins/newly synthesized Pain, bronchoconstriction, increased vascular permeability, inhibit platelet aggregation, attract neutrophils, and activate eosinophils

*Categories can overlap. ** Key effects—partial list

Immediately after an injury, arterioles in the area of injury briefly go into spasm and constrict to limit bleeding and the extent of the injury. The brief vasoconstriction is immediately followed by vasodilation. The vasodilation increases blood flow to the injured area in an attempt to dilute toxins and provide the area with essential immune cells (predominantly neutrophils), nutrients, and oxygen. The vasodilation, however, also increases capillary permeability, leading to edema. As permeability increases, leukocytes line the vessel wall in preparation for migration into the surrounding tissue. While the leukocytes are lining the vessel walls and accumulating (i.e., margination), endothelial cells in the vessel walls react to biochemical mediators that cause these vessels to retract. This retraction gives the leukocytes enough room to migrate (i.e., transmigration) into the interstitial space and begin the cleanup process of phagocytosis, or the engulfing and digestion of foreign substances and cellular debris.

BOX 2-1 Application to Practice Various pharmacotherapeutics are used in the treatment of the clinical manifestations of the inflammatory response. Review the following scenario. Describe which mediators and/or components of the inflammatory response are targeted by the medications listed.

Scenario: A 20-year-old woman has asthma. She is taking albuterol by inhaler as needed; fluticasone by inhaler every day; and montelukast orally every day. She states that she notes that her asthma is worse when she exercises so she is prescribed cromolyn inhaled.

The systemic response to the acute inflammation includes the development of fever, elevated white blood cell count, and release of acute phase proteins. Pyrogens are molecules that cause the systemic response of fever and are either endogenous (e.g., interleukin, prostaglandin E2) or exogenous (e.g., pathogens).

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Endogenous pyrogens cause fever in response to a pathogen or even in the absence of a pathogen. Pyrogens travel to the hypothalamus, the portion of the brain primarily responsible for controlling body temperature. There, they turn up the hypothalamic “thermostat” in a regulated manner. The body, through its thermoregulatory mechanisms, attempts to heat up the body to reach this new temperature, resulting in a fever. The body-heating mechanisms include shivering, cessation of sweating, vasodilation, and activation of the sympathetic nervous system to increase heat production. Fever is distinguished from other forms of hyperthermia (e.g., heat stroke) because the body temperature increase is regulated and thermoregulatory mechanisms of heating and cooling are functioning. Hyperthermia from heat stroke involves a dysfunctional unregulated increase in temperature along with an inability of the body to cool itself. Fever creates an unpleasant environment for bacterial growth. Mild fevers cause the spleen and liver to remove iron from the blood, which is required by many bacteria to reproduce. Fever increases metabolism, which facilitates healing and accelerates phagocytosis. In addition to the benefits of fever, there can also be deleterious effects such as the denaturation of vital proteins, especially enzymes, needed for biochemical reactions.

During the acute inflammatory process, the complement system and interleukin along with other mediators stimulates the bone marrow to produce more leukocytes, particularly neutrophils. The neutrophils phagocytize, release antimicrobials, and release their nucleus content to form traps to destroy injurious substances such as bacteria. Immature neutrophils (known as bands) outnumber mature neutrophils. Interleukins, in addition to stimulating fever and neutrophil proliferation, cause the liver to produce acute phase reactants. The most common reactants measured in the serum to evaluate the presence of inflammation are C-reactive protein (CRP), fibrinogen, and erythrocyte sedimentation rate (ESR).

Diagnostic Link

Acute Phase Reactants cute phase reactants are serum proteins that increase or decrease during acute or chronic inflammation and injury. The ESR reflects inflammation. Elevations, especially significant increases, are usually due to

infection, but noninfectious causes (e.g., anemia, renal disease) can also trigger elevations. CRP’s normal levels are not known, and formulas can be used to obtain an approximation for men or women based on age. Infections, particularly bacterial, tend to cause moderate to high increases. CRP rises and falls more rapidly than ESR. Fibrinogen, which is a major component of a clot, is elevated during inflammatory states. Acute- phase reactants that decrease are albumin, transferrin, and transthyretin.

Interferons Interferons are small proteins released from cells infected by viruses (FIGURE 2-2). These molecules diffuse from the site of invasion through the interstitial tissue and bind to receptors on the plasma membranes of uninfected cells. The binding of

interferons to uninfected cells triggers the synthesis of enzymes that inhibit viral replication. Consequently, viruses cannot replicate and spread when they enter the previously uninfected cells. Interferons do not protect cells already infected by a virus but rather stop the spread of the virus to new cells. In essence, interferon production is the dying cell’s attempt to protect other cells.

FIGURE 2-2 How interferon works.

Plasma Protein Mediators In addition to the cellular mediators, proteins that are part of the inflammatory response are continuously circulating within the plasma. The proteins are part of three systems—complement, clotting, and kinins. The complement system is a process that involves approximately 20 blood plasma proteins and enhances the action of antibodies. Complement proteins circulate in the blood in an inactive state. When foreign substances invade the body, these proteins become activated, and several pathways are taken to enhance pathogen destruction and participate in the inflammatory response. Only a few activities in this complex process are described here.

Five complement system proteins join together to form a large molecule, or membrane attack complex. The membrane attack complex becomes embedded in the plasma membrane of bacteria, creating an opening into which water flows. The influx of water causes the bacterial cells to swell, burst, and die. Other complement proteins stimulate vasodilation in an infected area as a part of the inflammatory response. Some complement proteins increase the permeability of vessels, allowing white blood cells and plasma to pass quickly through them to the infected area. Other complement proteins serve as chemical attractants, drawing macrophages, monocytes, and neutrophils to the infected area where they phagocytize foreign cells. Still other complement proteins bind to microbes, forming a rough coat on the invader that promotes phagocytosis.

The clotting system is activated during infection and injury. Like the complement system, various pathways are taken. The pathways ultimately participate in the inflammatory response by attracting (chemotaxis) neutrophils to the site of injury and causing increased vascular permeability. Part of the clotting system includes the transformation of fibrinogen into fibrin. This fibrin is used to wall off the injured area so that foreign substances are contained. A meshwork of new cells form to provide support for the healing process. Blood clotting begins if blood vessels have been damaged. Kinin system activation primarily leads to the development of bradykinin. Similar to histamine and prostaglandins released from mast cell degranulation, bradykinin causes pain, increased vascular permeability through vasodilation, neutrophil recruitment, and smooth muscle contraction (i.e., bronchoconstriction).

Chronic Phase of the Inflammatory Response The outcome of the acute inflammatory phase may be resolution or progression to chronic inflammation. The chronic phase can last weeks to months. This phase usually occurs because the acute response was not effective in eliminating or

repairing the injury or infection. Under certain circumstances, microorganisms are resistant to phagocytosis or even live within macrophages such as with Mycobacterium tuberculosis (tuberculosis) or Treponema pallidum (syphilis), and, thereby, there is a minimal acute inflammatory response. Other organisms such as Corynebacterium diphtheriae, Clostridium tetani, and Clostridium botulinum release toxins that remain after their death. The process of chronic inflammation, in contrast to acute inflammation, mainly consists of infiltration with monocyte macrophages and lymphocytes. The neutrophil and monocyte macrophages continue the cleanup. Granulomas, which consist of macrophages and lymphocytes, develop in an attempt to separate and contain the infection. Some infectious granulomatous diseases include tuberculosis, syphilis, leprosy, and brucellosis. Syphilis, leprosy, and brucellosis can also survive within macrophages and avoid clearance. Granuloma formation is not to be confused with granulation tissue development which is a step in tissue repair. Granulation tissue is a mixture of new vasculature and fibroblasts, which produces connective tissue fibers and collagen.

Adaptive Immunity Adaptive or acquired defenses are the body’s own individual immune system. These defenses recognize and attack antigens that make it through the innate defenses. Adaptive defense mechanisms are often stimulated and primed during the innate defense. There are two major adaptive approaches—cellular and humoral immunity. Key cells involved in these approaches are the T cells and B cells (FIGURE 2-3). T cells and B cells mingle with antigens as they circulate throughout the body’s fluids and peripheral lymphoid tissue, such as the tonsils, lymph nodes, spleen, and intestinal lymphoid tissue. This interaction serves either to destroy the antigen (T-cell function or cellular immunity) or to produce antibodies against the antigen (B-cell function or humoral immunity). T cells and B cells have receptors on their surfaces that develop during their maturation process and are prepared to recognize antigens.

FIGURE 2-3 Overview of adaptive immunity. Modified from Gould, B. (2014). Pathophysiology for the health professions (5th ed.). Philadelphia, PA: Elsevier.

Copyright Elsevier 2015.

Cellular Immunity Cellular immunity is a defense approach that is mediated by T cells. T cells are produced in the bone marrow, but then they enter the bloodstream and travel to the thymus for maturation, hence the name “T” cells. Two major types of T cells work to destroy antigens: 1) regulator cells, including helper T cells and suppressor T cells; and 2) effector cells, or killer T cells (i.e., cytotoxic cells) (Figure 2-3). Helper cells can further be subdivided into T-helper (Th) 1 and Th 2. The Th 2 cells activate, or call up, B cells to produce antibodies while the Th 1 cells are involved in the inflammatory process and the activation of macrophages. Helper cells secrete a protein termed CD4+, which is a major target of the human immunodeficiency virus (HIV).

The second type of regulator cells, suppressor T cells, turn antibody production off. Effector killer cells, or cytotoxic cells, destroy cells infected with viruses by releasing lymphokines that degrade cell walls. Cytotoxic cells are marked by the CD8+ protein on their surface. T cells work to protect the body against viruses, fungi, parasites, intracellular bacteria, and cancer cells. T cells are responsible for hypersensitivity reactions and transplant rejection.

Antigens must be processed and presented to the cell receptor for proper recognition by the T cells. This recognition system is important for the body to distinguish self from nonself. For some antigens, presentation can be accomplished by any cell, but for other antigens to be recognized by T cells, specialized antigen- presenting cells (APCs) are required. The dendritic cells from the bone marrow are important APCs. They are located all over the skin, respiratory system, and gastrointestinal system. Macrophages and B lymphocytes are two other key APCs. The antigen that is in the APC further binds to the major histocompatibility complex (MHC). The MHC encompasses a group of genes involved in immune function. The MHC genes include various cell markers, proteins, and antigens bound to a protein that then presents the antigen to the T cells. In humans, the MHC is called the human leukocyte antigen (HLA) system as the genes are expressed on the surface of the white blood cell. The human MHC and human HLA are synonymous. MHC genes are located on chromosome 6, and two different antigens will be on the cell surfaces—class I and II (i.e., regions). Class I cells include HLA-A, HLA-B, and HLA- C and are located on cells throughout. Class II cells are HLA-D, which are mainly in the immune system (B lymphocytes and monocytes), and are expressed on dendritic cells, macrophages, and B cells (all APCs). Class II cells present to the CD4+ helper T cells while class I cells present to the CD8+ suppressor and cytotoxic T cells. The adaptive system is often dependent on APCs. The MHC/HLA system is critical to

understanding organ transplantation and the predisposition to diseases (e.g., rheumatoid arthritis, type 1 diabetes mellitus). Antigen recognition and antigen binding triggers a response by other immune cells. Class III region consist of components of the complement system and class IV has other immune genes such as tumor necrosis factors.

Humoral Immunity B cells mature in the bone marrow where they differentiate into either memory cells or plasma cells, which produce immunoglobulins (Ig; antibodies) (TABLE 2-3). These cells eliminate extracellular bacteria, neutralize bacterial toxins, prevent viral reinfection, and produce an immediate inflammatory response. Each B cell has receptor sites for a specific antigen; when it encounters this antigen, the B cell becomes activated and multiplies into either plasma cells or memory cells. The antibody-producing cells produce millions of antibody molecules during their 24-hour life span. B cells can begin this antibody production within 72 hours after initial antigen exposure. Subsequent exposures to the antigen then trigger a quick response because memory cells recall the antigen as foreign and antibody production occurs rapidly. This reaction is referred to as acquired immunity (TABLE 2-4).

TABLE 2-3 Immunoglobulins and Their Functions

IgG Second response after IgM. Main defense against bacteria and can cross the placenta to protect the fetus against infections, giving it passive immunity. Eventually replaces IgM.

IgM First Ig formed in response to antigen. Fights blood infections and triggers additional production of IgG. Present in lymphocyte cells and the first antibody made by a developing fetus.

IgA Found in membranes of the respiratory and gastrointestinal tract, tears, saliva, mucus, and colostrum. Important in local immunity.

IgE Protects the body through its presence in mucous membranes and skin and is attached to mast cells and basophils. Responds to parasites and triggers allergic reactions.

IgD Present in blood serum in small amounts and on B-cell surfaces. Receptor for antigens and helps anchor cell membranes.

Modified from Gould, B. (2014). Pathophysiology for the health professions (5th ed.). Philadelphia, PA: Elsevier. Copyright Elsevier 2015.

TABLE 2-4 Types of Acquired Immunity

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Modified from Gould, B. (2014). Pathophysiology for the health professions (5th ed.). Philadelphia, PA: Elsevier. Copyright Elsevier 2015.

Learning Points

Microorganisms iruses: Viruses only survive and multiply by invading host cells, and, therefore, are similar to obligate bacteria. Viruses reside in neurons until they are reactivated. There are debates concerning whether

viruses are living creatures or simply molecules. Examples of viruses include herpes simplex 1 (e.g., oral sores).

Bacteria: Bacteria invade the extracellular (EC) or intracellular (IC) environments. EC bacteria cannot survive in the harsh intracellular conditions, and some penetrate tissue while others live on epithelial surfaces secreting toxins. Examples of EC bacteria include Pseudomonas aeruginosa (e.g., causes pneumonia, septicemia), Staphylococcus aureus (e.g., causes skin infections), Streptococcus pyrogenes (e.g., causes pharyngitis), and Haemophilus influenzae (e.g., causes pneumonia).

IC bacteria can be facultative or obligate. IC bacteria that are facultative invade host cells and have mechanisms to shield themselves from destructive IC lysozymal enzymes and humoral antibodies. Examples of IC facultative bacteria include Neisseria gonorrhoeae (e.g., causes sexually transmitted diseases), Legionella (e.g., causes pneumonia), and Mycobacterium (e.g., causes tuberculosis). IC bacteria that are obligate cannot live on their own and are dependent on the host cell for survival. Examples of IC obligate bacteria include Chlamydia trachomatis (e.g., causes sexually transmitted diseases).

Fungi: Fungi cause disease in the form of yeast in humans. An example is Candida albicans (e.g., causes oral thrush, vaginal candidiasis).

Protozoa: When they invade human body, they develop a parasitic relationship living off a host. Examples are Plasmodium (e.g., causes malaria), Giardia lamblia (e.g., causes giardiasis), Cryptosporidium (e.g., causes waterborne diseases and diarrhea), Toxoplasma gondii (e.g., causes toxoplasmosis).

Diagnostic Link

Evaluating Microorganisms aboratory diagnosis of microorganisms is usually accomplished through microscopic direct visualization, culture, antigen–antibody binding, or antigen or antibody detection. Organisms require microscopy in order

to be visualized (except for some parasites) and some organisms require staining for identification. Bacteria usually require staining, and the two key types are the gram stain and acid-fast techniques. A culture is another common method of microorganism identification. A culture involves growing the microorganism, usually bacteria, in vitro (i.e., outside the organism). There are various media and techniques used to identify the

I

organism; some of these can be accomplished within a relatively short period (e.g., 2 hours). Antigens bind with antibodies in a specific manner, and antigens and antibodies can be detected because of this binding. When reading a microorganism report, identify what was evaluated and how the evaluation was conducted— determine whether the evaluation was of the antibodies to an antigen (e.g., IgG, IgM for hepatitis), whether the organism was grown (e.g., as a culture for Streptococcus), and whether the organism was stained (e.g., acid- fast bacillus for Myobacterium tuberculosis).

Diagnostic Link

IgG and IgM gM and IgG are often measured to evaluate the immune response to a pathogen or vaccine. IgM is the first to respond and, therefore, rises after exposure. An elevated IgM is generally a marker of acute infection and will

decrease with time. IgG, on the other hand, is found throughout the body and responds later than IgM. Elevated IgG is a marker of long-term immunity and will be positive for life after exposure. A way to remember which indicates which is that with IgM, the immune system is creating memory (M), and with IgG, the infection is gone (G).

Active acquired immunity refers to immunity gained by actively engaging with the antigen—that is, through invasion or vaccination. In active immunity, the body makes antibodies, and protection is usually long term. Examples of active immunity include getting a varicella infection (chickenpox), and not getting the disease again or when a person receives the varicella vaccine and never gets varicella.

Passive acquired immunity refers to immunity gained by receiving antibodies made outside the body by another person, animal, or recombinant DNA. In passive immunity, the person is not actively producing antibodies and protection is short lived. Examples of passive immunity include mother-to-fetus transfer through the placenta and breastfeeding transference of antibodies. Exposure to rabies infection is often treated with a combination of immunoglobulin (passive) and a killed form of the virus (active).

The adaptive defenses change naturally with aging. These changes make older adults and the elderly more susceptible to developing infections and having worse outcomes. Diseases such as diabetes or heart failure, which are more prevalent with aging, further contribute to immune dysfunction because they directly impair aspects of the immune system or deplete the body’s reserves. The deterioration of the immune system as a result of aging is termed immune senescence. These changes include a reduced production of T cells and B cells and altered functioning of mature lymphocytes. Hematopoietic stem cells that differentiate into lymphocytes are fewer. B cells and T cells proliferate less and apoptosis rates are higher. The thymus gland involutes affecting T-cell maturation. Beneficial cytokine production decreases. B cells have a decreased capacity to produce immunoglobulins. More immune complexes and autoantibodies are present.

Other age-related adaptive immune system differences are evident in newborns who are also more susceptible to infections while their immune systems mature.

Normal term newborns have maternal antibodies, specifically IgG. Around 3 months, the maternal IgG drops, and the infant continues producing its own IgG. However, levels are remain low until about 6 months when newborn production becomes adequate. During this 3–6 months the infant is said to have a benign, physiologic hypogammaglobulinemia. T cells are not transferred from mother to newborn; however, the newborn produces T cells. Newborn T-cell function is limited; therefore, newborns are susceptible to infections.

Vaccines While getting an infection is the best way to get lifelong immunity against a pathogen, the outcome of an infection may be too risky, causing significant morbidity and even death. Vaccines were developed to stimulate the immune system to provide protection against infection and avoid the consequences of getting an infection. Vaccination response is influenced by 1) antigen characteristic and dose, 2) administration route (e.g., inhaled, oral), and 3) adjuvants added to enhance and modulate response (e.g., aluminum-based material, oil-in-water emulsions). Vaccines fall into two categories—1) live, attenuated and 2) inactivated. Live, attenuated vaccines are created from weakened wild viruses or bacteria that can replicate without causing diseases. Live, attenuated vaccines create an almost identical immune response as active infection. Some examples of live viral vaccines include paramyxovirus (mumps), rubella (German measles), varicella-zoster (chickenpox), and live bacterial vaccines include Salmonella serotype typhi (typhoid) and bacillus Calmette-Guérin (tuberculosis). Live vaccines tend to give longer immune protection; however, oral versions of live vaccines may not give as long- term protection as parenteral versions. Some people do not respond to one dose of a live vaccine, so multiple doses need to be given (e.g., measles, mumps, rubella). Live, attenuated vaccines can cause infections and are contraindicated in those who are immunocompromised. Live vaccines are fragile and must be protected from heat and light and stored properly.

Inactivated vaccines are made from whole or fractions of viruses or bacterial antigen or the toxin produced by the bacteria. The response stimulated is mainly humoral with little or no stimulation of cellular immunity. The organisms with inactivated vaccines do not replicate, and multiple doses and boosters are usually necessary. Whole virus vaccine examples include polio, rabies, and hepatitis A. Whole inactivated bacterial vaccines (e.g., cholera, plague, typhoid) are not available in the United States.

Fractional vaccines are either toxoid or subunit. There are three types of subunits —protein based, polysaccharide, and conjugate based. Toxoids, like one of the subunits, are protein-based vaccines (e.g., diphtheria and tetanus), and these are made by modifying the toxins produced by some bacteria; the modification does not cause disease. Subunit fractional vaccines are made from the antigenic part of a

pathogen (purified antigen) as opposed to the whole pathogen that has been killed. Subunits can be protein based by using a protein component to present the antigen (e.g., acellular pertussis, hepatitis B). Other subunits are only made from the polysaccharide wall that surrounds some bacteria (e.g., pneumococcus, meningococcal bacteria). The third type of fractional subunit vaccine are those made by conjugating a piece of the polysaccharide wall with a protein carrier (e.g., Haemophilus influenzae type b, meningococcal vaccine, or pneumococcal vaccine). The pure, polysaccharide (i.e., carbohydrate) -only based vaccines tend to be less effective than live vaccines or inactivated vaccines with a protein base. Additionally, the polysaccharide vaccines are often not very immunogenic. Children younger than 2 years do not respond consistently to these types of vaccines due to their immature immune systems, and these vaccines are, therefore, not effective or recommended in the young. An example is the pneumococcal polysaccharide vaccine 23, which is recommended after the age of 2. The antibody produced with polysaccharides is mainly IgM, which does not confer long-term protection. Inactivated vaccines do not cause disease from infection even in immunocompromised people.

Recombinant vaccines are those developed through genetic engineering technology and can include the use of the pathogen’s DNA, genetic medication of a pathogen, and a viral vector which is a virus that has been modified to insert genetic material into cells. Examples of recombinant vaccines include hepatitis B, human papillomavirus, and some influenza. Vaccine development and technology is rapidly changing, and the most up-to-date information and recommendations can be accessed at www.cdc.gov/vaccines.

Altered Immune Response A malfunction at any point in any of the numerous and highly complex immune responses can create a pathologic state. Malfunctions may include exaggeration (hypersensitivity), failure of self-recognition (autoimmunity), or diminution (immunodeficiency).

Hypersensitivity Hypersensitivity is an inflated or inappropriate response to an antigen. The result is inflammation and destruction of healthy tissue. Hypersensitivity reactions may be immediate, occurring within minutes to hours of reexposure to the antigen, or delayed, occurring several hours after reexposure. Hypersensitivity reactions can be categorized by the disease mechanism, of which there are four types—type I (IgE mediated), type II (tissue specific), type III (immune complex–mediated), and type IV (cell mediated) (TABLE 2-5). Hypersensitivity reactions can also be categorized by the type of antigen the immune system is responding to, such as self-antigens (autoimmunity), antigens from another person (alloimmunity), or environmental antigens (allergy). When a hypersensitivity reaction occurs, more than one mechanism can contribute. Hypersensitivity reactions can cause a localized or widespread response.

TABLE 2-5 Overview of the Hypersensitivity Reactions

RBCs, red blood cells. WBCs, white blood cells. SLE, systemic lupus erythematosus. Reproduced from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Hypersensitivity by Mechanism Type I Hypersensitivity

With type I hypersensitivity (FIGURE 2-4), allergens activate T cells (usually helper cells), which bind to mast cells. These T cells stimulate B cells to produce IgE antibodies specific to the antigen, which are commonly environmental. A reaction to an environmental antigen is termed allergy. The difference between a normal immune response and a type I hypersensitivity response is that the antibody produced is IgE instead of IgA, IgG, or IgM. The IgE coats the mast cells and basophils, making them sensitive to the allergen. At the next exposure to the same antigen, the antigen binds with the surface IgE. The binding of the antigen with the IgE causes mast cell degranulation and mediator (e.g., histamines, cytokines, and prostaglandins) release. The degranulation and mediator release further activates the inflammatory process, attracting neutrophils and eosinophils and triggering the complement system. Histamine is the mediator causing many symptoms. The effects of type I reactions include immediate inflammation and pruritus. Repeated exposure to relatively large doses of the allergens is usually necessary to cause this response. The reaction can be localized as occurs in asthma, allergic rhinitis, and food allergies. See chapter 5.

FIGURE 2-4 Pathogenesis of an allergy.

Widespread, immediate systemic reactions resulting from sudden release of mast cell and basophil mediator release is termed anaphylaxis. Anaphylaxis is usually the result of an IgE event, but IgG and immune complex/complement reactions may also occur. These three types of reactions are termed immunologic anaphylaxis. Mast cells and basophils may be activated without IgE, IgG, or immune complexes and the reaction is termed nonimmunologic anaphylaxis (formerly anaphylactoid). Examples of nonimmunologic reactions are red man syndrome, caused by vancomycin administration or erythema; pruritus; and edema with exposure to cold (cold urticaria). Clinically, the underlying immune event in anaphylaxis is often difficult to determine. While most environmental allergies are type I IgE mediated, some are type II and type III, such as when gluten from wheat causes gastrointestinal symptoms (e.g., celiac disease) with a penicillin allergy. Poison ivy, although an environmental allergen, causes a type IV hypersensitivity (see Table 2-

5). Treatment of type I reactions may include epinephrine, antihistamines, corticosteroids, and desensitizing injections, all of which will suppress inflammatory activity.

Type II Hypersensitivity Type II hypersensitivity (FIGURE 2-5) generally involves the destruction of antigens on target cells or tissue. The antigens may be intrinsic (self) or extrinsic (absorbed through exposure). The human leukocyte antigens (MHC/HLA) discussed in the Adaptive Immunity section are some examples of intrinsic antigens on cells. Some antigens are also located on certain tissues, such as on the prostate, which has prostate-specific antigen. In type II reactions, IgG or IgM antibodies bind with an individual’s own specific cell or tissue antigens, activating the complement system. The end result is destruction or a malfunctioning cell. Recognition of these cells by macrophages triggers antibody production. Type II hypersensitivity mechanisms include complement activation, leading to cell lysis, phagocytosis, and neutrophil or cytotoxic (natural killer) cells destroying the targets. Another type II mechanism involves an antibody binding with a cell surface receptor and blocking the action of this receptor. Examples of type II reactions include blood transfusion reactions and erythroblastosis fetalis. Treatment for these two reactions focuses on prevention and includes ensuring blood compatibility prior to transfusions, administering medication to suppress immune activity (e.g., corticosteroids and cyclosporine), and preventing maternal antibody development (e.g., Rho[D] with immune globulin [RhoGAM]).

FIGURE 2-5 Type II hypersensitivity reaction with lysis of red blood cells. Antibody reacts with cell surface antigens, resulting in complement fixation (c) and cell lysis.

Type III Hypersensitivity In type III hypersensitivity (FIGURE 2-6), circulating antigen-antibody complexes that have not been adequately cleared by the innate blood-borne immune cells accumulate and become deposited in tissues. Characteristics of the antigen- antibody complex will determine where and with what tissue the complex will bind. As opposed to type II reactions, type III reactions are not targeted toward a specific organ. However, tissues often affected in this way include the kidneys, joints, skin, and blood vessels. The accumulation of the complexes triggers the complement system, causing local inflammation and increased vascular permeability; in turn, more complexes accumulate as neutrophils and macrophages are activated.

Examples of type III reactions include autoimmune disorders (e.g., systemic lupus erythematosus and glomerulonephritis). The quality of the immune complex changes over time, and there can be several types at one time (e.g., small, intermediate, or large). The changing immune complexes and different types lead to varying symptomatology and causes the remissions and exacerbations seen in type III hypersensitivity. Treatment for type III reactions is disease specific.

FIGURE 2-6 Type III allergic hypersensitivity reaction. A. Antigen (Ag) and antibody (Ab) form complexes in the presence of excesss antigen B. The complexes are deposited in the vessel wall and fix complement (c). C.

Activated components of complement cause release of vasoactive materials from mast cells and chemotaxis of polymorphonuclear leukocytes. D. The end result is acute inflammation and destruction of the vessel wall.

Type IV Hypersensitivity

Type IV hypersensitivity involves a delayed processing of the antigen by macrophages. Once processed, the antigen is presented to the T cells (usually helper or cytotoxic cells), resulting in the release of cytokines that cause inflammation and antigen destruction. As opposed to the other types of hypersensitivity, type IV is not antibody mediated (FIGURE 2-7). These reactions can cause severe tissue injury and fibrosis. Examples of type IV reactions include tuberculin skin testing, transplant reactions, and contact dermatitis from poison ivy. Treatment for type IV reactions is disease specific.

FIGURE 2-7 Sensitized T lymphocytes attach foreign cells.”

Hypersensitivity by Antigen Alloimmunity

The immune system’s protective nature presents challenges for patients who require tissue and organ transplants and blood transfusions. Ensuring the best possible tissue match is critical for transplant success. Four types of tissue transplants are possible—allogeneic, syngeneic, autologous, and xenogenic. Allogeneic transplants are those in which the tissue used is from the same species and is of similar tissue type, but it is not identical. Most transplants use allogeneic tissue. Syngeneic transplants use tissue from the identical twin of the host. With autologous transplants, the host and the donor are the same person. An example of this type of transplant is someone storing up his or her own blood prior to a scheduled surgery. Xenogenic transplants use tissue from another species. An example of this type of transplant is the use of pig heart valves to replace diseased valves in a human. Donors may be live or a cadaver, but no matter the source used, making a close tissue match is fundamental to preventing rejection.

In organ transplantation, the immune system of the host targets the major histocompatibility complex on donor cell surfaces (see the Cellular Immunity section). The T cells are activated, cytotoxic cells begin destruction, and T cells facilitate B cell antibody production.

Rejection reactions are classified based on their timing. Hyperacute tissue rejections occur immediately to 3 days after the transplant. Such reactions occur due to a complement response in which the recipient has antibodies against the donor tissue. This complement response triggers a systemic inflammatory reaction. The response is so quick that often the new tissue has not had a chance to establish vascularization; as a result, the tissue becomes permanently necrotic.

BOX 2-2 Application to Practice Case 1: A 20-year-old woman comes in concerned that she has genital herpes as she has been having unprotected sex. She does not have any lesions but wants to be tested. An antibody test is done and the results revealed the following:

HSV 1 IgG type-specific antibody: < 0.90 (negative) HSV 2 IgG type specific antibody: > 1.10 (positive)

How would you explain these results to her? Can you tell if this is a recent or past infection? Can you tell how long ago she was infected?

Case 2: A patient arrives in the emergency department with possible anaphylaxis. An epinephrine intramuscular injection is administered. Describe the therapeutic actions of epinephrine as they apply to immune alterations in anaphylaxis.

Activity 1: There are many kinds of fungal infections. Describe the location and most common organism for the following diagnoses:

Vulvovaginitis Balanitis Balanoposthitis Onychomycosis Tinea capitis Tinea cruris Tinea corporis Tinea pedis

Activity 2: What are the differences between gram-negative and gram-positive bacteria? Which are more pathogenic? List examples of common organisms that are negative or positive.

Acute tissue rejections are the most common and treatable type of rejection. These reactions usually occur between 4 days and 3 months following the transplant. Acute reactions are cell mediated with mainly Th 1 cells producing interleukin 2 and interferon gamma, causing macrophage stimulation and resulting in transplant cell destruction (lyses) or necrosis. The patient exhibits manifestations of the inflammatory process including fever, redness, swelling, and tenderness at the graft site. Additionally, the patient may experience impaired functioning of the transplanted organ.

Chronic tissue rejection occurs from about 4 months to years after the transplant. This reaction is most likely due to an antibody-mediated immune response. Antibodies and complement molecules become deposited in the transplanted tissue vessel walls, resulting in decreased blood flow and ischemia.

Most rejection reactions are classified as host-versus-graft rejection; in other words, the host is fighting the graft. The graft fights the host in another type of reaction, known as graft-versus-host rejection. This potentially life-threatening type of reaction occurs with bone marrow or stem cell transplants. The immunocompetent graft cells recognize the host cells as foreign due to the host having antigens that are not on the graft and organize a cell-mediated (primarily T-cell) attack. The host is usually immunocompromised and unable to fight the graft cells’ actions.

Identifying the rejection reaction quickly is crucial to reversing it. Assessment including manifestations of a healthy and unhealthy transplant organ is paramount. For example, decreased urine output may indicate a failing kidney transplant. Diagnostic procedures include laboratory tests to identify immune and inflammatory activity (e.g., white blood count and erythrocyte sedimentary rate) and specific tests to determine functioning of the transplanted organ (e.g., renal panel and urinalysis).

Treatment for transplant rejection usually begins with prevention. Prevention starts with ensuring a tissue match and initiating immunosuppressive therapy (e.g., corticosteroids and cyclosporine). The transplant patient will likely require immunosuppressive therapy for life. Once a rejection is suspected, immunosuppression therapy is intensified to reverse it.

Autoimmunity More than 80 diseases are classified as autoimmune disorders. Some common disorders are systemic lupus erythematosus, inflammatory bowel disease (i.e., Crohn disease and ulcerative colitis), type 1 diabetes mellitus, and rheumatoid arthritis. In autoimmune diseases, the body’s normal defenses become self- destructive—that is, they fail to identify self-antigens within the host from nonself foreign antigens. Under normal circumstances, the immune system has the capacity to tolerate self-antigens and regulate them to avoid a maladaptive immune response. These mechanisms are central and peripheral tolerance. Central tolerance occurs in primary lymphoid tissue (e.g., thymus for T cells and bone marrow for B cells) when lymphocytes are maturing. With central tolerance, B or T cells that are autoreactive (bind to self) are destroyed or suppressed. In the secondary lymphoid tissue (e.g., lymph nodes, spleen) where B and T cells migrate, peripheral tolerance and self- antigens are simply not recognized. With a healthy immune system, self-recognition and tolerance are important mechanisms in shaping the adaptive immune system and maintainence as apoptotic cells and tissue debris needs to be removed. In addition to tolerance, self-antigens are often sequestered, and the immune system has regulatory mechanisms (e.g., B and T cells, cytokines) that limit the degree of immune reactivity.

Autoimmune disease can occur when things go wrong with tolerance, sequestration, and regulatory mechanisms. Reasons for tolerance failure and a misdirected response are unclear. However, an exogenous trigger and endogenous abnormalities (e.g., viral, genetic, medicinal, hormonal, environmental) with multiple mechanisms likely contribute to autoimmune disease development. The exogenous trigger may cause autoimmunity when the antigen (e.g., pathogen) looks like an antigen already present (a process called molecular mimicry). The immune system attacks the foreign antigen as well as the self-antigen because they look so similar. Some antigens such as viruses or bacteria act as superantigens and have the ability to bind to T cells that are nonspecific and mount an immune response. Some antigens modify the immune response (e.g., adjuvant effect) by increasing the immunogenicity (provoking immune response).

Several endogenous abnormalities can contribute to autoimmunity and can include abnormal antigen presentation. The immune system may have problems clearing cellular debris such as apoptotic cells. Other endogenous abnormalities include B cells and T cells responding inappropriately to signals or defects in autoantibody production. Imbalances in cytokines, such as tumor necrosis factor and interleukin, can derail the immune system.

Autoimmune disorders affect women more often than men, pointing to a possible hormonal influence in autoimmune development. Many autoimmune diseases can have family tendencies, pointing to genetic influences. Inheriting a gene can lead to susceptibility for acquiring a disease. The susceptibility, coupled with other factors

such as an infection or other environmental stimuli, can lead to autoimmune disorders. Some gene polymorphisms lead to several autoimmune disorders, while other gene mutations are only associated with one condition. Autoimmune disorders are more prevalent with aging as self-recognition regulatory systems become less effective.

In autoimmune disorder, there are two key ways the immune system attacks itself: by autoantibody or T-cell mechanisms. Some autoantibodies can mark an antigen for phagocytosis. This marking, called opsonization, occurs in diseases such as autoimmune thrombocytopenic purpura or hemolytic anemia. Autoantibodies can block receptors. As an example, autoantibodies can block insulin receptors, which leads to insulin-resistant diabetes mellitus. In Graves disease, an autoimmune hyperthyroid disorder, the autoantibodies-thyrotropin receptor antibodies (TRAb) which are also known as thyroid-stimulating immunoglobulins bind to thyrotropin receptors, leading to excess thyroid hormone production (thyroxine/T4 and triiodothyronine/T3).

Characteristics of autoimmune diseases can affect any tissue or organ in the body, such as the thyroid in Hashimoto thyroiditis, as well as multiple systems, such as rheumatoid arthritis. At times, having one autoimmune disorder can predispose or lead to the development of another. Some autoimmune disorders have the presence of multiple autoantibodies that do not cause pathology. An example is in myasthenia gravis, where rheumatoid factor or antithyroid antibodies are present yet cause no pathology. Autoimmune disorders are characterized by frequent progressive periods of exacerbations (worsening of symptoms) and remissions (easing of symptoms). Physical and emotional stressors frequently trigger exacerbations. Exacerbations are common, particularly in autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis.

Because of the somewhat mysterious nature of autoimmune disorders, diagnostic procedures often begin by eliminating all other causes. In general, diagnostic tests such as laboratory autoimmune antibody tests can be difficult to interpret. There are laboratory tests that are specific to the suspected autoimmune disorder (e.g., rheumatoid factor for rheumatoid arthritis), but these tests, as seen in the myasthenia gravis example, are not always specific. Treatment for autoimmune disorders is disease specific. Systemic lupus erythematosus is one of the most common autoimmune disorders and will be discussed in the next section while other autoimmune disorders will be discussed in the appropriate system chapter (e.g., autoimmune thyroiditis in chapter 10).

Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a chronic, inflammatory, autoimmune disorder that can affect any connective tissue. SLE occurs more often in women than

in men. In adults, the female-to-male ratio can range from 7:1 to 15:1. SLE is more common in Asians, Blacks, and Hispanic Americans in comparison to Whites. The incidence has increased dramatically due to improved diagnostic testing. Disease onset in 65% of cases is between the ages of 16 and 55. The disease is different in terms of ethnicity, gender, and age of onset. Men, for example, have a lower incidence but worse outcome. Manifestations are also different in men, who have a higher incidence of renal disease and hypertension, in comparison to women, who have a higher incidence of Raynaud phenomenon. Other examples of variances include worse renal outcomes for Black and Hispanic Americans and worse symptomatology in children.

Genetic alterations, such as the presence of susceptibility genes and absence of protective genes, predispose to the development of SLE, and SLE development is more likely when coupled with epigenetic influences. The higher incidence in women is attributed to X chromosome issues and to the effects of estrogen, progesterone, and prolactin on the immune system. Most of the hormonal effects can lead to heightened immune response and autoantibody production.

In SLE, B cells are thought to be activated and autoantibodies will bind with autoantigens (e.g., antinuclear antibodies) and form immune complexes. These immune complexes fight against the body’s own tissues, such as nucleic acids, red blood cells, platelets, and lymphocytes. Hyperactive helper T cells and subdued suppressor T cells are thought to create a prime environment for B cells to overproduce.

Clinical Manifestations Usually the symptoms a person has at the beginning of the disease or within the first few years remain throughout the course of their disease. SLE is an unpredictable disorder but most often affects the heart, joints, skin, lungs, blood vessels, liver, kidneys, hematologic function, and nervous system (TABLE 2-6).

TABLE 2-6 Common Manifestations of Systemic Lupus Erythematosus

Systemic Fatigue, fever, weight change (usually loss)

Musculoskeletal Myalgia, polyarthritis (migratory, symmetrical) with swollen and painful joints, without damage; arthralgia

Skin Butterfly rash with erythema on cheeks and over nose, or rash on body; photosensitivity—exacerbation with sun exposure; usually painless ulcerations in oral mucosa; hair loss

Kidneys Glomerulonephritis with antigen–antibody deposits in glomerulus, causing inflammation with marked proteinuria and progressive renal damage, nephrotic syndrome

Lungs Pleurisy—inflammation of the pleural membranes, causing chest pain

Heart Carditis—inflammation of any layer of the heart, commonly pericarditis

Blood vessels Raynaud phenomenon—periodic vasospasms in fingers and toes, accompanied by pain and vasculitis throughout (e.g., skin lesions, hepatic, coronary)

Central nervous system Psychoses, depression, mood changes, seizures

Hematologic Anemia of chronic disease, leukopenia, thrombocytopenia, lymphadenopathy, splenomegaly, thrombus (venous or arterial)

In bold: greater than 35% incidence at onset. Reproduced from Story, L. (2017). Pathophysiology: A Practical Approach, 3rd Edition. Burlington, MA: Jones & Bartlett Learning.

Diagnosis and Treatment Because patients with SLE can have a wide variety of symptoms and different combinations of organ involvement, diagnosis can be challenging. Clinical criteria have been developed to improve diagnostic accuracy. These criteria continue to evolve in attempts to get a universal consensus. Some patients suspected of having SLE may never develop enough of the criteria to qualify for a definite diagnosis; other patients accumulate enough criteria to merit SLE diagnosis only after months or years. When a person has four or more of the criteria, the diagnosis of SLE is strongly suggested. When evaluating a patient, these criteria can be used in patients presenting with common SLE symptoms (Table 2-6) although some are vague (e.g., fatigue, fever) and can be present in many other disorders.

Clinical Criteria for SLE Diagnosis Skin: Acute/subacute cutaneous—Malar rash (“butterfly” rash over the cheeks of

the face), photosensitivity; Chronic cutaneous lesions—(e.g., discoid lupus— rough, scaly, raised, red circular)

Oral ulcers—look like aphthous ulcer (i.e. cold sore) but can also be in nose Alopecia—usually patchy Synovitis—joint inflammation causes pain, swelling usually symmetrical, two or

more joints and can migrate Serositis (inflammation of the serous membranes that line the lungs [pleura],

heart [pericardium], and inner abdomen [peritoneum]) Hemolytic anemia Leukopenia (< 4,000/mm3) Lymphocytopenia (< 1,000/mm3) Thrombocytopenia (100,000/mm3) Neurologic disorder (e.g., brain irritation manifested as seizures or psychosis) Renal: RBC casts, Proteinuria (>0.5 g/24 hours), Positive biopsy (nephritis),

even if no other criteria is present RBC casts Protein/creatinine (> 0.5) Positive biopsy, even if no other criteria is present

In children and older adults, some clinical manifestations will vary. The diagnosis is usually made after the age of 5 years but is often present after the age of 10. While children can have the same clinical manifestations as adults, they most often present with fever, malaise, weight loss, small-joint arthritis, and renal disease. Additionally, their symptoms are usually more severe. Older adults usually have a milder presentation with higher incidence of sicca (e.g., dry eyes, dry mouth), serositis, and lung and musculoskeletal manifestations.

In addition to the common presentation and criteria, other tests can be helpful in evaluating patients for SLE. Routine laboratory tests would include a complete blood count and differential to evaluate for anemia and white blood cell and platelet abnormalities. A chemistry profile can evaluate renal function. A urinalysis may reveal casts and proteinuria. Immunologic tests for autoantibodies—of which at least one needs to be positive for diagnosis—will include testing for antinuclear antibodies, which is usually positive in most people with SLE; antibodies that are specific to SLE including anti–double-stranded DNA; and anti-Smith antibodies, which are very specific. Antiphospholipid antibodies are not unique to SLE, but it is one of the criteria. Low C3 and C4 complement levels (proteins that promote immune and inflammatory response) or a complete complement test (CH50), which checks all complements 1–9, can be done. A positive direct Coombs (measure of antibody bound to RBCs) test also can count as one criterion. Other appropriate testing procedures, such as liver function tests and echocardiography are selected for the patient on an individual basis. Tissue biopsies may also be necessary (e.g., of the skin and kidneys).

Treatment of SLE is directed at symptom management. General strategies include stress reduction, exercise, and sleep. Medications include nonsteroidal anti- inflammatory drugs (NSAIDs) to reduce pain and inflammation in joints, muscles, and other tissues. Corticosteroids may also be used to treat SLE. Corticosteroids are more potent than NSAIDs in reducing inflammation and restoring function when the disease is active and particularly when internal organs are affected. Corticosteroids, however, have multiple side effects (e.g., weight gain, risk for infection, hyperglycemia, and high blood pressure) that must be considered. Biologic disease- modifying antirheumatic drugs reduce pain and tissue damage as a result of inflammation. These drugs are more potent than NSAIDs and corticosteroids, but they carry significantly more risks, such as the risk for infection or organ damage. As the disease progresses, use of these agents may be necessary to prevent severe complications of SLE. Antimalarial drugs can treat fatigue, joint pain, rashes, and pleural inflammation by suppressing the immune system. Immunosuppressants may be used for patients with kidney and nervous system involvement. Additionally, plasmapheresis can remove antibodies and other immune substances from the blood to suppress immunity.

Immunodeficiency A diminished or absent immune response increases susceptibility to infections. Immunodeficiencies may be primary (reflecting a defect with the immune system) or secondary (reflecting an underlying disease or factor that is suppressing the immune system). Primary deficits involve basic developmental failures, many of which result from genetic or congenital abnormalities (e.g., hypogammaglobulinemia). Secondary or acquired immunodeficiency refers to a loss of immune function because of a specific cause; such causes may include infection, splenectomy, malnutrition, hepatic disease, drug therapy, or stress. The problem may be either acute or chronic. The most common forms of immunodeficiency are caused by viral infections or are iatrogenic reactions to therapeutic drugs (e.g., corticosteroids and chemotherapy). The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) are reviewed in this chapter, while other secondary immune disorders such as leukemia, multiple myeloma, and viral hepatitis will be discussed in other chapters as appropriate.

Primary Immunodeficiency Over 350 disorders are classified as primary immunodeficiency diseases (PID). Many deleterious genetic mutations are associated with these disorders. Some disorders are hereditary. These chronic disorders are rare. Innate defects such as dysfunctional, inadequate, or absent phagocytic capacity (e.g., asplenia, severe congenital neutropenia) can be present. Receptors on cells and the ability of cells to trigger important cellular processes can become defective, and the complement system can also be deficient (e.g., C3 deficiency). In the adaptive system, antibodies can be deficient (e.g., IgG and IgA disorders), or there can be B cell defects (e.g., IgA deficiency, hyper-IgM syndrome) or T cell defects (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome). Combined B cell and T cell defects may also be present, and often many classifications overlap. It is beyond the scope of this text to discuss each defect/disorder but a general overview is provided.

Clinical Manifestations Manifestations of PID can occur early in the newborn or in infancy as potential life- threatening infections. Children and adults with PID have a susceptibility to infections. Everyone gets an infection at some point in time. Normal frequency of infections in children usually include two or fewer respiratory infections (e.g., otitis media, bronchitis) in a year. PID presentation in adults is not as common, but normal frequency for adults is usually three or fewer infections (e.g., sinusitis, pneumonia) requiring antibiotics within a year. In PID, infections tend to be recurrent and/or chronic.

Regardless of frequency, a summary for suspicion for PID includes infections that

are:

Severe—requires hospitalization or intravenous antibiotics Persistent—will not completely clear up or clears very slowly Unusual—caused by an uncommon organism Recurrent—keeps coming back Familial—others in the family with a similar susceptibility to infection (www.primaryimmune.org)

Diagnosis and Treatment Newborn screening is recommended (and in some states mandated) for severe T- cell immunodeficiency. Diagnosis is based on clinical suspicion. A referral to an immunologist is warranted. Diagnosis and management is best handled by immunologists working with PID patients. Some laboratory tests are specific to the infection (e.g., site and organism). A complete blood count with differential will give information on lymphocytes and neutrophils. Flow cytometry can give detailed information pertaining to B cells and T cells. Testing may include antibody deficiencies by checking IgG, IgM, and IgA as well as complement testing (e.g., CH50). Vaccines may be given to evaluate if the person has developed antibodies (a normal, expected response). Carbohydrate and protein-based vaccine responses will be evaluated as a person may respond to one but not another. Genetic testing is often completed to identify the cause.

Prevention of infection is crucial in patients with PID and may include prophylactic antibiotic administration. Vaccine administration is not contraindicated for all patients with PID, but updates and guidelines need to be reviewed carefully. Treatment may include immunoglobulin replacement therapy, stem cell therapy, and gene therapy. Patients should get regular healthcare maintenance, such as dental care and primary care visits. Frequent illness can be burdensome, and mental health issues can be dealt with through counseling and support groups.

Secondary Immunodeficiency: HIV and AIDS AIDS is a deadly, sexually transmitted disease caused by the HIV, a retrovirus. HIV attacks and weakens the immune system. There are two primary strains of the virus —HIV-1 is the most prevalent strain in the United States, and HIV-2 is the most prevalent strain in Africa.

According to the Centers for Disease and Control and Prevention (CDC), in 2016, approximately 36.7 million people worldwide and 1.2 million people in the United States were living with HIV, but 1 in 8 (13%) of these people did not know they were infected. HIV is the seventh leading cause of death in individuals 25 to 44 years of age in the United States, down from the number one cause of mortality in this age

group in 1995. Most individuals infected are men, particularly gay, bisexual, or having sex with men. In 2014, men having sex with men accounted for 70% of all new cases of HIV infections. Diagnoses of new cases among women have declined 40% since 2005. Heterosexual contact is the most common (87%) mode of transmission for women. Cases involving female-to-female transmission (women having sex with women) are rare. In 2014, Blacks made up only 12% of the United States population but accounted for 44% of all new cases (particularly Black men) of HIV infections; however, Black women are also disproportionately affected. Of all women diagnosed with HIV in 2015 (CDC, 2017), 59% were Black, 17% White, and 19% Hispanic/Latina. The incidence of HIV in children is low, and 122 cases were diagnosed in 2016. For children under 13, most cases are transmitted from their mother. In terms of regional presence of HIV in the United States, the South accounted for most new HIV and AIDS diagnoses (54%/53%), persons living with HIV/AIDS diagnoses (44%), and AIDS deaths (47%) (CDC, 2017).

HIV is transmitted through direct contact with infected blood or body fluids (e.g., breastmilk, rectal and vaginal secretions, preejaculate/semen). HIV is contracted when these body fluids come in contact with mucous membranes located in the rectum, vagina, penis, or mouth. Contact usually occurs during sexual intercourse with receptive anal sex being the highest incidence followed by insertive anal sex and then penile–vaginal sex. The risk of contracting HIV from penile–vaginal sex is higher for women in comparison to men. Oral sex is a rare mode of transmission with fellatio conferring the highest risk, but the presence of blood and open areas in areas of contact would increase risks.

Ranking after sexual intercourse, injection drug use involving needle or syringe sharing, and other equipment sharing is the next highest mode of transmission in the United States. The risk of acquiring HIV from an accidental needlestick is minimal (1 in 300 or 0.3%), but the risk of transmission from sharing needles is significantly greater (1 in 150). From 1985–2013, 58 confirmed cases of occupational transmission to a healthcare worker and 150 possible exposures were reported. Of the 58 confirmed cases, 57 occurred before 1999, and only one new case occurred after 1999 (Joyce, Kuhar, & Brooks, 2015). However, underreporting is possible because such reporting is voluntary. There is a 13–40% chance of an infected mother transmitting infection to her child. The risk of transmission decreases to 1% with the administration of antiretroviral therapy early in the pregnancy. The antiretroviral drug most commonly used to prevent maternal transmission is Retrovir (zidovudine), which has a high safety index. HIV status can even be checked during labor and delivery, so antiretroviral therapy can be given during labor or within hours of delivery to reduce the incidence of transmission. Cesarean delivery can further decrease the risk of HIV transmission to the fetus, but vaginal delivery can occur under certain circumstances (e.g., on treatment with low viral load). Breastfeeding is also another method of mother-to-child transmission.

Other less common methods of transmission include the transfusion of blood or blood products or organ/tissue transplant. This risk is negligible due to extensive prescreening. Any contact of an open wound or bleeding from any source (e.g., gums) with another open area or mucous membrane, although rare, can lead to transmission. This mode of transmission is often dependent on such factors as amount of blood and entrance into the bloodstream. HIV is not transmitted by saliva alone, but if there is blood in the saliva, it may occur.

As a retrovirus, HIV requires a host to survive. The life cycle of HIV is important to understand as most pharmacologic agents are targeted toward a part of the cycle (FIGURE 2-8 and FIGURE 2-9). Once it gains access to the body, the virus targets macrophages, dendritic cells, and CD4+ helper T cells. The HIV outer surface has a glycoprotein 120 (GP-120) that binds to the CD4+ on dendritic cells (an antigen- presenting cell located on skin and mucosal tissue). Macrophages are also a target, and the virus GP120 needs to bind with a coreceptor known as chemokine receptor (CCR5) in addition to the CD4+ cells. To attach to the T cells, the virus GP120 must attach to another receptor called CXCR4 and the CD4+. Once attached and bound, the second part of the life cycle is known as fusion, which is the joining of the virus protein (glycoprotein 41), and the CD4+ membrane, which then allows entry. Once inside the CD4+ cells, it uses an enzyme, reverse transcriptase, to convert the viral RNA to DNA. The viral DNA then becomes integrated into the CD4+ cell’s own DNA with the help of another viral enzyme known as integrase. The infected CD4+ cell reproduces new viral RNA, viral capsid, and other HIV building blocks (protein chains). The HIV RNA and building blocks go to the surface of the cell to assemble into immature and noninfectious HIV. Once out of the cell, another enzyme, protease, breaks up the protein into smaller chains, which then form mature, infectious HIV. Meanwhile, the virus replicates and infects susceptible cells, releasing millions of viral copies into the bloodstream. Unfortunately, there is no HIV immune response. Each viral copy then attaches to a new CD4+ cell to start the process over again.

FIGURE 2-8 HIV cell. Reproduced from U.S. Department of Health and Human Services. The HIV Life Cycle. (2018). Retrieved from

https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/73/the-hiv-life-cycle-

FIGURE 2-9 The HIV life cycle.

Reproduced from U.S. Department of Health and Human Services. The HIV Life Cycle. (2018). Retrieved from https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/73/the-hiv-life-cycle-

Clinical Manifestations Once infected, an individual may not experience any symptoms, or they may be subtle and missed. Up to about 60% of individuals will develop flulike symptoms (e.g., fever, malaise, headache, sore throat, myalgia/arthralgia, nausea, diarrhea, rash, and lymphadenopathy). If the symptoms are prolonged or there are mucocutaneous lesions (e.g., shallow, demarcated ulcers with a white base and red area in the mouth, anus, penis or esophagus), then the suspicion even becomes higher for HIV. The stage with these clinical manifestations is referred to as the acute retroviral syndrome. This syndrome usually occurs within 4 weeks after infection. At this time, there will be a high viral load (e.g., > 1 million copies), decreased CD4+, and a high transmission potential (FIGURE 2-10). During this acute period, viral load fluctuates and then reaches a set point. After this brief early infection episode, the individual may remain asymptomatic for months to years, and the virus continues replicating but not as fast as during the acute phase. This stage is known as the clinical latency or chronic HIV infection stage. Depending on other health factors and behaviors, individuals can be in this stage for up to 10 years until they move into the late stage of infection and develop AIDS. The virus is methodically infecting and destroying CD4+ cells. As more and more CD4+ cells are destroyed, the individual begins to have symptoms (e.g., lymphadenopathy, diarrhea, weight loss, fever, cough, and shortness of breath). The individual becomes increasingly symptomatic as more CD4+ cells are destroyed. AIDS is defined as a CD4 count of less than 200 cells/mm3 or the development of an opportunistic infection (TABLE 2-7) regardless of the CD4+ count. In adults, normal CD4+ counts range between 500 and 1,500 cells/mm3. In children, AIDS is diagnosed when the CD4+ is less than 500 cells/mm3 (in 1- to 5-year-olds) and less than 750 cells/mm3 (in those < 1 year old).

FIGURE 2-10 CD4+ cell count and viral load following HIV infection.

TABLE 2-7 Opportunistic Infections

Bacterial pneumonia, recurrent (≥ 2 episodes in 12 months) Candidiasis of the respiratory tract and esophagus Invasive cervical cancer Fungal infections Parasitic and protozoan infections (> 1-month duration) Cytomegalovirus disease Encephalopathy Herpes simplex: chronic ulcers (> 1-month duration) Histoplasmosis Kaposi sarcoma Lymphoma Mycobacterium avium complex Mycobacterium tuberculosis Pneumocystis jirovecii (formerly carinii) pneumonia Progressive multifocal leukoencephalopathy Salmonella septicemia

Toxoplasmosis of the brain Wasting syndrome due to HIV (involuntary weight loss > 10% of baseline body weight) associated with either chronic diarrhea (≥ 2 loose stools per day ≥ 1 month) or chronic weakness and documented fever ≥ 1 month)

Life expectancy once AIDS is diagnosed is usually about 3 years unless a severe opportunistic infection occurs, and then life expectancy can decrease to 1 year. This disease trajectory can be altered by managing HIV with antiretroviral medications and developing a healthy lifestyle (e.g., exercise, healthy nutrition, safe sex, stress reduction).

HIV infection in infants and children may appear differently than the progression just described. Children who are HIV positive may experience the following manifestations:

Lymphadenopathy with hepatosplenomegaly early in the course Difficulty gaining weight Difficulty growing normally Problems walking Delayed mental development Severe forms of common childhood illnesses such as ear infections (otitis media), pneumonia, and tonsillitis

Opportunistic infections that are more prevalent in children include pneumocystis pneumonia, wasting syndrome, oral candidiasis, encephalopathy, cytomegalovirus infections, and frequent bacterial infections.

Diagnosis and Treatment Diagnosis is established through a set of laboratory tests as early as 2 weeks after exposure to the virus. There are three categories of testing—antibody-only testing, combination antigen and antibody testing, and viral detection (FIGURE 2-11). Antibody tests detect antibodies IgM and IgG against HIV-1 and HIV-2, usually within 3 weeks, but the time from HIV exposure to the test detecting the antibodies (i.e., the window period) can be up to 12 weeks (third-generation immunoassay).

FIGURE 2-11 Antibody-only testing, combination antigen and antibody testing, and viral detection. Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. Available at http://dx.doi.org/10.15620/cdc.23447.

Published June 27, 2014.

Antibody-only tests can be completed on saliva or blood. Antibody testing can be done at home or in a laboratory, and results can be obtained in less than 20 minutes for some tests. Most home tests evaluate antibodies. The HIV-1 Western blot and enzyme-linked immunoassay (ELISA) are first-generation immunoassay antibody tests for IgG only and are no longer recommended to establish diagnosis.

The next category (termed fourth generation) are combination antigen and antibody tests. The antibodies tested are for HIV-1 and HIV-2 and include IgG and IgM. The p24 protein makes up the capsid or viral core HIV, and antigen testing detects this HIV protein (see Figure 2-8 and Figure 2-9). The p24 antigen testing is for HIV-1 detection. This test can become positive within 6 weeks after infection. The fourth-generation combination test is recommended by the CDC (2014) as the initial screening test. If the test is negative, then no further testing is necessary. If the test is positive, then an HIV-1/HIV-2 antibody differentiation immunoassay (not Western blot or ELISA) should be done to confirm and detect whether there is an infection due HIV 1, HIV 2, or both. If the test is negative (for HIV-1 and/or HIV-2) or there is an indeterminate (HIV-1), then a viral RNA should be done. Viral detection is the third category of HIV test. Viral detection tests include the p24 antigen and HIV

genetic material. Of the genetic testing, HIV RNA is the most commonly used and other tests include HIV DNA and nucleic acid sequence based amplification. Viral detection occurs before antibodies are detected. Viral RNA testing is accomplished through a qualitative (nonnumeric) test referred to as nucleic acid testing (NAT) that checks for HIV-1. NAT uses a polymerase chain reaction (PCR) technology. Other laboratory methods can also be used to detect viral RNA other than PCR techniques. The viral RNA NAT test can be positive between 7 and 28 days after infection. Although viral RNA is the earliest indication of infection and the most accurate early in the infection period, the NATs are expensive and, therefore, not first line.

Once HIV/AIDS is confirmed, viral RNA is measured quantitatively, also with NAT; this is known as a viral load measurement. The plasma viral load, or number of viral particles per milliliter of blood, is mainly used to monitor disease status and management.

Viral detection testing is the most appropriate test for infants and young children because the mother’s circulating antibodies in the child will cause a “false” positive test. The aim of antiretroviral therapy is to reduce the viral load to a point that the body’s immune system can keep the virus in check. Viral load can also be an indicator of treatment success, along with other indicators (e.g., CD4+ count and presence of opportunistic infections).

Although there is no cure for AIDS, antiretroviral therapy is used to control the reproduction of the virus and slow the progression of the disease. Highly active antiretroviral therapy (HAART)—the recommended approach—includes three or more antiretroviral medications from different classes. The approved classes include nucleoside/nucleotide reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, integrase strand transfer inhibitors, fusion inhibitors, CCR5 antagonists, and postattachment inhibitors (see Figure 2-8). Pharmacokinetic enhancers may also be used to increase the effectiveness of the medication regimen. HAART has been very effective in suppressing HIV replication, but resistance can occur if the patient does not strictly adhere to the prescribed regimen. Genetic tests that can determine whether the patient’s particular HIV strain is resistant to a particular drug are available, and this information can be used to ensure that the best possible combination of drugs is prescribed. Other treatment strategies include medications to treat specific opportunistic infections as they arise, management of the numerous drug side effects (e.g., high cholesterol and blood glucose), and prevention of reexposure.

Continued exposure to HIV can increase the viral load and introduce another strain—both factors can accelerate the disease’s progression. Medications can also be taken to prevent the development of HIV and are termed preexposure prophylaxis (PrEP) and postexposure prophylaxis (PEP). PrEP can be offered to individuals who have a higher risk of exposure (e.g., sex with an HIV+ partner, high number of partners, inconsistent use of condoms). PEP is offered in situations after a potential

A

1. 2. 3.

exposure (e.g., healthcare worker needlestick, high-risk sexual behavior). For PEP to be effective, the regimen should be given as soon as possible after the incident (e.g., within 1 hour) but no later than 72 hours. Neither PrEP or PEP is a substitute for engaging in safe sex and adhering to blood precautions. An HIV vaccine has been in development for years, but an effective and safe vaccine has yet to reach the market.

Preventing HIV transmission is a worldwide public health priority. Prevention includes the following strategies:

Avoiding contact with bodily fluids Avoiding activities that increase risk of exposure to those bodily secretions (e.g., drug use and multiple sexual partners) Education Using condoms with every sexual experience PrEP and PEP Male circumcision (reduces the risk of female-to-male transmission of HIV and other sexually transmitted infections)

Learning Points

Antibiotic Stewardship ntibiotic resistance is a major public health threat. Some bacteria are resistant to more than one antibiotic in multiple classes. When resistance occurs, more toxic antibiotics often have to be used. In the United

States, an estimated 2 million people a year are diagnosed with a serious infection that is not responsive to usual antibiotic treatment. Healthcare providers too often prescribe antibiotics unnecessarily, such as for the common cold or inappropriately, such as choosing the wrong antibiotic. Antibiotic stewardship involves using antibiotics appropriately and safely. Efforts have been under way to target healthcare providers, patients, policy makers, and administrators to improve antibiotic prescribing. Antibiotic stewardship examples include using rapid diagnostic testing techniques to determine if an infection is viral, rendering antibiotics unnecessary. Other efforts to promote antibiotic stewardship include a recommendation to switch patients from intravenous to oral antibiotics as soon as possible.

BOX 2-3 Application to Practice Case 1: Mr. Jones, a 45-year-old man, is concerned that he has HIV as he had unprotected receptive anal sex with a man. Answer the following questions:

Which HIV test would be conducted first? If he contracted HIV, how many days after exposure would be needed before the test would be positive? Would you consider offering him PEP or PrEP, and, if so, why and when?

1.

2. 3.

Case 2: Mary, a 20-year-old woman, comes to the clinic complaining of unintentional weight loss and fatigue. She also states her knees and wrists are achy at times and she feels stiff in the morning for a few minutes. She feels like they are a bit swollen. She also noticed a rash around her cheeks. She had the symptoms for about 1 month. She has no past medical or surgical history. She takes no medications. Her physical exam is normal except for a malar rash and mildly edematous joints with pain upon range of motion. The tentative diagnosis is SLE.

A complete blood count, complete chemistry profile, and what other laboratory tests can be done to evaluate for SLE? What laboratory findings would correlate with SLE? Which clinical manifestations does Mary have that support the diagnosis of SLE?

Developing a Strong Immune System The key to preventing infectious diseases is building a strong immune system. Many people assume that the best way to stay healthy is to avoid exposure. However, the immune system requires early exposure to antigens to operate optimally because it is a memory system. Exposure to microbes is limited today because of small family units, good sanitation, and widespread antibiotic use. Research suggests that avoiding oversanitizing our environment can increase exposure to microbes earlier and help develop a stronger immune system.

Myth Busters

Despite efforts to educate the public, many misconceptions persist regarding HIV/AIDS.

Myth 1: I can get HIV by being around people who are HIV positive. Facts: Evidence has consistently demonstrated that HIV cannot be spread through touch, tears, or saliva. In addition, HIV is not stable outside the body. The virus cannot be transmitted through toilet seats, water fountains, eating utensils, exercise equipment, hugging, or kissing.

Myth 2: I can get HIV from mosquitoes. Facts: Although HIV spreads through blood, several studies have shown that mosquitoes cannot transmit HIV even in areas with high numbers of mosquitoes and HIV cases. Mosquitoes do not inject the blood they consume into the next person they bite, and the virus lives only a short time in the insect.

Myth 3: If I’m receiving treatment, I cannot spread HIV. Facts: Effective treatment can decrease the viral load in the blood, even to the point that the virus cannot be detected by a blood test. However, the virus can hide in other areas of the body, waiting for an opportunity to increase its replication again. The risk of transmission is lower when the viral load is lower, but transmission is still possible.

Myth 4: My partner and I are both HIV positive, so there is no reason to practice safer sex.

Facts: Continued exposure to HIV can increase the viral load and introduce another strain—both factors that can accelerate the disease’s progression. Practicing safer sex (e.g., wearing condoms and using other barriers) can limit exposure to HIV and other sexually transmitted infections.

• • • •

• • • • • • • • • • •

• • •

Myth 5: You cannot get HIV from oral sex. Facts: It is true that the risk of transmission through oral sex is lower than with other types of sex, but HIV can be transmitted by having oral sex with either a man or woman who is HIV positive.

BOX 2-4 Application to Practice Let us put the things you have learned about the body’s defenses into practice. Which of the following individuals would be at highest risk for impaired immune function?

A 23-year-old female who weighs 5% more than her ideal body weight A 78-year-old male with poorly controlled diabetes mellitus An 89-year-old male with controlled hypertension A 45-year-old female who was recently widowed

When considering this type of question, you start by counting things that might impair the immune system. The patient with the most risk factors is at the greatest risk. Eliminate any information that does not increase risk. For instance, being male or female does not impair immune function, so eliminate that factor from your consideration.

Let us look at each of the example patients. The 23-year-old is not in an increased age range and is fairly close to her ideal body weight; she has no risk factors. The 78-year-old is assigned one risk factor for his increased age and another for his chronic disease. Go ahead and give him another risk factor because his diabetes is uncontrolled—now he has three risk factors. The 89-year-old has one risk factor for his increased age and another for having a chronic disease, but his hypertension is controlled. He has two risk factors. Finally, the 45-year-old has only one risk factor, the stress of being recently widowed. After examining all of these patients, the 78-year-old male is at the most risk for impaired immune function owing to his three risk factors.

At-risk individuals and states, medications, or habits that specifically put individuals at risk for an impaired immune system include the following:

Being very young or very old Poor nutrition Impaired skin integrity Circulatory issues Alterations in normal flora due to antibiotic therapy Chronic diseases, especially diabetes mellitus Corticosteroid therapy Chemotherapy Smoking Alcohol consumption Immunodeficiency states

The following strategies can be employed to build a healthy immune system:

Increasing fluid intake Eating a well-balanced diet Increasing antioxidants and protein intake

• • • •

Getting adequate sleep Avoiding caffeine and refined sugar Spending time outdoors Reducing stress

Modified from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

C H A P T E R S U M M A R Y

Humans are in a constant state of warfare with often unseen enemies. The body takes a multilevel approach to prevent attacks and eliminate invaders. Problems can occur at any of these levels that can lead to overreactions, underreactions, and inappropriate reactions. These altered reactions can produce disease states that negatively affect the body. Multiple conditions can impair the body’s ability to battle, but when armed with the appropriate weapons, the body becomes a fighting machine that can withstand many a fierce invader.

R E F E R E N C E S A N D R E S O U R C E S

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Centers for Disease Prevention and Control (CDC). (2017). HIV/AIDS. Retrieved from Centers for Disease Control and Prevention and Association of Public Health Laboratories. (2014, June). Laboratory testing for the diagnosis of HIV infection: Updated recommendations. http://dx.doi.org/10.15620/cdc.23447

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McQuenn, C. (2017). Comprehensive Toxicology (3rd ed.). St. Louis, MO: Elsevier. Montecino-Rodriguez, E., Berent-Maoz, B., & Dorshkind, K. (2013). Causes, consequences, and reversal of immune system aging. The Journal of Clinical Investigation, 123(3), 958–965. http://doi.org/10.1172/JCI64096

National Institutes of Health, Human Microbiome Project (2019). Retrieved from https://www.hmpdacc.org/overview/

National Research Council (U.S.) Committee on Metagenomics: Challenges and Functional Applications. (2007). The new science of metagenomics: Revealing the secrets of our microbial planet: Why metagenomics? Washington, DC: National Academies Press. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK54011/

Pommerville, J. C. (2013). Alcamo’s fundamentals of microbiology (10th ed.). Burlington, MA: Jones & Bartlett Learning.

Porth, C. (2010). Essentials of pathophysiology (3rd ed.). Philadelphia, PA: Lippincott Williams & Wilkins. Principles of laboratory diagnosis of infectious diseases. In K. J. Ryan (Ed.), Sherris medical microbiology (7th ed.). New York, NY: McGraw-Hill. Retrieved from http://accessmedicine.mhmedical.com.ezproxy.fiu.edu/content.aspx?bookid=2268&sectionid=176081782

Professional guide to pathophysiology (3rd ed.). (2010). Philadelphia, PA: Lippincott Williams & Wilkins. Pulendran, B., & Ahmed, R. (2011). Immunological mechanisms of vaccination. Nature Immunology, 12(6), 509– 517.

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C H A P T E R 3

Hematopoietic Function

L E A R N I N G O B J E C T I V E S

Explain the process of normal hematopoietic function. Describe the structure and role of the lymphoid system. Compare and contrast the pathogenesis of blood cell alterations and disorders. Apply knowledge of hematopoietic and lymphoid system alterations, including various common disorders such as leukemia, lymphoma, anemia, and coagulopathy. Explain the clinical consequences of common blood cell disorders. Develop diagnostic and treatment plans for various blood cell disorders.

lood is the life fluid of the human body, and it is essential for health and homeostasis. The approximately 5 liters of blood continuously circulating in the human body provides nutrients and oxygen to tissues while aiding in the

excretion of waste products. Blood consists of plasma, blood cells, and platelets. Disease occurs when there are too few, too many, or dysfunctional blood components. These conditions can result from many causes that may be congenital, genetic (whether acquired or inherited), and environmental factors, but they can also be iatrogenic. Blood disorders often present with manifestations in multiple systems; therefore, an understanding of normal blood function, formation, and hemostasis are requisite to understanding how abnormalities develop.

Hematopoietic System Blood is both a viscous fluid and a connective tissue. Blood accomplishes its functions through its various components—the plasma (liquid protein), leukocytes (white blood cells), erythrocytes (red blood cells), and thrombocytes (platelets) (FIGURE 3-1) (TABLE 3-1). Plasma is a transport medium that carries the blood cells as well as antibodies, nutrients, electrolytes, hormones, lipids, and waste products. The most abundant of the plasma proteins is albumin, which creates colloid oncotic (osmotic) pressure as one mechanism to maintain fluid balance in blood vessels.

FIGURE 3-1 Blood composition.

TABLE 3-1 Summary of Blood Cells

Modified from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Leukocytes are key players in the inflammatory response and infectious process. Leukocytes consist of neutrophils, eosinophils, basophils, and mast cells. These cells are called granulocytes because of the granules in their cytoplasm. Because of their multiple nuclear lobes, they are also called polymorphonuclear leukocytes. The two other leukocytes are monocytes and lymphocytes whose nuclei are not multilobular and, therefore, are called mononuclear cells or agranulocytes (absence of cytoplasm granules). Granulocytes and monocytes are also phagocytes. Monocytes are precursors and differentiate into tissue macrophages, which are phagocytes. In adults, neutrophils are the most abundant type of leukocyte followed by lymphocytes. Infants during the first year of life, however, have an abundance of monocytes and eosinophils. Lymphocyte function diminishes with aging.

Erythrocytes are disk-shaped cells that carry oxygen to tissues and transport carbon dioxide out of the tissues for its subsequent removal from the body. Erythrocytes contain proteins such as hemoglobin, which binds to oxygen, giving blood its red color. The brighter the shade of red, the more the blood is saturated with oxygen. Hematocrit refers to how much of the blood volume comprises

erythrocytes. Thrombocytes, along with clotting factors, control coagulation. Carried passively

in the blood, thrombocytes are coated with a sticky material that causes them to adhere to irregular surfaces. Clotting is a quick chain reaction stimulated by the release of thromboplastin from damaged cells lining the blood vessels in the area of an injury. In conjunction with the initiation of the clotting cascade, platelets containing contractile proteins pull the edges of the wound together. Blood clots do not persist indefinitely; if they did so, they would clog up the entire circulatory system. Plasmin is an enzyme that dissolves clots once healing has occurred.

Hematopoiesis Hematopoiesis is the process of blood formation, and it occurs primarily in the bone marrow (FIGURE 3-2). Hematopoiesis requires an adequate supply of hematopoietic stem cells. These primitive cells are considered multipotent cells as they can differentiate into all blood cell types. The hematopoietic stem cells differentiate into myeloid and lymphoid progenitor cell lines. Differentiation leads to varying precursors for each of the different blood cells. Maturation of the various blood cells occurs in different areas such as the thymus (T lymphocytes), the bone marrow (B lymphocytes), peripheral blood (granulocytes, monocytes, erythrocytes), or tissue (plasma).

FIGURE 3-2 Hematopoiesis.

Hematopoietic stimulus for red blood cell production may include hypoxemia and blood loss, while the stimulus for white blood cell production may be infection and inflammation. In response to reduced oxygen supply, the kidneys (liver in the fetus) produce the growth factor erythropoietin (EPO). EPO is a physiologic regulator of red blood cell production. Erythropoietin is essential for erythropoiesis as it amplifies signals in the cells for continued development and differentiation of the progenitor and precursor cells. Recombinant erythropoiesis-stimulating agents, epoetin and darbepoetin, are synthetic versions of EPO. Synthetic EPO is used in some anemias such as those caused by chronic renal failure or chemotherapy. Erythrocytes come from the progenitor myeloid stem line. These myeloid cells develop into a pool of erythroblast precursors (e.g., proerythroblast).

While the red blood cell is developing, vitamin B12 and folic acid are necessary in addition to EPO. Vitamin B12 and folic acid are necessary for cellular DNA synthesis. Deficiencies can lead to several abnormalities, such as the inability of the cell to undergo nuclear division, premature apoptosis, and phagocytosis of precursor cells. Folic acid and vitamin B12 come from dietary sources. Folate is the natural form in food, and folic acid is the supplement added to foods. Both terms are often used interchangeably. Inadequate intake of folic acid (e.g., inadequate diet), impaired absorption (e.g., celiac disease, alcoholism), and impaired folic acid action (e.g., caused by phenytoin) lead to deficiency. Vitamin B12 absorption is reliant on a protein called intrinsic factor. This protein secreted by gastric parietal cells binds to the vitamin B12 and is then absorbed in the small intestine. Small amounts of folic acid are stored in the body, but vitamin B12 can be stored in the liver for long periods until needed. Both these vitamins are water soluble and excesses are excreted in the urine.

While the erythrocytes are developing, iron is needed for the heme portion of hemoglobin. Iron is either in a ferric (3+ oxidation) state or ferrous (2+ oxidation) state. Iron is obtained from dietary sources with heme iron (Fe2+ in heme) found mostly in animal products, while nonheme (Fe3+ nonheme) is mainly in plant foods and dairy products. Heme iron (ferrous) is more readily absorbed, but the nonheme (ferric) with Fe3+ must be reduced to ferrous 2+ for absorption. Nonheme and heme are absorbed through different mechanisms (FIGURE 3-3).

FIGURE 3-3 Role of the liver hormone hepcidin in iron absorption. Hepcidin will block iron absorption when iron stores are sufficient.

Once the iron is absorbed, it is in a free form and is labile (Fe3+ form). This labile iron cannot remain in this state because damaging reactive oxygen species can develop. The labile iron (Fe3+ form), the form that moves around, needs to be bound and used, transported, or stored. In the duodenum, several things occur with this labile iron. The iron can bind with apoferritin in the duodenum and become ferritin. The iron can be carried across the duodenal membrane to the blood by ferroportin. The ferritin binds to transferrin, which is the protein in blood that transports iron around the circulation. Some iron remains in the cell mitochondria for use to develop enzymes or heme. Most of the iron is taken to the bone marrow to make more hemoglobin during erythropoiesis, and about 75% of iron is in hemoglobin. Some

iron is also taken to the liver where it binds to transferrin receptors and gets stored as ferritin. Iron is also in the spleen where old red blood cells (RBCs) are broken down by macrophages releasing iron to be reused.

Hepcidin is a protein in the liver that tightly regulates dietary iron uptake and transport in several places such as the duodenum, liver, or spleen (FIGURE 3-4). The liver and spleen membranes also have ferroportin, which transports iron (Fe2+) across the cell membrane back into the blood where again it binds with transferrin (Fe3+) to be taken where needed. Iron is often going from a stable, usable ferrous (Fe2+) to labile, mobile ferric (Fe3+) state and then vice-versa. Hepcidin acts as a ferroportin inhibitor. When iron levels are high, hepcidin increases and binds to ferroportin, inhibiting the transport action across the cell membrane so less iron is absorbed. Low levels of iron leads to less hepcidin production and more can be absorbed. Many clinical disorders, such as chronic hepatitis C infection, alcoholism, chronic kidney disease, infections, and inflammation can alter hepcidin levels and lead to iron absorption problems (too much or too little). The only other mechanism for iron elimination is through normal processes such as menstruation, small amounts from desquamation in intestines, or disorders (e.g., hemorrhage).

FIGURE 3-4 Porphyrin ring.

Hemoglobin is the protein that carries oxygen and is made while the RBCs are developing. Hemoglobin has four separate subunits, and each subunit consists of a heme (iron and porphyrin ring) and a one-globin chain (alpha, beta, or delta) (FIGURE 3-5). Hemoglobin A comprises about 97–98% of the type of hemoglobin in a normal adult and consists of two subunits that are alpha chains and two that are

beta chains. The remaining 2–3% is composed of hemoglobin A2 and consists of two alpha and two delta chains. For oxygen to be transported and released, the iron in hemoglobin needs to be in the ferrous (Fe2+) state. Some diseases (e.g., hereditary methemoglobinemia or toxic ingestions of nitrites) and drugs (e.g., benzocaine) cause the normal oxygen-carrying ferrous state to become a noncarrying oxygen ferric state. The abnormal hemoglobin is called methemoglobin.

FIGURE 3-5 Iron absorption in the gastrointestinal tract.

During erythrocyte development, the cell gets smaller and loses its nucleus once most of the hemoglobin is synthesized. At this stage, the cell is called a reticulocyte. The time from the first precursor, proerythroblast, to development into a reticulocyte in the circulation is about 5 days. Once in the circulation, the reticulocytes complete

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their differentiation into mature erythrocytes whose life span is approximately 4 months.

Diagnostic Link

Reticulocyte Count reticulocyte count can be useful to evaluate bone marrow function or to distinguish between different types of anemia. The values are expressed as a percentage of RBCs or an absolute number and are a reflection

of recent bone marrow activity. A corrected reticulocyte count is often calculated and takes hematocrit value into account and is more accurate with anemia. The results should be evaluated in context of other diagnostic tests such as the hemoglobin, hematocrit, or the complete blood count. If there is an anemia due to blood loss or RBC destruction (e.g., hemolytic disease), the reticulocyte count will be high as the bone marrow tries to compensate. Low reticulocyte counts occur if the bone marrow is dysfunctional, as in bone marrow suppression, indicating a production problem. A low reticulocyte count may occur when the bone marrow is able to produce but does not have the proper requisites to make red blood cells such as iron, folic acid, vitamin B12, or erythropoietin. These deficiencies might occur with iron deficiency anemia, alcoholism, celiac disease or Crohn disease, or kidney disease, respectively. Reticulocyte counts are not diagnostic of any particular disease but rather are indicators of the status of RBC production.

Hemostasis Hemostasis is the process by which bleeding from an injury is stopped. The coagulation process needs to be limited to the area of injury so that blood flows in an unimpeded manner to unaffected areas. Hemostasis requires factors that promote coagulation as well as factors that inhibit coagulation. Normal hemostasis requires endothelial lining integrity and platelets. Hemostasis can be divided into two processes—primary and secondary (FIGURE 3-6).

FIGURE 3-6 Primary and secondary hemostasis.

When a vessel is injured, the goal is to decrease blood loss. The blood vessel quickly vasoconstricts reflexively under the influence of endothelin secreted by endothelial cells. Under normal circumstances, platelets are blocked from adhering

to the cell membrane by nitric oxide and prostacyclin, which are also secreted by the endothelial cells. During injury, nitric oxide and prostacyclin decreases, allowing platelet adhesion. The endothelial lining secretes von Willebrand factor (vWF), which, in response to injury, binds to the basement membrane. The platelet binds to the vWF via the Ib receptor, one of the two glycoprotein receptors on the platelet. The vWF is the glue or link between the platelets and the area of injury. The bound platelets then become active and change their shape. The platelets release various substances, which include vWF, serotonin (a vasoconstrictor), and adenosine diphosphate to activate platelets which all lead to aggregation (clustering). The platelets also release fibrinogen and calcium, which are both necessary for secondary hemostasis. The activated platelets release thromboxane A2, a potent vasoconstrictor, that acts in opposition to prostacyclin. Thromboxane A2 promotes further platelet activation and aggregation. The second glycoprotein receptor on the platelet, IIb/IIIa, binds with fibrinogen circulating in the blood, leading to further aggregation and resulting in what is termed a platelet plug.

This platelet plug is relatively weak and is strengthened by fibrin, an insoluble protein. The form of fibrin that is circulating through blood is fibrinogen, which is soluble. Fibrinogen becomes fibrin through activation of the coagulation cascade with the enzyme thrombin as a key mediator. This process represents secondary hemostasis. The coagulation factors involved in the cascade are in an inactive form. In this cascade, one factor activates another factor, which then activates the next factor, hence the term coagulation cascade. Two important cofactors, fibrinogen and calcium, are necessary for the coagulation cascade. The aggregated platelets (i.e., platelet plug) have a phospholipid surface where secondary hemostasis reactions occur. Inactive precursor coagulation factors such as prothrombin become active thrombin. Calcium released by activated platelets is necessary for some of the coagulation factors (II, VII, IX, and X) to be activated. Vitamin K produced by the liver produces the inactive (precursors) for these same factors (II, VII, IX, and X).

The coagulation cascade can be divided into the intrinsic and extrinsic pathway that both lead to a common pathway (FIGURE 3-7). The injured blood vessel triggers the extrinsic pathway tissue factor, which activates factor VII and, in turn, activates factor X. Activation of X leads to thrombin activation. Thrombin then activates intrinsic pathways going back up (XI, VIII, V, and VII), all contributing to fibrinogen becoming fibrin. The fibrin strands attach to the platelet plug (factor XIII) resulting in a fibrin meshed clot.

FIGURE 3-7 Cascade of events leading to the activation of insoluble fibrin, which provides the structural foundation for a blood clot.

Coagulation inhibitors are important in containing the clotting area. Protein C and S along with antithrombin III inactivate coagulation factors. The fibrin clot needs to be dissolved through the fibrinolytic system, which is activated during the

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coagulation process. Thrombin that activated the coagulation process also triggers the fibrinolytic system by stimulating inactive plasminogen to become active plasmin. Plasminogen is also activated by tissue plasminogen activator (t-PA) and urokinase. Plasminogen activators can be produced and used as therapeutic fibrinolytic agents (e.g., recombinant t-PA [alteplase]; streptokinase) that are used for myocardial infarction (t-PA, streptokinase) or ischemic stroke (t-PA).

Diagnostic Link

Assessing Clotting or Hemostasis he partial thromboplastin time (PTT) and activated clotting time are used to evaluate the intrinsic to common pathway (XII to I). The PTT is commonly used for managing heparin infusion dose. The

prothrombin time (PT) is used to evaluate the extrinsic pathway except for tissue factor (III), so from VII, X, V to II to I. The PT is used to monitor warfarin dose. Thrombin time is used to measure how much time it takes for a clot to form and evaluates fibrinogen activity. While PT, PTT, and activated clotting time are quantitative studies, thromboelastography is used to qualitatively evaluate coagulopathic bleeding. Thromboelastography measures the physical properties of the clot in whole blood and shows the interaction of platelets with the coagulation cascade (e.g., aggregation, clot strengthening, fibrin linking, and fibrinolysis). The clinician can use results of thromboelastography to pinpoint the cause of the hemorrhaging and determine which transfusion agents are warranted (e.g., cryoprecipitate, platelets, or fresh frozen plasma).

Lymphoid System All the lymphoid organs connect the hematologic and immune systems. The components include the thymus, which is the site of T cell maturation, and the bone marrow, which is the site of hematopoiesis. From the bone marrow, the cells are released into the circulation. Other lymphoid organs include the spleen and lymph nodes. The spleen acts as a blood filter clearing out old or abnormal RBCs and any foreign material from the bloodstream.

Lymph nodes, which are masses of lymphocytes and fibers, are interspersed throughout the body along lymphatic channels. As lymph flows through these channels, foreign substances and microorganisms are destroyed, and the immune system is activated. The tonsils and adenoids are composed of lymphoid tissue that form part of the immune system by trapping microorganisms that enter the nose or mouth. Lymphoid tissue such as Peyer patches is also found in the intestines.

BOX 3-1 Application to Practice Activity: Identify the part of the coagulation cascade in which the following medications have an effect and describe the effect: low molecular-weight heparin, unfractionated heparin, warfarin, direct thrombin inhibitors, and vitamin K.

Diseases of the White Blood Cells Leukocytes are a diverse group of cells that trigger the inflammatory process and combat infections. Normal white blood cell (WBC) levels range from 5,000 to 10,000 cells/mL3 of blood. Leukocytosis describes states characterized by increased WBC levels, and leukocytopenia refers to decreased WBC levels. Leukocytosis can indicate an active infectious process, whereas leukocytopenia can indicate an immune deficiency state (e.g., bone marrow suppression). The blood, by way of the circulatory system, transports leukocytes to the site of an infection. When the leukocytes arrive at the scene, they leak through the capillary wall to the site of trauma or invasion (FIGURE 3-8). Most leukocyte disorders originate from deficiencies of one or more of the varying leukocytes. Disorders are a result of increased production, increased destruction, alteration in function, or a combination.

FIGURE 3-8 Leukocyte movement.

Neutrophils Usually the first responders to arrive on the scene of an infection or inflammation, neutrophils are attracted by various chemicals released by infected tissue (FIGURE 3-9). The increased number of neutrophils is known as neutrophilia. The term granulocytosis is often used to describe neutrophilia as neutrophils are the most abundant of granulocytes. The infection triggering neutrophil release is usually bacterial, but some viruses or fungi can also stimulate neutrophils. These cells escape from the capillary wall and migrate to the site of infection. Once they get to the site, neutrophils phagocytize microorganisms, preventing the infection from spreading. As the neutrophils are fully used, the infected cells die and become part of the yellowish wound drainage, or pus. When the demand for neutrophils is higher than the supply, the bone marrow starts releasing immature leukocytes. When there are increased immature cells, the balance is disrupted, and clinically, it is termed a leukemoid reaction. If the infection or inflammation subsides and the bone marrow produces more granulocytes, the neutrophil counts go back up. Physiologic transient increases can occur with stress or exercise or during the third trimester of pregnancy and labor.

FIGURE 3-9 The role of neutrophils.

Neutropenia is the opposite of neutrophilia and refers to a decrease in circulating neutrophils to fewer than 1,500 cells/mL (the normal range is 2,000–7,500 cells/mL). When fewer of these first responders are available, the body is poorly equipped to fight infections. The degree to which the body can fight infections, especially bacterial infections, is related to the severity of the neutropenia. In other words, the lower the neutrophil count, the lower the body’s ability to fight infections. Causes of neutropenia may include infection and inflammation that are severe and/or

prolonged. With severe and prolonged conditions, the usage of neutrophil increases and the bone marrow cannot keep up with the demand. The bone marrow may also be suppressed due to therapies (e.g., radiation, immunosuppressants, chemotherapy) or diseases such as aplastic anemia and leukemia, which will all cause neutropenia. Periodic or cyclic congenital conditions are usually associated with defects in production. Neutropenia can be due to inadequate amounts of vitamins and other nutrients such as vitamin B12 and folate, which are necessary for hematopoiesis. At times, demand may be normal and production intact, but the cells are being destroyed in the circulation or sequestered. Hemodialysis, autoimmune disorders, and splenic disorders such as Felty syndrome lead to increased destruction.

Clinical Manifestations Clinical manifestations of neutropenia initially include signs and symptoms of bacterial and fungal infections (e.g., malaise, chills, and fever). The respiratory tract is the most common site of infection. Mouth ulcerations are also often associated with neutropenia, as are ulcerations of the skin, vagina, and gastrointestinal tract. Other manifestations of neutropenia will be dependent on the cause. Clinical manifestations of neutrophilia are also dependent on the cause (e.g., fever with infections).

Diagnosis and Treatment Diagnostic procedures center primarily on serum neutrophil levels and determining the cause of the neutropenia or neutrophilia. For neutrophilia, the clinician needs to determine why the demand is high. For neutropenia, the clinician needs to determine whether the demand is higher than what can be met, whether production is decreased, whether destruction is increased, or whether there is a combination. Identification and treatment of the cause are important, particularly with neutropenia as low levels can lead to life-threatening infections. A bone marrow biopsy may be performed to determine the cause of the neutropenia or neutrophilia. Treatment is guided by the diagnosis. Antibiotic therapy is used to treat infections as they develop. Hematopoietic growth factors such as granulocyte colony-stimulating factor may be used to stimulate maturation and differentiation of neutrophils.

Eosinophils and Basophils The number of eosinophils and basophils in circulation is low in comparison to neutrophils. Eosinophils are involved in the inflammatory response, most commonly type 1 allergic responses and asthma. These cells help control and augment the inflammatory response. Eosinophils can be high with parasitic infections as they

have toxins that can destroy parasites. Eosinophilia can also occur with malignancies or drugs. Basophils are involved in the inflammatory response and release histamine and other mediators. Basophilia can occur during immediate hypersensitivity reactions such as food allergies or hives. Since eosinophil and basophil counts are already low, the significance of eosinopenia or basopenia is usually clinically insignificant.

Lymphocytes and Monocytes Lymphocytes are one of the key cells involved in the immune response. Increased lymphocytes (lymphocytosis) is more likely to occur with viral infections such as hepatitis, herpes, or cytomegalovirus but may also occur with some bacterial infections such as pertussis. Since lymphocytes are derived from the lymphoid stem cells, lymphocytosis can occur with lymphocytic leukemia and lymphoma. Decreased lymphocytes (lymphocytopenia) occurs in immunodeficiency syndromes such as AIDS or due to destruction such as what occurs from radiation or chemotherapy. Lymphocyte disorders that are nonhematologic are covered in various respective chapters. Infectious mononucleosis which is commonly caused by the Epstein-Barr virus (EBV), causes a lymphocytosis. In infectious mononucleosis, the pharynx is often the target and pharyngitis the initial complaint. Monocyte alterations (monocytosis) often accompany neutrophil alterations. Since monocyte counts are normally low, monocytopenia in isolation is clinically insignificant. Repeated low counts of monocytes can occur with bone marrow failure or some leukemias. Infectious mononucleosis is discussed in the Upper Airway section of chapter 5.

Lymphomas Lymphomas are cancers that develop from malignant lymphocytes in the lymphoid tissues. They are the most common blood cancers, and lymphoma is the seventh most common cancer in adults and the fifth most common cancer in children (American Cancer Society, 2018). There are several subtypes of lymphoma, but the two main types are Hodgkin and non-Hodgkin lymphoma (NHL). Non-Hodgkin lymphoma is far more common than Hodgkin lymphoma (HL). Risk factors for both types of lymphoma include infection with the human immunodeficiency virus (HIV) or EBV. Additional risk factors for non-Hodgkin lymphoma include 1) the presence of an inherited immune or autoimmune condition, 2) infection with Helicobacter pylori or human T-cell leukemia/lymphoma virus type 1 (HTLV-1), and 3) exposure to pesticides.

Hodgkin Lymphoma Hodgkin lymphoma can start in any lymph node of the lymphatic system, but most often arises in the lymph nodes of the upper body (e.g., neck, chest, and upper

arms). The affected lymph nodes swell and compress surrounding tissue. Systemically, the cancer cells spread from one lymph node to the next through the lymphatic vessels. In rare cases, the disease spreads into the blood vessels and other structures, in a process that continues until late in the disease.

The two main types of HL are classical Hodgkin lymphoma (four subtypes), which accounts for 95% of HL, and nodular lymphocyte predominant Hodgkin lymphoma, which accounts for the remaining 5%. The types of lymphoma differ in the way the cancer cells appear under a microscope. Identification of which type the patient is experiencing is important because they grow and spread in different ways, and they are often treated differently.

The cancer cells of classic HL are unique; they are called Reed-Sternberg cells or Hodgkin cells (FIGURE 3-10). These cells are an abnormal type of B lymphocyte that is much larger than normal lymphocytes and do not look or function like normal B cells. The Reed-Sternberg cells, while low in numbers, can attract other cells; the cells become mixed together and the other cells become part of the neoplasm. The Reed-Sternberg cells are thought to arise from germinal centers and then proliferate into the lymphoid tissue. The germinal center is the location in lymph nodes or the spleen where mature B lymphocytes proliferate and differentiate into memory B cells or plasma cells. The germinal center is also the site where hypermutation of B cells’ immunoglobulin genes occurs, so they can recognize and bind to antigens. During hypermutation (i.e., normal gene rearrangements), the cells are at risk for mutations that become oncogenic. Errors in immunoglobulin gene arrangement result in defective lymphocytes. In HL, T lymphocytes also appear to have defects, contributing to a total lymphocyte decrease.

FIGURE 3-10 Reed-Sternberg cells associated with Hodgkin lymphoma. © David A. Litman/Shutterstock.

The incidence of classic HL is on the decline. Classic HL occurs primarily in adults 20–40 years of age, with equal prevalence across genders. A second peak occurrence is seen in men older than 55 years of age. Due to improvements in the treatment of classic HL, mortality has decreased by nearly 50% over the past 25 years. Over the same period, incidence has remained relatively steady. Prognosis is further improved when the disease is localized and is treated early, with many cases considered cured.

Nodular lymphocyte predominant Hodgkin lymphoma, in contrast to classic HL, has a different type of Reed-Sternberg cell called lymphohistiocytic cells. These cells retain normal B cells’ features and function, and the pathogenesis is unclear. The Epstein-Barr virus is implicated in classic HL but not nodular lymphocyte predominant HL. This type of HL tends to be more localized and grows slowly. Males are affected more than females. As in classic HL, there is peak incidence in children and then again in adults (around 30–40 years). The survival rate is high (> 80%).

Clinical Manifestations In up to 80% of patients, HL presents with a painless, enlarged lymph node in the neck and/or supraclavicular area. The other areas of lymphadenopathy include the axilla or inguinal nodes. The second most common initial presentation is the finding of a mediastinal mass on a chest X-ray. The mass may cause symptoms of retrosternal chest pain, cough, and difficulty breathing. Mediastinal nodes, which are not accessible on physical exam, are often seen on imaging studies. Although not as common, lymphadenopathy can occur in areas not accessible on physical exam (e.g., retroperitoneal area, mesentery) and in palpable areas (e.g., popliteal and epitrochlear areas). Persistent fever (> 100.4°F), night sweats, and unexplained weight loss (> 10% over 6 months) are called B symptoms. B symptoms can occur over weeks to months and are a sign of more advanced HL disease. Fatigue, malaise, and splenomegaly may occur. Pruritus, when associated with cancer, is termed paraneoplastic pruritus and occurs before or during the development of the cancer. In 10–30% of patients with HL, pruritus develops at some point during their disease course.

Clinical manifestations of the less common, nodular lymphocytic-predominant HL, vary from the classic. Most patients at presentation are in the early stages. Lymphadenopathy tends to be chronic. A mediastinal mass or B symptoms are not as common on initial presentation.

Diagnosis and Treatment Diagnostic procedures primarily center on biopsy of the affected lymph node. Biopsy samples reveal the presence of Reed-Sternberg cells for classic HL or lymphohistiocytic cells for nonclassic HL. Other diagnostic procedures consist of a physical examination, complete blood count, and chest X-rays.

A staging system is used to grade the severity and progression of the disease (FIGURE 3-11):

FIGURE 3-11 Stages of Hodgkin lymphoma.

Stage I: The lymphoma cells are in one lymph node group (such as in the neck or the underarm), or if the lymphoma cells are not in the lymph nodes, they are in only one part of a tissue or an organ (such as the lung). Stage II: The lymphoma cells are in at least two lymph node groups on the same side of (either above or below) the diaphragm, or the lymphoma cells are in one part of a tissue or an organ and the lymph nodes near that organ (on the same side of the diaphragm). Lymphoma cells may be in other lymph node groups on the same side of the diaphragm. Stage III: The lymphoma cells are in lymph nodes above and below the diaphragm. Lymphoma cells may be found in one part of a tissue or an organ (such as the liver, lung, or bone) near these lymph node groups. The cells may also be found in the spleen. Stage IV: Lymphoma cells are found in several parts of one or more organs or tissues, or the lymphoma cells are in an organ (such as the liver, lung, or bone) and in distant lymph nodes. Recurrent: The disease returns after treatment.

Staging is determined through the use of a computed tomography scan, magnetic resonance imaging, positron emission tomography scan, and bone marrow biopsy. Other staging procedures may include biopsies of other lymph nodes, the liver, or other tissue. After diagnosis, cancer treatment includes a combination of chemotherapy and radiation. Other treatments include bone marrow or stem cell transplant. With treatment, cure is likely in 75% of cases.

Non-Hodgkin Lymphoma Non-Hodgkin lymphoma (NHL) consists of a diverse group of malignancies. NHL can start at any age and in any lymph node but is more common in middle-aged to older adults. NHL accounts for 90% of lymphomas, while HL accounts for the remaining 10%. Non-Hodgkin lymphoma is more common in Whites compared to other ethnic groups. NHL malignancies are derived from mature B cells or T cells or their precursors and less commonly from natural killer cells. Each category of NHL has many subtypes. Approximately 5% of all childhood cancers are NHL, and three subtypes account for almost all pediatric cases of NHL (TABLE 3-2). Childhood NHL tends to be aggressive and fast growing. As with HL, B cells at the germinal center and T cell receptors must undergo normal gene rearrangements to be effective in the immune system. Errors can lead to defective lymphocytes. Three viruses associated with some NHL subtypes include Epstein-Barr virus, HTLV-1, and human herpesvirus 8. These oncogenic viruses integrate their genome into target cells. The genetic alterations that occur are mainly chromosomal translocations. With NHL, no Reed-Sternberg cells are present. Risk factors associated with non-Hodgkin lymphoma development include 1) the presence of an inherited immune or autoimmune condition, 2) infection exposure such as Helicobacter pylori, 3) toxins such as hair dyes or agricultural pesticides, 4) obesity, and 5) inflammatory gastrointestinal diseases such as Crohn disease or celiac disease.

TABLE 3-2 Non-Hodgkin Lymphoma in Children and Adolescents

Clinical Manifestations NHL can be divided into aggressive (fast-growing) and indolent (slow-growing) types.

Aggressive types (e.g., diffuse, large B-cell lymphoma, Burkitt lymphoma) will usually present acutely, with rapid mass growth, and B symptoms. Death can result within a few weeks without treatment. Indolent types (e.g., follicular lymphoma) may present with slowly developing lymphadenopathy, hepatomegaly, or splenomegaly. Patients may present with gastrointestinal tract lymphoma with symptoms such as anorexia, nausea, vomiting, and weight loss. Patients may have central nervous system lymphoma and present with headache, seizures, and lethargy. Other symptoms vary greatly across patients and some symptoms, such as pruritus, fatigue, and malaise, are similar to HL. In comparison to HL, NHL involves multiple nodes scattered throughout the body, and metastasis occurs in an unorganized manner. Metastasis is often present at diagnosis.

Diagnosis and Treatment Diagnostic tests and staging are similar to HL. Other diagnostic tests may include tumor markers, immunoglobulin studies, lumbar puncture, and serology tests for HIV and hepatitis. Treatment is dependent on the subtype and can include chemotherapy, radiation therapy, immunotherapy, or a combination of these. The prognosis for patients with this disease varies with each subtype, but it is worse than HL. While treatments are improving, survivors are at risk for long-term complications of therapy such as secondary malignancies, cardiovascular disorders, or endocrine disorders.

Multiple Myeloma Multiple myeloma (MM) is a cancer of the plasma cells that most often affects older adults. Because the plasma cells originate from B cells, MM is classified as a type of NHL. According to the American Cancer Society (2018), multiple myeloma is the third most common type of blood cancer. Over the past 20 years, incidence and mortality rates have remained relatively stable. The median age at diagnosis is 66, and rates are low before the age of 50 (10%). MM is more common in men than women. Additionally, Blacks have about twice the incidence and mortality rates of Whites.

In most cases, prior to the develop of MM and for unclear reasons, normal plasma cells begin to respond abnormally to antigens. The abnormal plasma cells make monoclonal (one type of) antibodies, and at this stage, the disorder is called monoclonal gammopathy of undetermined significance. These abnormal plasma cells are vulnerable, and if exposed to further insults such as genetic mutations, the condition can progress to MM. Other less common precursor plasma cell abnormalities such as smoldering myeloma or solitary plasmacytomas can also lead to MM, but monoclonal gammopathy of undetermined significance is the most common. The abnormal plasma cells overproduce abnormal immunoglobulins that

are intact or in fragments. The type of abnormal immunoglobulin that is usually produced is IgG and at times IgA. The most common chromosomal abnormalities in MM, as in many other hematologic cancers, are translocations. Deletions (e.g., of chromosome 17) and chromosomal number alterations (e.g., trisomy-47 chromosomes) can also cause MM. In MM, proto-oncogenes (e.g., RAS) are activated and tumor suppressor genes such as p53 are inactivated. The genetic alterations seem to occur during B-cell development in the bone marrow. After leaving the bone marrow, the abnormal B cells become activated by an antigen and differentiate into abnormal plasma cells with stimulation from T helper cells in germinal centers. The abnormal plasma cells then migrate back to the bone marrow, which normally contains 5% of plasma cells but after migration are > 10% in the bone marrow. The result of this bone marrow infiltration is bone destruction. In the bone marrow, the malignant plasma cells bind to bone marrow stromal cells, which regulate hematopoiesis.

Under normal circumstances, bone-building cells called osteoblasts regulate bone resorption by bone-chiseling osteoclasts. Osteoblasts regulate resorption by secreting the protein RANKL, which binds to RANK on the osteoclast, leading to osteoclastic activity. Osteoblasts can also secrete osteoprotegerin, which inhibits binding and, therefore, decreases osteoclastic activity. Various cytokines are produced, which affect osteoblastic and osteoclastic activity, and there is an abnormal response by the plasma cells in MM. Interleukin 3, as an example, leads to decrease osteoblast production. Interleukin 6 and tumor factor MIP1 α stimulates osteoclastic activity. The malignant plasma cells of MM secrete substances that decrease osteoprotegerin production and increase RANKL; therefore, osteoclastic activity increases. Ultimately, the balance is tipped toward increased bone resorption causing bone thinning, fractures, and bone pain. The bone breakdown causes calcium to be released, resulting in hypercalcemia.

The plasma cell interactions with the stromal bone marrow cells provide an excellent environment for proliferation, survival, and migration of the malignant plasma cells. The abnormal immunoglobulin produced by the plasma cells are called paraproteins or M proteins, with the M standing for monoclonal antibody. While albumin is usually the most common protein in blood, the M protein predominates due to the proliferation of malignant plasma cells. Immunoglobulins are glycoproteins that consist of two heavy chains that are different in each of the five classes (e.g., IgA or IgD) and two light chains. In MM, plasma cells produce not only abnormal immunoglobulins but also free light chains. The free light chains are small and pass through the kidneys. In the kidneys, amyloid deposits are formed, and these are detected in the urine as Bence Jones proteins. The free light chains can also build up in the liver, spleen, and heart. Increased infections occur due to suppression of normal B cells by the malignant cells.

Clinical Manifestations The onset of multiple myeloma is usually insidious, and malignancy is often well advanced upon diagnosis. Clinical manifestations of multiple myeloma can be remembered with use of the acronym CRAB (hypercalcemia [using the C], renal failure, anemia, bone lesions). Hypercalcemia causes neuromuscular dysfunction. Anemia, due to decreased erythropoiesis and renal failure, causes manifestations such as fatigue, pallor, dyspnea, and decreased activity tolerance. Bone lesions cause bone pain, and on imaging studies such as X-rays, lytic or punched-out lesions can be seen. The bones involved in MM are usually the vertebrae, ribs, pelvis/femur, clavicle, and scapula. Infections of the lungs (e.g., pneumonia) and urinary tract (e.g., pyelonephritis) are more common due to leukopenia.

Diagnosis and Treatment The diagnosis of multiple myeloma is often made incidentally during routine blood tests or imaging studies that are done while evaluating other conditions. The criteria for multiple myeloma includes monoclonal antibodies in bone marrow, urine, or blood as well as one or more of the CRAB features. Patients with suspected multiple myeloma should all have a serum protein electrophoresis which is used to analyze monoclonal proteins. The serum protein electrophoresis can detect the presence of M-protein and allows for measurement of the size of the M protein. The higher the amount of M protein, the higher the disease burden. Several other tests can be performed such as serum immunofixation to further determine whether the type of monoclonal protein is heavy or light chain. Bence Jones proteins may be present in urine or serum and are characteristic of MM. X-rays can be done but are not sensitive in detecting lesions. Imaging is important in the evaluation of MM and should consist of whole body, computed tomography, positron emission tomography or magnetic resonance imaging to evaluate bone destruction.

Multiple myeloma is not considered curable, but chemotherapy improves the remission rate. Additional treatments may include corticosteroids, angiogenesis inhibitors, targeted therapies, stem cell transplant, biologic therapy, radiation therapy, and supportive care. The median survival time is 3 years. Analgesics are used to treat bone pain. Blood dyscrasias, hypercalcemia, and renal impairment are treated as needed.

Myelodysplastic Syndrome Myelodysplastic syndrome (MDS) is characterized as a group of hematopoietic stem cell neoplasms that result in abnormal cell growth, differentiation, and maturation. The cells affected can include red blood cells, platelets, and mature granulocytes. Nearly one in three people with MDS will develop acute myeloid leukemia (AML). MDS was once considered a preleukemia and a disorder of low malignant potential,

but with increasing evidence, it is now considered a hematologic malignancy. The incidence of MDS increases greatly with age especially after 40 years, and the median age at diagnosis is 72 years. The overall incidence and prevalence is not clear as there have been inconsistent classifications and underreporting of cases; however, MDS is considered a common hematologic malignancy. Most cases of MDS are thought to occur from years of acquired accumulated somatic mutations that occur with aging. Over 50 recurrently mutated genes have been identified, and people with MDS have at least one and often more than one mutation. Other less common causes include mutation caused by environmental exposure (e.g., radiation, chemotherapy) or inherited mutations predisposing a person to myeloid disorders such as leukemia. The somatic mutations occur in the multipotent myeloid progenitor cell. These mutations cause change in precursor and mature cell morphology (e.g., shape, structure), abnormal differentiation, and, ultimately, various cytopenias (e.g., anemia, leukopenia, thrombocytopenia). The mutated cells’ microenvironment and host immune response will significantly influence the clinical manifestations of the disease. There are six main types of MDS recognized by the World Health Organization classification of 2016, each with varying diagnostic criteria and prognosis.

Clinical Manifestations Patients can be asymptomatic. Clinical manifestations are related to the type of cytopenia. Anemia manifestations, depending on the severity, may cause pallor, weakness, fatigue, and shortness of breath. Thrombocytopenia may cause bleeding disorders. Those individuals with neutropenia will have a higher chance of infections and manifest symptoms such as fever. Generalized arthralgia and bone pain can be an initial complaint. Weight loss and anorexia may be present.

Diagnosis and Treatment A complete history and physical examination are necessary. Diagnosis is based on the presence of one or more cytopenias that is otherwise unexplained. A complete blood count will often reveal anemia, which is present in 85% of patients, and neutropenia in approximately 50% of patients. Thrombocytopenia is evident in 25– 50% of cases. Bone marrow biopsy will be conducted and a high blast cell percentage (>5- ≤ 19%) will be present. Genetic testing will reveal various mutational abnormalities. In order to diagnose MDS, the clinical manifestations and diagnostic findings cannot be explained by another disorder such as human immunodeficiency virus (HIV), autoimmune disorders (e.g., systemic lupus erythematosus, immune thrombocytopenic purpura), or leukemia. Estimating prognosis is important to determine the likely course of the disease and inform treatment. Prognosis- estimating systems (e.g., World Health Organization prognostic scoring system) can

be used to determine disease outlook. Risks and benefits of treatment need to be considered relative to the disease prognosis. Treatments may include observation only and supportive care such as antibiotics for infections or transfusions (e.g., platelet, red blood cell). Treatments can also include hematopoiesis growth factors such as erythropoiesis-stimulating agents, chemotherapy, and stem cell transplant.

BOX 3-2 Application to Practice Match the case/descriptors with the most likely disorder.

Case/descriptor Disorder

Usually presents as painless, enlarged lymph node in neck

Hodgkin lymphoma

Bence Jones proteins Non-Hodgkin lymphoma

Reed-Sternberg cells Multiple myeloma

Hypercalcemia, bone pain Myelodysplastic syndrome

One third of cases progress to acute myelogenous leukemia

Most will present with anemia and neutropenia

Lymphohistiocytic cells

Burkitt lymphoma is a type

Black men more commonly affected than White men

Metastasis often present at diagnosis

Leukemias Leukemia is a cancer of the leukocytes. With this disease, the bone marrow stem

cells make abnormal leukocytes, or leukemia cells, that then travel through the vascular system affecting different organs. The proliferation and differentiation issues occur in mature or primitive leukocytes. Unlike normal blood cells, leukemia cells do not die when they should, so they sometimes begin crowding normal leukocytes, erythrocytes, and thrombocytes. This crowding makes it difficult for normal blood cells to function properly. The exact cause of leukemia is unknown.

According to the American Cancer Society (2018), leukemia is the ninth most common cancer in adults. Leukemia, specifically acute lymphoblastic leukemia, is the most common cancer among children; although, it affects 10 times as many adults as children. Incidence rates remained relatively consistent from 1999 to 2018, but the mortality rates decreased. Men are more likely to develop leukemia than are women. Other risk factors include exposure to chemical, viral, and radiation mutagens; smoking; use of chemotherapies; certain disease conditions (e.g., Down syndrome); and immunodeficiency disorders.

Leukemias are grouped on the basis of their cell line (myeloid or lymphoid) and as either acute (mostly primitive cells) or chronic (mostly mature cells). Acute leukemias tend to have a more rapid onset and progression. Chronic leukemias, in contrast, are more insidious in onset and less aggressive. The four most common types of leukemia include:

Acute lymphoblastic leukemia (ALL) Acute myeloid leukemia (AML) Chronic lymphoid leukemia (CLL) Chronic myeloid leukemia (CML)

Acute Leukemias The acute leukemias are characterized by abnormalities in immature (precursor) leukocytes. These immature cells are termed blast cells and are categorized based on their progenitor stem cell line origin—myeloblasts are from the myeloid line while lymphoblasts are from the lymphoid line (B progenitor cells or T progenitor cells). Of the acute leukemias, the incidence of AML is approximately 80% for adults and 20% in children. In children, the highest incidence occurs before the age of 1 and declines thereafter but increases with age again. The median age of diagnosis is 65–70. The overall incidence of AML in comparison to other cancers is rare. ALL is more common in children. ALL accounts for 75% of all leukemias and 29% of all types of cancers in children (CDC, 2014). The median age for diagnosis is 13, but the risk is highest in children less than 5 years of age. ALL peaks again after age 50 and accounts for approximately 20% of the acute leukemia incidences in adults. Slightly more males are affected with AML and ALL, and non-Hispanic Whites have the highest incidence.

The general pathogenesis of the acute leukemias involves genetic and epigenetic

changes in precursor cells that lead to abnormal proliferation, differentiation, maturation, and resistance to apoptosis (cell death). A small pool of cells amongst the leukemic cells have stem cell–like properties and can self-renew and maintain the leukemic state. The leukemic cells can crowd out the bone marrow, or normal hematopoiesis can be inhibited leading to a reduction in erythrocytes, thrombocytes, and other leukocytes.

The acute leukemias are genetically and phenotypically heterogenous. There are numerous subtypes of ALL and AML. Chromosomal alterations can include deletions (e.g., chromosome 5, 7, 9), inversions (e.g., 16), and translocations (swapping of DNA—the most common alteration). Some examples of translocations in adults with ALL include the translocation at 4 and 11 or a translocation of chromosome 9 and 22, which is known as the Philadelphia chromosome. Other examples of genetic alterations include defects in tumor protein p53 or Wilms tumor 1 gene (tumor suppressor genes) allowing for proliferation. Most mutations are not inherited but rather acquired or are new (de novo). Identification of the subtype is important as it defines severity, influences prognosis, and guides treatment.

Several risk factors are associated with the development and/or are causes of acute leukemia. Environmental factors include radiation exposure, chemotherapy, tobacco, or toxins such as benzene. The presence of other blood disorders such as myelodysplastic syndrome can lead to AML. Familial genetic or congenital abnormalities such as Down syndrome (trisomy 21), neurofibromatosis, or Fanconi anemia can increase risk. Other disorders that increase risks include HIV infection or thyroid disease. Obesity may be a risk factor. Despite the various risk factors, often exposure to an antecedent is not present and no etiologic factor is found.

Clinical Manifestations Acute leukemia clinical manifestations can be a result of the cytopenias. Anemia will cause pallor, fatigue, weakness, dyspnea, and dizziness. These symptoms are often out of proportion to the anemia. Thrombocytopenia may cause bruising, petechiae, and increased bleeding, such as from the nose and gums. Infections can be minor or recurrent, and fever may be present. Infections are related to the degree of neutropenia. Various other symptoms may include unintentional weight loss and anorexia. Bone and joint pains are more common in ALL, particularly in children. Physical findings, which are more common in ALL, include lymphadenopathy, hepatomegaly, and splenomegaly. Extramedullary sites of accumulated leukemic cells may lead to a variety of systemic manifestations such as leukemia cutis or cutaneous lesions. Although not as common, other systems such as the central nervous system can be affected. If the central nervous system is involved, the patient may complain of headache, seizures, and vision and balance problems. Other organ involvement can include the gonads and eyes. Since ALL and lymphoma originate from B cell or T cell disease, the two types of lymphoid cancers

have many overlapping features (see Lymphomas section).

Diagnosis and Treatment Diagnostic procedures include a history, physical examination, peripheral blood smears, complete blood count, and bone marrow biopsy. Laboratory findings will include anemia and thrombocytopenia. Leukemic blast cells (e.g., myeloblasts or lymphoblasts) will be present. Bone marrow biopsy and aspirate will reveal blast cells (≥ 20% for leukemia), chromosomal abnormalities, and abnormal morphology. Histiochemical staining of blood or bone marrow will be used to identify the type of leukemia.

The goal of treatment is complete remission. Maintenance therapy may be necessary. Chemotherapy is the mainstay of treatment for leukemia, and several courses may be necessary to eradicate the cancer. Chemotherapy is more effective for the acute types of leukemia than for the chronic types. Bone marrow transplants may be attempted if chemotherapy is unsuccessful. Other treatments may include targeted therapy, radiation, biologic therapy, surgery, and donor lymphocyte infusion.

Chronic Leukemias The chronic leukemias are characterized by abnormal proliferation of more mature cells. The cells have a similar appearance to normal cells but function abnormally. These leukemic cells are present in blood and bone marrow. CLL is the most common leukemia in adults. As with ALL, considerable overlap exists between CLL and lymphomas. Distinctions are made primarily by whether proliferation is in the blood (CLL) or is nodal (lymphoma). The median age of diagnosis is 70 years old, and CLL is rarely diagnosed in people under 40 years old. CML is more common in adults and almost all cases are in people over 50 years old. In both CLL and CML, risk is slightly higher in men and Whites have a higher incidence than other ethnicities.

The general pathogenesis of CLL involves proliferation of mostly mature malignant B cells. T cell involvement is rare. Hematopoiesis may be affected but is not as severe as in ALL. How the B cells transform is not well understood; however, CLL development is considered to be an interplay between genetics, epigenetics, and the microenvironment. Genetic factors are more likely than environmental risks such as pesticide exposure in the cause or risk for CLL.

CML is characterized by proliferation of mostly mature and maturing granulocytes that are fairly well differentiated. The several forms of CML depend on the lineage (e.g., neutrophils, eosinophils). CML is classified as myeloproliferative along with polycythemia vera, essential thrombocytosis, and primary myelofibrosis. In CML, the Philadelphia chromosome is present in 95% of patients, while in other leukemias, the chromosome is present but at a much lower rate (e.g., ALL 5–30%). The abnormal

chromosome is created during a translocation of a segment on chromosome 9, known as the Abelson (ABL) proto-oncogene, with a region on chromosome 22, known as the breakpoint cluster region (BCR). This translocation results in a BCR- ABL fusion gene on chromosome 22—the Philadelphia chromosome. The gene causes abnormal production of myeloid cells, which then leads to the start of CML.

Clinical Manifestations Most patients with CLL are asymptomatic at time of presentation. The most common abnormal physical finding is local or general lymphadenopathy with the upper part of the body (such as the cervical or axillary areas) frequently affected. Hepatomegaly and/or splenomegaly may be present. Other symptoms that are not as common at initial presentation include B symptoms which includes fever, night sweats, and unexplained weight loss. Neurologic or gastrointestinal involvement are not common. Manifestations at presentation will depend on the patient’s current disease stage.

CML has three clinical phases—chronic, accelerated, and blast crisis phase. At diagnosis, most CML cases are in the chronic phase and are asymptomatic or have very few manifestations. While there are a few criteria for each phase, the phases are generally determined by the blasts in peripheral blood and bone marrow. The chronic phase consists of < 10% blasts, accelerated consists of 10–19% blasts, and blast crisis phase has > 20% blasts. As a person progresses through the phases, manifestations become more prevalent and may include fatigue, malaise, weight loss, diaphoresis, abdominal pain and fullness, hepatomegaly, and splenomegaly. Blast crisis in CML is similar to AML. Progression from one phase to the next may be slow in the beginning (e.g., 1–2 years) but progresses faster with aging.

Diagnosis and Treatment Diagnosis of chronic leukemia is often made when a routine blood count comes back abnormal. CLL blood counts will reveal lymphocytosis; granulocytosis and monocytosis will be present with CML. Anemia or thrombocytopenia or thrombocytosis are usually mild. A peripheral blood smear and immunophenotyping will be done. Bone marrow aspirate and biopsy or nodal biopsy may be conducted. In CLL, immunoglobulins are not produced because plasma B cells do not differentiate; therefore, hypogammaglobulinemia (e.g., decreased IgG, IgA, or IgM) may occur.

•

• • • • • •

BOX 3-3 Application to Practice Review the case. Which type of leukemia (acute lymphocytic vs. acute myelogenous or chronic lymphocytic vs. chronic myelogenous) is most likely? Discuss the data supporting your decision.

Case A 13-year-old female presents with the recent onset of fatigue, fever 100°F, and epistaxis over the past week. She has no past medical history except for mononucleosis last year. She is generally very healthy. Physical exam findings unremarkable except for: Pale conjunctiva Multiple petechiae on lower legs Abdomen soft with hepatosplenomegaly Labs:

CBC Result Normal range

WBC 12.0 x103/mL 4.8–10.8 x103/mL

Hgb 8.0 g/dL 12.0–15.6 g/dL

Hct 25% 35–46%

RBC 5.0 x 106/mL 4.5–5.9 x106/mL

MCV 90 x μL/red cell 80–96.1 x μL/red cell

MCH 32 pg/red cell 27.5–33.2 pg/red cell

MCHC 31 g/L 33.4–35.5 g/L

Platelets 45,000/mL 150–400,000/mL

Blasts 85% 0%

CBC = complete blood count; WBC = white blood cells; Hgb = hemoglobin; Hct = hematocrit; RBC = red blood cells; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration

Treatment may vary from observation to aggressive management with various therapeutic agents such as monoclonal antibodies, chemotherapy, radiation, and stem cell transplantation. Targeted therapy, such as tyrosine kinase inhibitors, which block BCR-ABL, are standard treatment for chronic-phase CML. Survival and prognosis is variable and dependent on the type of CLL or the phase of diagnosis for CML. Patients in the advanced CML phase are less responsive to treatment.

Diseases of the Red Blood Cells Erythrocytes are the most prevalent blood cell in the human body—millions can be found in a single drop of blood (the normal range is 4.2–5.9 million cells/mL). These cells function primarily to transport oxygen to the tissue and the waste products for excretion. Most diseases of the red blood cells (RBCs) are related to the quantity or quality of the erythrocytes. Too few RBCs cause anemia and too many cause polycythemia vera.

Anemia Anemia is a common acquired or inherited disorder of the erythrocytes that impairs the oxygen-carrying capacity of the blood. This condition can result from 1) a decreased production of RBCs such as from lack of requisites such as iron or bone marrow dysfunction and 2) increased loss of RBCs such as would occur with destruction or blood loss. Anemias can be classified in different ways. One classification is by the cause of the anemia (e.g., increased destruction, blood loss, inadequate production); however, these categories can overlap (TABLE 3-3). Another common classification is by the morphology or hemoglobin content of the RBCs (e.g., microcytic-hypochromic) (FIGURE 3-12) (TABLE 3-4). In clinical practice, morphology is the more common classification used. Some anemias respond quickly to treatment and cause no sequelae; whereas others can cause lifelong problems. The clinical manifestations of anemia reflect the decreased oxygen-carrying capacity. Regardless of the cause of anemia, manifestations include weakness, fatigue, pallor, syncope, dyspnea, and tachycardia. The degree of symptomatology correlates with the severity of the anemia, with mild anemia causing fewer problems. Severe anemia can cause more pronounced symptoms, and compensatory mechanisms can become overwhelmed, resulting in an anemia that is life threatening. Compensatory mechanisms will involve the hematologic, cardiovascular, and respiratory systems by way of increased erythropoiesis, vasodilation to increase blood flow, and increased respiratory rate, respectively.

FIGURE 3-12 Mean corpuscular volume changes with anemia.

TABLE 3-3 Anemias by Etiology

Inadequate production Examples

Lack of requisites—bone marrow functioning

Iron: dietary lacking, chronic blood loss, decreased absorption, decreased release B12: dietary lacking, absorption Folic acid: dietary lacking, absorption

Bone marrow dysfunction Anemia of chronic disease/inflammation Reduced precursors: not maturing (e.g., aplastic anemia) Bone marrow suppression: drugs, chemotherapy, irradiation

Excessive loss

Blood loss External or internal

Defects shortening survival Hemolytic anemia (e.g., sickle cell disease, thalassemia)

TABLE 3-4 Common Labs in Anemia

Test Purpose Interpretation

Hemoglobin (Hgb) Amount of hemoglobin in blood Low: anemia High: polycythemia

Hematocrit (Hct) Percent of intact RBCs in whole blood Low: anemia High: polycythemia

Mean corpuscular volume (MCV)

Average volume of patient RBCs Low: microcytic High: macrocytic Normal: normocytic

Mean corpuscular hemoglobin concentration (MCHC)

Average concentration of hemoglobin per RBC (size of RBC taken into account)

Low: hypochromic High: hyperchromic Normal: normochromic

Mean corpuscular hemoglobin (MCH)

Amount of Hgb per RBC Alterations same reasons as MCV

Red cell distribution width Variations in sizes of the RBCs (i.e., anisocytosis)

Low: uniformity in size High: large variation in RBC size or shape (i.e., poikilocytosis)

Reticulocyte count Immature erythrocytes Low: problems with production of RBCs High: increased need for RBCs

Plasma iron Requisite for Hgb synthesis (heme component)

Low: increased need, lack of intake, poor absorption High: increased absorption, excess intake

Total iron-binding capacity (TIBC)

Amount of iron capable of binding to transferrin (indirect measure of transferrin availability)

Low: excess iron High: deficiency in iron

Transferrin Transports iron around circulation (TIBC can be used as indirect measure)

Low: excess iron High: deficiency in iron

Transferrin saturation Amount of transferrin saturated with iron Low: deficiency in iron High: excess iron

Ferritin Stored iron Low: deficiency in iron High: excess iron; acute phase reactant so may be high independent from iron stores

B12 Requisite for RBC production Low: B12 deficiency High: liver disease; myeloproliferative disorders

Folate Requisite for RBC production Low: folate deficiency

Anemia is diagnosed in adults (> 18 years of age) when hematocrit is less than 41% in males and less than 37% in females; that is, hemoglobin concentration falls to less than 13.5 g/dL in males and less than 12 g/dL in females. Hematocrit is the percentage of RBCs in whole blood and the hemoglobin is the concentration of hemoglobin in whole blood (Table 3-4). The RBC count is the number of red blood

cells in the volume of whole blood. Normal values vary by age under the age of 18. Treatment depends on the specific type of anemia experienced.

Decreased Production of RBCs When the bone marrow is functioning properly, a decrease in RBCs will result in precursor increase and an acceleration of erythropoiesis to make more reticulocytes. The factors necessary for stimulation of RBC production are erythropoietin and nutrients such as iron, vitamin B12, and folic acid. Deficiencies in any of these will result in a decreased production leading to anemia. Bone marrow dysfunction in the form of suppression or inadequate precursors from disease or treatment will result in decreased RBC production. Iron deficiency anemia and megaloblastic anemia are disorders of decreased RBC production.

Iron Deficiency Anemia—Microcytic According to the World Health Organization (2016), iron deficiency anemia is the most widespread anemia in the world. This type of anemia is most commonly seen in women of childbearing age, children younger than 2 years of age, and the elderly. Iron deficiency anemia occurs when the supply of iron necessary to produce hemoglobin is inadequate to meet the demand of hemoglobin production. It may be caused by decreased iron consumption, decreased iron absorption, or increased loss because of bleeding (e.g., menstruation, gastrointestinal cancer). Decreased iron intake is a common cause of deficiency, particularly in developing countries.

Iron is ingested through animal and plant sources. Although the average American ingests more than 10 mg of iron each day, which is within the recommended daily allowance, only about 10% of the ingested iron is actually absorbed. Infants, children, and adolescents need a higher intake of iron to meet the demands of rapid growth and increased muscle mass. In children, inadequate iron intake is usually the cause of anemia. Blood loss, whether overt or occult, is a more likely cause in U.S. adults as iron intake is usually adequate. Menstrual blood loss can cause approximately 1 mg of iron to be lost per day. Blood loss can occur acutely (e.g., as a result of trauma) or chronically (e.g., from gastrointestinal bleeding). Blood loss may not be overt, and evaluation for gastrointestinal malignancy is warranted with adults over 50 years old, nonmenstruating women, or those at risk for colorectal cancer. Problems of iron absorption are not as common as deficiencies due to decreased intake or blood loss. Absorption of iron occurs in the upper gastrointestinal tract (maximum in duodenum). Various disorders such as celiac disease, atrophic gastritis, Helicobacter pylori infection, and bariatric surgery affect the mucosal cells responsible for absorption through different mechanisms. When an iron deficiency exists, hemoglobin synthesis diminishes. Erythrocytes will

become pale (hypochromic) because the cells have less hemoglobin and small (microcytic) because the cell is trying to accommodate to the decreased hemoglobin (FIGURE 3-13).

FIGURE 3-13 Iron deficiency anemia. Courtesy of Dr. Gordon D. McLaren/CDC.

Clinical Manifestations In addition to the previously mentioned anemia signs and symptoms (e.g., fatigue), the following clinical manifestations may be associated with iron deficiency anemia: cyanosis of sclera, brittle nails, spoon-shaped nails (koilonychia), decreased appetite especially in children, headache, irritability, stomatitis, unusual food cravings (pica), and delayed healing. Neurocognitive impairments can occur in the elderly, often manifested as confusion and memory loss. Children may develop irreversible neurologic damage without adequate iron, and manifestations could include slower visual and auditory processing, decreased attention span, learning difficulties, and motor impairment.

Diagnosis and Treatment

Diagnosis of iron deficiency anemia is made by conducting a history and physical as well as evaluating laboratory findings. Diagnostic procedures for iron deficiency anemia include a complete blood count, serum ferritin, serum iron, and transferrin saturation (see Table 3-4). Serum ferritin and iron levels will be low. Transferrin will be high as the body is trying to compensate for the low iron levels by increasing transport. TIBC is high so that more iron can be delivered. Despite an attempt to increase binding and transportation of iron, there is not enough iron to actually bind to transferrin so the transferrin saturation is low. Additional tests such as fecal occult blood test, colonoscopy, and endoscopy may be performed to determine the cause (see Figure 3-12). The American Academy of Pediatrics recommends routine screening for anemia in children at 1 year of age, but other organizations such as the U.S. Preventive Services Task Force do not recommend screening due to a lack of evidence of the benefits.

BOX 3-4 Application to Practice Case 1: Mr. Hernandez is a 59-year-old Hispanic man who presents for an annual physical exam. He has no complaints or concerns at the visit.

Past medical history: hypertension. Medications: lisinopril 10 mg orally every day. Allergies: penicillin (causes hives). Social history: truck driver, divorced. Quit smoking 5 years ago after smoking one pack per day for 20

years, drinks three to four beers a week. Vital signs: temperature 98.6°F; pulse 74 beats per minute; respirations 18 breaths per minute; blood

pressure 124/76 mm/Hg; body mass index 31. Health maintenance: refuses the influenza shot; has never had a colonoscopy. Family history: he is adopted. His physical exam is unremarkable. Mr. Hernandez’s complete metabolic profile was within normal limits

and his complete blood count with differential revealed the following results:

CBC Result Normal range

WBC 9.0 x 103/mL 4.8–10.8 x 103/mL

Hgb 10.6 g/dL 14–18.0 g/dL

Hct 32% 42–52%

RBC 3.20 x 106/mL 4.7–6.1 x 106/mL

• • • •

• • •

MCV 78 x μL/red cell 80–96.1 x μL/red cell

MCH 32 pg/red cell 27.5–33.2 pg/red cell

MCHC 31 g/L 33.4–35.5 g/L

Platelets 278/mL 150–400,000/mL

CBC = complete blood count; WBC = white blood cells; Hgb =hemoglobin; Hct = hematocrit; RBC = red blood cells; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration

Answer the following questions based on this scenario: Describe the type of anemia present (e.g., microcytic, macrocytic, normocytic) and list the results that

support your decision. Describe additional diagnostic tests to be ordered and explain why they will be ordered. Describe the top two most likely diagnoses and explain why you made these choices.

Case 2: A 22-year-old man comes in because he was shaving and felt a lump on his neck. He states the lump is not painful and he noticed it about 2 weeks ago. He states he’s been more tired than usual for the past month and attributes this to his hectic schedule with work and school. He has not noticed any other changes in his health and denies other symptoms such as fever, weight loss, and difficulty swallowing. The remainder of his history is as follows:

Past medical and surgical history: tonsillectomy and adenoidectomy; mononucleosis Medications: none Allergies: none Social history: smokes pot two to three times a week and uses no other drugs; drinks four to five beers on weekends; denies tobacco use; business major in college; not in a relationship for past 6 months.

A complete physical exam was done and is unremarkable except for the presence of a cervical lymph node that is 2 centimeters, rubbery, and fixed.

Hodgkin lymphoma is suspected. Answer the following questions based on this scenario:

What other clinical manifestations are consistent with Hodgkin lymphoma? What are other possible diagnoses to explain these manifestations? What diagnostic tests (e.g., CBC) will be done, and what are the expected findings if the diagnosis is Hodgkin lymphoma?

Treatment includes the identification and resolution of the underlying cause of the iron deficiency anemia. Other strategies to increase iron levels include increasing consumption of iron-rich foods (e.g., liver; red meat; fish; beans; raisins; and green, leafy vegetables) or administering oral or intravenous iron replacement. Additionally, foods or supplements high in vitamin C should be increased because vitamin C increases the absorption of iron. Infants below the age of 1 may get adequate intake from breast milk but need supplementation with the introduction of food. Cow’s milk is not a good source of iron and should be avoided. Iron-rich formula is recommended.

Megaloblastic Anemia—Macrocytic

Vitamin B12 (cobalamin) and folic acid are necessary for the normal development of RBCs and other bone marrow cells such as thrombocytes and leukocytes. The impaired DNA synthesis, due to vitamin B12 and folic acid deficiency, is characterized by delayed nuclear development but normal cytoplasm development (i.e., nuclear- cytoplasmic aysynchrony). The aysynchrony causes large developing cells called megaloblasts and large mature cells that are macrocytic (FIGURE 3-14). Cell color is unaffected, and, therefore, the anemia is normochromic. Vitamin B12 and folic acid deficiencies also cause premature precursor cell death through phagocytosis or apoptosis. While there are commonalities in causes of these two deficiencies, the mechanisms are different and are discussed separately.

FIGURE 3-14 Pernicious anemia. © LindseyRN/Shutterstock.

Folic Acid Folic acid as a water-soluble B vitamin is eliminated in urine, and a small quantity

(0.5 to 20 mg) is stored in the body. Therefore, folic acid must be regularly replenished through dietary intake. Folic acid is the supplement added to foods, and folate is the natural form in food. Both terms are often used interchangeably. Deficiencies can occur within a short period, such as weeks, depending on the degree of insufficiency or if demand is high. Inadequate dietary intake, while not as common in countries that fortify foods with folic acid such as the United States, occurs usually due to poor overall food intake or lack of a varied diet. Poor intake is common in chronic alcohol use, anorexia nervosa, or malnutrition from illness. Deficiencies can also be due to states of increased needs such as during pregnancy, lactation, or hemodialysis. Absorption of folic acid occurs in the small intestines— duodenum and jejunum. Dysfunctional intestinal surfaces or removal of intestinal surfaces can cause malabsorption. Patients who have undergone gastric bypass or other intestinal surgery or have an inflammatory gastrointestinal disorder such as Crohn disease, ulcerative colitis, or celiac disease are at higher risk for deficiency. Commonly used medications that interfere with folate metabolism include methotrexate for rheumatoid arthritis and several cancers, or antibiotics such as trimethoprim or antiseizure drugs such as carbamazepine. Genetic disorders that affect folate are rare.

Vitamin B12 Vitamin B12 absorption requires intrinsic factor, which is a glycoprotein produced by gastric parietal cells. The binding of vitamin B12 and intrinsic factor is facilitated by pancreatic enzymes in the duodenum. The bound vitamin B12-intrinsic factor complex is then absorbed by the ileum and carried through the bloodstream. As opposed to folic acid, vitamin B12 stores (about 5 mg) are more abundant, and deficiencies can take longer to develop (e.g., 1 year or longer). Inadequate dietary intake can lead to deficiencies. Good dietary sources of vitamin B12 are in meats and dairy products; therefore, patients who restrict intake of these products (e.g., vegans) may become deficient. However, foods can be fortified with vitamin B12 as different forms (e.g., cyanocobalamin, methylcobalamin). Deficiencies due to dietary intake are less common and absorption issues are more likely.

The most common cause of deficiency is known as pernicious anemia. At one time, this anemia was fatal, and the term pernicious, which means harmful or destructive, was used to describe this anemia. With pernicious anemia, autoantibodies target gastric parietal cells. The autoantibodies impair production and cause destruction of intrinsic factor and other gastric secretions, causing gastric mucosal atrophy. The immune response is thought to involve CD4+ T cells. Autoimmune diseases such as chronic (metaplastic) atrophic gastritis, Hashimoto thyroiditis, Graves disease, and diabetes mellitus type 1 are comorbid illnesses associated with pernicious anemia. Prior Helicobacter pylori infection is thought to

elicit the autoimmune response as the bacteria produces antibodies that react with enzymes on parietal cells.

In addition to autoantibodies, vitamin B12 absorption can be affected by other disorders through a different mechanism. Gastric surgery such as bariatric surgery or gastric cancer surgery causes a reduced secretion of intrinsic factor and decreased absorption. Surgery or diseases affecting the small intestine (e.g., Crohn disease, celiac disease) reduces absorption. Pancreatic diseases such as pancreatic insufficiency or chronic pancreatitis affect absorption by not providing the necessary enzymes for vitamin B12 to dissociate from food proteins. Several medications reduce absorption. Long-term use of medications such as antacids (H2 receptor blockers and proton pump inhibitors) reduce gastric acid, thereby, affecting vitamin B12 ability to bind to intrinsic factor. Calcium is another element that is needed for normal vitamin B12-intrinsic factor complex to be absorbed. Metformin reduces vitamin B12 absorption by altering calcium action, predisposing users to B12 deficiency. In patients with preexisting B12 deficiency, the use of nitrous oxide (i.e., laughing gas), whether as an anesthetic or recreationally (e.g., whippets), may inactivate B12 and precipitate an acute onset of anemia and neurologic or psychiatric symptoms. Genetic disorders as a cause of deficiency are rare.

Food cobalamin malabsorption is a term used to describe a disorder where vitamin B12 deficiency occurs as a result of an inability to absorb dietary vitamin B12 despite adequate intake. The disorder is common in older adults and often does not result in anemia. Predisposing risk factors for malabsorption are similar to those that cause megaloblastic anemia such as atrophic gastritis, antacid use, and chronic alcohol use.

Clinical Manifestations (Vitamin B12 and Folic Acid) Manifestations of vitamin and folic acid deficiency can be similar to other anemias (e.g., fatigue, shortness of breath, glossitis). With vitamin B12 and folic acid deficiencies, as with other anemias, the worse the severity, the worse the symptoms. Vitamin B12 deficiency manifestations take longer to develop in comparison to folic acid deficiency. Vitamin B12 deficiency is associated with the development of neuropsychiatric symptoms that are generally not present in folic acid deficiency. These symptoms can become irreversible. The neurologic manifestations can include symmetrical paresthesias more often in the lower extremities with decreased vibratory sense. Proprioception (awareness of body position) and gait can be altered. Several other neuropsychiatric manifestations can include memory and mood alterations such as irritability, depression, or personality changes. Although the exact mechanism is not clear, the neurologic problems occur because of a breakdown in myelin. The neurologic effects may be seen before anemia is

diagnosed.

Diagnosis and Treatment Diagnostic tests for megaloblastic anemia include a complete blood count and peripheral blood smear. The results will reveal macrocytic RBCs (high MCV) with a low reticulocyte count. Other tests include serum vitamin B12 and folate levels. Homocysteine (an amino acid) levels are elevated in both deficiencies. Vitamin B12 is a cofactor with methylmalonic acid (MMA), resulting in the production of coenzyme A that is necessary for cellular function. If there is insufficient vitamin B12, then the MMA levels will rise as the MMA is not being used. MMA is normal with folic acid deficiency. Testing for antibodies to intrinsic factor (i.e., anti-IF) can be used to detect pernicious anemia. Antibody testing for parietal cells (i.e., anti-parietal cell antibodies) can be conducted, but the tests are not as specific for pernicious anemia or gastritis. The Schilling test, which measures vitamin B12 absorption, was commonly used but has been replaced by the other antibody tests. Other diagnostic tests may be necessary to identify underlying causes such as Crohn disease or ulcerative colitis. Treatment consists of replacement with oral or parenteral vitamin B12 or folate. Vitamin B12 is also available in sublingual and nasal preparations. If the B12 deficiency is due to absorption problems, parenteral replacement is recommended. Periconceptional folic acid supplementation is recommended for women planning to become pregnant to prevent neural tube defects.

Anemia of Chronic Disease/Inflammation—Normocytic Anemia of chronic disease (ACD), also known as anemia of chronic inflammation, is the second most common anemia, after iron deficiency anemia. The anemia is caused by many different chronic diseases or inflammation (e.g., cancer, chronic kidney disease, congestive heart failure, and infections). ACD has similar features regardless of whether it is caused by disease or inflammation. These features include a decreased RBC production by the bone marrow and shortening of RBC survival. Several mechanisms underlie ACD. The chronic inflammation results in cytokine release (e.g., interleukin 1, interleukin 6, tumor necrosis factor). These inflammatory cytokines may lead to RBC precursor apoptosis, decreased erythropoietin receptor on progenitor cells, and decreased erythropoietin secretion by the kidney cells. Iron storage and transport become dysfunctional. The cytokines, particularly interleukin 6, cause increased release of hepcidin by the liver. Hepcidin under normal circumstances regulates iron uptake by inhibiting ferroportin (transports iron across the cell membrane). With increased levels of hepcidin in ACD, less iron is absorbed and iron becomes trapped in macrophages. Transferrin and ferritin dysfunction may also contribute to iron trapping. The anemia produced

by ACD is often mild to moderate. RBCs are produced and develop to maturity so the RBCs are normocytic and normochromic. In approximately 25% of patients, ACD can be microcytic and hypochromic. Clinical manifestations of ACD contribute a little to the symptomatology of whatever underlying disease is causing the anemia. In other words, the underlying disease, which might be chronic kidney disease or cancer, is probably causing most of the patient’s manifestations.

Diagnosis and Treatment Diagnosis is usually made by completing a history and physical, which will reveal chronic disease or chronic inflammation. Anemia is usually mild to moderate with ACD. The reticulocyte count is usually low reflecting a decrease in bone marrow production. Inflammatory markers and acute phase reactants such as erythrocyte sedimentation rate may be elevated, reflecting inflammatory process. Other studies such as iron, total iron-binding capacity, and transferrin are low as iron is not absorbed or is sequestered. Transferrin saturation is normal. Iron levels are low with iron deficiency anemia and ACD; however, the transferrin saturation is low and the total iron-binding capacity is high with iron deficiency anemia. Ferritin is normal, but it is also an acute phase reactant, so ferritin levels may be high. Treatment includes resolving the underlying disorder and the anemia if it becomes severe.

Aplastic Anemia—Normocytic Aplastic anemia is a rare but serious type of anemia that is a result of the bone marrow failing to produce multipotent hematopoietic stem cell precursors. This leads to a lack of erythrocytes, leukocytes, and platelets, which is referred to as pancytopenia. The cells that are present, while low in numbers, are mature, normocytic, and normochromic. A lack of these blood cells leads to a series of complications that could include infections, bleeding, hypoxia, fatty replacement of marrow, and death. Aplastic anemia may be temporary or permanent. Causes of aplastic anemia include the following:

Idiopathic conditions Autoimmune conditions (e.g., systemic lupus erythematosus and rheumatoid arthritis) Medications and treatments (e.g., chemotherapy and radiation) Viruses Toxins (e.g., pesticides, arsenic, and benzene) Genetic abnormalities (e.g., myelodysplastic syndrome) Infectious diseases (e.g., EBV, cytomegalovirus, parvovirus, and HIV) Pregnancy (the anemia often resolves after delivery) Cancer

Clinical Manifestations Clinical manifestations include signs and symptoms of general anemia (e.g., weakness, pallor, and dyspnea), leukocytopenia (e.g., recurrent infections), and thrombocytopenia (e.g., bleeding). As blood cell levels decline, clinical manifestations worsen.

Diagnosis and Treatment Diagnostic tests for aplastic anemia include a complete blood count and bone marrow biopsy. Prompt treatment of the underlying causes and any complications as they arise is crucial for positive outcomes. Treatment of underlying causes may include discontinuation of medications or treatments. Treatment of complications may include the following measures:

Oxygen therapy Infection control measures (e.g., hand washing, avoiding groups, and avoiding fresh flowers) Infection treatment (e.g., antibiotics) Bleeding precautions (e.g., electric razors, soft-bristle toothbrushes, and injury prevention) Hematopoietic stimulants (e.g., erythropoietin and colony-stimulating factors) Immunosuppressant therapy (e.g., cyclosporine and methylprednisolone) Anti-infectives (e.g., antibiotics and antiviral medications) Blood and platelet transfusions Bone marrow transplants

Excessive Loss of RBCs Erythropoiesis may remain relatively intact, and anemia can be due to loss of RBCs as a result of acute blood loss (see the Iron Deficiency Anemia—Microcytic section for information on chronic anemia). RBC loss may be due to various disorders that cause RBC destruction in the intravascular space (e.g., disseminated intravascular coagulation, transfusion reaction, hemoglobinuria) or extravascular space (e.g., autoimmune hemolytic anemia) or there can be defects shortening the life span (e.g., megaloblastic, thalassemia major). Acute blood loss due to trauma will cause a normocytic, normochromic anemia as the bone marrow increases normal production to replace the RBCs and compensate for the loss. Destruction of RBCs occurs with hemolytic anemias. Due to the accelerated destruction, the bone marrow may not be able to keep up with the demand.

Causes of hemolytic anemia may be idiopathic, autoimmune, genetic, infectious (e.g., malaria), blood transfusion reactions, and blood incompatibility in the neonate. There are several types of hereditary hemolytic anemias. These hereditary disorders

can be categorized into those that cause enzyme deficiencies (e.g., glucose-6- phosphate dehydrogenase), plasma membrane mutations/defects (e.g., hemoglobinuria), and hemoglobin abnormalities (e.g., sickle cell disease and anemia, as well as thalassemia). Specifics in regard to pathogenesis, clinical manifestations, diagnosis, and treatment vary based on type. Two of the more common hemolytic anemias, sickle cell disease and thalassemia, are discussed.

Sickle Cell Disease Abnormality in the genes coding for the globin portion of hemoglobin characterize the group of hereditary disorders known as sickle cell disease (SCD). In the United States, SCD is considered one of the most common inherited blood disorders. SCD is much more common in Blacks (1 out of every 500 births). Sickle cell disease is also seen in people from South America and Central America (1 in 1,000–1,400), the Caribbean, the Middle East, and the Mediterranean. Hemoglobin A comprises about 97–98% of the type of hemoglobin in a normal adult. The globin portion of hemoglobin consists of two α-globin chains and two β-globin chains, and, therefore, hemoglobin A is designated as α2β2. (See Figure 3-4). The remaining type of hemoglobin in an adult is hemoglobin A2, which has alpha and delta chains, and hemoglobin F, which has alpha and gamma chains. The hemoglobin F is the main type in fetal blood. In SCD, a mutation occurs in the HBB gene, which provides instructions for making the β-globin chain. While the mutation of HBB can cause different abnormal hemoglobin, one of the clinically significant types is hemoglobin S (HbS). The HbS changes the shape of the red blood cell into a sickle (FIGURE 3- 15). The HbS is designated as α2βS2, reflecting that the two β-globin chains have an S mutation. The allele for the sickle cell gene is codominant—so if a person inherits one abnormal gene (HbS) and one normal gene (HbA), then the hemoglobin will be HbAS and the person has sickle cell trait and is a heterozygous carrier. Persons with sickle cell trait do not usually have symptoms of SCD because fewer than half of their erythrocytes are sickled. However, conditions of increased oxygen demand (e.g., high-intensity exercise, high altitude) or dehydration can precipitate sickling, which then causes hemolysis and vascular occlusions due to the clumping of the sickled cells. Awareness of being a carrier is also important for preconception counseling. The mode of SCD transmission follows an autosomal recessive pattern (see chapter 1).

FIGURE 3-15 Sickle cell anemia. Courtesy of Janice Haney Carr/Sickle Cell Foundation of Georgia: Jackie George, Beverly Sinclair/CDC.

A child from two heterozygous parents would have a 25% of no disease, 25% chance of SCD, and 50% chance of having the trait. As opposed to the trait, those with SCD will inherit two abnormal hemoglobin genes that replace the two β-globin chains. In SCD, at least one needs to be HbS, and there are various other types of SCD, which include:

Hemoglobin Sβ0 thalassemia—absent β-globin production; common Hemoglobin Sβ+ thalassemia—reduced (but not absent) β-globin production; common Hemoglobin SC, α2 CS2—common Hemoglobin SD—not common Hemoglobin SE—not common Hemoglobin SS, α2 βS2 sickle cell anemia; most common and most severe disease

Regardless of the type of hemoglobin S (e.g., SD, SE, SC), the shape of erythrocytes are distorted, especially when the body’s supply of oxygen is low. The erythrocytes have an abnormal crescent or sickle shape (sickling) (Figure 3-15). These fragile, sickle-shaped cells deliver less oxygen to the body’s tissues. These cells also can clog easily in small blood vessels and break into pieces that disrupt blood flow (vasoocclusive crisis). These sickled RBCs have a short survival time. Hemolysis occurs as does anemia due to decreased RBCs. SCD clinical manifestations, clinical course, and treatment vary depending on the type. The most common type with the most severe manifestations, sickle cell anemia, will be discussed next.

Sickle Cell Anemia—Normocytic Those persons who inherit the hemoglobin S gene from both parents, creating a homozygous allele pair, have sickle cell anemia. Sickle cell anemia is the most common of the sickle cell disease types, and the disease is more severe because almost all of the individual’s erythrocytes are abnormal. Sickle cell anemia and SCD are sometimes used interchangeably, but SCD is best used as an umbrella term for patients with at least one sickle hemoglobin S. With sickle cell anemia, the RBCs are normocytic and normochromic as erythropoiesis is not affected.

Clinical Manifestations Clinical manifestations (FIGURE 3-16) usually do not appear in newborns because fetal hemoglobin (i.e., hemoglobin F) protects the red blood cells from sickling. The fetal hemoglobin is replaced by adult hemoglobin, however, when a child reaches 4 to 5 months of age. Swelling and pain in the hands and feet (dactylitis), often in conjunction with a fever, is usually the first symptom of sickle cell anemia in the infant. The swelling results from the sickled cells occluding the blood vessels and blocking blood flow in and out of the hands and feet. Manifestations due to hemolysis include fatigue, irritability, pallor, and jaundice. Most patients, in addition to the signs of hemolytic anemia, will experience acute painful episodes, or crises, that can last for hours to days. Pain is caused by obstruction of small blood vessels as

the sickled cells clog up the vessels, leading to ischemia and necrosis. The pain during these vasoocclusive crises is usually described as sharp, intense, and stabbing. The common location of pain is the lower back, chest, abdomen, and long bones. The number and severity of these crises vary among patients, but episodes can be triggered by dehydration, stress, high altitudes, fever, menses, and extreme temperatures. Underlying acute complications, some of which have severe morbidity and mortality, must be considered when a patient is having an episode of acute pain. In between the intermittent acute pain episodes that can be erratic at times is underlying chronic pain that most experience. The chronic pain has more of a neuropathic component with hyperalgesia, sensitization to pain, and opiod hyperalgesia. Neuropathic pain develops more as the patient gets older. Sensitization means a person has a heightened sensitivity to pain and has more pain with less provocation. Opioid hyperalgesia refers to a phenomenon where a patient becomes more sensitive to certain painful stimuli with opioid administration. Chronic complications can develop in many systems (Figure 3-16). Because of improved disease understanding and management, most patients with sickle cell anemia now live into their 50s.

FIGURE 3-16 Pathophysiology of sickle cell disease.

Diagnosis and Treatment Carriers of the defective sickle cell gene can be identified by hemoglobin electrophoresis, a simple blood test that measures and identifies types of abnormal hemoglobin. Additionally, the sickle cell test can determine whether the hemoglobin is normal or sickled. A complete blood count and bilirubin test are useful in

determining diagnosis and progression. There is no single best treatment for all people with SCD. Stem cell transplants

are the option for a cure. Medications such as hydroxyurea and l-glutamine are available to reduce the frequency of crises. Avoidance of sickling triggers is also helpful. Other strategies include the following measures:

Oxygen therapy Hydration Pain management (e.g., nonopioids and opioids, relaxation techniques, distraction) Infection control measures Vaccinations Blood transfusions Bone marrow transplants Genetic counseling for those persons with sickle cell trait

Thalassemia—Microcytic Thalassemia is another hereditary type of hemolytic anemia, which results in abnormal hemoglobin. The abnormal hemoglobin is a result of an abnormal quantity of one of the two protein chains, resulting in α-thalassemia or β-thalassemia. Thalassemia occurs most frequently in persons of Mediterranean descent. Other ethnic groups affected by thalassemia include those of Asian, and Indian descent and Blacks.

β-Thalassemia, as in SCD, is caused by a mutation in the HBB gene. The most common mode of inheritance is an autosomal recessive pattern, and some cases present in an autosomal dominant pattern. The HBB mutation can cause a complete absence of β-globin (β0) synthesis. The HBB mutation can also cause a reduced amount of β-globin (β+) synthesis (FIGURE 3-17). There can be some normal hemoglobin A or none. β-Thalassemia is categorized by the severity of symptoms. Major thalassemia (Cooley anemia) is a more severe type of anemia with increased symptomaticity while minor/intermediate types cause a less severe anemia and disease. Thalassemia minor is also called thalassemia trait. The severity is determined by whether the mutation is heterozygous (e.g., β+/β0) or homozygous (e.g., β0/β0).

FIGURE 3-17 HBB mutation.

With an absence or reduction in β-globin chains in β-thalassemia, alpha chains accumulate and become excessive. The α-globin is unstable and precipitates, causing destruction of erythroblasts by phagocytes in the bone marrow. Mature RBC with abnormal α-globin are destroyed in the spleen. The anemia produced is microcytic and hypochromic.

α-Thalassemia is not as common as β-thalassemia. α-Thalassemia occurs due to mutations in the HBA1 and HBA2 genes of which there are two copies each. These genes direct α-globin chain synthesis. There are many different types of α- thalassemia, such as hydrops fetalis (loss of all α-globin genes) and HbH disease (loss of three of four α-globin genes). Inheritance patterns are complex because of the different number of gene combinations that may occur.

Clinical Manifestations Patients with α- or β-thalassemia minor or the traits may be asymptomatic or have milder anemia symptoms (e.g., pallor, weakness, fatigue). The symptoms may not appear until later in childhood. Patients with β-thalassemia major or some variants of α-thalassemia (e.g., HbH) have more severe anemia manifestations and complications. In these severe anemias, symptoms appear at a younger age (e.g., less than 2 years old). Infants with hydrops fetalis, which is also known as α- thalassemia major, are usually stillborn or die shortly after birth due to heart failure and severe anemia. In β-thalassemia major, the manifestations and complications include delayed growth and development. Children will have skeletal deformities such as dental malocclusion and prominent facial bones. Iron overload (hemosiderosis and hemochromatosis) occurs due to too much absorption as the body tries to compensate for ineffective erythropoiesis and is also a result of treatment from blood transfusions. Iron overload causes hepatomegaly and liver disorders. Splenomegaly occurs because of the increased RBC destruction. With treatment, some of the manifestations may not be evident. Heart failure can lead to early death.

Diagnosis and Treatment A positive family history and physical findings supported by laboratory studies are used to diagnose thalassemia. Erythrocytes will appear microcytic and hypochromic. They vary in size and morphology (e.g., target cells, teardrop cells). Iron deficiency presents with a microcytic-hypochromic anemia like thalassemia (particularly minor); therefore, recognition of differences are important. RBC levels are high in thalassemia but may be low in iron deficiency anemia. Iron levels in thalassemia major or intermedia tend to be high, but the levels may be normal in thalassemia minor. In iron deficiency, the iron levels will be low. Hemoglobin electrophoresis will

be conducted, and hemoblobin abnormalities will be present with thalassemia. Treatment may not be necessary in mild cases of thalassemia. Severe cases, however, can cause early death due to heart failure, usually between the ages of 20 and 30. The heart failure occurs due to myocardial iron deposition. If treatment is warranted, it includes blood transfusion, chelation therapy, bone marrow transplants, and splenectomy.

Polycythemia Polycythemia is the term used to describe above-normal increases in RBCs and hemoglobin. Two types include primary polycythemia, also known as polycythemia vera (PV) and secondary polycythemia. Any disease or circumstance that leads to decreased oxygen levels triggers a compensatory increased erythropoietin release from the kidneys, leading to RBC production. People living in high altitudes have a physiologic polycythemia. In relative polycythemia, there is not a true increase in RBC and hemoglobin but, rather, the appearance due to a reduction in plasma (e.g., dehydration, obesity). Chronic heart and lung conditions such as chronic obstructive lung disease, pulmonary fibrosis, and congenital heart disease are associated with decreased oxygen levels and may result in polycythemia.

PV is a primary disorder in which the bone marrow produces too many blood cells. This primary polycythemia is referred to as “true” PV. This rare condition is considered a neoplastic disease because of the uncontrolled proliferation of cells. PV falls into the category of myeloproliferative neoplasms along with chronic myeloid leukemia, essential thrombocythemia, and primary myelofibrosis.

PV occurs due to a mutation in the JAK2 gene which is present in all patients with PV, but the mutation is also present in other myeloproliferative disorders. The role of the JAK2 gene is controlling cellular growth from hematopoietic stem cells. The mutated clone cells develop without the usual necessary erythropoietin. In addition to increased RBCs, thrombocytes and leukocytes are increased to a lesser degree. The exact cause of this mutation, which occurs most frequently in men, is unknown. Most cases of PV are acquired and inheritance is rare. The most common age for diagnosis is around 60 years old, and the disorder is rare in children or young adults. As blood cell numbers increase, so does the blood volume and viscosity. Blood vessels become distended and blood flow is sluggish.

Clinical Manifestations The following manifestations may be present at or prior to diagnosis. The manifestations (in relative order of frequency) are visual disturbances (e.g., ophthalmic migraine, transient blindness), hypertension, and splenomegaly. Pruritus after contact with water is present in about one-third of patients and can be present up to 3 years prior to diagnosis. The cause of pruritus is not clear. Theories include

histamine release along with other cytokines or cool water contact causing vasoconstriction with prostaglandin and platelet aggregation. Some patients’ pruritus is relieved with aspirin. Vasomotor and microvascular thrombotic changes can lead to symptoms such as burning pain in the hands or feet with erythema, pallor, or cyanosis (erythromelalgia), and paresthesias. Serious complications such as arterial and venous thrombosis (e.g., myocardial infarction, stroke) or hemorrhaging or transformation to other neoplasms (e.g., acute myeloblastic leukemia) are not common. Gouty arthritis is also associated with PV due to the high turnover of RBCs causing increased uric acid production. Gastrointestinal disease (e.g., peptic ulcer disease, erosions) are attributed to changes in blood flow and inflammatory response (e.g., histamine release).

Diagnosis and Treatment Diagnosis is often made incidentally when a complete blood count, as part of routine exam or done for other reasons, reveals an increased hemoglobin. PV should be suspected under those circumstances unless the polycythemia can be attributed to a disorder of chronic hypoxemia or other secondary disorders. Erythromyalgia and aquagenic pruritus are characteristic and indicative of PV. Low serum erythropoietin and peripheral blood mutation of JAK2 are considered diagnostic of PV. With other causes of increased RBCs and hemoglobin, erythropoietin levels are usually normal or high. Bone marrow aspiration and biopsy may be conducted depending on findings and for further confirmation. Treatment is not curative, and goals are to relieve symptoms and improve survival through prevention of complications. Strategies are centered on risk stratification based on age and history of clotting. Treatment may include phlebotomy and low-dose aspirin, which should be administered cautiously with bleeding. Chemotherapy/cytoreductive agents, specifically hydroxyurea, is first line of treatment. Gout, hypertension, and other associated disorders are managed per usual guidelines, taking into consideration PV treatment potential interactions.

Iron Overload Iron overload can be a result of increased intake or absorption. Multiple packed cell transfusion as therapy in disorders such as thalassemia, SCD, or myelodysplastic syndromes can cause iron overload. While not as common, administration of iron or iron-containing products, either in excess or therapeutically, can lead to overload. Diseases that increase absorption can include inherited anemias such as thalassemia and SCD; therefore, the disorder and the treatment can lead to iron overload. Liver disease such as chronic hepatitis causes inflammation and increased ferritin along with other acute phase reactants and the release of iron stored in the liver, causing iron increases. Hereditary hemochromatosis is a genetic disorder

caused by several mutations on genes (e.g., HFE, HAMP) that regulate iron absorption, transport, and storage. Hereditary hemochromatosis has four types, with types 1 and 4 occurring in adult men around the age of 40–60 and type 2 occurring in childhood. Type 1 in women usually occurs after menopause as women compensate with increased iron loss with menstruation, pregnancy, or lactation. Type 3 occurs somewhere in between these ages. Of the types of hemochromatosis, type 1 is the most common, and types 2, 3, and 4 are rare.

Excess iron saturates transferrin until capacities are exceeded. The iron starts binding to other proteins such as albumin. The nontransferrin-bound iron excesses are absorbed by cells that have mechanisms to take in the iron in this form. The liver, heart, endocrine organs (e.g., pancreas), and joints can all take in this extra iron. The iron then gets chemically transformed in affected organs and become a reactive oxygen species causing tissue damage, inflammation, and fibrosis.

Clinical Manifestations Iron overload manifestations are often nonspecific and develop slowly. At times, manifestations become evident once there is organ damage such as heart failure or hepatic fibrosis. The multiple manifestations are usually related to the damage caused by the excess iron and dependent on which organs are affected. Patients can present with symptoms of diabetes, hypothyroidism, osteoporosis, and integumentary conditions such as hyperpigmentation. Type 2 hemochromatosis (juvenile-onset disorder) may manifest due to alterations in sex hormones, leading to symptoms such as delayed sexual maturation or amenorrhea after a period of normal menstruation.

Diagnosis and Treatment The complete blood count may be normal or reveal different anemias depending on the underlying cause of the iron overload. Iron levels, ferritin, and transferrin saturation are high. The total iron-binding capacity (indirect measure of transferrin) will be low reflecting the inability to bind. Hepatic enzymes may be altered with liver involvement. Magnetic resonance imaging of the heart or liver may reveal iron deposition. A liver biopsy may also be done. Phlebotomy can aid in diagnosis and treatment, as every 500 milliliters removed is equivalent to approximately 200–250 milligrams of iron. Patients with iron overload might have 5,000 milligrams stored. If phlebotomy (usually a few times a week) leads to a decrease in ferritin level, then this decrease is consistent with a diagnosis of iron overload. Chelation therapy is another treatment option. The goal of treatment is prevention of organ damage caused by iron overload.

Diseases of the Platelets Platelets are vital components of the coagulation process. Normal platelet levels range from 150,000 to 350,000 cells/mL3. Diseases of the platelets include issues in quantity and quality of platelets. Thrombocytosis refers to increased platelet levels, and thrombocytopenia describes decreased platelet levels. Thrombocytosis increases the risk of thrombus formation, while thrombocytopenia increases the risk of bleeding and infection. Qualitative issues refer to alterations in how the platelet functions. In these circumstances, platelet count is normal but bleeding time is prolonged. Congenital disorders that alter platelet function are rare (e.g., Bernard- Soulier syndrome, Scott syndrome). More commonly, platelet function alterations are due to drug effects (e.g., aspirin), system diseases (e.g., those of the liver or kidney), or other hematologic disorders (e.g., leukemia).

Thrombocytopenia Thrombocytopenia refers to low platelet levels. The lower the number of platelets, the higher the risk for life-threatening bleeding. Levels below 15,000 cells/mL3 can result in spontaneous bleeding with no trauma. The bleeding can result in mucous membrane manifestations such as petechiae (< 3 mm pinpoint capillary hemorrhage), purpura (≥ 3 mm, < 1 cm), and ecchymoses (large area > 1 cm). Bleeding from other systems such as the gastrointestinal tract (e.g., hematochezia) or respiratory tract (e.g., hemoptysis) can also occur. Thrombocytopenia occurs due to a decreased production or increased destruction of platelets or a combination of both. Bone marrow disorders will lead to a decreased production and occurs with nutritional deficiencies in iron, B12, or folate. Alcohol use, whether acute or chronic, may cause impaired hematopoiesis. Many drugs such as quinidine, acetaminophen, and methyldopa can lead to an immune drug-dependent antibody binding that causes platelet destruction. A medication history, therefore, is important when evaluating for causes of thrombocytopenia. During pregnancy, up to 10% of women can develop a transient benign reduction in platelets (usually to 100,000–150,000/ µL), but more severe syndromes such as preeclampsia or hemolysis, elevated liver function tests, low platelets syndrome may be present with lower values. Fluid resuscitation or massive blood transfusion (e.g., > 10 units of packed cells) can cause a dilutional thrombocytopenia. Platelets may be decreased due to blood loss. The most common cause of thrombocytopenia that is isolated (no other disorders) is primary immune thrombocytopenia. Disorders can also stimulate autoimmune antiplatelet antibodies leading to secondary immune thrombocytopenia.

Learning Points

Heparin-Induced Thrombocytopenia (HIT)

A dministration of heparin can lead to life-threatening thrombocytopenia and thrombosis. The reaction is more

common with unfractionated (4%) versus low molecular weight (0.1%) heparin. Antibody IgG, with no IgM response, attacks platelet factor IV with resultant platelet activation and thrombin activation. Increased

platelets lead to thrombosis with opposing increase in platelet consumption and subsequent decrease in platelets. Heparin can cause a mild, inconsequential decrease in platelets to 100,000/µL, but HIT usually causes a 50% decrease. HIT onset can be as early as 4 days and up to 10 days after administration of heparin. The treatment is withdrawal and switching to a nonheparin anticoagulant with precaution due to the continued risk of bleeding.

Immune Thrombocytopenic Purpura Immune thrombocytopenic purpura (ITP) is a hypocoagulopathy state resulting from the immune system destroying its own platelets (autoimmunity). The disorder can be primary and not associated with an underlying disorder or secondary occurring due to another condition. The condition causing the ITP is usually written in parenthesis in secondary ITP (such as hepatitis C associated). Secondary ITP causes include autoimmune diseases (e.g., systemic lupus erythematosus), immunizations from a live vaccine, infections (e.g., HIV, hepatitis C, Helicobacter pylori), and cancer.

ITP development is autoantibody mediated. The key mechanism is circulating IgG produced by B cells reacting with the surface glycoprotein IIb/IIIa. The platelets are then destroyed in the spleen with some destroyed in the liver and bone marrow. Other mechanisms, such as autoreactive cytotoxic T cells, impair production.

Primary ITP (i.e., idiopathic thrombocytopenia purpura) is the most common cause of isolated thrombocytopenia and occurs due to increased platelet destruction and decreased production. Primary ITP can be either acute or chronic (> 12 months). Acute ITP is more common in children, and the peak age of presentation is 2–4 years old. This form of the disease typically has a sudden onset and is self- limiting, often lasting less than a week and usually resolving within 6 months. Chronic ITP is more common in adults aged 20–50 years and in women, has a slower onset, and spontaneous resolution is rare. After age 65 years, there is a higher incidence in men. Severe bleeding does not usually occur in adults and in children occurs in < 10% of cases. Prognosis is usually good for both acute and chronic ITP.

Clinical Manifestations Adults and children with ITP are often asymptomatic. Manifestations, when present, include abnormal bleeding (e.g., petechiae, epistaxis, and hematuria). Purpura lesions are usually in distal dependent areas and are nonpalpable and nonblanchable.

Diagnosis and Management Thrombocytopenia is often an incidental finding during laboratory evaluation, whether done routinely or for evaluation of other reasons. Diagnostic procedures will

be directed toward identifying possible causes of the decreased platelets. The history, physical, and complete blood count may provide apparent reasons (e.g., anemia). Isolated thrombocytopenia is usually a diagnosis after other possibilities for the thrombocytopenia have been excluded. Examples of diagnostic tests may include hepatitis profile, HIV testing, bone marrow biopsy, and humoral studies.

The overall goal of treatment is to increase the platelet count to a level to prevent severe bleeding, and if present, manage the severe bleeding. Thrombocytopenia treatment may not always be necessary. Therapies are often individualized. Treatment strategies may include glucocorticoid steroids and immunoglobulins to prevent further platelet destruction. Rituximab can reduce B cells in autoimmune disorders or thrombopoietin receptor agonists can stimulate platelet production. Splenectomy, plasmapheresis, and plateletpheresis can be considered.

Thrombotic Thrombocytopenic Purpura Thrombotic thrombocytopenic purpura (TTP) is a coagulation disorder resulting from a deficiency of an enzyme, a disintegrin and metalloproteinase with thrombospondin domain 13 enzyme (ADAMTS13), which is necessary for cleaving von Willebrand factor (vWF). The result is platelets aggregating around the large vWF molecules and increased clotting, which decreases available platelets. Fewer platelets can lead to bleeding; therefore, TTP is characterized by microthrombi in the microvasculature, thrombocytopenia, and bleeding. The clots are composed of vWF and platelets. Causes include hereditary mutations of ADAMTS13 gene, and the mode of transmission is autosomal recessive. Hereditary TTP is rare, and a worldwide registry has 150 families. Hereditary TTP is more common in infants and children. Acquired disorders are the most common causes of TTP and are due to autoantibodies IgG inhibiting the ADAMTS13 enzyme. Acquired TTP may occur with conditions such as bone marrow transplants, cancer, pregnancy, infections, or medications.

Clinical Manifestations TTP manifestations can be acute or insidious. Multiple systems can be involved. Neurologic manifestations can include memory changes, headache, confusion, and changes in consciousness. The individual may present with renal insufficiency, renal failure, or fever. Cardiovascular manifestations can include chest pain, congestive heart failure, and myocardial infarction. Gastrointestinal symptoms include pain, nausea, vomiting, and diarrhea. The pancreas, adrenal glands, and spleen may also be affected while the lungs are usually spared.

Diagnosis and Treatment Diagnostic procedures for TTP include a history, physical examination, complete

blood counts, peripheral blood smears, lactate dehydrogenase (LDH) levels, and bilirubin. LDH levels are high, reflecting tissue injury along with high indirect bilirubin. Reticulocytes are also high. Fragments of RBCs, called schistocytes, may be present on RBC smears. In addition to thrombocytopenia, a microangiopathic (small vessel disease) hemolytic anemia is present. Coagulation tests are usually normal. Plasmapheresis is the treatment for TTP. Additionally, a splenectomy and glucocorticoid steroids may be necessary.

Thrombocythemia Thrombocythemia (i.e., thrombocytosis) refers to an increase in platelet count. Secondary thrombocytosis can occur due to pooling of platelets in the circulation after splenectomy or as a reactive response to infections and inflammations. Secondary thrombocytosis is usually self-limiting with no sequelae. Primary thrombocytosis (i.e., essential thrombocythemia) is a myeloproliferative neoplasm. Polycythemia vera, primary myelofibrosis, and chronic myeloid leukemia are malignancies associated with thrombocytosis.

Diseases of Coagulation or Hemostasis Coagulation factor disorders, like platelet diseases, can increase bleeding. Impairments in one factor, such as in hemophilia, are usually inherited. Disorders of multiple coagulation factors are usually due to alterations in synthesis (e.g., liver disease) or inappropriate activation of coagulation (e.g., disseminated intravascular coagulation). Thrombophilia are disorders that lead to hypercoagulability. Several inherited and possible genetic mutations are associated with increased risk for thrombosis.

Hemophilia Hemophilia A, or classic hemophilia, involves a deficiency or abnormality of clotting factor VIII. Hemophilia B involves abnormality of clotting factor IX. Hemophilia A is more common, with an incidence of 1 in 5,000 males worldwide, and hemophilia B occurs in 1 in 20,000 males worldwide. Both are X-linked recessive bleeding disorders. Factor VIII and IX are part of the intrinsic pathway that lead to factor X activation. The severity of the disorder varies depending on the amount of factor present in the blood, but those with hemophilia A usually have a more severe disease than hemophilia B.

Clinical Manifestations Severe forms of hemophilia become apparent by 1 month, and milder forms are usually diagnosed by 1 year of age. Bleeding is the main symptom of the disease and sometimes occurs when an infant is circumcised. Additional bleeding problems may be seen when the infant starts crawling and walking. Mild cases may go unnoticed until later in life, when they are detected during surgery or trauma. Internal bleeding may happen anywhere, and bleeding into joints, or hemarthrosis, is common. Other manifestations include petechiae, bruising, gastrointestinal bleeding, and hematuria.

Diagnosis and Treatment Diagnosis of hemophilia includes examination of bleeding studies. Platelets, bleeding time, and prothrombin time are usually normal, but partial prothromboplastin time, activated partial prothromboplastin time (aPTT), and coagulation time are prolonged. However, aPTT may be normal, in mild cases. Serum levels of factor VIII and IX are low. Genetic testing is done to identify the gene mutation (i.e., F8 for hemophilia A and F9 for hemophilia B).

Treatment strategies include replacing clotting factors through transfusions that are plasma derived or recombinant such as Advate (antihemophilic factor, a

recombinant DNA product) for hemophilia A. To prevent a bleeding crisis, patients can be taught to give factor VIII or IX concentrates at home prophylactically or at the first signs of bleeding. People with severe forms of the disease may need regular preventive treatment. Mild hemophilia may be treated with desmopressin (DDAVP), which helps the body release factor VIII that is stored within the lining of blood vessels. Additionally, bleeding precautions should be employed (e.g., electric razors, soft-bristle toothbrushes, and injury prevention).

Von Willebrand Disease Von Willebrand disease is the most common hereditary bleeding disorder. It results from a deficit of von Willebrand factor, which ordinarily causes platelets to aggregate and adhere to the vessel wall in times of injury. Mild cases are often undiagnosed, but incidence is estimated at 1 in 100 to 10,000. Several forms of von Willebrand disease are distinguished:

Type 1 von Willebrand disease is the most common (70–80%) and mildest form. It follows an autosomal dominant inheritance pattern. The level of von Willebrand factor in the blood is reduced. Because this form is often very mild, most cases go undiagnosed. Type 1 does not usually cause spontaneous bleeding, but significant bleeding can occur with trauma or surgery. Type 2 von Willebrand disease occurs in 15–20% of cases. It can be either autosomal dominant or recessive, and four subtypes exist. In type 2, the building blocks (multimers) that make up the von Willebrand factor are smaller than usual or break down easily. Bleeding with this type are usually moderate to severe. Type 3 von Willebrand disease follows an autosomal recessive inheritance pattern. Severe bleeding problems are seen with this type due to the lack of measurable von Willebrand factor and factor VIII. Type 3 is the rarest form. Acquired type von Willebrand disease occurs in persons with Wilms tumor, congenital heart disease, systemic lupus erythematosus, and hypothyroidism.

Clinical manifestations of von Willebrand disease include abnormal bleeding. Diagnosis requires bleeding studies (e.g., bleeding time, prothrombin time, and partial prothromboplastin time) and factor VIII levels. Treatment, if needed, includes infusions of cryoprecipitate or administration of desmopressin; desmopressin increases the release of von Willebrand factor and factor VIII. Clotting factor concentrates of vWF and factor VIII can be administered. Additionally, measures are used to control bleeding and prevent injury, such as using pressure dressings.

Disseminated Intravascular Coagulation Disseminated intravascular coagulation (DIC) is a life-threatening disorder that occurs as a complication of other diseases and conditions, such as serious acute

I

infections. The incidence is estimated at 1% of tertiary hospital admissions. Normally, during injury, clotting factors (Figure 3-7) become activated and travel to the injury site to help stop bleeding, and then through fibrinolysis, the clot is dissolved. However, in persons with DIC, coagulation and fibrinolysis become abnormally active. In fact, they may become active as an inappropriate immune reaction. Consequently, small blood clots form within the blood vessels, and some of these clots can occlude blood supply to tissue and organs. Over time, the clotting factors become used up. When this happens, the person is at risk for serious bleeding from even a minor injury.

Learning Points

DIC bleeding pattern n DIC, hypercoagulation uses up all the available clotting factors. Once available clotting factors are utilized, the patient begins excessively bleeding. In other words, the individual clots, clots, clots, and then bleeds,

bleeds, bleeds!

Reproduced from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

It is not clear why certain disorders lead to DIC. In DIC, various disorders may expose the blood to procoagulant stimuli through different mechanisms. Bacteria, as an example, may activate coagulation; while with sepsis from meningococci, particles of tissue factor are found in the blood. Trauma from burns and head injury causes damage and possible release of procoagulants. Other conditions associated with DIC include:

Blood transfusion reaction Cancer (e.g., leukemia, aplastic anemia, and metastatic carcinoma) Pregnancy complications (e.g., retained placenta after delivery, abruptio placentae, and eclampsia) Recent surgery or anesthesia Sepsis Severe liver disease Cardiac arrest Poisonous snake bites

Clinical Manifestations Clinical manifestations of DIC can be multisystem. Tissue and organ ischemia occur from microvascular and macrovascular thrombosis. DIC affects the cardiovascular, pulmonary, renal, hepatic, and central nervous systems. Manifestations of multisystem organ damage can include altered mentation, seizure, angina,

tachycardia, hypotension, and oliguria. Cyanosis is usually symmetrical and can occur in fingers, toes, and breasts. Underlying organ damage may not be evident immediately, and often bleeding is the first sign that something is wrong. The patient may start bleeding from intravenous sites or other invasive areas. Petechiae, epistaxis, hematuria, and other signs of bleeding may occur.

Diagnosis and Treatment Diagnostic procedures for DIC consist of complete blood counts. Platelet counts decrease rapidly. Coagulation studies such as thrombin time, prothrombin time, and partial prothromboplastin time will reveal prolonged clotting times. Many other disorders can alter these tests, and they are not specific to DIC. Fibrin degradation products are the most specific and includes a D-dimer test, which is a protein fragment produced from clot breakdown. DIC causes high D-dimer levels. Fibrinogen function can be measured; levels would be low, reflecting the consumption of clotting products that occurs in DIC. Anticoagulation factors such as antithrombin III, protein C, and protein S are also consumed and would be decreased. Management of DIC is complicated but starts with the identification and treatment of the underlying cause. The treatment of the DIC disorder itself is a delicate balance between preventing clots and treating bleeding (FIGURE 3-18).

FIGURE 3-18 Understanding DIC and its treatment.

1.

a. b. c. d.

2.

Thrombophilia Thrombophilia refers to a state of increased coagulation. Thrombophilia is due to an abnormality in the coagulation system that leads to the tendency to form venous thromboembolisms. Antiphospholipid syndrome is an acquired type of thrombophilia. This syndrome is caused by a primary autoimmune disorder or may occur with other autoimmune disorders such as systemic lupus erythematosus. Women are more commonly affected, and diagnosis is usually between the ages of 30 and 40 years. Arterial and venous clots are a complication, and women often have miscarriages or are predisposed to preeclampsia. Inherited causes of thrombophilia are commonly due to factor V Leiden and prothrombin mutations. Other less common causes are elevated factor VIII, hyperhomocysteinemia, and deficiencies in antithrombin, protein C, and protein S.

Whether the disorder is inherited or acquired, most individuals who have the disorder develop a clot in the presence of another inciting or prothrombotic state like immobilization or cancer. While there is a higher tendency for a person with the disorder to develop a clot, this tendency alone is insufficient to cause a clot. Those individuals with inherited thrombophilia will develop venous thromboembolism at a younger age, may have a strong family history of clots, or develop a clot in an unusual site like the portal, hepatic, or mesenteric veins. Some individuals also have a history of recurrent spontaneous clots. However, a first episode may not happen until a person is older and has a case of a venous thromboembolism.

Treatment is dependent on the degree of risk for thrombosis and may include aspirin, dipyridamole, warfarin, heparin, or supplemental concentrates of the deficient factor (e.g., protein C, antithrombin III). Further discussion of venous and arterial thrombosis is covered in chapter 4.

BOX 3-5 Application to Practice Case: Parents recently received confirmation that their 2-month-old son has sickle cell anemia. They are somewhat anxious. Answer the following questions:

The parents brought in a hemoglobin electrophoresis report and want you to explain the results. Which of the following indicates sickle cell anemia?

HgAS HgAC HgSS HgSD

They are confused because they are both Hispanic and they thought this was a disease that only occurred

3.

4.

in Black children. Explain the ethnic/racial distribution of this disease. Explain the inheritance pattern. The parents want to know symptoms of the disease. Explain the signs and symptoms that may be seen in an infant with sickle cell anemia. Discuss healthcare education you will provide the parents regarding how to care for their child.

C H A P T E R S U M M A R Y

Blood serves many purposes in the body. If this life fluid does not function properly, the body cannot maintain health and homeostasis; therefore, problems with any types of blood cells can lead to widespread and life-threatening problems. Hematologic problems can result from a variety of origins but usually lead to abnormal cell numbers or function. Timely identification and treatment of these disorders is vital for positive health outcomes.

R E F E R E N C E S A N D R E S O U R C E S

American Cancer Society. (2018). Cancer facts and statistics 2018. Retrieved from https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and- figures/2018/cancer-facts-and-figures-2018.pdf

Centers for Disease Control and Prevention (CDC). (2014). Epstein-Barr virus and infectious mononucleosis. Retrieved from http://www.cdc.gov/epstein-barr/

Chiras, D. (2015). Human biology (8th ed.). Burlington, MA: Jones & Bartlett Learning. Copstead, L., & Banasik, J. (2014). Pathophysiology (5th ed.). St. Louis, MO: Elsevier. Dean, L. (2006, April 26). Mutations and blood clots: How point mutations in clotting factor genes conspire to increase the risk of thrombosis. In L. Dean & J. McEntryre (Eds.), Coffee break: Tutorials for NCBI tools. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK2318

DeBruin, M., Dorresteijn, L., van’t Veer, M., van der Pal, H., Kappelle, A., Alman, B., & van Leeuwen, F. (2009). Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. Journal of National Cancer Institute, 101(13), 928–937.

Elling, B., Elling, K., & Rothenberg, M. (2004). Anatomy and physiology. Sudbury, MA: Jones and Bartlett Publishers.

Girelli, D., Nemeth, E., & Swinkels, D. W. (2016). Hepcidin in the diagnosis of iron disorders. Blood, 127(23), 2809–2813. http://doi.org/10.1182/blood-2015-12-639112

Kaushansky, K., Lichtman, M. A., Prchal, J. T., Levi, M. M., Press, O. W., Burns, L. J., & Caligiuri, M. (Eds.). Williams hematology (9th ed.). New York, NY: McGraw-Hill. Retrieved from http://accessmedicine.mhmedical.com.ezproxy.fiu.edu/content.aspx?bookid=1581&sectionid=94301148

Porth, C. (2014). Essentials of pathophysiology (9th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. Professional guide to pathophysiology (3rd ed.). (2010). Philadelphia, PA: Lippincott Williams & Wilkins. Schick, P. K. (2006). Anemia. Retrieved from https://www.ashacademy.org/Product/index/98006810 U.S. Cancer Statistics Working Group. (2018). U.S. cancer statistics data visualizations tool, based on November 2017 submission data (1999–2015): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute. Retrieved from www.cdc.gov/cancer/dataviz

World Health Organization. (2016). Micronutrient deficiencies. Retrieved from https://www.who.int/nutrition/topics/vad/en/

T

C H A P T E R 4

Cardiovascular Function

L e a r n i n g O b j e c t i v e s

Discuss normal cardiovascular anatomy and physiology. Differentiate disorders of the heart layers, valves, and electrical system. Differentiate systolic and diastolic heart failure. Differentiate congenital heart disorders. Describe how dyslipidemia affects the cardiovascular system. Differentiate disorders of the arterial and venous vasculature and lymphatic system. Describe the correlation between dyslipidemia, atherosclerosis, and arterial disorders. Explain the development and progression of shock. Summarize how various disorders cause impaired cardiac output and impaired tissue perfusion. Explain the clinical consequences of impaired cardiac output and impaired tissue perfusion. Design diagnostic and treatment plans for cardiovascular disorders.

he cardiovascular system is composed of the heart, blood vessels, lymphatic system, and blood. This chapter focuses on normal and abnormal states of the heart and blood vessels. The components of the cardiovascular system work

together to maintain life. Additionally, these components play a crucial role in the functioning of other systems. This pivotal role begins early in life when the fetus is about 4 weeks old and lasts until the end of life. Disorders of the cardiovascular system are common and complex, as they often affect other systems. Cardiovascular disorders will likely be encountered in any clinical setting and often occur in association with other disorders.

Anatomy and Physiology The cardiovascular system is similar to the plumbing in a house. Both have a pump (the heart), a network of pipes (the blood vessels), and fluid (blood). The cardiovascular system delivers vital oxygen and nutrients to cells, removes waste products, and transports hormones. Circulation is divided into two branches— pulmonary and systemic (FIGURE 4-1). In the pulmonary circulation, the waste product—carbon dioxide—is exchanged for oxygen in the lungs through diffusion (FIGURE 4-2). In the systemic circulation, blood carries oxygen and nutrients to all cells and waste products to the kidneys, liver, and skin for excretion. To accomplish these transportation functions, the cardiovascular system requires a properly functioning heart to propel the blood by rhythmic contractions. The blood circulates through three types of vessels—arteries, capillaries, and veins. The lymphatic system assists in maintaining homeostasis by returning excess fluid from the body’s tissues to the circulatory system as well as by playing a vital role in the immune system. The following sections review the basic anatomy and physiology of the cardiovascular system. (See chapter 2 for a discussion of immunity.)

FIGURE 4-1 The cardiovascular system.

FIGURE 4-2 Pulmonary gas exchange.

Heart Roughly the size of a closed fist, the heart is a muscular organ that pumps blood throughout the body. Men’s hearts are usually slightly larger at 0.45% of body weight while women’s are 0.40% of body weight. The heart is the workhorse of the cardiovascular system, pumping blood through the body’s 50,000 miles of blood vessels and beating approximately 100,000 times per day. If you received a dollar for every heartbeat, you would be a millionaire in just 10 days. The heart can quickly adjust its rate to meet the ever-changing needs of the body.

The heart is in the thoracic cavity between the lungs and behind the sternum. The pericardial sac, or pericardium, encloses the heart to provide protection and support. Between the two layers of the pericardium (inner visceral and outer parietal) there is pericardial fluid. The amount of fluid contained in the pericardial space is approximately 50 mL. This fluid protects the heart against trauma from surrounding structures, invasions of foreign organisms, and friction from the constant movement. The pericardium provides support in terms of anchoring the heart and prevents overdistention. The pericardium contains receptors that can reflexively cause a change in blood pressure and heart rate.

The outer layer of the heart wall is the epicardium. The myocardium, the middle layer of the heart, is the muscle portion of the organ. The walls of the ventricles, especially the left ventricle, are thicker than the atrium because of the distance and pressures against which those chambers must pump blood. The atria are receiving chambers that pump blood to their respective ventricles. The ventricles pump blood to the low-pressure lungs and the high-pressure systemic circulation (15 mmHg and 92 mmHg, respectively).

The endocardium is the inner epithelial layer of the heart that makes up the cardiac valves; these valves function to ensure one-way flow of blood through the heart (FIGURE 4-3).

FIGURE 4-3 Heart valves. © Phil Degginger/Alamy Stock Photo.

Cardiac Cycle

Understanding the blood flow through the heart is essential to understanding structural alterations and appreciating how they result in decreased cardiac output and/or altered tissue perfusion (FIGURE 4-4). As illustrated in blue in Figure 4-4, blood low in oxygen and rich in carbon dioxide enters the right side of the heart from the systemic circulation through the superior vena cava and the inferior vena cava. These veins empty blood directly into the right atrium. From the right atrium, blood flows quickly during ventricular diastole (i.e., atrial systole) through the tricuspid valve to the right ventricle. At the end of diastole, the atria contracts (i.e., atrial kick) to push the last amount of blood to the right ventricle. At this time, right ventricular pressure increases, and the tricuspid valve closes. The right ventricle pressure is higher than pulmonary artery pressure, causing the pulmonic valve to open, and ventricular contraction (i.e., systole) causes blood flow to the pulmonary arteries. The pulmonary arteries then carry the blood to the lungs for oxygenation. Pressure and volume in the right ventricle drop, and ventricular relaxation causes closure of the pulmonic valve.

FIGURE 4-4 Blood flow through the heart.

The newly oxygenated blood returns from the lungs to the heart through the pulmonary veins. From the pulmonary veins, blood enters the left atrium, and the same cycle as described on the right occurs simultaneously through left-sided structures. The left atrium blood flows quickly through the mitral valve to the left ventricle, and the atrial kick forces the remaining blood through. Left ventricular pressure increases, causing mitral closure. The left ventricle pressure becomes higher than aortic pressure, opening the aortic valve, and ventricular contraction causes blood flow to the aorta. At this point, the blood is transported to the body. The coronary arteries receive oxygenated blood when blood is going from the atria to the

ventricles (diastole) and not when the ventricles are contracting, supplying the rest of the body. The reason for the supply time being reversed for the coronaries is that when the ventricles are contracting there is high pressure in the chambers and most of the coronary vessels are closed. Both atria fill and contract simultaneously; likewise, both ventricles fill and contract simultaneously.

Conduction System Left to their own devices, cardiac muscle cells would contract individually, which would create a disorderly and ineffective contraction. The muscle cells are able to contract in an organized manner, however, due to the internal electrical stimulus initiated by a pacemaker. These electrical impulses are called action potentials. Basically, the heart’s pacemaker acts like a generator creating an impulse for every heartbeat. Conductivity is the ability of cells to transmit electrical impulses. The ability of the cells to respond to electrical impulses is referred to as excitability. Cardiac cells are able to generate an impulse to contract even with no external nerve stimulus, a process called automaticity. When impulses travel through the cardiac cells, the result is a shortening of muscle fibers, which then causes contraction and pumping out of blood (i.e., systole). Between impulses, the fibers rest and go back to their usual length, which is when filling (i.e., diastole) occurs. See chapter 1 for further discussion of cellular function.

All cardiac muscle cells can initiate impulses, but normally the conduction pathway originates in the sinoatrial (SA) node located high in the right atrium (FIGURE 4-5). The SA node generates impulses faster than other areas (e.g., atrioventricular [AV] node, His bundle, Purkinje fibers) with pacemaker and automaticity capacity. Therefore, the SA node takes the lead and is the pacemaker of the heart, and other areas follow. Impulses originating in the SA node travel through the right and left atria, resulting in atrial contraction. The SA node automatically generates impulses ranging from 60 to 100 beats per minute (sinus rhythm). The impulse then travels to the AV node, which is located in the right atrium adjacent to the septum. Although it does not usually initiate impulses unless the SA node begins failing, the intrinsic rate of impulses in the AV node is 40–60 beats per minute. The impulses are delayed, or move slowly, through the AV node so that the atria contracts right before the ventricle to allow for complete ventricular filling.

FIGURE 4-5 Electrical conduction through the heart.

Next, the impulses move in rapid succession through the bundle of His; right and left bundle branches, which divide into the left anterior and posterior bundles; and Purkinje network of fibers. The flow of this impulse stimulates ventricular contraction. If the impulses fail to fire from the SA or AV node, the ventricles will attempt to pace themselves. The ventricles can generate impulses at 20–40 beats per minute, which may not result in adequate cardiac output because the ventricles may beat before they have a chance to fill with blood. These optional pacemakers in the heart function as a fail-safe mechanism to sustain life.

The conduction of the cardiac impulse produces an electric current that can be read by electrodes attached to the skin at various points of the body, producing an electrocardiogram (EKG) (FIGURE 4-6). Organized depolarization (an increase in electrical charge through the exchange of ions across the cell membrane) of the

cardiac cells generates cardiac muscle contraction. On the EKG reading, atrial contraction is represented by depolarization in the P wave, and ventricular contraction is represented by depolarization in the large QRS complex. The more intense the contraction, the higher the wave or complex. Because the force required for the atria to pump blood into the ventricles is minimal compared to the force required for the ventricles to pump blood to the entire body, the P wave is smaller than the QRS complex. The T wave represents repolarization, or recovery, of the ventricles. In repolarization, the ions line up on both sides of the cell membrane in preparation for depolarization. Repolarization of the atria does not appear on an EKG because it is hidden by the other, more prominent waveforms. Abnormal variations in the EKG, known as arrhythmias or dysrhythmias, may indicate acute problems, such as infarction or electrolyte imbalances.

FIGURE 4-6 Characteristic features of a normal electrocardiogram. P = atrial depolarization, which triggers atrial contraction.

QRS = depolarization of AV node and conduction of electrical impulse through ventricles. Ventricular contraction begins at R.

T = repolarization of ventricles.

P to R interval = time required for impulses to travel from SA node to ventricles.

ST segment = complete ventricular depolarization.

Q to T interval = complete electrical systole.

Cardiac muscle cells require sodium (Na+), potassium (K+), calcium (Ca+), and chloride (Cl-) ions to initiate and conduct electrical signals as well as the resulting muscular contraction (see FIGURE 4-7). Pharmacologic agents have an effect on different phases of the action potential. To initiate the depolarization that creates contraction, the sodium–potassium pump shifts these ions to generate a charge. Ca+ balance is required for muscle contractility, especially in a muscle that contracts many times each minute. Additionally, the neurologic system controls cardiac function, and it requires Na+ balance to function properly.

FIGURE 4-7 Cardiac action potential of myocardial cells.

The brain (specifically the medulla) monitors and controls cardiac function

through the autonomic nervous system, endocrine system, and cardiac tissue. These functions include the rate of contraction (chronotropic effect), rate of electrical conduction (dromotropic effect), and strength of contraction (inotropic effect). Receptors in the brain, heart, blood vessels, and kidneys continuously monitor body functions to maintain homeostasis. Chemoreceptors detect chemical changes in the blood, and baroreceptors, located in the carotid arteries, detect pressure in the heart and arteries. If homeostasis is interrupted, receptors begin to fire, and neurotransmitters or hormones that activate either the sympathetic nervous system (SNS) or the parasympathetic nervous system (PNS) are released. Stimulating the SNS releases norepinephrine from nerve endings on the heart and other catecholamines (e.g., epinephrine), which circulate through the bloodstream and bind with receptors on the heart. The beta (β) and alpha (α) receptors are the most abundant and have more of an effect. The beta-1 receptors are located on the conduction system and myocardium and beta-2 are on the myocardium and smooth muscles (e.g., bronchial smooth muscle). When stimulated, heart rate and contractility increase (beta-1, beta-2) and the blood vessels will vasodilate (beta-2). The beta-2 effects on the vascular tone is small as beta 1 is the predominant receptor on the heart. Beta-2 stimulation also leads to bronchodilation. An opposing receptor is beta-3, and stimulation of this receptor leads to reduced contractility. The alpha receptors cause vasoconstriction (alpha-1) or centrally mediated vasodilation (alpha-2) to keep blood pressure in balance. Several medications to lower heart rate and blood pressure act through these receptor mechanisms. Some examples include beta-adrenergic blocking agents, which block beta-1 and beta-2 receptors (first generation nonselective beta blockers), thereby decreasing heart rate and contractility. Second generation beta blockers are cardioselective, blocking mainly beta 1 receptors (e.g., atenolol, bisoprolol). Another class of beta blockers (e.g., carvedilol) which are nonselective are also alpha-1 receptor blockers thereby dilating blood vessels. Nonselective beta blockers, because they block the beta-2 receptors, can cause bronchoconstriction. Parasympathetic nervous system stimulation, specifically the vagal nerve, causes release of acetylcholine, which decreases heart rate and reduces contractile strength. Vagal nerve stimulation, which may occur with emotional distress from any situation like blood drawing, will cause a drop in heart rate and blood pressure referred to as a vagal or vasovagal reaction.

Blood Vessels The heart’s blood is supplied by the coronary arteries (see FIGURE 4-8). Two main arteries arise from the root of the aorta and divide into the right (RCA) and left (LCA) coronary arteries. These vessels branch out several times throughout the heart and the percent of flow and pattern of their branching varies among individuals. The LCA divides into the anterior descending artery, which supplies the front of the heart, the left and right ventricles, and the interventricular septum. The second LCA division is

the circumflex, which supplies the left atrium and lateral left ventricle wall. The RCA supplies the right atrium and right ventricle and posterior part of the heart including the back of the interventricular septum. The coronary arteries have multiple connections within and between each other called anastomoses. The flow through the anastomosis provides critical collateral circulation when it is not sufficient from the RCA or LCA for various reasons such as occlusions. New collateral vessels can even be formed when there are problems with flow. Understanding coronary artery supply is necessary to be able to interpret 12-lead EKG (there are 12 tracings each reflecting various areas of the myocardium) and understand consequences of a coronary artery occlusion. As an example, an occlusion in the left anterior descending artery can result in left ventricular damage., This damage will be reflected in the V3, V4 tracings on the 12-lead EKG as these leads represent the myocardium that is supplied by the left anterior descending artery (left ventricle).

FIGURE 4-8 Coronary arteries.

The systemic blood vessels are the intricate highway system along which the blood travels. Arteries carry blood away from the heart, while veins carry blood back to the heart. Left ventricular contractions project blood through the arteries, while valves in the veins assist in moving the blood back to the heart against gravity. The veins that have valves are those in the arms and legs. Once arteries leave the heart, they begin branching into smaller vessels called arterioles (FIGURE 4-9). These

vessels continue branching into even smaller, thin-walled vessels called capillaries. Their thin walls allow oxygen and nutrients to shift out of the capillaries into the cells. Additionally, carbon dioxide and waste products shift from the cells into the capillaries. This exchange occurs through diffusion. Once blood is utilized at the cellular level, the blood moves through the capillaries and transitions into larger vessels known as venules. The venules continue to merge into larger vessels until they become veins, much as small streams unite to form a river. (See chapter 1 for a discussion of cellular function.)

FIGURE 4-9 The circulatory system.

Generally, arteries carry blood rich in oxygen and nutrients, while veins carry

blood saturated with carbon dioxide and metabolic waste. One exception to this pattern occurs in the pulmonary arteries and veins. The pulmonary arteries carry oxygen-depleted blood away from the right side of the heart to the lungs for gas exchange (Figure 4-2). Following gas exchange in the lungs, the oxygen-saturated blood returns to the left side of the heart through the pulmonary veins.

The walls of the blood vessels consist of three layers (FIGURE 4-10). The composition of the three layers varies among the different type of blood vessels. In general, the tunica intima is the smooth, thin, inner layer of the blood vessels known as the endothelium. The tunica media, the middle layer, is composed of smooth muscle that is responsible for the vessel’s ability to change diameter. The outer layer, the tunica adventitia, consists of elastic and fibrous connective tissues that provide the necessary elasticity to accommodate the rush of blood with each cardiac contraction. Arteries also have a layer of elastic fiber in the tunica media and adventitia (externa) of some arteries that allow them to accommodate for high pressures. The small venules, capillaries, and arterioles do not have this elastic tissue, making them susceptible to damage when pressure increases. Large veins and arteries also have blood vessels called vasa vasorum and nerve endings on the adventitia that are not present on other vessels. The smooth muscle layer of arteries and arterioles is also much thicker than veins. Capillaries only have an endothelial layer.

FIGURE 4-10 The walls of the blood vessels are composed of three layers of tissue: the endothelium, elastic tissue, and the connective tissue. A Artery; B capillary; C vein.

Artery photo: © Cabisco/Visuals Unlimited, Inc.; Capillary photo: © Ed Reschke/Photolibrary/Getty Images; Vein photos: © Cabisco/Visuals Unlimited, Inc. and © Dr. John D. Cunningham/Visuals Unlimited, Inc.

Blood Pressure and Cardiac Output The heart, conduction system, and blood vessels and their functions are all interconnected and influenced by many variables (FIGURE 4-11). The pressure within the walls of blood vessels created by blood flowing through is what is known as blood pressure. The pressure in the artery when the left ventricle contracts is systole, and the pressure in the arteries at rest is diastole. This pressure is described as a fraction with the systolic measurement as the numerator and the diastolic measurement as the denominator. According to the American Heart Association (2017), a normal blood pressure reading should be less than 120/80 mmHg to maintain health and limit chronic disease risk. The average pressure in the arteries in one systole–diastole cycle is the mean arterial pressure and is considered an

overall average pressure in the arteries. The mean arterial pressure as opposed to blood pressure can be used as a determinant of adequate perfusion. Pulse pressure is the difference between the systolic and diastolic pressures and represents the force the heart generates each time it contracts. The pulse pressure gives an indication of the stroke volume and the elasticity of the arterial wall. Various control mechanisms are in place to keep blood pressure at a range that is adequate for tissue perfusion.

FIGURE 4-11 Factors affecting cardiac output.

Cardiac output and systemic vascular resistance significantly affect blood pressure (BP = CO × SVR, where BP is blood pressure, CO is cardiac output, and SVR is systemic vascular resistance). Cardiac output refers to the amount of blood the heart pumps in one minute. This amount is determined by stroke volume and heart rate (CO = SV × HR, where SV is stroke volume, and HR is heart rate) (Figure 4-11). Stroke volume is the amount of blood ejected from the heart with each contraction. Not all the blood in the heart is ejected. The amount pumped out with each cycle relative to how much blood volume there is at the end of diastole is called the ejection fraction (EF), and it is expressed as a percentage. The ejection fraction is a commonly used measurement to determine how well the ventricle is functioning. Various imaging techniques such as an echocardiogram or computed tomography (CT) can measure the EF. The stroke volume is influenced by the preload, afterload, and contractility. The pressure created in the left ventricle by the volume of blood at the end of diastole (left ventricular end diastolic pressure) is what constitutes the

preload. Concepts in reference to pressure and volume are generally centered around the left side of the heart; however, the right side of the heart also responds similarly to the left. The preload pressure causes the cardiac muscle fibers to lengthen and the tension relationship to change. The fibers change and shorten to provide the best contraction. The preload will vary depending on how much blood volume blood is going into the left ventricle and how much volume stays in the ventricle after it contracts (systole). A key determinant of preload is volume, and measurements can be used as a gauge for ventricular volume.

Afterload is the pressure (resistance) the ventricle must overcome to eject blood (aortic pressure for the left ventricle and pulmonary pressure for the right ventricle). The left ventricle afterload is not only impacted by the aortic pressure and aortic valve functioning but also the systemic vascular resistance (SVR). The afterload is inversely related to contractility and preload because the afterload creates opposition to muscle fiber shortening. Afterload is often equated with SVR. The resistance that is created is dependent on whether the arterioles are constricted (increasing SVR) or dilated (decreasing SVR). The diameter changes are under the influence of the sympathetic nervous system. Neurotransmitter binding with alpha-1 receptors leads to vasoconstriction and binding with beta-2 receptors leads to vasodilation.

The third variable affecting stroke volume and, in turn, cardiac output and ultimately blood pressure, is the contractility of the heart. The end-diastolic volume (left preload) causes the ventricle muscle to stretch and contract. Norepinephrine is a dominant catecholamine that increases contractility along with epinephrine and dopamine. Acetylcholine, another neurotransmitter, depresses contractility. Hormonal influences from the thyroid will increase contractility.

The Frank-Starling law explains the myocardial length–tension relationship and preload. The law states that the more the myocardial stretch, the greater the contraction. The myocardial stretch is created by the end-diastolic volume and the muscle fibers. The muscle fibers reach a certain length at a certain speed, and these factors will determine the force of contraction. The principle is similar to when you stretch a rubber band. The more you stretch a rubber band the more forceful the snap when released. There is, however, a limit to this law, and beyond a certain point the muscle fibers will lose contractile ability. Overstretching over time will eventually cause the rubber band to lose elasticity; when stretched and released, it will barely snap. The same is true with heart muscle fibers—if they are already dilated from heart disease (i.e., unable to stretch), the heart will not contract effectively.

Laplace’s law can explain factors influencing afterload, which is a pressure that is opposite to preload. In Laplace’s law, wall stress (i.e., tension) is due to pressure in the ventricle and the radius (i.e., diameter), which is inversely related to wall thickness. In other words, the wall stress is influenced by pressure, diameter, and wall thickness. Wall stress affects metabolic demands, and the higher the wall stress

the greater the metabolic demand. As an example, the ventricle has to increase its contractile force to overcome the increased pressure within the chamber. If the diameter of the blood vessel or heart chamber has an increased radius, then the heart has to increase its contractile force to supply the larger diameter. When the ventricle wall thickness increases, the opposite happens, and like a bodybuilder’s big muscle, the heart does not have to contract as hard. To summarize, increasing radius or pressure increases wall stress, and increasing wall thickness decreases wall stress. Cardiac disorders can disrupt this balance, leading to increased wall stress with resulting increased metabolic demands and decreased perfusion.

Other factors can influence blood pressure by directly or indirectly regulating systemic vascular resistance, contractility, or blood volume. Baroreceptors located throughout the body (e.g., carotid, aorta) and changes in blood pressure due to position or volume changes will trigger vessel diameter and heart rate changes and contractility. The baroreceptors sense drops in blood pressure, causing the heart rate to increase, vessels to constrict, and the contractility to increase to maintain perfusion. The reverse happens with an increased blood pressure. Aging causes changes to these receptors that make them less effective and leads to a slower response. When an elderly person changes position from sitting to standing, the receptors do not respond as quickly (i.e., blood pressure does not rise) and hypotensive signs such as dizziness or blurred vision occur. This response is termed postural hypotension.

Aside from the adrenal gland hormones (epinephrine and norepinephrine), other hormones involved in blood pressure regulation include antidiuretic hormone (ADH), aldosterone, and angiotensin II. ADH, also known as vasopressin, increases water reabsorption in the kidney, which increases blood volume. Additionally, ADH is a vasoconstrictor, which increases SVR.

The renin–angiotensin–aldosterone system (RAAS) in the kidneys is a vital control and compensatory mechanism that becomes activated when renal blood flow is decreased, as is often the case in hypotensive states (FIGURE 4-12). When renal blood flow decreases, renin is released from the kidneys, activating angiotensin I, which is then converted to angiotensin II (a vasoconstrictor) through the actions of angiotensin-converting enzyme in the lungs. Aldosterone secretion is also stimulated. Aldosterone (from the adrenal cortex) increases the reabsorption of Na+ and Cl- in the kidneys; Na+ attracts water, which, like ADH, increases blood volume. In hypotensive states, this mechanism raises blood pressure and maintains the blood supply to vital organs. In chronic disease states such as hypertension, this mechanism is inappropriately activated because of reduced blood flow (vasoconstriction) to the kidneys, further contributing to the hypertension. In contrast to ADH and aldosterone, natriuretic hormones (e.g., atrial natriuretic peptide) cause loss of Na+, Cl-, and water.

FIGURE 4-12 Role of kidneys in blood pressure.

The endothelial lining of blood vessels releases various vasoactive chemicals. The chemicals either cause vasoconstriction (e.g., thromboxane, prostaglandin) or vasodilation such as nitrous oxide or endothelium-derived relaxing factor. Angiotensin II is in the vascular tissues and blocks vasodilators (e.g., nitrous oxide).

Lymphatic System The lymphatic system is an extensive network of vessels and glands that returns excess fluid (about 3 liters per day) in body tissue to the circulatory system and

works with the immune system. Interstitial fluid surrounds cells and provides a medium through which nutrients, gases, and wastes can diffuse between the capillaries and the cells. Capillaries are continuously replenishing this fluid. Normally, the fluid outflow from the capillaries exceeds the fluid returned. Lymph capillaries absorb the excess fluid (FIGURE 4-13). This fluid, or lymph, drains from these capillaries into larger vessels and ducts (right lymphatic duct and thoracic duct) that empty into large subclavian veins at the base of the neck. The movement of lymph occurs in much the same way that blood travels through the veins, with the assistance of valves and body movement. (See chapter 2 for a discussion of immunity.)

FIGURE 4-13 The lymphatic system. (A) The lymphatic system consists of vessels that transport lymph—that is, excess tissue fluid—back to the circulatory system. (B) Lymph is picked up by lymphatic capillaries that drain into

larger vessels. Like the veins, the lymphatic vessels contain valves that prohibit backflow. Lymph nodes are interspersed along the vessels and serve to filter the lymph.

The lymphatic system also includes several organs and tissue—lymph nodes, the spleen, the thymus, the bone marrow, and tonsils. These organs primarily function in the immune response. Lymph fluid contains antigen-presenting cells and lymphocytes that go from node to node waiting to respond to antigens. Located in clusters throughout the body, lymph nodes are a network of fibers and irregular channels that slow down the lymph flow. As the lymph passes through the nodes, the fibers filter out bacteria, viruses, and cellular debris. Numerous macrophages line the channels to phagocytize microorganisms and other material.

Normally, the rate at which lymph is produced equals the rate at which it is removed. In some body states, the amount of lymph produced exceeds the capacity of the system. For example, burns can cause extensive damage to capillaries, causing them to leak fluid into the tissues. This flooding results in excessive fluid in the tissue, or edema. Fluid can also leak into the tissues as a result of lymphatic vessels becoming occluded, often because of infection.

Understanding Conditions That Affect the Cardiovascular System When considering alterations in the cardiovascular system, organizing them based on basic structures such as the pump (heart) and the vasculature can increase understanding. Disorders of either of these basic structures can lead to impaired cardiac output or tissue perfusion and often a combination of both. Alterations in pump function can occur due to disorders in the valves, conduction system, and the various layers of the heart wall. The vasculature system can be categorized by disorders of the veins and arteries (including the coronary arteries). Since the vasculature is located throughout the body, most diseases will involve the vasculature. Many diseases of the heart and vasculature are life threatening, so quickly determining the source of the problem will lead to appropriate intervention. Prevention and maintenance of cardiovascular health are crucial to maintain quality of life and reduce the burden of so many diseases associated with cardiovascular dysfunction.

Impaired Cardiac Output: Heart Disease Pericarditis Pericarditis refers to an inflammation of the pericardium—the sac that surrounds, protects, and supports the heart. This inflammation is most commonly triggered by viral infections (usually after a respiratory infection), but it may result from bacterial, fungal, or parasitic infections. Some common viruses implicated are coxsackievirus and other echoviruses, herpes simplex, cytomegalovirus, and human immunodeficiency virus. Other causes are noninfectious and can be related to myocardial infarction, thoracic trauma including those that are iatrogenic (e.g., surgery, postcardiac interventions, radiation) or noniatrogenic (e.g., accident). Malignancy can cause pericarditis, whether from primary tumors or, more commonly, secondary tumors, particularly from the breast, lung, or lymphoma. Other causes of pericarditis include autoimmune conditions, particularly systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and, rarely, metabolic disorders (e.g., uremia or myxedema) and various pharmacologic agents (e.g., procainamide or phenytoin).

During the inflammatory process, fluid shifts from the capillaries to the space between the pericardial sac and the heart. The fluid type may be a clue to the underlying cause. The fluid may be serous, as with heart failure; purulent, such as with infections; serosanguinous, as occurs with neoplasms or uremia; or hemorrhagic, as seen with aneurysms or trauma. As the pericardial tissue becomes inflamed, the swollen pericardial tissue rubs against the swollen cardiac tissue, creating friction.

Fluid can accumulate slowly or quickly in the pericardial cavity, creating a pericardial effusion. Usually conditions that cause a rapid effusion can progress to life-threatening cardiac tamponade. Slower, larger effusions or even those loculated and not affecting the whole pericardium can also lead to tamponade (FIGURE 4-14). In cardiac tamponade, the fluid accumulates in the pericardial cavity to the point that it compresses the heart. This compression prevents the heart from stretching and filling during diastole, initially affecting the right side of the heart due to its lower pressure. The decreased right-side stretching and filling causes blood to back up into the venous circulation, causing right-sided heart failure and a reduction in left ventricle filling. The result is a decreased cardiac output. Arterial pressures then fall (because of the decreased cardiac output), venous pressures rise (because of the accumulation of blood within the systemic circulation), and the pulse pressure narrows (because of the arterial and venous pressure changes). Additionally, the heart sounds are muffled upon auscultation because the excess fluid drowns out the sound. Heart failure, cardiogenic shock, and death can result from cardiac tamponade.

FIGURE 4-14 Cardiac tamponade.

Pericardial inflammation that becomes chronic can lead to constrictive pericarditis. In constrictive pericarditis, the pericardium becomes thick and fibrous from the chronic inflammation and causes the visceral and parietal layers to adhere. The constriction results in a situation similar to tamponade with reduced cardiac filling, decreasing cardiac output, and systemic congestion. Tamponade due to constrictive pericarditis develops slowly as opposed to other causes of tamponade that develop quickly.

Clinical Manifestations Clinical manifestations of pericarditis include the following symptoms: dyspnea and chest pain. The pain is usually in the anterior chest and is described as sharp and sudden. The pain increases with deep inspiration or lying flat (when the pericardium is closest to the chest wall) and decreases when the patient sits up and leans forward. Flulike symptoms including fever, chills, malaise, and myalgia may be present depending on the cause. Physical examination findings include a pericardial friction rub, which is a grating sound heard usually between the lower left sternal border and cardiac apex when the breath is held. The rub may be intermittent. If

there is an effusion, the heart sounds may be muffled. Sudden acute tamponades present as shock with a low blood pressure, jugular vein distention, and muffled heart sounds—referred to as Beck’s triad. Tamponade also causes tachypnea, tachycardia, and other signs of cardiovascular collapse. If there is a slower accumulating tamponade, right-sided heart failure manifestations will be present with dyspnea, tachycardia, jugular vein distention, ascites, hepatomegaly, and edema. The manifestations in constrictive pericarditis are similar (e.g., dyspnea, fatigue, edema) to pericarditis with or without tamponade but are slower in onset.

Diagnosis and Treatment Diagnosis of pericarditis is accomplished through a history and physical examination. Some EKG changes in acute pericarditis include inflammatory changes with diffuse ST segment elevation with no Q waves or reciprocal changes as seen in myocardial infarction (MI). Echocardiogram and/or CT may demonstrate an effusion, wall thickening, and constriction. Chest X-rays, complete blood count (CBC), and magnetic resonance imaging (MRI) or other tests such as a pericardial biopsy may be necessary to aid in diagnosis. Treatment focuses on the underlying cause (e.g., antibiotics for infection) and reducing the inflammation (e.g., nonsteroidal anti- inflammatory medications and colchicine are effective in reducing the development of fibrosis). Steroidal anti-inflammatory drugs can be considered if nonsteroidal anti- inflammatory medications are contraindicated. Analgesics may be administered to manage pain. Additionally, bed rest is important to reduce metabolic needs and cardiac workload. Oxygen therapy can increase available oxygen. Pericardiocentesis may be performed to withdraw excess fluid from pericardium, or a pericardiectomy (a surgical procedure in which a window is created in the pericardium) may be performed to release constriction and allow excess fluid to drain into the pleural cavity.

Infective Endocarditis Infective endocarditis (IE) (previously called bacterial endocarditis) is an infection of the endocardium. Infections are more common on or near the heart valves but can occur anywhere on the endocardium. The organisms commonly involved will vary depending on whether the valve is native or prosthetic and whether the infection is community acquired or nosocomial. Staphylococcus aureus commonly found on the skin and the gastrointestinal tract is the most common causative organism in IE. S. aureus is an organism that often causes infection due to healthcare contact such as surgery, hospitalization, or procedures (American Heart Association, 2015). Injection drug users have a higher incidence of IE from S. aureus. Viridans streptococci, commonly found in the mouth, account for many cases of community-acquired IE. Enterococcus species—bacteria commonly found in the gastrointestinal tract—are

another frequent causative organism. Less common causes include other bacterial species, viruses, fungi, rickettsia, and parasites.

IE is more common in adults as there is a higher incidence of valvular disease, implanted cardiac devices, exposure to healthcare-related procedures (e.g., intravenous catheters), and injection drug use. Advances in health care have increased survival among children with congenital heart disease leading to a subsequent higher risk of developing IE. Neonatal and pediatric disease management in intensive care units has become more complex, involving more invasive procedures such as central line placements. As a consequence, nosocomial infections are a common cause of IE in children, even in those with no heart disease. Rheumatic heart disease, which is not as prevalent in the United States, is more of a predisposing factor for IE in developing countries.

The pathogenesis of IE involves endothelial damage, which attracts platelets and stimulates thrombus formation. Bacteria start adhering to the linings and go into the thrombus where the bacteria are protected by the fibrin clots. Vegetation (including platelets, fibrin, microorganisms, inflammatory cells, and granulomatous tissue) collects on the internal structures because of damage from the infection, much like the process that occurs when a boat’s anchor is placed in a body of water for an extended length of time and barnacles develop. With each heart contraction, some of this vegetation is dislodged and ejected from the heart. These small thrombi move throughout the body, collecting in the microcirculation and creating microhemorrhages (e.g., petechiae and hematuria). The thrombi can also travel to other locations, in which case they are known as embolisms, and become lodged there. These emboli can cause serious and often life-threatening complications such as myocardial infarction, stroke, seizures, and pulmonary embolism. In addition, the heart valves can become scarred and perforated (FIGURE 4-15). If untreated, infective endocarditis is usually fatal, especially when it involves the valvular structures.

FIGURE 4-15 Infective endocarditis. Courtesy of Leonard V. Crowley, MD, Century College.

Clinical Manifestations Clinical manifestations of infective endocarditis will depend on whether IE presents acutely or subacutely. Acute signs and symptoms tend to be worse (e.g., higher fever) than subacute. IE may infect different valves and to different degrees, which also influences presentation. Systemic involvement varies and may include the lungs, kidneys, eyes, musculoskeletal system, and neurologic alterations. Infectious and inflammatory manifestations include fever, chills, myalgias, arthralgias, and malaise. A heart murmur may be new or worsened. Heart failure may be present. Skin and mucous membranes findings may include petechiae (bleeding capillaries), painful red nodules on the finger and toe (Osler nodes), nonpainful hemorrhages on the palms and soles (Janeway lesions), and splinter hemorrhages under the nailbed. Arterial emboli can occur in up to 50% of patients and symptoms will vary depending on which organ has the emboli. Renal dysfunction and hematuria may occur with kidney involvement.

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Diagnosis and Treatment Due to the high variability in disease presentation and challenges in diagnosis, criteria were developed to define and aid clinicians. This schema is known as the modified Duke criteria and incorporates clinical, laboratory, and echocardiogram findings. Some of the criteria include bacteremia such as positive blood cultures, echocardiogram findings such as a new regurgitant valve or a mass on valve, and predisposing risks or fever. Several exclusion criteria for IE include a likelihood of an alternative diagnosis or resolution and nonrecurrence of symptoms with ≤ 4 days of antibiotics. Other diagnostic procedures for IE include a CBC, erythrocyte sedimentation rate, C-reactive protein, immune complex titers, urinalysis, serum rheumatoid factor, EKG, and chest X-ray. Treatment is based on management of the identified causative agent (e.g., antibiotics for bacteria or antifungal agents for fungi). The anti-infective therapy for IE is often long-term (a minimum of 4 weeks). Other treatments are initiated to maintain cardiac function and treat other symptoms and include bed rest, oxygen therapy, and antipyretic agents. Repair or replacement of cardiac valves may be indicated when there is heart failure, uncontrolled infection, or higher mortality with medical treatment only (e.g., S. aureus with vegetations and septicemia). Antibiotic prophylaxis prior to certain dental procedures may be necessary in certain high-risk patients such as those with prosthetic cardiac valves or congenital heart disease to prevent IE.

Diagnostic Link

Echocardiogram chocardiograms are noninvasive tests frequently used to evaluate the structure and function of the heart. An echocardiogram produces images and recordings through ultrasound (high-frequency sound waves).

The echocardiogram can be used to evaluate the pericardium (for effusion); ventricles (for hypertrophy, dilatation, wall motion, and thrombi); valves (for stenosis and regurgitation); great vessels (for aortic dissection); and septal areas (for trauma or congenital disease). The echocardiogram generates anatomic images in different modes: one-dimensional (M mode), two-dimensional, and three-dimensional. The test can be a transthoracic echocardiogram (TTE) where the transducer is on the chest wall or a transesophageal echocardiogram (TEE), where the transducer is placed in the esophagus. There are no contraindications for the TTE, but evaluation limitations exist when the patient has a thick chest wall like in an obese patient or rib crowding like in an underweight patient. The TEE requires intravenous and local anesthesia and, therefore, is a bit more complex to perform. The TEE is a useful adjunct when the TTE evaluation is inconclusive or limited and more detailed information is needed. Doppler While the different modes generate anatomic images in echocardiogram, the addition of Doppler-ultrasound provides hemodynamic data of the velocity and direction of blood flow through the valves, pulmonary artery, and veins. An echocardiogram can be done with contrast to evaluate shunts (e.g., patent foramen ovale) and many other additions and enhancements can be done. Technologic advances are being evaluated to enhance the capacities of the frequently used echocardiogram.

Myocarditis Myocarditis is an inflammation of the myocardium. The incidence of this disease is difficult to determine as the pathophysiology is poorly understood, there are many

clinical presentations making diagnosis difficult, and at least several weeks (in some cases a decade) lapse between exposure of the causative agent and the development of symptoms. Myocarditis can be caused by infectious and noninfectious agents. Infectious causes are usually due to a virus (e.g., influenza, coxsackie, cytomegalovirus, adenovirus, hepatitis C, herpes, HIV, or parvovirus). Other organisms causing myocarditis are bacterial (e.g., Lyme disease, Chlamydia, Mycoplasma, or Streptococcus), or fungal (e.g., Aspergillus, Candida, Cryptococcus, or Histoplasma). A common origin is Chagas disease in developing countries, particularly Latin America (Mexico, Central America, and South America), which is caused by a parasite, Trypanosoma cruzi. Noninfectious causes may include allergic reactions, chemical exposure, radiation, or inflammatory disorders (e.g., rheumatoid arthritis or sarcoidosis). With myocarditis, organisms, blood cells, toxins, and immune substances penetrate the myocardium and can result in muscle fiber dysfunction and degeneration that impairs contractility and conduction. Most cases of myocarditis are benign, but some cases result in heart failure, dilated cardiomyopathy, dysrhythmias, and thrombi development. The term inflammatory cardiomyopathy is sometimes used instead of myocarditis when there is cardiac muscle dysfunction.

Clinical Manifestations The patient may be asymptomatic or present with flulike symptoms, chest pain usually from pericarditis, syncope, palpitations, and joint pain/swelling. Physical exam findings will also vary and can include fever, a pericardial rub, tachyarrhythmias, and less commonly, bradyarrhythmias. Signs of heart failure or cardiogenic shock will be present in severe cases.

Diagnosis and Treatment Diagnosis of myocarditis is accomplished through a history, physical examination, and blood cultures. EKG may reveal sinus tachycardia, pericarditis, or myocardial infarction changes. The cardiac enzyme troponin is more commonly elevated than creatinine kinase. Endomyocardial biopsy is considered a gold standard for diagnosis but is a risky procedure and not necessary in every case. Other tests can include a CBC, erythrocyte sedimentation rate, chest X-rays, and echocardiogram. Management centers on treating the causative agent (e.g., antibiotics for bacteria and antifungals for fungi). Antipyretics, anticoagulants, antidysrhythmics, diuretics, and immunosuppressants (e.g., corticosteroids or nonsteroidal anti-inflammatory drugs) may be used to treat symptoms or complications. Increasing bed rest, restricting activity, and limiting fluids can reduce cardiac workload.

1. 2. 3.

Valvular Disorders Valvular disorders cause disruption of normal blood flow through the heart. These disorders are distinguished based on the valve affected and the type of alteration. Valvular disorders can be congenital or acquired. Two types of alterations are stenosis and regurgitation. Aortic and mitral valve disease are more common due to the higher pressures and workload on the left side of the heart.

BOX 4-1 Application to Practice Mrs. Fulcher is a 58-year-old married homemaker who was recently discharged from the hospital because of recurrent infective endocarditis. Her most recent episodes were a S. aureus infection of the mitral valve 12 months ago and a Streptococcus mutans infection of the aortic valve 1 month ago. During her most recent hospitalization, an echocardiogram showed aortic stenosis, moderate aortic insufficiency, chronic valvular vegetation, and moderate atrial enlargement. In addition, Mrs. Fulcher has a history of chronic joint pain.

After being home for 1 week, Mrs. Fulcher was readmitted to the telemetry floor with endocarditis. She reports chills, fever, fatigue, joint pain, malaise, and a headache for the last 24 hours. At admission, Mrs. Fulcher’s blood pressure was 172/48 mmHg (supine) and 100/40 mmHg (sitting), her pulse was 116, respirations were 20, and her temperature was 101.9°F. She was orientated to person, place, and time but was drowsy. Physical exam further revealed a murmur; clear and bilaterally equal lung sounds; extremities with 2+ pitting tibial edema; no peripheral cyanosis; and multiple petechiae on the skin of her arms, legs, and chest. She also has hematuria.

Upon admission, IV infusion of normal saline at 125 mL/hr and vancomycin IV every 8 hours was ordered to be continued over the next 4 weeks. Other routine medications ordered included furosemide (Lasix), amlodipine (Norvasc), and metoprolol (Lopressor).

What is the significance of the orthostatic hypotension, the wide pulse pressure, and tachycardia? What is the significance of the hematuria, joint pain, and petechiae? For which complications of embolization should Mrs. Fulcher be assessed?

Modified from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Stenosis is a narrowing of a structure—in this discussion, heart valves. When the valves are stenosed, blood moving through the valve is reduced, causing blood to back up in the chamber just before the valve. Atresia refers to a lack of the valve opening (e.g., the valve cusps may be fused together) that would otherwise allow blood flow. Pressures in the overfilled chambers increase to pump against the resistance of the stenosed valve. Because the heart (specifically the chamber) is working harder, hypertrophy of the chamber develops. Hypertrophy and increased workload escalate the heart’s oxygen demands, but the decreased cardiac output resulting from the stenosis makes it difficult to meet these increased demands. The

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cardiac output ultimately decreases, leading to clinical deterioration. Other heart disorders such as cardiomyopathy and heart failure can develop. Aortic stenosis is one of the most common valvular diseases in the United States.

Regurgitation, also called insufficiency or incompetence, occurs when the valve leaflets do not completely close, so blood continuously leaks. Additionally, heart valves normally allow blood to flow in one direction; incompetent valves, however, allow blood to flow in both directions. This regurgitation of blood increases the amount of blood that must be pumped and, in turn, increases the cardiac workload. The increased workload contributes to hypertrophy developing in the affected chambers. Additionally, the increased blood volume in the heart causes the chambers to dilate to accommodate the larger volume. Valves can also be both stenotic and incompetent such as when the mitral valve annulus (fibrous ring around valve) becomes calcified. Valve calcification can occur secondary to degenerative changes, atherosclerosis, and other diseases. Due to the calcifications, the mitral valve is unable to close properly (regurgitation) leading to an ineffective contraction and the calcifications cause a narrower opening (stenosis).

Valvular disorders may have a number of causes such as congenital defects, infections, endocarditis, rheumatic fever, hypertension, myocardial infarction, cardiomyopathy, and heart failure. Some diseases affect more than one valve, such as in Marfan syndrome where the aortic and mitral valve can become regurgitant. One valve disorder may be the cause of another valve disorder such as in mitral valve stenosis. Mitral stenosis causes backup of blood into the lungs, causing a rise in pulmonary pressures, and, ultimately, right-sided heart issues develop with tricuspid and pulmonic valve changes. When considering valvular disease, it is important to identify the affected valve as well as think of the blood flow consequences, whether forward or backward, caused by the diseased valve.

Learning Points

Mitral Valve Prolapse itral valve prolapse (MVP) is caused by structural abnormalities in the leaflets, chordae, or annulus of the valve. MVP is a common valve disorder and is the most common cause of mitral regurgitation; however,

MVP does not always result in regurgitation. The structural abnormalities can occur due to many disorders such as connective tissue disease (e.g., Marfan syndrome), myocardial infarction, von Willebrand disease, and skeletal abnormalities. MVP causes the valve leaflets to billow into the left ventricle or flail and prolapse into the left atrium during systole (FIGURE 4-16).

FIGURE 4-16 Normal mitral valve leaflets (left) compared with prolapsing mitral leaflets associated with mild mitral insufficiency (right).

Clinical Manifestations Clinical manifestations are the consequences of the flow alterations, the valve involved, the nature of the alteration, and the severity (TABLE 4-1). As an example, aortic stenosis causes classic manifestations such as syncope, angina, and heart failure. Angina occurs because oxygen supply is reduced as the heart is working hard to eject blood through a stenotic aortic valve and is unable to meet the demands. Angina even occurs with normal coronary arteries. Ventricular hypertrophy, which is compensatory at first, will lead to heart failure. Syncope, which is usually exertional, can be caused by a decreased cardiac output. Aortic stenosis may exist for many years without symptoms or with minimal symptoms until it becomes notably stenotic (e.g., 1 cm2).

TABLE 4-1 Clinical Manifestations of Valvular Stenosis and Regurgitation

Modified from Huether, S., & McCance, K. (2000). Understanding pathophysiology (2nd ed.). St. Louis, MO: C. V. Mosby.

Diagnosis and Treatment Valvular heart disease can be diagnosed with a history and physical examination and evaluation with an echocardiogram. Other diagnostic tests are ordered to evaluate causes or consequences of the valve disease and can include heart catheterization, chest X-rays, EKG, or MRI. Management is geared toward the actual or potential consequences of the valve disease such as heart failure, cardiomyopathy, and symptomatology. Medications often used to treat valvular disorders include diuretics, antidysrhythmics, vasodilators, angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic blocking agents, and anticoagulants that decrease the workload on the heart and prevent thrombi. Additional strategies may include oxygen administration and a low-sodium diet. Valve replacement may be with a mechanical valve or a biologic valve (pig, cow, or human). Mechanical valves

generally have a longer duration, but patients will need to be on lifelong anticoagulation while those with biologics do not need to be on anticoagulation. Factors determining the use of a particular valve include anticoagulation risk and age as biologics deteriorate fast and are not the best for the young. Aortic stenosis or regurgitation can be medically managed, but most patients will ultimately need valve repair or replacement. Mitral stenosis and regurgitation can be treated medically first, but there are circumstances when repair or replacement is necessary urgently (e.g., acute mitral regurgitation caused by an MI or chest trauma). In addition to replacement valve repair can include techniques such as valvotomy. This technique involves percutaneously introducing a catheter with a balloon that goes through the stenotic valve and is inflated to clear the calcifications.

Cardiomyopathy Cardiomyopathies are disease of the heart muscle that can lead to several types of structural (e.g., hypertrophy) and functional (e.g., systolic/diastolic dysfunction) changes. The structural and functional changes in cardiomyopathy can cause heart failure. Most cardiomyopathies are classified into three groups—dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (FIGURE 4-17). These three groups are descriptive of the morphology (structure), function, and phenotype (observable characteristics) of the cardiomyopathy. Many cardiomyopathies develop due to genetic abnormalities. The type of genetic abnormalities is not incorporated in the three-group scheme. Several newer classifications also incorporate genetic information (e.g., MOGE(S)). Genetic testing can provide information pertaining to the etiology and used to identify patients at risk before structural and functional changes occur. Other diseases such as myocardial infarction and hypertension cause heart muscle damage. However, newer definitions of cardiomyopathies have been proposed by major societies such as the World Health Organization and the American Heart Association and these definitions exclude cases of heart muscle damage as a result of coronary artery disease, valvular disease, hypertension, or congenital heart disease. In the literature, often cardiomyopathies may still be described as hypertensive cardiomyopathy or ischemic cardiomyopathy. The classification of ischemic and nonischemic cardiomyopathy is also not preferred.

M

FIGURE 4-17 Comparing cardiomyopathies.

Learning Points

Cardiomyopathy Classification OGE(S) stands for:

M morphofunctional phenotype O organ involvement G genetic or family inheritance pattern E etiologic description S functional status.

MOGE(S) is one example of a cardiomyopathy classification incorporating genetic information. Descriptors are listed under each heading much like the concept of the tumor size, nodal involvement, and metastatic progress cancer staging system.

Over 100 genes are linked or may be linked with cardiomyopathy. Although cardiomyopathies may be nongenetic, most are inherited, and most are autosomal dominant with some recessive and X-linked inheritance pattern. The gene mutations associated with cardiomyopathy cause a wide variety of clinical presentations and disease severity. In addition to the mutation, other factors such as lifestyle and genomic variation can influence clinical presentations. There have been many advancements in identifying which genomic variations are benign or pathologic. People with the identical mutations may have different clinical presentations. Some individuals have the genotype but never develop cardiomyopathy as a result of incomplete or reduced penetrance. Within each of the three categories of cardiomyopathy, there are heterogenous structural and functional changes and risk. For example, a person with hypertrophic cardiomyopathy can have a dilated or restrictive pattern. Some cardiomyopathies are associated with lethal cardiac rhythms that cause sudden cardiac death, but some people with the same type of cardiomyopathy are not at risk. Through genetic testing, identifying those at risk for lethal arrhythmias is possible. Individuals known to be at risk could prophylactically get an implantable cardioverter-defibrillator to manage the lethal arrhythmias. A person with a genetic mutation associated with cardiomyopathy may be asymptomatic or have minor symptoms for many years (e.g., until age > 50 years) before manifestation of the disease. Identifying people before the disease starts underscores the importance of genetic testing. The delayed manifestation described is an example of the genetic concept of age-dependent penetrance. This type of penetrance is similar to a man becoming bald as he gets older.

While new classifications exist, the three groups (hypertrophic, restrictive, dilated) will be used to discuss cardiomyopathy clinical manifestations. Treatment protocols are also based on this classification (see TABLE 4-2).

TABLE 4-2 Cardiomyopathy Classification

Dilated cardiomyopathy develops when the ventricles become enlarged (dilated) and there is systolic dysfunction. Usually this condition starts in the left ventricle and eventually affects the right ventricle. Although the ventricles are enlarged, the wall thickness is normal. As systolic function worsens, there is backflow with increasing pulmonary vascular resistance and development of pulmonary hypertension. Myocardial fibrosis contributes to the development of arrhythmias and heart failure. Risk for developing DCM increases with age. The incidence is higher in Black men, and they have a higher mortality rate. DCM due to nonischemic events has a higher prevalence rate than DCM due to ischemic causes. Most patients who receive heart transplants have dilated cardiomyopathy.

Many noncardiac causes of DCM are due to genetic and systemic abnormalities. Systemic abnormalities include cardiotoxic substances; infections; and autoimmune, metabolic, and hormonal disorders. Heavy alcohol use (> 10 years) is a common cause of DCM in the United States. Other cardiotoxins include long-term cocaine use even without coronary disease and stimulants such as methamphetamine and 3,4-methylenedioxymethamphetamine (known as MDMA and ecstasy).

Chemotherapeutic anthracycline-based agents (e.g., doxorubicin and daunorubicin) are also cardiotoxic and cause DCM. Many other drugs (e.g., decongestant pseudoephedrine, attention-deficit/hyperactivity disorder medications) can lead to DCM when abused or taken in large quantities.

Up to 50% of DCM cases are caused by genetic abnormalities. Mutations affect sarcomere and cellular mechanisms. One example is peripartum-related DCM (PPCM), which is thought to be caused by chromosomal abnormalities. In addition to chromosomal abnormalities, inflammation and autoimmunity may also cause PPCM, but most often the cause is unknown. The incidence of PPCM is increasing as a result of more frequent recognition, older age in pregnancy, and multiple births (e.g., twins, triplets). Black women have a higher incidence of PPCM. The risk of death due to PPCM is extremely low overall but is higher in Black women in comparison to other ethnic groups. In women with DCM, recurrence is substantial in subsequent pregnancies.

Human immunodeficiency syndrome (HIV) can lead to DCM. Some theories of pathogenesis of HIV and DCM include viral invasion (HIV or other viral coinfection) of myocardial cells, long-term immunosuppression, cardiotoxicity from HIV drugs, or substance abuse.

Autoimmune disorders (e.g., SLE, scleroderma, rheumatoid arthritis), although rare, can cause restrictive and dilated cardiomyopathy. Obesity (particularly severe) causes ventricular dysfunction and structural changes (i.e., dilation, hypertrophy). Obese individuals often have cardiovascular disorders, such as hypertension and atherosclerosis, that also affect the myocardium. The comorbidities of obesity and the obesity-related myocardial changes lead to an increased risk of DCM. Long-term thyroid disorders can cause myocardial injury and lead to DCM, although rare. Some other disorders associated with DCM, which often present at first as restrictive or with dilated and restrictive features, include sarcoidosis (granulomas on various organs), amyloidosis (abnormal protein deposits in the heart and other organs), and hemochromatosis (increased iron). Intense emotions or stress can cause an interestingly named DCM called takotsubo, which is a Japanese octopus-trapping jar. Other terms for takotsubo DCM are stress cardiomyopathy, broken heart syndrome, and apical ballooning syndrome. The overall incidence of takotsubo DCM is not known but can be present in up to 2% of individuals who present with some ischemic syndromes. Takotsubo DCM is more common with aging, and women have a much higher incidence. In the pediatric population, most cardiomyopathies are DCM and familial. Other causes of DCM in the pediatric populations are similar to some adult causes already discussed.

Unlike dilated cardiomyopathy, which mainly affects systolic function, hypertrophic cardiomyopathy mainly affects diastolic function. HCM is common, affecting 1 out of 500 people (NIH, 2016). HCM is a common cause of sudden cardiac death in young people, especially young athletes. In HCM, the hypertrophied

ventricular wall becomes stiff and unable to relax during ventricular filling. With a reduction in ventricular filling, cardiac output decreases while atrial and pulmonary pressures increase. The septum between the ventricles is the most common place of hypertrophy (FIGURE 4-18). In addition to hypertrophy, the myocardium becomes fibrotic and forms scars. These scarred areas can incite arrhythmias such as ventricular tachycardia and atrial fibrillation. The blood vessel lumens are compressed due to the thick walls, which reduces blood flow and causes ischemia. Hypertrophic cardiomyopathy occurs with or without outflow obstruction.

FIGURE 4-18 A comparison of normal cardiac function with malfunction characteristic of hypertrophic cardiomyopathy. A Normal heart, illustrating unobstructed flow of blood from left ventricle into aorta during

ventricular systole. B Hypertrophic cardiomyopathy, illustrating obstruction to outflow of blood from left ventricle by hypertrophied septum, which impinges on anterior leaflet of mitral valve.

HCM is the most common familial heart disease and is inherited through an autosomal dominant pattern. Mutations of the sarcomere (functional unit in the heart muscle) gene occur. Like DCM, age dependence and incomplete penetrance is present. The average age of disease development in HCM is 40. Despite having the genotype, some people remain without disease development, and many different disease expressions are possible with the same mutation.

Restrictive cardiomyopathy is the least common of the cardiomyopathies but is more common in parts of South and Central America, India, Asia, and Africa. This type of cardiomyopathy is characterized by rigidity of the myocardium and diastolic dysfunction. The ventricular rigidity does not allow for proper filling, and pressure in the ventricle increases. The atrium enlarges as a consequence. Wall thickness is usually normal, and systolic function is unaffected or mildly affected; therefore, cardiac output is maintained until worsening of the disease. In restrictive cardiomyopathy, fibrosis and myocyte damage are usually due to infiltrative disorders. The various disorders include amyloidosis, hemochromatosis, sarcoidosis, connective tissue disorders, and radiation exposure. As with the other cardiomyopathies, genetic mutations are implicated in the development.

Clinical Manifestations Patients with cardiomyopathy can be asymptomatic for years. The clinical manifestations will also vary greatly depending on the type of dysfunction and the stage of disease presentation (e.g., early, late). General symptoms for cardiomyopathies are due to the structural and functional changes. The underlying disorder may also affect different parts of the heart directly. For example, the valves may be affected by the infiltrative disorders in restrictive cardiomyopathy. In all the cardiomyopathies, backflow pressures and volume eventually lead to atrial enlargement. Right- and/or left-sided heart dysfunction will lead to symptoms depending on the predominant side affected.

Diagnosis and Treatment Obtaining a detailed family history is important in identifying hereditary patterns. Any history of sudden cardiac death or early death from cardiac disease should be questioned extensively because often people just assume the death was due to a heart attack. In addition to a complete history and physical, an echocardiogram will be done. Cardiac imaging may include nuclear studies. An EKG may be done to

evaluate for arrhythmias and conduction abnormalities. A myocardial biopsy may be necessary, particularly in restrictive cardiomyopathy.

Treatment varies depending on the type and cause. Treatment may be supportive with a focus on relieving heart failure symptoms by decreasing afterload and enhancing contractility. General pharmacologic treatments usually include ACE inhibitors, diuretics, digoxin, beta-adrenergic blocking agents, and antidysrhythmic agents to decrease the cardiac workload. Other treatment strategies include an implantable cardioverter-defibrillator, pacemaker, valve repair, and heart transplant. Anticoagulation may be necessary to prevent stroke in those with atrial fibrillation. Additionally, lifestyle modification includes a low-fat, low-sodium diet, tobacco cessation, regular physical activity, and abstinence from alcohol or other cardiotoxins.

In HCM, surgical removal or ablation of excess myocardium may be necessary for those patients who do not respond well to medications. If there is obstruction with HCM, controlling the heart rate and decreasing contractility is important as uncontrolled heart rate and increased contractility may worsen the obstruction and lead to sudden cardiac death. Pharmacologic agents with negative inotropic effects such beta-adrenergic blocking agents and calcium channel blockers are often used. Hypovolemia amid HCM with obstruction can worsen symptoms. Additionally, strenuous activity (e.g., running) or competitive sports should be avoided as most cases of sudden death associated with HCM have occurred with these types of activities.

Electrical Alterations The normal myocardium rhythmically contracts (depolarization) and relaxes (repolarization), and there is synchronization between the atria and ventricles. An electrical stimulus (i.e., action potential) precedes this cycle. An action potential is caused by electrically charged particles (e.g., Na+, K+, Ca+) that flow in and out of the cardiac cell membrane. Normally, the electric impulses originate in the SA node, the natural pacemaker of the heart. This impulse follows a predictable, consistent path. While cardiac cells can create their own impulses without external stimuli, the rate is mostly regulated by the autonomic nervous system. Sympathetic stimulation increases the rate while parasympathetic (vagal) stimulation decreases the rate. Normal electric conduction is referred to as sinus rhythm, whereas deviations from normal are referred to as dysrhythmias or arrhythmias.

Dysrhythmias are usually categorized as slow (bradyarrhythmias) or fast (tachyarrhythmias) and occur due to problems with impulse formation, conduction, or both. Abnormal impulses can be generated at an abnormal rate from the SA node or from an ectopic site (an area that is not the SA node). Impulses can also be conducted abnormally. Conduction can be slowed or blocked.When the block is at the AV node, the impulse cannot get through despite the SA firing, and another,

slower pacemaker site (e.g., AV junction) takes over. When the bundle of His or both bundle branches are blocked, SA impulses will also be blocked. If only one bundle is blocked, the impulse from the SA node is transmitted and goes through the bundle that is not blocked. The path of conduction continues through a modified route, resulting in a longer time for the ventricles to depolarize (QRS ≥ 0.12 sec) and a change in the QRS shape.

Bradyarrhythmias are usually caused by problems in the SA node or in the AV conduction system. Most tachyarrhythmias occur due to firing from multiple ectopic foci and/or reentry mechanisms. With reentry, an impulse becomes its own circuit, firing continuously and at a fast rate. The various areas of reentry can include the atria (e.g., atrial flutter, atrial fibrillation), ventricles (e.g., ventricular tachycardia), and AV node (e.g., supraventricular tachycardia). Impulse conduction can deviate from the normal path through abnormal accessory pathways between the atria and ventricle that develop congenitally. These accessory pathways are in different locations and can conduct impulses faster and bypass normal pathways. Impulses can travel through these fast pathways in different manners depending on their locations (e.g., from atria to the ventricle and then back through the AV node to the atria) in a circuitlike manner. The accessory pathway can cause tachyarrhythmias.

Dysrhythmias vary in severity and are classified according to their origin (FIGURE 4-19). The most common dysrhythmia in adults is atrial fibrillation, and the most common in children is supraventricular tachycardia. The effects of dysrhythmias on cardiac output and blood pressure are partially influenced by their site of origin, which also determines the dysrhythmias’ clinical significance. Causes of dysrhythmias are numerous and can include the following conditions: acid–base imbalances, hypoxia, congenital heart defects, connective tissue disorders, degenerative changes (e.g., aging), drug toxicity, electrolyte imbalances (especially K+, Ca+); stress, myocardial hypertrophy, ischemia, or infarction.

FIGURE 4-19 Types of cardiac dysrhythmias. Reproduced from Arrhythmia recognition: The art of interpretation, courtesy of Tomas B. Garcia, MD.

Rhythm descriptions and appearances may vary particularly when there are multiple abnormalities (e.g., atrial flutter with a left bundle branch block produces a wide QRS).

Clinical Manifestations Clinical manifestations may vary according to the specific dysrhythmia. Some dysrhythmias may be asymptomatic, whereas others can cause sudden death. The danger and symptoms depend on the extent they reduce cardiac output. Some general manifestations of dysrhythmias include palpitations, fluttering sensation, skipped beats, fatigue, confusion, syncope, and dyspnea. Physical exam will reveal an abnormal heart rate and/or rhythm. Other findings will be dependent on the cause (e.g., myocardial infarction) and/or the consequences (e.g., heart failure, shock).

Diagnosis and Treatment Diagnostic procedures for dysrhythmias include a history, physical examination, and EKG. Additional tests may be performed to identify the underlying cause and may include invasive electrophysiologic studies. Pharmacology is the mainstay of treatment and may include beta-adrenergic blocking agents, calcium channel blockers, and antiarrhythmics (e.g., amiodarone). Other interventions may include an internal cardiac defibrillator, pacemaker, cardioversion, defibrillation, and ablation. Avoiding triggers such as caffeine, tobacco, and stress can decrease the occurrence and severity of some dysrhythmias.

Atrial Fibrillation Atrial fibrillation (AF) is one of the most common supraventricular tachyarrhythmias in adults and the incidence increases significantly over the age 60. AF significantly increases the risk of stroke (fivefold), heart failure (threefold), dementia, and mortality (twofold). When a patient with AF has a stroke, it is likely to be worse than a stroke due to other causes. AF is characterized by rapid, chaotic, ectopic atrial impulse formation (over 400 impulses a minute) causing an ineffective quivering atrial contraction (Figure 4-19). The AV node normally acts as a gatekeeper and prevents most of these impulses generated in AF from traveling to the ventricles. However, the AV node can become less effective, allowing too many impulses to get through, resulting in a dangerously high ventricular rate (e.g., 200 impulses per minute). The number of impulses that are conducted is usually variable, causing the classic description of AF being irregularly irregular. The ineffective atrial quivering type contraction causes blood to pool, promoting clot formation (usually in the left atrium). The ventricles do not fill adequately, which leads to an insufficient volume being ejected. The fluctuating heart rate (usually fast) also contributes to variations in ventricle filling/ejection. These factors can cause a decrease in cardiac output and potential embolization—most commonly to the brain (stroke).

AF can be classified by the duration: paroxysmal (≤ 7 days), persistent (> 7 days), long persistent (> 12 months), and permanent. In permanent AF, normal sinus

rhythm (NSR) does not seem achievable, or efforts at restoration are no longer being attempted. Chronic is often used to describe AF clinically, but this term has varying definitions. Since AF can be asymptomatic at times, the duration can be hard to determine. However, the duration can be a clue to the cause when known and can guide therapeutic decisions. Paroxysmal and persistent AF usually occur due to an area in the atria that is generating impulses ectopically or through reentry mechanisms. Once AF becomes persistent or permanent, structural and/or electrophysiologic changes are likely to exist.

Structural changes in the atrial tissue and/or electrical system can trigger AF and cause it to recur or be sustained. AF is often associated with heart diseases and may be a cause of the disease or due to the disease. Common diseases such as hypertension, coronary artery disease, heart failure, and valvular disorders can lead to structural changes such as atrial dilation, hypertrophy, inflammation, and fibrosis. Atrial inflammatory changes and fibrosis occur with aging or cardiac surgery and can be present even when there is no heart disease. The rapid heart rate of AF causes cell necrosis and apoptosis, which further affects impulse response and conduction. These changes create an environment for more arrhythmias. Infiltrative diseases cause the deposition of substances such as amyloid fibrils or intracellular iron that infiltrate cardiac tissue and promote AF. Noncardiac disorders such as hyperthyroidism, sleep apnea, obesity, alcohol, and other drugs promote AF. Electrophysiologic alterations leading to AF include ectopic impulse formation, reentry abnormalities, and autonomic nervous system stimulation. RAAS stimulation causes structural and electrical changes that can lead to AF.

Clinical Manifestations Patients with AF may be asymptomatic or have variable symptoms depending on the ventricular rate and other comorbid diseases causing or associated with AF. Patients may complain of tiring easily and may struggle with exercise. Patients may experience palpitations, dizziness, or syncopal episodes. When the heart rate is high, hemodynamic compromise can occur, particularly in people with heart failure or those who already have cardiovascular impairment.

Diagnosis and Treatment Diagnosis will be made with a history, physical, and an EKG, which confirms the presence of AF. An echocardiogram is also important to evaluate cardiac structure and function. Labs will include electrolyte, renal, and hepatic analysis; thyroid panel; and a CBC. Additional tests can include additional rhythm monitoring (e.g., telemetry or Holter monitoring), and a chest X-ray to reveal pulmonary disease (e.g., pulmonary edema) or cardiac disease (e.g., enlargement). A transesophageal echocardiogram is ordered to evaluate for left atrial (LA) thrombi or to determine risk of LA thrombi development. Exercise testing is done to evaluate rate control.

Electrophysiologic studies may be conducted to evaluate for other arrhythmias that occur with AF such as atrial tachycardia or to determine sites for ablation.

Management of AF involves rate control and/or rhythm control as well as anticoagulation for stroke prevention. Rate control can be achieved with beta adrenergic blocking agents, calcium channel blockers, and cardiac glycoside (e.g., digoxin). Amiodarone can be considered in those who do not respond to the other agents. Rhythm control involves cardioversion, AV nodal blocking agents (e.g., calcium channel blockers), and ablation. Antiarrhythmics can be used to attempt to convert AF to sinus rhythm. The CHA2DS2-VASc score can be calculated to evaluate the risk of ischemic stroke in patients with AF. CHA2DS2-VASc stands for congestive heart failure, hypertension, age, diabetes mellitus, sex, and vascular disease history. Each criterion is given a point value, and the higher the score, the more likely the risk of thromboembolism. The score can be used to determine the need for anticoagulation. Most patients will need anticoagulation. A direct thrombin inhibitor (e.g., dabigatran) or factor Xa inhibitor (e.g., rivaroxaban or apixaban) is used if they have nonvalvular AF. Warfarin can be used as an alternate and in those with valvular AF. Aspirin combined with clopidogrel is not as efficacious but is another option. Stroke prevention can also be accomplished with percutaneous occlusion or surgical excision of the left atrial appendage. Pacemakers and implantable cardioverter- defibrillators can be implanted to prevent AF. Treatment strategies will include avoidance of factors that caused or contribute to AF such as alcohol cessation and weight loss.

Heart Failure Heart failure is a condition in which the heart has a problem with ventricular filling or ejection, which then leads to a decreased cardiac output and inadequate perfusion. These problems occur due to structural or functional impairment. Heart failure is the consequence of many disorders, but the most common risk factors include hypertension, metabolic syndrome, diabetes mellitus, and atherosclerotic disease. One of the top causes of death from cardiovascular disease is heart failure, with a 50% death rate usually occurring within 5 years of diagnosis (American Heart Association, 2017). Heart failure incidence increases dramatically after the age of 65. Heart failure is more prevalent in men, but women live longer so half of heart failure cases are in women. Both non-Hispanic Black men and women have a higher incidence and mortality from heart failure than non-Hispanic Whites, which correlates with the higher incidence of hypertension, diabetes mellitus, and obesity seen in this population. More people are surviving and living longer with heart disease such as MI or valve disease because therapies are better. These diseases, however, can lead to heart failure, so the incidence of heart failure is rising.

Heart failure is often called congestive heart failure; however, this term has

become less commonly used as many patients with heart failure do not exhibit manifestations of volume overload (congestion). Heart failure is often categorized as systolic or diastolic heart failure, but many patients have normal ejection fraction (EF), meaning there is no systolic dysfunction. Therefore, two categorizations for heart failure are preferred—heart failure with reduced EF (HFrEF) for systolic dysfunction and heart failure with preserved EF (HFpEF) for diastolic dysfunction. These two categories are used for left-sided heart disease. Right-sided heart failure is a result of right ventricle impairment and is most often a consequence of left-sided heart failure. Right ventricle impairment can also occur with pulmonary diseases that cause pulmonary hypertension and this is termed cor pulmonale (i.e., pulmonary heart disease). The term cor pulmonale is generally not used when the right-side dysfunction is due to left-sided heart failure. Right-sided heart failure can also be the result of other disorders that cause pulmonary hypertension such as, pulmonic and tricuspid valve stenosis. Most people with heart failure will present with clinical manifestations due to dysfunction on the left and right, and many people also have elements of systolic and diastolic dysfunction.

Causes of HFrEF and HFpEF are different but often overlap. The most common causes of either type of heart failure are coronary artery disease (60–75%) and hypertension (75%). Valvular disorders, cardiomyopathy, myocarditis, fibrosis (e.g., sarcoidosis and amyloidosis), and chronic dysrhythmias are other cardiac causes of heart failure. Noncardiac causes include drug effects such as anticancer drugs, antidiabetics, and appetite suppressants, chronic lung diseases, anemia, thyroid disorders, and thiamine deficiency (beriberi). Rheumatic heart disease and Chagas disease are frequent causes of heart failure in other countries. HFpEF is more prevalent in older women with hypertension. Other common risks more frequently seen in patients with HFpEF are diabetes, obesity, coronary artery disease, and dyslipidemia.

Several compensatory mechanisms are activated in times of decreased cardiac output (FIGURE 4-20). Initially, the SNS is stimulated with catecholamine release (epinephrine and norepinephrine), which causes vasoconstriction, increases heart rate, contractility, and antidiuretic hormone secretion. With SNS stimulation and decreasing cardiac output, renal perfusion decreases, which activates RAAS. Renin, angiotensin, and aldosterone are released, which leads to fluid retention, vasoconstriction, cell hypertrophy, cell death, and myocardial fibrosis. These compensatory mechanisms increase cardiac output in the beginning, but they eventually lead to excessive preload and afterload. The compensatory mechanisms eventually become inadequate to meet the body’s metabolic needs, and excessive myocardial oxygen demand and an increased preload result in decreased contractility and decompensation. Left ventricle (LV) remodeling refers to changes in the mass, volume, and shape of the heart and occurs in response to decompensation and injury. The remodeling includes myocyte loss, decreased

contractility, loss of support structure, LV dilation, and hypertrophy. Beta-adrenergic desensitization (so there is less response) occurs and cellular metabolic processes are affected. In addition to the SNS and RAAS stimulation causing remodeling, other contributors of remodeling include inflammatory cytokines such as endothelin (vasoconstrictor), tumor necrosis factor, and reactive oxygen species. Systolic function is impaired, and EF declines to ≤ 40% (HFrEF), making heart failure clinical manifestations more evident.

FIGURE 4-20 Course of heart failure. ACE- angiotensin converting enzyme

ADH- antidiuretic hormone

ARNI- angiotensin receptor-neprilysin inhibitor

ARBS- take off the S and then it stands for angiotensin receptor blocker

CHF- change both to HF and then it stands for heart failure

LV- left ventricle

SNS- sympathetic nervous system

In patients with HFpEF, systolic function is mildly impaired to normal (i.e., preserved) and stroke volume and cardiac output are maintained, and so the EF is > 40%. The dysfunction in HFpEF is during diastole with decreased ventricle filling from abnormal myocardial relaxation and decreased compliance (stiffness). Up to 50% of left heart failure is categorized as HFpEF. Most patients have a combination of both.

Clinical Manifestations Heart failure can present as an acute or chronic problem. Acute heart failure can be new onset of HF or an exacerbation of worsening chronic heart failure. Acute heart failure may be related to a temporary condition and can resolve with treatment of that condition. Chronic heart failure, in contrast, is a progressive condition with exacerbations.

The clinical manifestations of heart failure depend on the side affected and on the severity. The manifestations of right-sided failure reflect systemic fluid accumulation , while left-sided failure is characterized by pulmonary fluid accumulation (TABLE 4- 3). Left-sided symptoms are a result of ineffective left ventricular contractility. As cardiac output falls, blood that is not being pumped into the body backs up first in the left atrium and then in the pulmonary circulation, leading to pulmonary congestion. Main complaints are dyspnea with exertion and fatigue. As the disease worsens, symptoms start to occur with less activity and even at rest. Orthopnea (shortness of breath when supine) is a late symptom and occurs due to fluid shifts from the peripheral to the central circulation. The fluid shifts occur while in a supine position and results in increased pulmonary pressure. Increased pressure around bronchial vessels and the increased airway resistance causes paroxysmal nocturnal dyspnea. Paroxysmal nocturnal dyspnea symptoms include coughing and wheezing that wake patients up at night. If blood continues to accumulate, pulmonary edema and right- sided heart failure will develop. Right-sided heart failure is a result of ineffective right ventricular contraction. Because of this condition, blood does not move appropriately out of the right ventricle. Blood backs up first in the right atrium, and then the peripheral circulation, causing increased pressures in the peripheral capillary bed.

The patient begins to gain weight, as fluid is not excreted by the kidneys. Tissue becomes edematous, as pressures in the capillaries push fluid out of the circulatory system. Most patients have a combination of left- and right-sided heart failure and therefore manifestations will reflect a combination of both.

TABLE 4-3 Clinical Manifestations of Left- and Right-Sided Heart Failure

Left-sided heart failure Right-sided heart failure

Basic effects Decreased cardiac output and pulmonary congestion

Decreased cardiac output and systemic congestion

Key manifestations Pulmonary congestion, dyspnea, and activity intolerance

Edema and weight gain

Forward effects (decreased output)

Fatigue, weakness, dyspnea, exercise intolerance, and cold intolerance

Fatigue, weakness, dyspnea, exercise intolerance, and cold intolerance

Compensations Tachycardia, pallor, secondary polycythemia, and daytime oliguria

Tachycardia, pallor, secondary polycythemia, and daytime oliguria

Backup effects Symptoms: orthopnea, cough, shortness of breath, paroxysmal nocturnal dyspnea, hemoptysis Signs: inspiratory crackles, wheezing, hypertension or hypotension, S3 gallop, cyanosis, mitral/tricuspid murmur

Symptoms: anorexia, early satiety, nocturia, headache Signs: dependent edema in feet/ankles, sacral area, hepatomegaly, splenomegaly, ascites, distended neck veins, S4 gallop

Modified from Story, L. (2017). Pathophysiology: A practical approach (3rd ed). Burlington, MA: Jones & Bartlett Learning.

Diagnosis and Treatment The American College of Cardiology and the American Heart Association have a classification system based on stages (A–D) to determine the severity of the heart failure and identify treatment strategies. Patients at stage A are at risk, and patients at B have structural disease but no symptoms yet. Patients in stage C and D have clinical heart failure. Once patients are staged, they cannot go backwards. For example, they can go from A to B but never back to A. Another common classification system is for patients who already have heart failure symptoms (i.e., stage C or D). This system—New York Heart Association classes (I–IV)—is used to evaluate functional capacity symptoms of heart failure with activity. Patients can go back and forth with New York Heart Association classes (i.e., III–II or I–II).

Diagnosis, staging, and class determination are based on a history and physical and diagnostic tests. These diagnostic tests will include an echocardiogram to evaluate function and causes. A brain natriuretic peptide or N-terminal pro brain natriuretic peptide, which is a hormone released by the ventricles in response to

overstretching, will be measured. A chest X-ray may reveal signs of fluid retention such as pleural effusions and vascular congestion. Thoracic ultrasonography can be used at the bedside in those who are critically ill and in life threatening situations where imaging is needed immediately. Thoracic ultrasonography can be used to evaluate for acute cardiopulmonary respiratory failure, pleural effusion, and pneumothorax. A 12-lead EKG may expose causes and coexisting disorders that occur with heart failure such as atrial fibrillation and myocardial infarction, but no finding is specific to heart failure. Other routine labs include urinalysis, CBC, a chemistry profile with calcium and magnesium, lipid panel, liver function, and thyroid- stimulating hormone evaluation. Other additional blood work may be ordered if there is suspicion of certain causes of the heart failure (e.g., HIV, hemochromatosis). With patients who are hospitalized, additional tests may include a troponin test, arterial blood gases, cardiac catheterization, and myocardial biopsy depending on causes and status.

Management of heart failure begins with identifying and treating the underlying causes and managing comorbidities that contribute to worsening heart failure. Additional strategies include lifestyle modification (e.g., weight reduction, tobacco cessation, reduced salt consumption, fluid restriction, and exercise). Pharmacotherapeutic agents that are mainstays for HFrEF are angiotensin- converting enzyme (ACE) inhibitors (to stop the renin–angiotensin–aldosterone cycle), angiotensin receptor blockers (ARBs), or an angiotensin receptor neprilysin inhibitors (ARNIs). The latest pharmacologic addition, ARNIs, are a combination of an ARB with an inhibitor of the enzyme neprilysin. Neprilysin causes the breakdown of beneficial natriuretic peptides, which help to maintain fluid homeostasis; by inhibiting the breakdown, natriuresis can occur. All patients with heart failure should be on either an ACE, ARB, or ARNI and a selective beta-1–adrenergic blocking agent or an alpha-1, beta-1, beta-2 receptor blocker (to slow the heart rate and thereby increase diastolic filling). Not all beta blockers are effective (e.g., short- acting metropolol) and reviewing the latest guidelines is important. Ivabradine, which blocks If (one of the current systems in the SA node), can be used with a beta blocker to reduce the heart rate. Additional medications can be added depending on circumstances and can include diuretics (preferably loop diuretics, which act at the loop of Henle to prevent sodium or chloride reabsorption), which are used for patients with volume overload. For those patients with persistent symptoms, hydral- nitrates hydralazine and isosorbide dinitrate (vasodilators) can be added and are particularly useful in Blacks with heart failure. Aldosterone receptor agonists such as spironolactone can be considered in select patients (e.g., New York Heart Association stage II–IV with EF < 35%). Aldosterone agonists act at distal tubules as opposed to the loop diuretics, but the results are the same with diuretic effects through Na+, Cl-, and water excretion. Inotropic agents (increase myocardial contractility) such as digoxin can be used. Milrinone (phosphodiesterase inhibitor)

and dobutamine (adrenergic agonist) are examples of two inotropic agents that can be administered as an intravenous continuous infusion for heart failure. These medications can be for short- or long-term use. Certain categories of pharmacotherapeutics are often used in cardiovascular diseases or other disorders that have no benefit or can even worsen heart failure. These medications include calcium channel blockers, which can depress contractility. Nonsteroidal anti- inflammatory drugs (NSAIDs), which are sold over the counter and often prescribed for pain, can cause Na+ and water retention. Unfortunately, treatment guidelines for HFrEF have not been as effective or adequately evaluated in patients diagnosed with HFpEF. Treatment of HFpEF is mainly focused on managing blood pressure, symptoms, and risk factors.

Device therapy for HF can include implantable cardioverter-defibrillators and a biventricular pacemaker (i.e., cardiac resynchronization therapy). As patients worsen and/or decompensate, additional therapy may include advanced therapies such as ultrafiltration (volume overload), potent vasoconstrictors (e.g., vasopressin antagonists), intra-aortic balloon pump, and other methods to support cardiovascular decompensation. Mechanical circulatory support can be achieved with the use of ventricular assist devices (FIGURE 4-21), which act as a pump to circulate blood and can be used temporarily while the patient recovers and/or awaits a heart transplant. Ventricular assist devices can be used as destination therapy (until removal or death) for those who cannot get a transplant, and they can live long-term with the device.

FIGURE 4-21 Left ventricular assist device.

Congenital Heart Defects Congenital heart defects (CHD) include a number of structural issues that may be

present at birth, affecting 1% of live births in the United States (NIH, 2011). CHDs are the most common type of birth defects and a leading cause of infant death and illness (CDC, 2019b). Some CHDs will not be present until adulthood. Some defects are asymptomatic and found only during routine examination. Due to advances in treatment, adults with CHD now outnumber children with CHD (Triedman & Newburger, 2016). The structural and functional impairments can range from simple to complex and involve the myocardium, heart valves, and vessels near the heart. According to the AHA (2017), there are 18 recognized distinct CHDs. Ventricular septal defects are the most common type, accounting for up to 34% of all CHD. Examples of congenital heart defects include the following conditions (TABLE 4-4):

TABLE 4-4 Congenital Heart Defects

*Disorder from most to less common (all ≥ 5% incidence). Incidence statistics vary slightly depending on source. LA, left atrium; RA, right atrium; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; PA, pulmonary artery; RV, right ventricle; LV, left ventricle; VSD, ventricular septal defect; htn, hypertension; AV, atrioventricular; PFO, patent foramen ovale; ASD, atrial septum defect; ↓, decreased; ↑, increased.

Septal defects—holes in the wall that separates the atria (ASD) and ventricles (VSD), including patent foramen ovale (PFO), an opening between atria fails to close (FIGURE 4-22)

FIGURE 4-22 Ventricular septal defect.

Patent ductus arteriosus (PDA)—failure of the ductus arteriosus, the vessel between the aorta and the pulmonary artery, to close after birth Valve disorders (e.g., stenosis, atresia, regurgitation) Coarctation of the aorta—narrowing of the aorta Transposition of the great arteries—the aorta and the pulmonary artery are switched in position Tetralogy of Fallot—a combination of pulmonary valve stenosis, a large ventricular septal defect, misplacement of the aorta directly over the ventricular

septal defect, and right ventricular hypertrophy

Heredity may play a role in some heart defects. Genetic abnormalities are presumed to be present in most congenital heart disease. In addition, some genetic disorders (e.g., Down syndrome), fetal exposure to tobacco and certain medications (e.g., oral retinoid for acne), and maternal health status (e.g., preexisting diabetes, obesity) can cause and increase the risk of congenital heart disease.

The defects can cause alterations in blood flow with abnormal shunting of blood (FIGURE 4-23) through abnormal opening (e.g., septal defects) or through normal fetal openings that did not close. Some defects do not shunt blood but alter blood flow due to obstructions (e.g., stenotic valves, aortic narrowing). Abnormal flow can occur due to large vessel defects or abnormal attachments (e.g., transposition of great vessels). Some defects cause cyanosis while others are acyanotic. Some defects are a mixture of shunting and obstructions (e.g., tetralogy of Fallot).

1. 2. 3. 4. 5.

FIGURE 4-23 Blood flow patterns in common congenital abnormalities. The patent ductus arteriosus is a description for the image which it is under.

Clinical Manifestations Various clinical manifestations may be present and are dependent on the type and severity of the defect (Table 4-4). General manifestations may include a heart murmur, dyspnea, tachypnea, fatigue, chest pain, or difficulty gaining weight. With VSD and ASD, a murmur may not be detected until 2 weeks after birth when the pulmonary vascular resistance (PVR) normally decreases. The ventricular and atrial chamber pressures are higher than the PVR, and a murmur from shunting through the defect can be heard. Some defects cause shunting of oxygenated blood to deoxygenated blood (left to right side shunt) and an increase in pulmonary blood flow; these defects are generally considered acyanotic (e.g., VSD, ASD, PDA). Some defects cause a shunting of deoxygenated blood to oxygenated blood (right to left side shunt) and a decrease in pulmonary blood flow; these defects are considered cyanotic (e.g., tetralogy of Fallot). Obstructive lesions (e.g., coarctation of the aorta, pulmonary stenosis, aortic stenosis) do not generally cause shunting but rather flow is decreased to the respective outflow tract. Obstructive defects often lead to heart failure, hypotension, and if on the right side (e.g., pulmonary stenosis) pulmonary congestion and cyanosis can be present. Murmurs in obstructions are created by the turbulent flow through the narrowed valve or vessel.

BOX 4-2 Application to Practice You are examining a 5-week-old infant and hear a systolic murmur at the lower left sternal border. You suspect a ventricular septal defect. The parents are concerned and have several questions.

What is the cause of a ventricular septal defect? What problems will our baby have due to his VSD? How does the defect create these problems? What diagnostic tests will be ordered? What treatment will our baby need?

Diagnosis and Treatment Diagnostic procedures for congenital heart defects include a history, physical examination, fetal ultrasound, echocardiogram, EKG, chest X-ray, cardiac

catheterization, or cardiac magnetic resonance imaging (MRI). Treatment depends on the type and severity of the defect. Strategies may include repair with a heart catheterization or with surgery. Surgeries may include dilating narrowed openings (e.g., valve stenosis), closing defective openings (e.g., VSD/ASD), cutting away defective areas (e.g., coarctation of the aorta, PDA), reattaching vessels (e.g., transposition of the great arteries), or heart transplant. Medications are used to manage symptoms and complications (e.g., diuretics, antidysrhythmic agents, antihypertensives). Additional measures such as mechanical ventilation and inotropic support may be necessary to support cardiovascular function. The ductus arteriosus normally closes completely by 21 days or less. In some CHD cases, it may be preferable to close the ductus arteriosus sooner; however, it is preferable that the ductus remain open for longer in other circumstances. Prostaglandin can be used to keep the ductus arteriosus open, and inhibition will lead to closure.

Impaired Tissue Perfusion: Vascular Disorders Vascular disorders can be divided into arterial and venous disorders, and they can occur in peripheral or coronary vessels. Categorizing the disorders in this manner will help with understanding the underlying mechanisms and consequences of the vascular injury. Dyslipidemia is a common culprit, causing arterial disease and subsequent atherosclerosis. Arterial and venous abnormalities can significantly impair tissue perfusion and create an environment for thrombus formation and potential embolization.

Arterial Disorders Aneurysms Walls of arteries can weaken, and areas can balloon outward, a condition known as aneurysm (FIGURE 4-24). This weakening happens much like a worn spot on a tire or a bulge in an old balloon. Just like the tire and the balloon, an aneurysm can rupture when the pressure builds inside the wall or when the wall becomes too thin. When it ruptures, blood spills out of the circulatory system, also known as exsanguination. Aneurysms may also develop slow leaks as opposed to rupturing. Aneurysms can occur in any artery, but some common locations include the aorta, particularly the abdominal and thoracic areas, and intracranial vessels. Other areas are the femoral and popliteal arteries. Intracranial aneurysms will be discussed in chapter 11.

FIGURE 4-24 Aneurysm. This X-ray shows a ballooning of one of the arteries in the brain. If untreated, an aneurysm can rupture, causing a stroke.

© wenht/iStock/Getty Images.

The most common causes of aneurysms are atherosclerosis and hypertension. Atherosclerosis and subsequent plaque formation reduce elasticity and cause erosion. Blood traveling through narrowed arteries, like in hypertension, causes a lot of force on the arterial walls, leading to weakening and potential aneurysm development. Other factors that increase the risk of developing an aneurysm include genetic predispositions and congenital disorders (e.g., Marfan syndrome). Disorders that damage the arterial walls such as dyslipidemia and tobacco usage can lead to aneurysms. Diabetes mellitus, although associated with atherosclerosis, in epidemiologic studies has been inversely associated with the risk of aneurysm development. The reason for this inverse relation is unclear but theories include possible protective effects from antidiabetic agents (e.g., metformin). Injury (e.g., trauma) and infections (e.g., syphilis) can also cause aneurysms. The incidence of aortic aneurysms increases with age (> 65 years), and prevalence is higher in men.

True aneurysms are those that affect all three layers of the vessel. Two major types of true aneurysms exist—saccular and fusiform (FIGURE 4-25). The most common site of true aneurysms is the abdominal aorta. A saccular aneurysm is a

bulge on the side of the vessel. A fusiform aneurysm affects the entire circumference of the vessel. A false aneurysm, in contrast to true aneurysm, does not affect all three layers of the vessel but occurs when there is vessel damage. The damaged vessel causes blood to leak into the surrounding area (e.g., hematoma) or the injury leads to blood traveling and splitting the media layer. This splitting is known as a dissection (FIGURE 4-26). The larger the aneurysm, the greater the likelihood of rupture.

FIGURE 4-25 Types of aneurysms.

FIGURE 4-26 Aortic dissection. Courtesy of Dr. Donald Yandow, Department of Radiology, University of Wisconsin School of Medicine and Public

Health.

Clinical Manifestations Clinical manifestations of aneurysms may vary based on their location. Most aneurysms are asymptomatic until they rupture. Before rupture, thoracic aorta aneurysms can cause pressure around surrounding areas such as the lungs and esophagus. This pressure causes dysphagia, chest pain, dyspnea, and cough. Abdominal aorta aneurysms may cause a pulsating abdominal mass as well as flank and back pain. Once an aneurysm rupture occurs, symptoms intensify (e.g., severe pain, worsening dyspnea) and cardiovascular collapse can occur due to life- threatening bleeding.

Diagnosis and Treatment Diagnosis of aneurysms often occurs incidentally during a routine physical examination or during imaging studies (e.g., X-ray) done for other purposes. If clinical manifestations are present, diagnostic procedures are necessary to confirm the diagnosis and can include an echocardiogram, CT, MRI, and arteriography (i.e., angiography). The goal of treatment is to prevent rupture or limit expansion by eliminating or treating causes (e.g., controlling blood pressure). Management of cardiovascular risk factors can include statin and antiplatelet therapy. Smoking cessation is crucial as there is a high association of rupture with continuation of smoking. The presence of symptoms with an aneurysm increases the chance of rupture and surgical repair is often indicated. Even in the absence of symptoms

surgical repair may be indicated. As an example, if an aortic aneurysm has a diameter greater than 5 cm, surgery may be done to prevent rupture even in an asymptomatic patient. The larger the aortic aneurysm, the higher the risk of rupture. There is a high mortality once rupture occurs, and immediate surgery is required. Screening for abdominal aortic aneurysm is recommended for men ages 65–75 years who have smoked or have a family history.

Dyslipidemia Dyslipidemia, or hyperlipidemia, refers to an elevated level of lipids in the blood. These lipids include cholesterol and triglycerides (fats) and phospholipids. While cholesterol and fats are different types of lipids, the term cholesterol is often used in place of lipids and/or used interchangeably with fats. High lipid levels are associated with an increased risk and severity of cardiovascular diseases such as atherosclerosis, coronary artery disease, hypertension, and stroke. In the United States from 2013 to 2016, a total of 27% of people over the age of 20 had high cholesterol levels (i.e., ≥ 240 mg/dL) or were taking a cholesterol-lowering medication (CDC, 2017). Of the 27% total, approximately 29% were males and 25% were females. The prevalence of high cholesterol among those 6–19 years of age in the United States from 2011 to 2014 was 7.4% (CDC, 2019). In the younger age group, girls had a higher incidence than boys. In both the young and old, obesity is associated with a higher cholesterol level.

Lipids are not soluble in water or plasma, and while some lipids are hydrophobic, others have a hydrophilic component (e.g., phospholipid). For the lipids to be transported around the body, they have to be bound to a carrier protein such as an apolipoprotein. The bound lipids are termed lipoproteins. Lipids are important in providing and storing energy, cellular membrane composition, steroid hormone production (e.g., testosterone, estradiol), and production of bile acids.

Lipids are introduced into the bloodstream in two ways—diet and liver production (FIGURE 4-27). Dietary cholesterol is found in animal products, and dietary triglycerides are found in saturated fats (e.g., fried foods and cakes). Often the foods high in fats are also high in cholesterol. The human liver makes more cholesterol than the body could possibly use, so even though cholesterol is necessary for survival, eating it is not necessary. When dietary fats and cholesterol are ingested, they are transported around by chylomicrons (bundles of lipoproteins). These chylomicrons are found in the small intestine. The chylomicrons consist primarily of triglycerides (> 80%), and the remainder are phospholipids, cholesterol, and protein. Chylomicrons’ role, therefore, is to supply the tissues with fat from dietary ingestion. Remnants of chylomicrons are transported to the liver. In the liver, several lipoproteins are synthesized. Lipoproteins are classified according to their density. This density is based on the number of triglycerides, which are low in density, versus

the number of proteins, which are highly dense (FIGURE 4-28 and FIGURE 4-29). In other words, triglyceride number and degree of density are inversely proportional. The main classes of lipoproteins are chylomicrons, very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), intermediate-density lipoproteins (IDLs), and high-density lipoproteins (HDLs). The highest triglyceride level (i.e., low density) starts with the chylomicrons and the level of triglyceride diminishes in the following order: VLDL, LDL, IDL, HDL. The most significant of these lipoproteins in terms of cardiovascular injury and protection are LDL and HDL.

FIGURE 4-27 Transportation of lipids in the blood.

FIGURE 4-28 Low-density lipoprotein and key protein, cholesterol, phospholipid, and triglyceride.

FIGURE 4-29 High-density lipoprotein and key protein, cholesterol, phospholipid, and triglyceride.

T

L

There are primary and acquired dyslipidemias. Acquired dyslipidemia is more common and development is usually polygenic and influenced by environmental factors (e.g., diet, obesity). Primary dyslipidemia is inherited and monogenic, and is often not related to external factors such as diet and it is not as common as acquired dyslipidemia. The primary dyslipidemias include disorders of triglycerides, apolipoproteins, cholesterol, or a combination. The most common primary dyslipidemia is hypercholesteremia, which is usually a result of LDL receptor mutation and defects in breakdown.

Learning Points

Triglycerides riglycerides are fats in blood. Fat is mainly stored in adipose tissue. Triglycerides are made of glycerol and three fatty acid chains. The fats can be saturated (have more hydrogen bonds) or unsaturated (have fewer

hydrogen bonds). An unsaturated fat can be further divided into either monounsaturated and polyunsaturated. So what does this all mean in terms of lipids and diet? Saturated fat molecules are tightly packed, making them solid at room temperature. So think of butter, cooking lard, and cheese. Saturated fats are also high in animal products (meat and dairy) and plant-based oils such as coconut and palm kernel oil. Saturated fats have been associated with higher cholesterol levels, heart disease, stroke, and diabetes. Healthier types of fats are those that are monounsaturated or polyunsaturated. Examples of monosaturated fat sources include olive, canola, peanut, and sesame oils (nontropical oils) that are all in liquid form at room temperature. Monounsaturated fats are also found in avocados, peanut butter, and other nuts and seeds. Polyunsaturated fats are found in walnuts, soybeans, corn oil, sunflower, and tofu. Omega-3 and omega-6 fatty acids are types of polyunsaturated fats that can only come from dietary sources (i.e., essential fatty acids) and are found in sources such as salmon, chia, and flaxseed. Trans fats are actually unsaturated fats that are naturally found in small amounts in some food products (e.g., meats and dairy), and when consumed in small quantities, do not have negative health effects. However, trans fats have been produced artificially to make liquid vegetable oils more solid, resulting in a high quantity of trans fats in many food products (e.g., fried foods, doughnuts, cookies, icings, and processed snacks). Foods made with trans fats can be stored longer and are inexpensive to use, and trans fats add flavor and texture to food. Trans fats have a more negative impact on health than saturated fats, but both raise cholesterol levels as well as increase risk for heart disease, stroke, and diabetes. Trans fats are banned in cooking products in several parts of the United States. All fats, regardless of type, contain approximately 9 calories per gram. While there are many diets proposing a high fat consumption, recommendations from the American Heart Association (2014) are to reduce and replace saturated and trans fats for healthier monounsaturated and polyunsaturated fats.

Learning Points

Cholesterol DL is known as the” bad” cholesterol. because the small, dense molecules of LDL are damaging. Most serum cholesterol is made up of LDL. You can remember LDL as the “lousy” cholesterol. Because it is the

bad cholesterol, you want the LDL level as low as you can get it. Ways to decrease LDL through lifestyle modifications include dietary changes such as avoiding high-cholesterol, high-fat foods.

HDL is known as the good cholesterol because it assists in removing some of the cholesterol from the bloodstream. You can remember this point by considering it the happy cholesterol. Because it is the “good” cholesterol, you want the HDL level as high as you can get it. Ways to increase HDL through lifestyle modifications include tobacco cessation and exercise.

Clinical Manifestations Dyslipidemia is often asymptomatic until it develops into other diseases (e.g., atherosclerosis, coronary artery disease, or stroke). At that point, the symptoms are related to those diseases. Cholesterol screening and lipid profiles can identify specific lipid abnormalities. Further testing (e.g., angiography, ultrasound, and nuclear scanning) can be conducted to determine the development of other diseases and complications.

Diagnosis and Treatment Diagnosis can be made by laboratory analysis of a comprehensive lipid panel. Other diagnostic tests that can be used to aid in cardiovascular risk identification or in determining treatment options include the ankle brachial index, calcium score, and inflammatory markers such as C-reactive protein and lipoprotein-associated phospholipase-A2. The goal of treatment is to normalize lipid levels and prevent complications. The commonly used clinical guideline for cholesterol management has been developed and updated by multiple organizations such as the American College of Cardiology and the American Heart Association (Grundy et al., 2018). Treatment regimens to lower lipid levels include lifestyle modifications such as consumption of low-cholesterol, low-fat foods, routine exercise, and weight reduction. Pharmacologic treatment is predominantly based on LDL levels and other clinical criteria (e.g., cardiovascular disease or risk). Pharmacologic agents should be initiated in all patients over 21 years old with clinical atherosclerotic cardiovascular disease (ASCVD) and in those with LDL levels ≥ 190 mg/dL. Examples of ASCVD include angina, myocardial infarction, peripheral artery disease, stroke, or transient ischemic attack. For those between the ages of 40 and 75 years who have diabetes mellitus and/or atherosclerotic risk (i.e., > 5%), pharmacologic therapy may be necessary in addition to lifestyle modifications. Atherosclerotic risk can be calculated using age, sex, race, blood pressure, total cholesterol, LDL and HDL levels, history of diabetes, and hypertension. Online calculators (e.g., www.cvriskcalculator.com/) and mobile applications can be used to provide a risk calculation. In patients under 21 years old and in those over 75 years, risk of cardiovascular disease and pharmacologic versus benefits must be individually evaluated.

While a wide range of lipid-lowering pharmacologic agents exists, pharmacologic treatment primarily focuses on use of HMG-CoA reductase inhibitors (also known as statins). HMG-CoA reductase is an enzyme used by the liver during the manufacture of cholesterol and inhibition will therefore decrease production. Statins also facilitate breakdown of LDL so that cholesterol can be reabsorbed. Statin therapy is either moderate or high intensity. Moderate-intensity therapy refers to lowering LDL levels by ≥ 50% (e.g., atorvastatin 10–20 mg or rosuvastatin 5-10 mg), while high-intensity therapy refers to lowering LDL by 30–50% (e.g., atorvastatin 40–80 mg or

rosuvastatin 20-40 mg). Other pharmacologic agents are not commonly prescribed but include bile acid sequestrants, cholesterol absorption inhibitors, nicotinic acid, fibrates, and omega-3 fatty acids. In 2017, the Food and Drug Administration approved a new medication, evolocumab, that works by increasing liver clearance of LDL by inhibiting the protein PCSK9. This protein usually decreases the number of receptors involved in LDL clearance, and thereby inhibition will increase the number of receptors available for LDL clearance.

BOX 4-3 Application to Practice Mr. Delano comes in to discuss the results of cardiovascular diagnostic tests. He is a 61-year-old White man with no complaints.

Past medical history: left hip osteoarthritis and gout. Past surgical history: none. Allergies: none known. Medications: allopurinol 100 mg by mouth once a day. Social history: one to two alcoholic drinks three times a week; smokes one cigar every other month;

exercises for 1 hour six times a week; retired nurse—works per diem at hospital once a week. Family history: mother, father, and one brother with hypertension; one brother with dyslipidemia. Physical exam: vital signs: temperature 98.5°F, pulse 60 beats per minute, respiration rate 20 per minute,

and blood pressure 134/67 mmHg; height 180 cm; weight; 85.5 kg; body mass index 26.3; physical exam unremarkable.

Cardiovascular diagnostics:

Lipid panel Results Optimal values

Cholesterol, total 239 mg/dL < 200

HDL cholesterol 57 mg/dL ≥ 40

Triglycerides 128 mg/dL < 150

LDL cholesterol 156 mg/dL < 100

Cholesterol-to-HDLC ratio 4.2 calculated ≤ 3.5

Non-HDL cholesterol 182 mg/dL < 130

Lipoprotein subfractions

LDL particle number 1,722 nmol/L < 1,260

1. 2. 3. 4. 5.

6.

a. b. c. d.

LDL small 258 nmol/L < 162

LDL medium 511 nmol/L < 201

HDL large 6,091 nmol/L > 9,386

Apolipoproteins

Apolipoprotein B 120 mg/dL < 80

Lipoprotein (a) 33 nmol/L < 75

Inflammatory markers

HS CRP 0.5 mg/L < 1.0

Lp-PLA2 activity 93 nmol/min/mL < 75

CT cardiac scoring screen 23 (mild amount) < 99

Lp-PLA2, lipoprotein-associated phospholipase-A2.

Answer the following questions based on this scenario:

Which of the cardiovascular diagnostic values demonstrate dyslipidemia and risk for atherogenesis? Interpret and describe lipoprotein subfractions and apolipoproteins results. Which of the cardiovascular diagnostic values are in the cardioprotective range? What lifestyle recommendations, such as diet and exercise will be made based on these results? What is his ASCVD risk score? What parameters (e.g., blood pressure) are used to calculate the risk score? In addition to lifestyle recommendations, what pharmacotherapeutics are recommended? Choose all that apply.

None Aspirin Statin Nicotinic acid

Atherosclerosis Atherosclerosis is a chronic inflammatory disease characterized by thickening and hardening of the arterial wall. The result is decreased perfusion, ischemia, and infarct. Atherosclerosis can occur in any part of the vascular system but most commonly occurs in coronary arteries, the thoracic and abdominal aorta, popliteal and femoral arteries, and carotid and cerebral arteries (FIGURE 4-30).

FIGURE 4-30 Possible complications of atherosclerosis.

Many causes contribute to atherosclerosis development, such as dyslipidemia and smoking (TABLE 4-5). Some causes are modifiable (e.g., diet, obesity) while others are not (e.g., aging, gender, family history). The innermost protective vessel

wall layer, the endothelium, is injured and becomes dysfunctional, initiating the atherosclerotic process regardless of the cause. The development of atherosclerosis proceeds through various stages (FIGURE 4-31). Endothelial injury begins early in life, progresses over time, and worsens with aging. Endothelial injury triggers the immune and inflammatory system, and the endothelial lining that is normally a protective barrier becomes dysfunctional.

FIGURE 4-31 Pathogenesis of atherosclerosis. Pathogenesis of atherosclerosis. A In the first stage, low density lipoprotein-cholesterol (LDL) is deposited in the

endothelium and undergoes oxidative modification, resulting in oxidized LDL (oxLDL). OxLDL stimulates endothelial cells to express adhesion molecules (vascular cell adhesion molecule-1 [VCAM-1], P-Selectin) and various chemokines (e.g., Monocyte Chemoattractant Protein-1 (MCP-1), Interleukin 8 [IL-8]). This leads to a recruitment of monocytes, which transmigrate into the intima and differentiate to pro-atherogenic macrophages; B Macrophages harvest residual oxLDL via their scavenger receptors and add to the endothelial activation and, subsequently, leukocyte recruitment with the secretion of Tumor Necrosis Factor α (TNF-α) and IL-6; C The

increasing plaque volume promotes neovascularization. Proliferating smooth muscle cells (SMCs) stabilize the nascent fibrous plaque. With deposition of fibrin and activated platelets on the dysfunctional endothelium that expresses tissue factor (TF) and von Willebrand factor (vWF), a pro-thrombotic milieu is formed; D Foam cells can undergo apoptosis and release cell-debris and lipids, which will result in the formation of a necrotic core. In addition, proteases secreted from foam cells can destabilize the plaque. This can lead to plaque rupture, in which

case extracellular matrix molecules (e.g., collagens, elastin, TF, vWF) catalyze thrombotic events.

Steinl, D., & Kaufmann, B. (2015). Ultrasound imaging for risk assessment in atherosclerosis. International journal of molecular sciences, 16(5), 9749-9769.

TABLE 4-5 Risk Factors for Atherosclerosis and Coronary Artery Disease

Modified from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Nitric oxide, a vasodilator produced by the endothelial cells, is diminished, leading to an inability to maintain vascular tone and antithrombotic activity (i.e., prevention of platelet adhesion). Reductions in nitric oxide additionally allow for cellular proliferation and leukocyte adhesion. LDL enters the intimal layer and becomes oxidized. Oxidation results in a change in LDL which facilitates accelerated LDL uptake by macrophages. Inflammatory cytokines and the oxidized LDL stimulate endothelial cells to release molecules (e.g., vascular cell adhesion molecule-1 and P-selectin) that lead to monocyte binding. Monocytes enter the endothelial lining and travel to the intima and become macrophages. These macrophages start ingesting LDL. The macrophages full of oxidized LDL look like foam from the sea and are termed foam cells. The foam cells are considered the early stage of the atheroma (i.e., plaque). The foam cells release cytokines (e.g., tumor necrosis factor and interleukins) and growth factors as well as leukocytes, such as T lymphocytes, are recruited. Lipid continues to accumulate in the intimal layer, forming a fatty streak. These fatty streaks develop and are evident at a young age, such as at 15 years of age. Cytokines induce more endothelial activation, and the smooth muscle proliferates into the intima. The smooth muscle cells, sensing the damage, start to form a fibrous cap made of proteins such as collagen and elastin around the fatty streak. The fibrous cap and fatty streak are what make up a fibrous plaque. Eventually, calcium and a necrotic lipid core become part of the plaque. The plaque bulges into the lumen of the artery, resulting in a smaller vessel radius, and resistance to flow is increased. The arterial walls become stiff and not as compliant. A fragile microvascular network begins supplying the plaque as it continues to grow.

The plaque may slowly cause narrowing and be stable. However, plaques can also be prone to rupturing and cause an acute obstruction, and these plaques are considered unstable. Generally, atherosclerosis and the resulting obstruction are a clinically silent disease, meaning no symptoms are apparent. When obstruction becomes significant (e.g., 70% lumen stenosis), symptoms of ischemia, such as angina or claudication, can begin to occur, particularly during increased myocardial demand (e.g., exercise). Unstable plaques can rupture without significant stenosis

and blood flow impairment. Acute vascular events, such as myocardial infarction or stroke, are usually due to plaque rupture as opposed to vessel narrowing. Platelets aggregate, the clotting cascade is stimulated, and a thrombus forms when the plaque ruptures (Figure 4-31).

Clinical Manifestations Much like dyslipidemia, atherosclerosis is often asymptomatic until complications develop. At that point, clinical manifestations will be related to those specific disorders. The various disorders are discussed elsewhere in this chapter (e.g., angina in Coronary Artery Disease section).

Diagnosis and Treatment Diagnostic procedures for atherosclerosis include tests that identify contributing factors (e.g., lipid panel, C-reactive protein, and homocysteine levels). Increased C- reactive protein levels indicate the presence of inflammation and are considered a risk factor for atherosclerosis. Other diagnostic procedures are used to determine whether complications have developed (e.g., angiography, ultrasound, and nuclear scanning).

Treatment for atherosclerosis is like that for dyslipidemia. In addition, angioplasty opens occluded arteries (FIGURE 4-32), bypass procedures detour blood around the occlusions, laser procedures disintegrate the plaque, and atherectomy removes the plaque. B-complex vitamins can help lower homocysteine levels if warranted.

H

FIGURE 4-32 Principles of angioplasty.

Peripheral Artery Disease Atherosclerosis can cause injury to any part of the vascular system, but the extremities are often affected. When the upper or lower extremities are affected, it is commonly termed peripheral artery disease. Peripheral artery disease is also the designation used to include arterial occlusive disorders due to other nonatherosclerotic disorders. Risk factors for peripheral artery disease development are similar to those for atherosclerosis, particularly factors that also affect the coronary circulation (e.g., dyslipidemia, smoking). Peripheral artery disease is a risk equivalent for the development or presence of coronary artery disease. The risk factors for peripheral artery disease include advanced age (i.e., > 70), diabetes mellitus, dyslipidemia, smoking, or other factors that increase risk for atherosclerosis, such as hypertension.

Diagnostic Link

Diagnostic Link-Homocysteine omocysteine is an amino acid commonly obtained from eating meat. High levels in the serum are associated with development of cardiovascular and cerebrovascular disorders such as development of

atherosclerosis and thromboembolic disorders. The mechanism by which high levels causes vascular disorders is unclear. Vitamins, particularly folate, vitamin B6, and vitamin B12, are necessary for homocysteine metabolism, and deficiencies can result in increased levels. Other causes of increased levels include chronic kidney disease (reduced clearance and metabolism), smoking, and certain medications such as metformin (for type 2 diabetes mellitus), methotrexate (for rheumatic disorders). Levels can be reduced with vitamin supplementation and eating a healthier diet (e.g., increased vegetables, fruit, and low fat diet). However, most research has found that reducing levels does not prevent or reduce the incidence of vascular disorders.

Clinical Manifestation Extremity peripheral artery disease is often asymptomatic. Manifestations will be present once the stenosis is sufficient to cause a decreased perfusion. Manifestations will include extremity pain (upper and lower), particularly pain that is present during physical activity and relieved with rest. This pain is termed intermittent claudication. The pain worsens with elevation of the extremity as blood is diverted away from the distal tissue. The pain improves with extremity dependence as blood then flows down to the extremity. Lower extremity peripheral artery disease pain can be in the calf (popliteal artery), thigh (femoral artery), or buttock/hip (aortoiliac artery). The pain may be unilateral or bilateral. If the aortoiliac artery is affected, the femoral pulses may be diminished, and erectile dysfunction may present. If the popliteal or femoral arteries are affected, distal pulses (i.e., pedal, posterior tibialis) will be diminished. Foot claudication may be present and indicates disease of the tibial or peroneal arteries. As occlusion worsens, manifestations may

include signs of poor perfusion such as lower extremities that are dry, cool, shiny, and hairless. Nonhealing ulcers (i.e., ischemic ulcer) may be present over bony areas and look “punched out” (FIGURE 4-33). Necrotic areas may be evident as the severity of occlusion worsens. The skin may appear whitish or bluish when elevated due to decreased blood flow and reddish when dependent due to increased blood flow. Once an occlusion becomes severe, pain may be present even at rest and cause limb pain that is diffuse rather than focal. The diffuse, acute, and, severe pain is the result of obstruction due to thrombosis. The sudden presence of the six Ps —pallor, pulselessness, paresthesia, paralysis, poikilothermia (i.e., cold), and pain are ominous findings. Urgent recognition and action, such as surgical revascularization, are necessary to save the limb.

FIGURE 4-33 Arterial insufficiency ulcer; arterial wound.

Most commonly, upper extremity peripheral artery disease presents as unequal blood pressure readings in the arms (> 15 mmHg). The collateral circulation in the

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upper arms often compensates for upper arm stenosis or occlusions, and manifestations are not as common. If present, upper extremity peripheral artery disease can have similar manifestations to lower extremity peripheral artery disease (e.g., pain that increases with activity and resolves with rest). Patients with upper extremity peripheral artery disease often have lower extremity peripheral artery disease.

Learning Points

Color Change in Darker Skin kin color changes such as pallor (whitish), cyanosis (bluish), and erythema (redness) are often signs of altered perfusion. However, the criteria are different for a person with a darker skin tone. In a darker

skinned person, pallor and cyanosis may be described as more gray (ashen) or whitish. When skin is erythematous, blanching should be evaluated by applying pressure to the skin. This pressure temporarily decreases blood flow and causes a white (blanched) area. When pressure is released, the skin color returns; hence, this area is termed blanchable. When the area is nonblanchable, the color does not become white but, rather, stays as is. Dark skin does not blanch but, rather, the skin may become darker when pressure is applied. Erythema will appear as a darker area (hyperpigmented) or lighter area (hypopigmented).

Diagnosis and Treatment Diagnosis is accomplished with a history and physical examination. The initial diagnostic test for upper extremity peripheral artery disease will be duplex ultrasound. Duplex ultrasound (combination of doppler—checks blood flow—and regular ultrasound—creates images) will reveal stenosis or occlusion. Blood pressure measurements in different arteries (i.e., segmental blood pressures) can be evaluated and used to calculate the ankle brachial index (ABI) for lower extremity peripheral artery disease or the wrist brachial index for upper extremity peripheral artery disease. The ABI is the initial diagnostic exam and is often done with a dupplex doppler ultrasound for lower extremity peripheral artery disease. The ABI is calculated by measuring the systolic pressure in the right and left brachial artery and dorsalis pedis as well as posterior tibial in a supine position. The highest foot pressure is then divided by the highest arm pressure. Doppler or plethysmographic waveforms are often done with the ABI to localize what part of the artery is affected. The ABI measurements can be accomplished at the bedside but is preferably conducted in a diagnostic center; it can be done at rest and/or after exercise. An ABI of ≤ 0.90 is diagnostic for peripheral artery disease. Angiography with computed tomography (CTA) or magnetic resonance (MRA) may be indicated depending on the severity of symptoms or if findings from other diagnostic tests are questionable. Laboratory evaluation will be the same as those for atherosclerosis and dyslipidemia (e.g., lipid panel, homocysteine, C-reactive protein).

Treatment focuses on risk reduction strategies as in atherosclerosis and dyslipidemia such as smoking cessation, weight loss, diabetes mellitus, and

hypertension management. For those with symptomatic peripheral artery disease, antiplatelet therapy with aspirin or clopidogrel are recommended to reduce other cardiovascular events (e.g., MI, stroke). Cilostazol is an antiplatelet medication but is often not tolerated due to side effects (e.g., headache, diarrhea, palpitations). Treatment will include an exercise program that consists of activities such as warm up and cool down as well as gradual increase in walking. The exercise program is efficacious when done under supervision or with guidance. Treatments may also include revascularization, angioplasty, and stenting.

Coronary Artery Disease When atherosclerosis develops in the arteries supplying the myocardium, coronary artery disease develops. Despite great advancements in treatment, cardiovascular disease (including coronary artery disease) remains the leading cause of death in the United States for men and women. Coronary artery disease accounts for most of the cardiovascular deaths (AHA, 2017). In coronary artery disease, often termed coronary heart disease, blood flow diminishes in the coronary arteries, causing subsequent oxygen reduction (i.e., ischemia) to the cardiac muscle. Coronary artery disease due to atherosclerosis is the most common cause of ischemia. Coronary vasospasm (i.e., Prinzmetal angina) is another cause of myocardial ischemia and may occur with or without atherosclerosis. Myocardial ischemia can occur under any circumstance where myocardial oxygen demand supersedes coronary supply. Normal coronary arteries are usually able to compensate when demand is increased. With coronary artery disease, the vessels may not be able to compensate, and increases in demand (e.g., hypotension, anemia, or valve disease) can cause ischemia. Myocardial ischemia is usually due to a combination of both increased demand and inadequate supply. Myocardial ischemia may or may not cause permanent damage, or infarction, to the myocardium. Coronary artery disease can also cause heart failure, dysrhythmias, and sudden death. Additional contributing factors for coronary artery disease—some modifiable and some not— are the same as those for atherosclerosis (e.g., diabetes mellitus, hypertension, and tobacco) (Table 4-5).

Clinical Manifestations Coronary artery disease clinical manifestations are a result of myocardial ischemia and are a common cause of chest pain. The term used for ischemic chest pain is angina pectoris or simply angina. Ischemia causes the sensation of angina due to an accumulation of lactic acid and metabolic waste products (e.g., reactive oxygen species, adenosine). This accumulation can stimulate nerves that correspond to the same dermatome as the heart, causing the pain to radiate to other parts of the body such as the lower jaw, neck, left arm (uncommonly right), epigastrium, and rarely, the

back. The chest pain with angina is often described as pressure, heaviness, or tightness in the center or left side of the chest. Some patients who have angina may say they do not have pain but rather discomfort or indigestion. The chest pain is often diffuse, as opposed to localized in a particular area, and often starts gradually. Angina may be accompanied by cool, clammy extremities, diaphoresis, exertional shortness of breath, lightheadedness, and fatigue. Gastrointestinal symptoms may include nausea and vomiting, belching, and indigestion. Angina is not usually described as sharp, knifelike, or aching. The pain does not increase with movement or palpation and does not worsen with breathing like with pleuritis. Physical examination may reveal no findings or increased heart rate, blood pressure, extra heart sounds (e.g., S3, S4), or murmurs.

New onset of angina (< 2 months) may present as stable or unstable. Stable angina refers to ischemia that is initiated by increased demand (e.g., activity) and relieved with the reduction of that demand (e.g., rest). In addition to activity, situations that can increase demand include a cold environment, sexual intercourse, stress, or stimulants such as cocaine. The duration of angina is often less than 5 minutes.

The angina is considered unstable when it becomes unpredictable, occurs at rest, or increases in frequency or duration (e.g., > 20 minutes). Unstable angina is considered a preinfarction state and, along with myocardial infarction, is considered an acute coronary syndrome. However, unstable angina ischemia is reversible, but once there is an infarction the tissue death is irreversible.

Prinzmetal angina (i.e., vasospastic angina or variant angina) is a type of angina that occurs due to vasospasm in the coronary arteries without atherosclerosis. The incidence is rare (2 in 100 angina cases) (AHA, 2015), and patients are likely to be younger (i.e., < 50 years). Risk factors are not the same as in other forms of angina except for smoking; however, Prinzmetal angina can occur in those with atherosclerosis. The vasospasm is a result of arterial smooth muscle hypercontractility. The vasospasm often occurs at night (e.g., midnight to early morning) due to increased vagal tone and increased sympathetic activity that occurs at night. Endothelial dysfunction such as increased oxidative stress or increased vasoconstriction from endothelin contributes to vasospasms. Manifestations are similar to other types of angina except the pain is mainly at rest and occurs at night.

Microvascular angina is caused by dysfunction in the coronary microvasculature (i.e., prearterioles and arterioles). Patients are usually younger and more often women in comparison to patients with angina from coronary artery disease. Various mechanisms are thought to cause dysfunction in these small vessels, and many mechanisms are similar to other causes of angina development such as endothelial dysfunction from smoking, hyperlipidemia, and diabetes. The small vessels have an imbalance in vasomotor tone with an increase in vasoconstriction and a decrease in vasodilation. The vessels normally affected by

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coronary artery disease may be normal with microvascular angina. Manifestations are similar to other types of angina, but pain can occur at rest or exertion and the duration of pain is at times longer.

Diagnosis and Treatment Diagnosis of coronary artery disease is often made clinically with a history consistent with angina manifestations and risk factors. Diagnostic procedures for coronary artery disease, particularly if angina is present, is an EKG. The EKG is often normal, but chronic ischemia can cause EKG changes (usually ST-segment depression). An ambulatory EKG (monitoring done over an extended period of time) can be done. Other diagnostic tests can include a stress test, which will further confirm the diagnosis of coronary artery disease and is useful in evaluating severity. Evaluating for associated risk factors includes diagnostic tests similar to those for atherosclerosis such as a lipid panel and metabolic panel. Cardiac biomarkers such as troponin will be normal if the angina is transient and intermittent. Coronary arteriography is indicated in some cases of angina to confirm and evaluate the severity of an obstruction.

BOX 4-4 Application to Practice Mrs. Jameson, a 60-year-old woman, comes into the clinic complaining of chest pain, which has occurred three to four times since her last visit 4 months ago. She describes the pain as a squeezing, substernal pressure that is worse after climbing stairs in her home. The pressure resolves after 2 minutes of rest. During the last two episodes, she felt like she had indigestion and became a bit nauseous. The last episode of chest pressure was 2 days ago.

Medications: Metformin 1,000 mg by mouth once daily Lisinopril 30 mg by mouth once daily

Allergies: none known. Social history: quit smoking 2 years ago; smoked 1 pack per day for 30 years (30 pack years); diet high in

saturated fats; says she eats whatever she wants; attempts to exercise, walks one to two times a week; widowed for 2 years.

Past medical history: htn for 10 years; type 2 diabetes mellitus for 5 years. Past surgical history: appendectomy as a child. Family history: mother died of breast cancer age 60; father died of MI age 57; no siblings. Physical examination: vital signs: temperature 98.0°F, pulse 76 per minute, respirations 20 per minute, BP

130/76 mmHg.

Answer the following questions:

What is the likely diagnosis?

2. 3.

4. 5.

What are the most common causes of this disease and which one is the most likely in Mrs. Jameson? Describe the risk factors for coronary artery disease and the mechanism by which atherosclerotic plaque develops. How does coronary artery disease lead to the symptoms Mrs. Jameson is experiencing? How is coronary artery disease different in women in comparison to men?

Treatment focuses on preventing myocardial infarction by reducing modifiable risk factors through the same strategies used to treat dyslipidemia and atherosclerosis (e.g., dietary changes, tobacco cessation, physical activity, weight reduction, stress reduction, diabetes management, hypertension control, angioplasty, bypass procedures, laser procedures, antiplatelet agents, anticoagulants, thrombolytics, and lipid-lowering medications). Medications to specifically treat the angina include nitrates, beta-adrenergic blocking agents, and calcium channel blockers to vasodilate the coronary arteries and increase the oxygen supply. Nitrates and calcium channel blockers are first-line therapy for Prinzmetal angina. Nitrates may not be as effective in patients with microvascular angina. Oxygen therapy may also be used to increase oxygen supply. Ranolazine, a sodium channel blocker, is one of a newer class of medication for angina that reduces angina and increases exercise capacity.

Myocardial Infarction Myocardial infarction (MI) is death of the myocardium from a sudden blockage of coronary artery blood flow (FIGURE 4-34). MI, like unstable angina, is an acute coronary syndrome. The acute coronary syndromes are usually the result of the sequelae of atherosclerosis—coronary artery disease whether silent or symptomatic, and persistent ischemia or obstruction (FIGURE 4-35). Risk factors for such an event include those for atherosclerosis, including dyslipidemia, diabetes mellitus, hypertension, stress, and tobacco. Death from cardiovascular disease is usually a result of cardiac damage after an MI. Every 40 seconds, a person dies of an MI (AHA, 2017). Myocardial infarction, while usually associated with coronary artery disease and plaque thrombus formation, can also occur in circumstances without coronary artery disease. Any circumstance when oxygen supply and demand are imbalanced can cause a myocardial infarction. Procedures meant to be therapeutic such as percutaneous coronary intervention, stents, and coronary artery bypass carry risks of a MI.

FIGURE 4-34 Myocardial infarction. A An overview of a heart and coronary artery showing damage (dead heart muscle) caused by a heart attack. B A cross-section of the coronary artery with plaque buildup and a blood clot. Reproduced from National Heart, Lung, and Blood Institute. (2015). What is a heart attack? Retrieved from

http://www.nhlbi.nih.gov/health/health-topics/topics/heartattack/

FIGURE 4-35 Stable angina and acute coronary syndromes.

In most cases of MI, an unstable plaque tears or ruptures, triggering platelet aggregation, the coagulation cascade, and thrombus formation (Figure 4-31). As a result, the vessel becomes occluded, and the myocardial oxygen supply cannot meet the body’s demand for oxygen. An MI occurs in progressive stages as the blood flow to the myocardium decreases. Cells can become ischemic within 10 seconds and die in about 20 minutes as the coronary blood and oxygen supplies dwindle. Cellular death proceeds from the subendocardial layer all the way through to the full heart muscle thickness (i.e., transmural). The degree and location of the infarct is dependent on several factors and includes the severity and duration of the ischemia, the artery affected, and the amount of collateral circulation. Most infarcts occur in the left ventricle, resulting in acute pump failure and risk for heart failure, cardiogenic shock, and death. With an infarction, the electrical system is also affected; therefore, dysrhythmias often develop. Just as muscle tissue is supplied by certain coronary arteries, the electrical system components, such the SA or AV node, are supplied by certain arteries (e.g., right coronary artery or left circumflex). The trigger for the MI is not always known but may be similar to those precipitating

unstable angina such as physical exertion, outside activity in cold weather, and severe emotional stress. An MI can also occur during sleep or rest.

MIs are categorized into two groups—non–ST elevation MI (NSTEMI) or ST elevation MI (STEMI) (Figure 4-34 and FIGURE 4-36). The ST segment is normally isoelectric (goes to baseline on an EKG). With myocardial ischemia with no ST elevation, there is most likely an unstable plaque that may or may not develop a thrombus. In these circumstances, partial obstruction is present, and these patients either have unstable angina or an NSTEMI. The manifestations are similar, and the distinction between unstable angina and NSTEMI can be made by evaluating cardiac biomarkers (TABLE 4-6). Unstable angina biomarkers are not elevated until hours after the onset of pain, while with an NSTEMI, myocardial damage is more severe, and necrosis occurs and biomarker elevations are quicker. The ST segment is elevated as well as biomarkers with STEMI. The occlusion in STEMI is usually complete. Some NSTEMIs and STEMIs lead to the development of a pathologic Q wave. Pathologic Q waves are wider and deeper than normal Q waves and they are a reflection of an area of tissue that is electrically dead. They can take several hours to days to develop and once present they rarely disappear. MIs can be referred to as Q wave MI (usually STEMI) or non–Q wave MI.

FIGURE 4-36 Myocardial infarction. A Sectioned heart showing myocardial infarction of the posterior left ventricle. B Severely occluded coronary artery with calcification from an elderly woman with a fatal myocardial

infarction.

A: © SIU/Visuals Unlimited, Inc.; B: © Dr. Gladden Willis/Visuals Unlimited, Inc.

TABLE 4-6 Cardiac Biomarkers

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Clinical Manifestations Some people do not experience symptoms of MI or the symptoms are atypical and not perceived as harmful to the patient and care is not sought. Such an asymptomatic MI is known as a silent MI. The risk for a silent MI is higher in those with known coronary heart disease but the risk is even higher in persons who have diabetes mellitus, neurologic dysfunction such as neuropathy, or history of a prior MI because of decreased pain innervations. Women and the elderly are also more likely to have silent MIs. When clinical manifestations of an MI are present, they are similar to those with unstable angina. Patients who are having an MI often voice a sense an impending doom. The intensity of the pain is high, and the duration can be longer than angina (e.g., 30 minutes). MI pain does not respond to pain relief measures such as rest or sublingual nitroglycerin. The elderly who are having an MI are more likely to present with atypical symptoms such as dyspnea, weakness, syncope, palpitations, altered mental status, and confusion. Physical examination may reveal cool, moist skin, and the patient may be restless and agitated. Signs of increased sympathetic tone will be tachycardia and hypertension, and the reverse occurs with increased vagal tone—bradycardia and hypotension. Other signs will be dependent on the artery occluded, such as left ventricle dysfunction with left coronary artery occlusion. Right ventricular infarction will cause blood flow backup signs including jugular vein distention and edema. Dysrhythmias and EKG changes (Figure 4-19; FIGURE 4-37) can manifest. These changes might include bundle branch block, ventricular tachycardia, ventricular fibrillation, and asystole.

FIGURE 4-37 EKG ischemia and infarction patterns. A Normal EKG for comparison. B Mild ischemia demonstrated by inverted T wave. C Moderate ischemia demonstrated by slight ST-segment depression and inverted T wave. D and E ST-segment elevation myocardial infarction. F ST-segment myocardial infarction with

prominent Q wave indicating more severe myocardial damage.

Modified from Introduction to 12-Lead ECG: The Art of Interpretation, courtesy of Tomas B. Garcia, MD.

Diagnosis and Treatment Diagnosis of an MI is based on a history, physical examination, EKG (Figure 4-36), and cardiac biomarker result (Table 4-6). Other diagnostic tests may include stress testing, nuclear imaging, and angiography. Treatment is complex and depends on when the individual sought treatment (FIGURE 4-38).

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FIGURE 4-38 Treating an MI.

Complications are more likely to occur when MIs are not treated early and aggressively. Prognosis hinges on early identification and treatment—ideally within 90 minutes of symptom onset. Early interventions will include pain management with the use of morphine and nitrates. Antiplatelet therapy with aspirin is administered at initial presentation. Immediate reperfusion therapy (e.g., thrombolytics, percutaneous coronary intervention) should be accomplished within 30 minutes of presentation for those who meet criteria and have no contraindications. Percutaneous coronary intervention is preferred but if there is a long anticipated delay then thrombolytic therapy should be instituted. Thrombolytic therapy involves the use of agents that stimulate the activation of plasminogen to plasmin (i.e., plasminogen activators). Therapeutic fibrinolytic agents used in MI include recombinant agents such as TNK- tPA (tenecteplase), and t-PA (alteplase) and streptokinase (derived from beta- hemolytic streptococcus cultures) (Figure 4-31). Percutaneous coronary interventions include procedures such as balloon angioplasty (opens the occlusion) and stent placement (prevent abrupt artery closure) The two types of stents include drug-eluting and bare metal stents. Laser procedures (e.g., laser atherectomy) may be indicated. In certain clinical situations coronary artery bypass graft may be necessary (e.g., multivessel coronary artery disease with complex anatomy).

Antiplatelet therapy with platelet P2Y12 receptor blockers (e.g., clopidogrel)or a glycoprotein IIb/IIIa receptor inhibitor (e.g., abciximab) and other agents is indicated if angiography or percutaneous coronary intervention is undertaken. Beta blockers should be initiated within 24 hours. After that point, treatment options and ability to reverse damage become limited. After an MI, taking steps to prevent another MI through lifestyle modifications (e.g., dietary changes, tobacco cessation, physical activity, weight reduction, stress reduction, diabetes management, and hypertension control) is vital. Long-term pharmacologic treatment will include antiplatelet agents, anticoagulants, beta blockers, lipid-lowering medications, and an annual influenza vaccine. Contracting the flu can cause another MI, therefore an influenza vaccine is highly recommended.

Learning Points

Myocardial Infarction (MI) Treatment nitial treatment of an MI can be remembered using the acronym MONA:

M morphine O oxygen N nitroglycerin A aspirin

Initiating these strategies during the triage and assessment period is critical to achieve optimal patient outcomes.

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Kawasaki Disease Kawasaki disease, previously known as mucocutaneous lymph node syndrome, is a systemic vasculitis (i.e., vascular inflammation) that affects children. While considered rare, it is one of the most common types of vasculitis in children. Kawasaki disease incidence is highest in children of Asian and Pacific Islander descent; however, other races and ethnicities can be affected. Boys are more likely to be affected, and the incidence is highest in children under the age of 5.

Arteries are usually the affected blood vessels. The cause of the vessel inflammation and vascular damage is unknown but thought to be a response to a stimulus such as an infection or toxin. Since the disorder is prevalent in a specific population and in family members, genetic factors may contribute to disease development. Most cases are self-limiting and resolve within 12 days; however, serious cardiovascular complications such as coronary artery aneurysm, myocardial infarction, and heart failure can occur.

Clinical Manifestations Fever is one of the key manifestations in children with Kawasaki disease. Characteristically, the fever has a longer duration (> 5 days) than fever from other disorders. The fever is usually above 101.3°F (38.5°C) and remains high despite administration of antipyretics. Diagnostic criteria are based on fever and a combination of at least four of five criteria that may be present during this acute febrile period. These diagnostic criteria include various mucocutaneous inflammatory signs, including 1) bilateral conjunctivitis (no exudates); 2) oral mucositis with dry, cracked lips, and a strawberry tongue; 3) rash in trunk, extremities, and perineal area that is erythematous and desquamates; 4) hands/palm and feet/sole edema and erythema; or 5) cervical lymphadenopathy with one node that is at least > 1.5 cm.

Manifestations that are not part of the diagnostic criteria but may be present include arthritic joint pain usually of the knee, ankle, or hip. Cardiovascular findings may present in the acute phase (i.e., < 10 days) or after and may include abnormal heart sounds such as a gallop or muffled tones; coronary artery dilation; aneurysms of the brachial artery or the coronary artery; and reduced perfusion signs including cool, cyanotic extremities. Other nonspecific manifestations can include gastrointestinal complaints such as diarrhea, vomiting, and decreased intake. Irritability or lethargy, cough, and rhinorrhea are other manifestations.

Diagnosis and Treatment The diagnosis of Kawasaki disease is based on fever (≥ 5 days) and the presences of four out of five diagnostic criteria previously described. Laboratory findings that support the diagnosis include elevated acute-phase reactants such as estimated sedimentation rate and C-reactive protein; leukocytosis such as immature neutrophils, thrombocytosis (i.e., increased platelets), and elevated liver enzymes. An echocardiogram is done at diagnosis to evaluate cardiac status. Echocardiograms should be done routinely (e.g., at 2 and 6 weeks) to monitor for cardiovascular complications.

Initial treatment involves the administration of a single infusion of intravenous immunoglobulin and several days of aspirin to reduce the risk of cardiovascular complications. Intravenous immune globulin is most effective if administered within 10 days. Concerns about Reye syndrome with aspirin use in children must be considered. Reye syndrome, however, is usually associated with aspirin use for treatment of varicella or influenza. Recovery from Kawasaki disease is usually complete, particularly with treatment, and cardiovascular effects into adulthood are rare. Live vaccine administration should be postponed until approximately 11 months after receiving immune globulin as antibodies formed may affect the effectiveness of the vaccine.

Raynaud Disease Raynaud disease is a peripheral vascular disease not associated with atherosclerosis as with peripheral artery disease. Raynaud disease is a result of vasospasm of the small arteries and arterioles, most often of the hands, that occurs because of sympathetic (alpha-2 adrenergic) stimulation (FIGURE 4-39). The vasospasms are triggered by cold exposure and stress. The disease is more common in women and those with a family history. Smoking, vascular disorders (e.g., cardiac disorders), and migraines increase risk for development. The age of onset is in adolescence and young adulthood. Raynaud phenomenon describes the state in which such vasospasm occurs in association with an autoimmune disease (e.g., systemic lupus erythematosus and scleroderma). During episodes of vasospasms, the patient will have a “white attack,” characterized by demarcated skin pallor due to constricted blood flow. Following the pallor, the patient will have a “blue attack,” reflecting cyanosis from tissue hypoxia. The attack can last up to 20 minutes. With resolution of the attack, reperfusion causes skin color to return to normal. In addition to hand pain, patients can complain of numbness, clumsiness, and aching. Diagnosis for Raynaud disease and phenomenon is confirmed by a history and physical examination. Diagnostic tests will include nail fold capillaroscopy (performed by placing oil on periungual area and examining under an opthalmoscope) to distinguish between the disease and the phenomenon. Other

diagnostic tests (e.g., thermography, angiography) can be used to evaluate vascular responses in the distal extremities. Treatment involves minimizing cold exposure and keeping the body warm with exposure. Stress management will reduce attacks. To abort an attack, the hands can be warmed with moving or rubbing the hands or placing them under warm water. Smoking and sympathomimetics such as decongestants or amphetamines should be avoided. If nonpharmacologic agents are ineffective, calcium channel blockers can be used.

FIGURE 4-39 Raynaud phenomenon. © Twinschoice/iStock/Getty Images.

Arterial and Venous Disorders Buerger Disease Thromboangiitis obliterans, or Buerger disease, is a peripheral vascular disease not associated with atherosclerosis as with peripheral artery disease. Buerger disease can affect arteries and veins. Buerger disease is an inflammatory condition of the blood vessels in the extremities caused by smoking (FIGURE 4-40). Tobacco, particularly homemade cigarettes using raw tobacco, causes inflammation in the vessel lumen with thrombus formation. Smoking cigars or marijuana and chewing

tobacco have also been implicated in the development of Buerger disease. The incidence is more prevalent in men (up to 90%) than women (up to 30%), and the onset is around 40 years old. Clinical manifestations include ischemic pain in the distal vessels, particularly in the toes and fingers. As time progresses, proximal arteries are affected and become occluded. Usually more than one extremity is affected. Often phlebitis with nodules along an affected vein are present. Patients can have pale extremities when exposed to cold as in Raynaud disease. The extremities can develop ulcerations and gangrene from the ischemia. Diagnosis is predominantly based on history of smoking, younger age, and clinical presentation. Biopsy is only necessary in unusual presentations, but it is the only way to confirm a diagnosis. Discontinuation of all forms of tobacco use is necessary to stop the progression of the disease and significantly reduce pain. Other treatments provide symptom relief and can include vasodilators, spinal cord stimulation, and sympathectomy.

FIGURE 4-40 Thromboangiitis obliterans. © Medicimage/Visuals Unlimited, Inc.

Thrombi and Emboli A thrombus is a blood clot that consists of platelets, fibrin, erythrocytes, and leukocytes. Such clots can form anywhere in the circulatory system (TABLE 4-7). Three conditions—endothelial injury, sluggish blood flow, and increased

coagulopathy (collectively referred to as Virchow triad)—promote thrombus formation (FIGURE 4-41). When a vessel wall is injured, the endothelial damage attracts platelets and inflammatory mediators to the site, thereby stimulating clot formation. Stagnant blood flow allows platelets and clotting factors to accumulate and adhere to the vessel wall. Hypercoagulopathy states promote clot formation inappropriately. (See chapter 3 for a discussion of hematopoietic function.)

FIGURE 4-41 Virchow triad.

TABLE 4-7 Comparison of Venous and Arterial Thrombi

Venous thrombus and arterial thrombus images © James Heilman, MD. Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

The consequences of thrombus formation may include occlusion of a blood vessel or embolus development. An embolus occurs when a portion or all of the thrombus breaks loose and travels through the circulatory system, eventually becoming embedded in a smaller vessel. In addition to thrombi, any other bodies (e.g., air, fat, tissue, bacteria, amniotic fluid, tumor cells, and foreign substances) traveling through the circulatory system can become emboli.

Emboli that originate in the venous circulation, such as with deep vein thrombus, travel to the right side of the heart and then on to the pulmonary circulation, creating a pulmonary embolism (FIGURE 4-42). Superficial venous thrombosis can extend into the deeper veins and lead to pulmonary embolism. Venous thrombi are more common than arterial thrombi due to the presence of valves and a lower pressure blood-flow environment. Most emboli in the arterial system originate in the left side of

the heart and travel to other organs such as the brain and heart, causing an infarction.

FIGURE 4-42 Pulmonary embolism.

Clinical Manifestations Clinical manifestations of thrombi and emboli depend on whether they are arterial or venous as well as their location (Table 4-7). Many patients with deep vein thrombosis are asymptomatic. When manifestations are present, they include pain, edema (usually unilateral), warmth, erythema, and possibly dilated veins. Arterial thrombi can lead to ischemia of varying degrees. Manifestations of arterial thrombi will include decreased pulse and cyanosis/pallor, and edema is minimal to absent. Critical obstruction will be manifested as the six Ps (see Peripheral Artery Disease section).

Diagnosis and Treatment Diagnostic procedures will initially include Doppler ultrasound. Photoplethysmography is a noninvasive test that involves the use of an optical technique (e.g., infrared light) to measure blood flow. Other noninvasive tests can include arterial or venous angiography (CT or MRI). If there is critical ischemia, evaluation can be done with a catheter-based arteriogram or in a surgical suite.

Treatment of thrombi and emboli centers on prevention. Venous emboli require anticoagulation urgently during the first 10 days, which is the most likely time for development of recurrent thrombi. Then, patients usually require anywhere from 3 to 12 months of continuing anticoagulation, and some patients are on anticoagulation indefinitely. Choice of anticoagulation (e.g., low molecular weight heparin, factor Xa inhibitors) are weighed against the risks of bleeding. Other therapies can include the insertion of an intravenous catheter filter or direct administration of thrombolytics into the blood clot or thrombus removal (e.g., extraction, thrombectomy). When the patient has received anticoagulation, nonpharmacologic therapy can commence and includes increasing mobility, hydration, antiembolism hosiery, and sequential compression devices. These measures are the key to preventing thrombus formation. Arterial thrombi treatment includes anticoagulation, thrombolysis, and embolectomy. However, emergency revascularization is warranted in those with limb-threatening ischemia, which can occur within 4 hours. An amputation is indicated when the extremity is not viable. Compression therapy is generally contraindicated for patients with arterial disease as perfusion can worsen. Once the patient is stable and treatment has been initiated, a thorough evaluation of the etiology for the thrombus or embolus should then become the focus.

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BOX 4-5 Application to Practice Compare the following two scenarios.

Scenario 1: Mr. Fernandez is a 62-year-old man who comes into the clinic complaining of left lower leg swelling that started 5 days ago. He says the leg hurts but mainly when he walks and does not get better after rest. He denies any trauma or fever. He returned from an international trip 2 days before the swelling started. He is healthy except for hypertension, which is well controlled with a daily thiazide diuretic.

Scenario 2: Mr. Kraft is a 65-year-old man who comes in complaining of lower leg pain that he has had for the past 3 months. He says both his legs cramp up in his calves when walking. He sits down to rest and the cramps go away. He denies any trauma or fever. He has smoked 1 pack of cigarettes a day for the past 35 years. He has type 2 diabetes for which he takes metformin twice a day. Answer the following questions based on these two scenarios:

In which scenario are the history findings consistent with a venous disorder and which is consistent with an arterial disorder? What are the most likely venous and arterial disorder diagnoses? Describe the pathogenesis of these venous and arterial disorders. What would be expected physical examination findings with a venous disorder and which with an arterial disorder? Which diagnostic tests and treatment are indicated for a venous disorder? For an arterial disorder?

Venous Disorders Varicose Veins Varicose veins or varicosities, are dilated, tortuous, engorged veins (3 mm), that develop because of improper venous valve function (FIGURE 4-43). Telangiectasias (< 1 mm) and reticular veins (1–3 mm) describe the dilation of smaller veins that can develop from venous dysfunction. The enlarged veins are most commonly found in the legs, but they can also occur in the esophagus (esophageal varices), the rectum (hemorrhoids), and the vulva (usually during pregnancy). Increased venous pressure and blood pooling cause the veins to enlarge, stretching the valves. The valves become incompetent, blood flow is reversed, and venous pressure and distention are further increased. Venous pressure that is prolonged and persistent results in another venous disorder known as chronic venous insufficiency. The increased venous pressure causes the capillary pressure to increase, causing fluid and pigment to leak out, leading to edema and skin discoloration. The edema is usually pitting; it can be in the ankle area or extend to the knees and, in severe cases, the thighs. As a result, stasis pigmentation (brown skin discoloration referred to as hemosiderin stains), subcutaneous induration (thick, hardened skin), dermatitis (skin inflammation), and thrombophlebitis (vein inflammation resulting from a thrombus) can occur. The pressure caused by the edema can decrease circulation, resulting in metabolic needs not being met. Failure to meet cellular oxygen and nutrient needs can lead to necrosis and venous stasis ulcers (FIGURE 4-44).

FIGURE 4-43 Varicose vein. © Audie/Shutterstock.

FIGURE 4-44 Venous leg ulcer.

The following factors increase a person’s risk for developing varicosities:

Genetic predisposition Pregnancy (lower extremity and vulvar) Obesity Prolonged sitting or standing Alcohol abuse and liver disorders (esophageal varices) Constipation (hemorrhoids)

Clinical Manifestations

Varicose veins may be asymptomatic or are usually minor and include the following signs and symptoms: irregular, purplish, and bulging veins, edema, and fatigue as well as aching, numbness, and tingling in the legs. Manifestations may worsen with development of chronic venous insufficiency, which results in shiny, pigmented, hairless skin on the legs and feet, as well as ulcer formation. The telangiectasia and reticular veins that appear like a web of red and blue veins are commonly called spider veins.

Diagnosis and Treatment Diagnosis of varicosities is usually accomplished through visualization during physical examination. Additional tests may initially include a duplex Doppler ultrasound. Photoplethysmography and venogram are other diagnostic tests. Treatment ranges from conservative to invasive and includes the following measures:

Rest with the affected leg elevated Compression stockings Avoiding prolonged standing or sitting Exercise Sclerotherapy (injection of a sclerosing agent that produces fibrosis inside the vessel) Surgical removal Endovenous ablation (use of radiofrequency or laser energy to cauterize the vein)

Other venous varicosities (esophageal) manifestations and treatment are discussed in chapter 9.

Lymphedema Lymphedema refers to swelling, usually in the arms and legs, because of lymph obstruction (FIGURE 4-45). This swelling can occur on its own (primary) or because of another disease or condition (secondary). Primary lymphedema is rare and related to a congenital absence or decreased number of lymphatics. Secondary lymphedema is usually related to one of the following events:

FIGURE 4-45 Lymphedema. © Anthony Ricci/ShutterStock.

Surgery (when lymph nodes and lymph vessels are removed or severed, as with a mastectomy) Radiation (causes scarring and inflammation of lymph nodes or lymph vessels, restricting the flow of lymph fluid) Cancer (occludes lymphatic vessels) Infection (can infiltrate lymph vessels and lymph nodes, restricting the flow of lymph fluid) Injury (damages lymph nodes or lymph vessels)

Clinical Manifestations Clinical manifestations may not appear for months to years before edema and skin changes are evident. Patients complain of heaviness in their legs. Edema is usually pitting and improves with limb elevation. The edema may be unilateral or bilateral,

and it usually occurs in the extremities. As the disorder progresses, elevation becomes ineffective in reduction of edema, and pitting is not as pronounced as the underlying tissue becomes fibrotic and fatty. Later stages include skin changes such as hyperpigmentation, ulceration, and thickening (referred to as brawny edema). The skin begins to appear thick and rough like elephant skin (elephantiasis). Lymphedema and chronic venous insufficiency may have similar presentations and often coexist.

Diagnosis and Treatment Diagnostic procedures consist of a physical examination, MRI, CT, Doppler ultrasound, and nuclear imaging. Diagnostic testing is geared toward looking for a cause (e.g., neoplasm). Treatment of lymphedema includes the following measures:

Sequential compression devices Compression stockings Exercise Massage therapy (complex decongestive physiotherapy) Antibiotics (to treat existing infections) Benzopyrone agents (to increase lymphatic flow) Diuretics (to remove excess fluid as it returns to the circulatory system) Surgery (to remove excess skin)

Conditions Resulting in Decreased Cardiac Output and Altered Perfusion Hypertension Hypertension is a prolonged elevation in blood pressure. It is one of the most prevalent chronic health conditions in the United States, affecting 45.6% of U.S. adults (AHA, 2017); hypertension is prevalent worldwide. Hypertension is the leading risk factor for cardiovascular disease (e.g., coronary artery disease, myocardial infarction, heart failure, and stroke). The incidence of hypertension in U.S. youth age 12–19 years is 4%, which is a decline from previous statistics (CDC, 2018). The young with hypertension are more likely to be obese. Cardiovascular risk (e.g., hypertension, obesity, and diabetes) in the young often continues into adulthood. In adults and the young, hypertension is higher in non-Hispanic Blacks and Hispanics in comparison to non-Hispanic Whites. Men and boys have a higher incidence; however, the incidence in women after menopause (e.g., around 55 years old) is similar to men.

Determinants of blood pressure are cardiac output (i.e., HR × SV) and systemic vascular resistance (see Figure 4-11). These variables will change in an attempt to maintain a blood pressure adequate to perfuse tissues. Changes in any of these variables, whether transient or sustained, can result in an increase in blood pressure. In hypertension, arterial systemic vasoconstriction is sustained. The sustained vasoconstriction occurs due to a complex interaction between dysfunctional cardiovascular and renal systems, specifically the sympathetic nervous system, renin–angiotensin–aldosterone system, and plasma volume regulation. These systems become dysfunctional as a result of polygenic (i.e., multiple genetic variants) and epigenetic abnormalities as well as environmental factors including obesity and diet. Over 100 genes are involved in blood pressure regulation.

In hypertension, the cardiovascular system dysfunction includes SNS overreactivity resulting in an increased heart rate and vasoconstriction (FIGURE 4- 46). The SNS overreactivity is due to catecholamine increases and/or catecholamine receptor sensitivity. Vascular changes such as remodeling and increased insulin resistance occur as a response to the SNS overreactivity, but, in turn, these changes further stimulate the SNS. Vascular remodeling refers to changes in lumen size due to inflammation, apoptosis, and fibrosis, which causes an increase in resistance. The vascular changes also include endothelial dysfunction with imbalances in nitric oxide (vasodilator) and endothelin (vasoconstrictor). Insulin is a hormone that can have a protective or detrimental effect on the vascular system. Protective influences include such responses as vasodilation and anti-inflammatory actions. Detrimental effects include vasoconstriction, proinflammatory effects, and Na+ retention. These insulin effects are altered in hypertension.

FIGURE 4-46 Development of hypertension.

In the renal system, the RAAS is also overreactive. This overreactivity and a decreased renal perfusion from the SNS effects lead to renin release. Renin release causes angiotensin II production, which is a powerful vasoconstrictor. Na+ and water are reabsorbed. Aldosterone is released, which further promotes Na+ and water retention (Figure 4-12). Overall, blood volume increases. The increased volume stimulates the release of natriuretic hormones that normally act to reduce Na+ retention and promote water excretion while causing vasodilation. These natriuretic hormones, however, are dysfunctional in hypertension, leading to worsening of vasoconstriction. The RAAS dysfunction also causes vascular changes. In addition to the dysfunction described, several risk factors cause or exacerbate hypertension.

The risk factors for developing hypertension include the following:

Age: Vessel compliance decreases with aging. Race: Hypertension is more prevalent in Blacks, and the possible reasons include higher incidence of low birthweight infants (possible impaired renal growth), less nocturnal blood pressure decline, diet higher in sodium and low in potassium, and higher genetic susceptibility Family history: Genetic factors. Overweight or obesity: Increased RAAS and SNS activity, inflammation, insulin resistance, endothelial dysfunction, and vascular remodeling. Adipokines (cytokines released by adipose tissue) are changed with obesity and may cause vascular dysfunction. Physical inactivity: Increases heart rate, which increases cardiac workload; increased insulin resistance; and possible vascular and endothelial dysfunction. Tobacco use: Nicotine immediately raises blood pressure temporarily, and the chemicals in tobacco can cause vascular dysfunction. High-sodium diet: Too much sodium causes fluid retention, which increases blood pressure. Some patients are salt sensitive while for others salt intake does not have as much of an influence on blood pressure. There are no practical tests to determine who falls into which category. Low -potassium, -calcium, and -magnesium diet: These elements help balance the amount of sodium in cells; without enough, too much sodium accumulates in the blood. High vitamin D intake: This factor has an uncertain effect, though vitamin D may affect the RAAS. Excessive alcohol consumption: Over time, heavy drinking—that is, more than two to three drinks in one sitting—can cause hypertension via several mechanisms such as SNS and RAAS dysfunction. Stress: High levels of stress can lead to a temporary, but dramatic, increase in blood pressure.

Hypertension is divided into two major forms—primary and secondary. In most hypertension cases (95%) in adults, there is no identifiable cause. This type of hypertension, called primary hypertension or essential hypertension, tends to develop gradually over many years. The other cases of hypertension (5%) are caused by an underlying condition. This type of hypertension, called secondary hypertension, tends to appear suddenly or manifests as stable blood pressure that becomes labile. In secondary hypertension, blood pressure levels are higher than in primary hypertension. Secondary hypertension tends to be resistant to antihypertensive agents in recommended doses and with multiple agents. Those patients with secondary hypertension tend to be younger (e.g., < 30), may not be obese, or have a family history. A variety of conditions and medications can lead to secondary hypertension, such as:

Renal disease (e.g., renal artery stenosis, polycystic kidney disease, and diabetic nephropathy) Adrenal gland disorders (e.g., primary aldosteronism, pheochromocytoma) Sleep apnea syndrome Certain congenital heart defects (e.g., coarctation of the aorta) Endocrine disorders (e.g., Cushing syndrome, hypothyroidism, hyperparathyroidism) Certain medications (e.g., birth control pills, hormone replacement therapy, antihistamines, decongestants, and glucocorticoid steroids) Illegal drugs (e.g., cocaine and amphetamines)

Occasionally, hypertension is classified as isolated systolic hypertension or isolated diastolic hypertension, depending on which measurement is elevated. Often, elderly persons have higher systolic readings and lower diastolic readings (i.e., increased pulse pressure) because of aging changes (e.g., decreased vascular compliance). Isolated systolic hypertension with an increased pulse pressure is associated with an increased risk for cardiovascular diseases (e.g., stroke, MI, and renal dysfunction). Isolated diastolic hypertension is associated with increased risk for cardiovascular events in younger people.

Hypertension can also occur during pregnancy, posing a serious health threat as one of the top causes of maternal death. A spectrum of hypertension disorders can occur in pregnancy, including gestational hypertension and preeclampsia/eclampsia. Gestational hypertension (i.e., ≥ 140 mmHg systolic or ≥ 90 mmHg diastolic) is defined as the onset of hypertension at ≥ 20 weeks with resolution 12 weeks after birth. If the hypertension does not resolve, the diagnosis becomes chronic hypertension. If proteinuria is present with gestational hypertension, then the diagnosis is preeclampsia (formerly known as toxemia). If there is no proteinuria, other diagnostic criteria for preeclampsia can include thrombocytopenia (< 100,000 cells/µL), impaired liver function tests, renal insufficiency (elevated serum creatinine), pulmonary edema, or cerebral/visual disorders. Preeclampsia can be further classified as severe when there are several diagnostic criteria present and/or a systolic blood pressure that is ≥ 160 mmHg and/or a diastolic that is ≥ 90 mmHg. The diagnosis of preeclampsia with grand mal seizures is termed eclampsia. A woman may have had hypertension prior to pregnancy and develop what is termed superimposed preeclampsia/eclampsia.

Multiple factors increase the risk for developing preeclampsia; some of these include hypertension, renal disease, diabetes mellitus (type 1 or 2), multiple fetuses, maternal age younger than 18 years or older than 35 years, obesity, and autoimmune disorders (e.g., SLE). Preeclampsia develops as a result of placental vascular alterations that cause placental decreased perfusion, hypoxia, and ischemia. The maternal inflammatory reaction is activated in response to the

placental alterations with resulting endothelial dysfunction, systemic inflammation, and a thrombotic state. The kidneys and liver are particularly affected by the placental hypoperfusion, so alterations are included in the diagnostic criteria (e.g., increased creatinine, proteinuria, and abnormal liver function tests). The cardiovascular system and brain are also damaged by the endothelial dysfunction, causing fluid shifts and vasospasm (e.g., pulmonary edema, headaches). The hematologic changes occur as a result of fluid shifts and the inflammatory response (e.g., thrombocytopenia, increased prothrombin time [PT] or partial thromboplastin time [PTT]). Poor fetal development and placental abruption may result.

Management of hypertension in pregnancy focuses on early identification and frequent evaluation for complications such as preeclampsia (e.g., liver enzymes, proteinuria). Fetal well-being will be monitored regularly with ultrasounds and nonstress tests. Early delivery, such as at 37–38 weeks, may be necessary. Preeclampsia is managed similarly with frequent evaluation and early delivery. Prevention and nonpharmacologic measures are geared toward protecting the mother and the fetus. If preeclampsia has severe features or eclampsia is present, treatment measures include bed rest and magnesium sulfate (to prevent and treat seizures). Severe hypertension can be managed with hydralazine, labetalol, or nifedipine.

Clinical Manifestations Hypertension, particularly primary hypertension, is called the silent killer because many people do not have symptoms. Often by the time symptoms become evident, the hypertension is advanced, or the blood pressure is remarkably high. When present, clinical manifestations include fatigue, headache, malaise, and dizziness.

During a history and physical examination, clinical manifestations may reveal target end-organ damage (e.g., left ventricular hypertrophy, retinal hemorrhages). The higher the blood pressure and the longer it goes uncontrolled, the greater the damage. Uncontrolled high blood pressure can lead to numerous target end-organ complications:

Cardiovascular system: Atherosclerosis, left ventricle hypertrophy, ischemia, infarction, aneurysms, heart failure, sudden death, and peripheral artery diseases Kidneys: Decreased glomerular filtration rate, glomerulosclerosis, and renal failure Brain: Transient ischemic attacks, stroke, and aneurysm Eyes: Exudate, hemorrhage, retinopathy, and vision loss

Hypertension can be part of a cluster of disorders known as metabolic syndrome that is associated with increased cardiovascular risks. Other components of the cluster include increased waist circumference, high triglycerides, low HDL, impaired fasting

glucose, and insulin resistance.

Diagnosis and Treatment Diagnosis of hypertension is based on accurate measurement of blood pressure and repeated high readings (i.e., during more than two visits with or without out-of-office confirmation). The values defining hypertension vary per national guidelines and organizations. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) (James et al., 2014) defines hypertension as a systolic ≥ 140 mmHg and/or diastolic ≥ 90 mmHg. Therapeutic target goals are ≤ 150/90 mmHg for those over 60 years of age and goals for all others is ≤ 140/90 mmHg. In 2017, the American Heart Association and the American College of Cardiology (AHA/ACC) redefined hypertension as systolic ≥ 130 mmHg and/or diastolic ≥80 mmHg. Diagnostic criteria are dependent on which guideline is used; however, clinical judgment remains paramount in choosing a course of action (e.g., risk of cardiovascular disease, therapy risk/benefits). Additionally, target goal recommendations from the American Diabetes Association and the National Kidney Foundation vary slightly in their therapeutic target goals for those with diabetes and chronic kidney disease (e.g., < 140/80 mmHg).

Accuracy of blood pressure measurement is important in diagnosis. The following should be done while measuring the blood pressure:

Seat the patient in a chair with feet on floor and back supported for a few minutes. The patient should avoid caffeine, exercise, and smoking 30 minutes prior to measurement. Do not engage the patient in conversation during measurement. Support the arm at the right atrium level (i.e., sternum midpoint). Use calibrated sphygmomanometer with appropriate cuff size (e.g., encircles 80% of the arm). Repeat measures should be separated minimally by 1 minute.

If readings are high in the office or the patient describes normal levels outside the office, a patient may have “white coat hypertension.” In these circumstances, home measurement or ambulatory monitoring should be conducted. The cutoff for hypertension with home/ambulatory monitoring varies again based on guidelines interpreted but is generally less than clinical measurements (e.g., ≥ 125/75 mmHg). Normally, the blood pressure dips by 10% at night, and the patient is diagnosed with nocturnal hypertension if dipping does not occur. Cardiovascular risk may be higher with nocturnal hypertension than in those whose pressure dips at night.

Hypertension can be diagnosed at initial screening (i.e., one reading) if blood pressure is high (e.g., systolic ≥ 160 mmHg and/or diastolic ≥ 100 mmHg) with target

end-organ damage, or blood pressure is systolic ≥ 180 mmHg and/or diastolic ≥ 120 mmHg. Hypertensive urgency, which can be at an initial visit or subsequent encounters, is defined as a blood pressure systolic ≥ 180 and/or diastolic ≥120 mmHg in a patient who is relatively asymptomatic (e.g., mild headache) and there is no evidence of acute target end-organ damage (e.g., ischemia). A hypertensive emergency (i.e., malignant hypertension) is defined as the same blood pressure as an urgency but the patient is symptomatic and/or with evidence of acute/ongoing target organ damage.

In addition to blood pressure measurement, diagnostic evaluation will center on identifying a cause and determining the presence of any complications and cardiovascular risks. Diagnostic testing for those newly diagnosed will include an EKG and laboratory tests (e.g., urinalysis, CBC, lipid panel, and chemistry panel for glucose, calcium, creatinine, potassium, and thyroid profile). Other exams are dependent on presence or suspicion of other disorders such as an albumin creatinine ratio for chronic kidney disease or an echocardiogram for heart failure. In primary hypertension, these results may all be normal.

The prognosis for persons with hypertension depends on treating any underlying causes and maintaining blood pressure control. Early detection and treatment are crucial to prevent or minimize cardiovascular risks and complications. Treatment of hypertension is based on ACC/AHA 2017 standards (FIGURE 4-47) with recognition that other guidelines (JNC 8 standards) exist. Adhering to a protocol will increase the likelihood of successful blood pressure control. Lifestyle changes are the mainstay of prevention and treatment. These changes can be implemented in those individuals who have or are at risk for developing hypertension. Dietary changes are the cornerstone to these lifestyle changes and include adequate potassium intake and the Dietary Approaches to Stop Hypertension (DASH) diet (NIH, 2015). The research-driven DASH diet includes the following recommendations:

FIGURE 4-47 Blood pressure threshold and recommendations for treatment and follow-up. ASCVD = arteriosclerotic cardiovascular disease

Limiting saturated fat, cholesterol, total fat, and salt Focusing on fruits, vegetables, and fat-free or low-fat dairy products Increasing whole grains, fish, poultry, beans, seeds, and nuts Minimizing sweets, added sugar and sugary beverages, and red meats

Limiting salt consumption to 2,300 mg (less than a teaspoon) per day has been shown to lower blood pressure. Further restricting salt intake to 1,500 mg per day can lower blood pressure to an even greater extent. The 1,500 mg restriction is advised for individuals diagnosed with hypertension, diabetes, and chronic kidney disease as well as Blacks, middle-aged individuals, and older adults. Following these guidelines, particularly the salt recommendations, can significantly decrease the risk for developing hypertension.

Other lifestyle changes that can help prevent or treat hypertension include being active, maintaining a healthy weight, smoking cessation, stress management, and alcohol consumption (if used) in moderation. Additionally, individuals should have their blood pressure measured regularly with a home monitor and by healthcare

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professionals. These readings should be documented in a blood pressure journal (including the blood pressure reading, date, time of day, activities just before the reading, and any symptoms) and brought to visits with the healthcare provider. Home care monitoring devices should be periodically brought into the office to compare measurements.

Numerous pharmacologic agents are used to treat hypertension. Based on ACC/AHA 2017 guidelines, the initial choice of therapy should be a thiazide or thiazide-type diuretic, an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) or a calcium channel blocker. These pharmacologic agents can be prescribed either as a single agent or in combination depending on blood pressure level and goal. ACEI, ARB, and direct renin inhibitors, however, should never be administered together due to potential serious harm. Other antihypertensive pharmacotherapeutic categories include diuretics (e.g., loop, potassium sparing), beta blockers (e.g., cardioselective, alpha/beta receptor combined), alpha-1 blockers, centrally acting drugs, and direct vasodilators (i.e., direct renin inhibitors).

Learning Points

Antihypertensive Pharmacotherapeutics mnemonic to summarize all the categories of antihypertensive is ABCD:

A ACEI; ARB; alpha-1 blockers B beta blockers; alpha/beta C calcium channel blockers; centrally acting drugs D diuretics; direct vasodilators

Shock Shock is a clinical syndrome resulting from inadequate tissue and organ oxygenation because of decreased perfusion, decreased oxygen delivery, increased oxygen use, or abnormal oxygen use. Shock occurs due to a problem with the heart (pump), the vasculature (vessel), or volume, or a combination. Any changes in the variables that affect blood pressure (e.g., tissue perfusion), which are determined by cardiac output (i.e., stroke volume × heart rate) and systemic vascular resistance, can cause shock. Shock can be classified into three categories—distributive, cardiogenic, and hypovolemic—based on its precipitating factors. Distributive shock is also known as vasogenic (e.g., neurogenic, septic, and anaphylactic), and examples of hypovolemic shock include hemorrhagic shock and burn shock. Septic shock is the most common type of shock and is the leading cause of death in the intensive care unit, while hemorrhagic shock is the most common type of shock in trauma patients. Some patients have more than one type of shock.

Shock progresses through three stages that are common to all types of shock— compensatory (i.e., pre-shock), progressive (i.e., decompensated), and irreversible

(i.e., refractory). Compensatory mechanisms are bodily responses that become activated when arterial pressure and tissue perfusion decrease and that represent an effort to maintain cardiac and cerebral function. Early signs of decreased perfusion may be simply tachycardia, modest changes in blood pressure (low or high), and an elevated lactate level due to anaerobic metabolism. These compensatory mechanisms include the activation of the SNS and RAAS. The pituitary and adrenal medulla release hormones in response to decreased perfusion. The compensatory mechanism responses overlap and, while described separately, work together to maintain heart and brain function. Reversal is possible at this stage with restoration of tissue and organ oxygenation. In general, cardiac output is diminished and a compensatory increase in systemic vascular resistance is present with hypovolemic and cardiogenic shock (i.e., there are volume and pump issues). In distributive shock (i.e., there is a vessel issue), systemic vascular resistance is diminished with a compensatory increase in cardiac output.

The progressive stage of shock begins when these compensatory mechanisms fail to maintain cardiac output. Tissues continue becoming hypoxic, lactic acid continues to build up, and metabolic acidosis develops. This acidotic state further impairs cardiac functioning, causing sluggish blood flow and increasing the risk for disseminated intravascular coagulation. Irreversible end-organ damage occurs as the shock progresses, leading to respiratory and cardiac failure (FIGURE 4-48).

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FIGURE 4-48 Progression of shock. ACTH = adrenocorticotropic hormone

In distributive shock, vasodilation causes the inappropriate distribution of plasma/blood (volume) from the vasculature into the tissue. The primary problem, therefore, is with the vasculature, while in general, the volume is adequate and the pump is unaffected. The inappropriate volume distribution ultimately leads to poor perfusion as with other types of shock.

Three types of distributive shock are distinguished—neurogenic, septic, and anaphylactic. Neurogenic shock occurs as a result of central nervous system injury (e.g., severe brain injury, thoracic spinal cord level 6 or higher/cervical cord injuries). Below the level of the injury (e.g., below T6), sympathetic tone is impaired or blocked, resulting in a loss of sympathetic tone in vascular smooth muscle and massive vasodilation. The vasodilation causes blood to pool in the venous system, leading to decreased venous return, cardiac output, and blood pressure. The compensatory mechanisms of tachycardia and vasoconstriction from the SNS are not present in response to hypotension. However, the parasympathetic response remains intact and is unopposed, so the patient will have bradycardia. In neurogenic shock, the patient will have a triad of bradycardia, vasodilation, and hypotension.

Learning Points

Spinal Shock pinal shock and neurogenic shock are two different disorders although both can be due to spinal cord injury and can occur together. Spinal shock is not considered a true shock but rather is an altered physiologic

state in response to spinal cord injury (the cord is shocked by injury). This causes the loss of motor and sensory function such as flaccid paralysis, anesthesia, or loss of reflexes below the level of injury. The manifestations usually occur immediately after the injury. Recovery can occur in hours to weeks.

In septic shock, an organism’s endotoxin or exotoxins activate an immune reaction. Septic shock is on a continuum that starts off with a systemic inflammatory immune response syndrome (SIRS). SIRS can be a response to any inflammatory or clinical insult that is infectious or noninfectious (e.g., pancreatitis, ARDS). SIRS can progress to septicemia (blood infection), then sepsis (systemic response to infection), and at the end of the continuum is septic shock. In comparison to neurogenic shock, the inappropriate distribution of volume in septic shock is a result of inflammatory mediators causing increased capillary permeability, capillary pooling, and fluid shifts from the vascular compartment to the tissue. This inappropriate distribution of volume leads to a falling cardiac output and multiple organ dysfunction syndrome (MODS). Common causes of septic shock are bacterial species, specifically gram-negative bacteria (e.g., Escherichia coli, Pseudomonas aeruginosa, Klebsiella, Acinetobacter). Gram-positive bacteria (e.g., staphylococci,

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streptococci) infection causes sepsis but not necessarily shock in comparison to gram-negative infections. Other less frequent organisms are fungal (e.g., Candida albicans, Candida glabrata, Aspergillus), and these infections are more likely to progress from sepsis to shock. Viruses (e.g., Cytomegalovirus, influenza A and B) are organisms that can also cause shock.

Learning Points

SIRS Diagnostic Criteria IRS diagnostic criteria include two or more of the following findings: tachypnea (> 20/minute), tachycardia (> 90/minute), PaCO2 of less than 32 mmHg, and temperature decrease (< 38°C) or increase (> 38°C) and

a white blood cell count that is either low (< 4,000 cell/mm3) or high (> 12,000 cell/mm3) or higher than 10% bands.

Anaphylactic shock is a widespread, immediate systemic reaction resulting from a sudden release of mast cells and basophil mediators. Most causes of anaphylaxis are immune mediated with immunoglobulin E as the most likely type of response. Food (e.g., peanuts, shellfish, milk, eggs) is a common cause of anaphylaxis in children, while insect venom (e.g., wasps, bees), and medications (e.g., antibiotics) are the most likely immunoglobulin E–mediated anaphylactic triggers in adults. Other immunologic mechanisms can cause IgG mediated anaphylaxis. Nonimmunologic agents can also cause anaphylaxis (i.e., they are anaphylactoid) where triggers such as radiocontrast agents directly activate mast cells and basophils. Additionally, anaphylaxis causes can be idiopathic. Anaphylactic shock leads to a cascade of events similar to that of septic shock, except that the mediators differ. Bronchospasm and laryngeal edema occur that can impair respiratory status. Early detection of anaphylaxis is critical to prevent anaphylactic shock. (See chapter 2 for a discussion of immunity.)

Cardiogenic shock results when the pump fails. The heart cannot contract, fill, or eject, leading to an inability to maintain adequate cardiac output. A myocardial infarction (usually anterior wall) is the most common cause, and usually greater than 40% of the left ventricle has been affected. Cardiomyopathies, arrhythmias such as sustained ventricular tachycardia, and other intracardiac disorders such as a dissecting aorta can lead to cardiogenic shock. Noncoronary causes are referred to as obstructive shock and include tension pneumothorax, pulmonary embolism, and tamponade. As with other shock, compensatory mechanisms such as increased heart rate and vasoconstriction are triggered, but these mechanisms increase cardiac workload and oxygen consumption, further worsening contractility. Consequently, tissue and organ perfusion decreases, leading to MODS.

Learning Points

C Lowering Salt Intake

utting back on salt intake can be challenging on many levels. First, eating large amounts of salt over time decreases taste sensation on the tongue, such that foods without it will lack flavor initially. Those taste

buds will wake up again with a little time. Gradually decreasing salt intake may help with this transition. For instance, have patients start by not adding salt to food once it is prepared, and then begin changing how food is prepared.

Second, salt is used in many foods of convenience as a preservative. In today’s fast-paced society, these foods have become commonplace and almost a necessity. Unfortunately, processed foods (e.g., canned food, boxed meals, frozen dinners, and sandwich meats) usually contain large amounts of salt. Additionally, salt is often added to meats to preserve them, even when those meats are already naturally high in salt (e.g., pork).

Third, the practice of eating outside the home in a wide range of restaurants has increased. Salt content is difficult to control when others are preparing the food.

Finally, salt is hidden in many seasonings and condiments. As people attempt to move away from salt, they may turn to these seasonings and condiments to enhance flavor—but these items may be just as bad as using salt. Seasonings that have salt in their name have salt in their contents (e.g., seasoning salt, garlic salt, and onion salt). Condiments such as hot sauce and mustard also have high salt content.

The following recommendations can help people cut back on salt and avoid foods with hidden salt content: Eat at home using fresh foods as much as possible. Attempt to purchase foods on the perimeter of the grocery store (where the fresh foods can be found) and avoid items in the center (where most of the processed foods can be found). Limit consumption of pork and cured meats. Use seasonings that are salt free or MSG free (e.g., garlic powder, onion powder). Read the labels of all products, paying attention to the sodium (salt) content and serving sizes.

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

In hypovolemic shock, venous return declines because of intravascular volume losses that are hemorrhagic (e.g., penetrating trauma bleeding) or nonhemorrhagic (e.g., burns). In hemorrhagic hypovolemic shock, the patient loses blood; in nonhemorrhagic hypovolemic shock, he or she loses other fluids. In hypovolemic shock, preload drops, decreasing ventricular filling and stroke volume. As cardiac output falls, tissue and organ perfusion decreases.

Clinical Manifestations Clinical manifestations of shock vary based on the stage, type, and cause of the shock. Ultimately, all manifestations reflect the impaired tissue perfusion and poor oxygenation. General manifestations include the following signs and symptoms: tachycardia (except neurogenic); hypotension; tachypnea with increased work of breathing; changes in level of consciousness such as restlessness, agitation, confusion; cold, clammy skin progressing to mottled skin and cyanosis; and decreased urine output (i.e., < 30 mL/hr). Hyperlactatemia and metabolic acidosis are often present in shock.

MODS is a complication of shock that starts during the progressive stage and can result in multiple organ failure and death. Clinical manifestations of MODS are multiple and system wide. Dysfunction and failure of these organs is discussed in

corresponding chapters as listed next.

Acute respiratory distress syndrome (chapter 5) Renal disease (chapter 7) Disseminated intravascular coagulation (chapter 3) Encephalopathy (chapter 11)

Diagnosis and Treatment Diagnosis of shock is based on the underlying disorder (e.g., hemorrhage or hypovolemic shock), clinical findings, including hypotension or oliguria, and diagnostic exams. Diagnostic procedures for shock are varied but will often include basic diagnostic evaluations consisting of a CBC with differential, basic chemistry panels (e.g., blood glucose), renal and liver function tests, cardiac biomarker testing, natriuretic peptide testing, coagulation studies, D-dimer serum levels, and a chest X- ray. EKG, echocardiogram, ultrasounds, and CT scans are some other diagnostic tests. If infection is suspected then diagnostic testing may include cultures of blood culture, urine, and lungs.

BOX 4-6 Application to Practice Mr. Jones, a 70-year-old professor, is 7 days post–laparoscopic cholecystectomy. He denies any pain at the surgical site, but he is complaining of fatigue, heart palpitations, and some shortness of breath. He says the palpitations started 2 days ago and last a few minutes.

He denies fever, chest pain, nausea, vomiting, and diaphoresis. Past medical history: anterior wall MI 3 years prior. Social history: drinks three to four glasses of liquor a day, which he has done for 20 years; quit smoking

after MI 3 years ago. Medications: metoprolol 50 mg once daily; simvastatin 40 mg once daily; aspirin 81 mg once daily. He

forgets to take his aspirin often and misses a dose of other medications about once a week. Allergies: no known drug allergies. Physical examination: vital signs—temperature 97.5°F; pulse 118/minute and irregular; respirations

20/minute; blood pressure 126/74 mmHg. General: alert and oriented. Neck: no jugular vein distention, no bruits. Cardiovascular system: irregular rhythm, no gallops or murmurs. Lungs: bibasilar, fine crackles. Skin: warm and dry with no edema, cyanosis. Other: 12-lead EKG with evidence of anterior wall MI and atrial fibrillation with a ventricular rate of 118.

Answer the following questions:

1. 2. 3. 4.

T

T

What are possible reasons for Mr. Jones’s new-onset atrial fibrillation? Describe atrial fibrillation. What are risks associated with atrial fibrillation? What is Mr. Jones’s CHA2DS2-VASc score? What are treatment recommendations based on this score?

Modified from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Diagnostic Link

Point-of-Care Ultrasonography he use of bedside ultrasonography allows for the rapid examination of many organs (e.g., heart, lung, abdomen) in order to identify a possible cause for shock. Ultrasonography is portable, relatively

inexpensive, and there is no exposure to radiation. Ultrasonography can also be used as a guide to therapy (e.g., peritoneal drainage) and to determine the effectiveness of treatment (e.g., after pericardiocentesis). The key disadvantage of bedside ultrasonography is the decreased sensitivity in comparison to other definitive diagnostic modalities. As an example, an echocardiogram is preferred over a bedside sonogram if cardiac effusions are complex.

Prompt treatment is crucial for positive patient outcomes. Management of shock includes the identification and treatment of the underlying cause. Goals are to restore and maintain tissue perfusion. Rapid fluid resuscitation is the mainstay of therapy in shock. Crystalloids are preferred unless the shock is from hemorrhaging; then blood products are best. Treatment will include cardiovascular monitoring and respiratory maintenance with therapies such as oxygen or mechanical ventilation. Pharmacologic agents often used are vasopressors such as norepinephrine or dobutamine. Other pharmacologic agents are dependent on the type of shock and can include vasodilators, beta blockers, alpha agonists, phosphodiesterase inhibitors, steroids, antihistamines, and anticoagulants. Infections will be treated with antibiotics or antifungals depending on the organism. Patients may require an intra- aortic balloon pump, ventricular assist device, or extracorporeal membrane oxygenation. (See chapter 5 for more on pulmonary function.)

Learning Points

One-Hour Sepsis Bundle he sepsis bundle, as other bundles, is a set evidenced-based practices that have been proven to improve outcomes when provided collectively (Resar et al., 2005). The Surviving Sepsis Campaign was started in

2002 by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. The sepsis bundle’s latest update was 2018 (www.survivingsepsis.org). The 1-hour sepsis bundle begins once sepsis or septic shock elements are identified. The bundle consists of the following five steps: 1. Measure lactate level. Remeasure if initial lactate is > 2 mmol/L. 2. Obtain blood cultures prior to administration of antibiotics. 3. Administer broad-spectrum antibiotics. 4. Begin rapid administration of 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L. 5. Apply vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain mean

arterial pressure ≥ 65 mmHg.

C H A P T E R S U M M A R Y

The cardiovascular system is responsible for transporting the body’s life fluids to maintain a delicate internal balance. This system has a reciprocal relationship with all the other systems—one in which problems in one system create problems in another system. Problems in the cardiovascular system are highly prevalent and most likely will be encountered in any setting. Understanding these issues is vital to provide appropriate care. Prevention of cardiovascular issues often includes lifestyle changes. Early identification and treatment of these conditions are crucial to improve outcomes.

R E F E R E N C E S A N D R E S O U R C E S

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C H A P T E R 5

Pulmonary Function

L E A R N I N G O B J E C T I V E S

Discuss normal pulmonary anatomy and physiology. Differentiate upper and lower respiratory infectious disorders. Differentiate restrictive and obstructive disorders. Differentiate pleural disorders. Describe the major types of lung cancer. Summarize how various disorders cause impaired ventilation and perfusion. Describe the clinical consequences of impaired ventilation and perfusion. Apply understanding of alterations in the pulmonary system when describing various common disorders such as respiratory infections, pleural disorders, malignancy, obstructive disorders, and restrictive disorders. Develop diagnostic and treatment considerations for various pulmonary disorders.

he pulmonary system includes the organs and structures associated with breathing and gas exchange. The structures of the pulmonary system are grouped into two branches—the upper respiratory tract (oral cavity, nasal

cavity, paranasal sinuses, pharynx, and larynx) (FIGURE 5-1) and the lower respiratory tract (trachea, bronchi, bronchioles, and alveoli). This chapter focuses on normal and abnormal states of the pulmonary system. The respiratory tract functions automatically to provide cells with oxygen and to remove carbon dioxide waste. Disorders of the pulmonary system can become serious quickly because of the body’s critical need for oxygen.

FIGURE 5-1 The upper respiratory tract.

Anatomy and Physiology The pulmonary system provides vital oxygen and removes toxic carbon dioxide through the act of breathing. The respiratory tract allows a person to breathe in and out approximately 23,000 times each day or over half a million times a month. The act of breathing allows for gas exchange of oxygen and carbon dioxide. Oxygen is necessary for cells to produce energy through cellular metabolism; carbon dioxide is the waste product of this process. Through its gas exchange functions, the pulmonary system plays a pivotal role in maintaining homeostasis.

The pulmonary system consists of two basic functional divisions—an air- conducting portion and a gas-exchanging portion (TABLE 5-1). The air-conducting portion delivers air to the lungs, while the gas-exchanging portion allows gas exchange to occur between the air and the blood (Figure 5-1). The gas-exchanging portion of the respiratory tract includes the lungs with their millions of alveoli and capillaries (FIGURE 5-2).

FIGURE 5-2 The pulmonary system. This illustration shows the air-conducting portion and the gas-exchange portion of the human respiratory system. The insert shows a higher magnification of the alveoli where oxygen

and carbon dioxide exchange occurs.

TABLE 5-1 Summary of the Pulmonary System

Organ Function

Air Conducting

Nasal cavity Filters, warms, and moistens air; also transports air to pharynx

Oral cavity Transports air to pharynx; warms and moistens air; helps produce sounds

Paranasal sinuses: Frontal, maxillary, ethmoid, sphenoid

Warms and moistens air

Pharynx Transports air to larynx

Epiglottis Covers the opening to the trachea during swallowing

Larynx Produces sounds; transports air to trachea; helps filter incoming air; warms and moistens incoming air

Trachea and bronchi Warms and moistens air; transport air to lungs; filter incoming air

Bronchioles Control air flow in the lungs; transport air to alveoli

Gas Exchange

Alveoli Provide area for exchange of oxygen and carbon dioxide

Modified from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Air enters the respiratory tract through the nose and mouth, then travels to the pharynx. Infants up to the age of 3 months primarily breathe through their nose as opposed to the mouth. Nasal congestion in an infant, therefore, can significantly impair breathing. The paranasal sinuses are four air-filled extensions of the nasal cavity that act to warm and moisten the air. The anterior ethmoid sinus consists of an ostiomeatal complex, which opens into the middle turbinate located on lateral wall of the nose. The complex is a drainage pathway for the frontal, maxillary, and ethmoid sinuses. The pharynx joins the larynx, or voice box (FIGURE 5-3). The larynx is made of cartilage and plays a central role in swallowing and talking. When food is swallowed, the larynx rises so that it is closed by the epiglottis. This process prevents food and liquids from entering the lungs, where they would cause severe irritation. Even so, food does occasionally enter the lungs, often triggering the cough reflex (a primitive protective reflex). The larynx works much like the strings of a guitar or violin to produce sound—tightening and loosening to change pitch. It opens up into the trachea, or windpipe. From the trachea, the air travels to the mainstem bronchi, where it branches into the right and left bronchi, for each lung (FIGURE 5- 4). The left bronchus is narrow and positioned more horizontally than the right bronchus; the right bronchus is shorter and wider than the left bronchus and extends downward more vertically. Because of the difference in size between the two bronchi, objects are more easily inhaled (aspirated) into the right bronchus.

FIGURE 5-3 The vocal cords. A Uppermost portion of the respiratory system showing the location of the vocal cords. B Longitudinal section of the larynx showing the location of the vocal cords. Note the presence of the false vocal cord, so named because it does not function in phonation. C View into the larynx showing the true vocal

cords from above.

c: © CNRI/Science Source.

FIGURE 5-4 The bifurcation of the trachea at the carina into the right and left mainstem bronchi. © David M. Martin, MD/Science Source.

Inside the lungs, the bronchi branch extensively into a series of smaller and smaller tubes, or bronchioles, until they reach the alveoli. This branching from larger to smaller tubes mimics the vessels in the cardiovascular system. Children’s airways are much smaller than those of adults, making them more vulnerable to obstructions. With advanced aging, the airway diameter also decreases, leading to increased

airflow resistance. The walls of the bronchioles are also like the vessel walls in that they mostly consist of smooth muscle. The smooth muscle allows for constriction and dilation of the bronchioles to control air flow. When oxygen needs are higher (e.g., during exercise or stress), the airways dilate more to allow more air to enter the lungs. In times of normal or decreased oxygen needs (e.g., during sleep), the airways may narrow (constrict) slightly. Disease processes may cause constriction to the point of impeding air flow—a dangerous development.

The air entering the respiratory tract often contains particles that can be harmful. These particles may include infectious organisms such as bacteria, viruses, and fungi, as well as environmental agents like dust, pollen, and pollutants. The pulmonary system, as part of the innate immune defense, is equipped to filter out some of these particles as well as to protect the body against those that gain entry. The air-conducting portion of the respiratory tract filters many particles by trapping them in the mucous layer (FIGURE 5-5). Mucus is a thick, sticky substance produced by the goblet cells in the epithelial lining of the nose, trachea, and bronchi. This epithelial lining also contains many cilia, or hairlike projections, that move in a wavelike motion to propel the mucus and trapped particles upward to the mouth, where they can be removed through coughing, sneezing, and expectorating (spitting out). Cigarette smoking and air pollution can decrease mucus production and destroy cilia, increasing the risk of respiratory infections. Alcohol consumption can paralyze cilia, also increasing infection risk.

FIGURE 5-5 Mucus trap. A Drawing of the lining of the trachea. Mucus produced by the mucous cells of the lining of much of the pulmonary system traps organisms and other particulates in the air. The cilia transport the mucus toward the mouth. B Higher magnification of the lining showing a mucous cell and ciliated epithelial cells.

© Jose Luis Calvo/Shutterstock.

Additionally, the immune system is outfitted with immunoglobulin A (IgA) cells in the pulmonary system; these cells prevent the attachment and invasion of bacteria and viruses on mucous membranes. Macrophages are also present around the alveoli in the lungs; they keep the lungs clean by phagocytizing particles that gain access to this area (FIGURE 5-6). Once the macrophages fill with particulates, they move into the surrounding connective tissue. When an unusually large number of particulates are present (e.g., with cigarette or marijuana smoking and when breathing in heavy pollution), the lungs become blackened by the accumulation of the particles.

FIGURE 5-6 The alveolar macrophages.

The air-conducting portion of the respiratory system also moistens and warms incoming air. An extensive network of capillaries lies beneath the epithelium of the respiratory tract. These capillaries release moisture into the incoming air, humidifying it to prevent drying of the respiratory tract. The warm blood circulating through the capillaries heats this air prior to entering the lungs, protecting the lungs from cold temperatures. As the air leaves the respiratory tract, much of the water that has been added to the air condenses onto the slightly cooler lining of the nasal passages. The condensation is recycled for the next inhalation to conserve water and contributes to runny noses on cold days.

Alveoli are the site for gas exchange with the bloodstream (FIGURE 5-7). Oxygen is delivered to the alveoli by the air-conducting portion of the pulmonary

system, and carbon dioxide is brought to the lungs by the circulatory system. During childhood, the alveoli increase in size and number, and they continue to mature for several years. By adulthood, each human lung contains approximately 150 million alveoli, which collectively create a surface area approximately the size of a tennis court for gas exchange. The alveoli and capillaries are often a single cell layer thick, which further facilitates gas exchange. Interstitial connective tissue supports the capillaries. The amount of gas exchanged depends on the total surface area available and the thickness of the alveoli and capillary walls. The more surface area and the thinner the layers, the more rapidly gas diffuses. With normal aging, the alveolar ducts degenerate and become dilated, causing the alveolar sacs to enlarge, resulting in a decreased surface area.

FIGURE 5-7 Gas exchange in the lungs.

Gas exchange in the alveoli requires adequate ventilation, which is the process of air reaching the alveoli, and sufficient perfusion of blood to the alveoli. The ventilation-to-perfusion ratio, or VQ ratio, is a measurement of the efficacy and adequacy of these two processes. In the ideal lung, inspired air reaches all the alveoli and all the alveoli have the same blood supply. In reality, neither alveolar ventilation nor capillary blood flow is uniform. The supply of air and blood never match perfectly, even in healthy persons. Because of gravity, the lower parts of the

lungs have greater blood flow than the upper parts. Distribution of alveolar ventilation from the top to the bottom of the lungs is also uneven. Normal ventilation is 4 liters of air per minute, and normal perfusion is 5 liters of blood per minute. This difference makes the expected VQ ratio 4:5, or 0.8. A VQ ratio higher than 0.8 indicates that ventilation exceeds perfusion, and a VQ ratio less than 0.8 indicates poor ventilation. Some respiratory disorders involve ventilation problems, whereas others result from perfusion issues. In any event, the result is impaired gas exchange. A VQ lung scan is a nuclear medicine scan where radioactive particles are inhaled to assess airflow, and particles are also given intravenously to assess blood flow. A VQ scan can be used to evaluate for pulmonary emboli, which would cause decreased or absent perfusion in areas of the lung.

When air is inhaled, gases are exchanged between the alveoli and the capillaries; carbon dioxide is removed through expiration, and oxygen is delivered to cells by the cardiovascular system. Various gases (oxygen, carbon dioxide, nitrogen) and water are in atmospheric air, the alveoli, and blood. These gases diffuse between the alveoli, blood, and tissues because they each exert different pressures. For example, oxygen’s partial pressure is high in the alveoli in comparison to oxygen’s partial pressure in the pulmonary capillaries, so oxygen will diffuse into the pulmonary capillaries. In contrast, the partial pressure of carbon dioxide is low in the alveoli and high in the pulmonary capillaries, so carbon dioxide will diffuse into the alveoli. The delivery of oxygen to the tissues is dependent on the amount of oxygen content in the blood, the amount of oxygen saturated to hemoglobin, and the partial pressure of oxygen. Oxyhemoglobin, which forms in the lungs, is the combination of oxygen and hemoglobin (i.e., hemoglobin saturation with oxygen—SaO2). Oxyhemoglobin travels to the cells where oxygen is released and hemoglobin is reduced (i.e., hemoglobin desaturation). The rate at which hemoglobin binds and releases oxygen (i.e., affinity of hemoglobin for oxygen) is affected by several factors such as temperature and pH and is graphically described in the oxyhemoglobin dissociation curve (FIGURE 5-8).

H

C

FIGURE 5-8 Oxyhemoglobin dissociation curve. The lower portion of the normal (purple) line represents the body’s tissue, and the upper half of the normal (purple) line represents the lungs. Diseases and other conditions

will change the affinity. At a PO2 of 80, saturation minimally changes. Decreased oxygen affinity, when hemoglobin releases more oxygen, occurs when tissue needs more oxygen and causes a shift to the right.

Increased oxygen affinity, when hemoglobin holds on to oxygen, causes a shift to the left.

Learning Points

Partial Pressure ow are pressures determined? The atmospheric pressure is the total of all the pressure exerted by the different gases in the air. At sea level, this pressure is 760 mmHg. Each gas has a different concentration

in the atmosphere and, therefore, will exert a different pressure. The pressure each gas exerts is known as partial pressure and is designated by a capital P before the gas (e.g., PO2; PCO2). Atmospheric air consists of 21% oxygen and the PO2 is, therefore, 160 mmHg (e.g., 760 mmHg × 0.21 = 160 mmHg). When you see PaO2, the a refers to arterial.

Learning Points

Carbon Monoxide Poisoning arbon monoxide is a gas that is the byproduct of pollutants in the air. A high percentage is in motor vehicle exhaust and in faulty heating systems. Smoke from fire, generator exhaust, and paint thinner are some

other sources of carbon monoxide. This colorless, odorless gas is readily inhaled. Carbon monoxide has a high affinity for hemoglobin (200–250 times more than oxygen), and the result is an abnormal hemoglobin called carboxyhemoglobin. Carboxyhemoglobin does not transport oxygen. The result is hypoxemia. Carbon monoxide poisoning causes hundreds of deaths a year; > 400 unintentional deaths (CDC, 2018a). The amount of exposure and how quickly it is recognized and treated will determine the outcome.

The distensibility of the lungs is resisted by fluids in the alveoli that create surface tension. This tension is created by the attraction of water molecules on the surface of the alveoli, and this tension acts to collapse and increase pressure in the alveoli. However, the surface of the alveoli contains a substance called surfactant. Surfactant is a lipoprotein produced by alveoli cells (type II pneumocytes) that has a detergent-like quality. This watery substance reduces surface tension on the alveoli, which enhances pulmonary compliance (elasticity) and prevents the alveoli from collapsing. Because pressure in the lungs is negative compared with atmospheric pressure, walls of the alveoli tend to draw inward, making them collapse. This pressure is much like that seen with a vacuum-sealed pack of coffee. The pressure and the risk of collapse further increase at the end of expiration. Surfactant promotes reinflation of the alveoli during inspiration. Disease states and other conditions can decrease surfactant, leading to the collapse of the alveoli (a condition called atelectasis). For example, premature infants lack surfactant as it is not produced until about 20 weeks’ gestation, and airway secretions start at around 30 weeks. Synthetic surfactant may be administered to overcome any inadequacies in production.

The process of breathing is largely involuntary and controlled by the medulla oblongata in the brain. This center is located in the brainstem, which controls many vital body functions (e.g., heart rate, blood pressure, and temperature). Breathing includes two phases: inspiration (inhalation) and expiration (exhalation).

Inspiration is an active neural process that begins when nerve impulses travel from the brain to the diaphragm, the dome-shaped muscle that separates the thoracic and abdominal cavities (FIGURE 5-9). These impulses cause the diaphragm to contract, lower, and flatten, which draws air into the lungs. Inspiration also involves the intercostal muscles between the ribs. Nerve impulses cause intercostal muscles to contract, lifting the ribs up and out. Contraction of the diaphragm and intercostal muscles changes intrapulmonary pressure, causing air to naturally flow into the lungs. With aging, the chest wall becomes less compliant as the intercostal and diaphragmatic muscles lose mass. In aging, the bone and joints are affected by calcifications and structural changes due to osteoporosis (e.g., kyphosis). Elastic recoil of lung tissue is reduced. These normal physiologic changes can lead to alterations in activity tolerance. However, the effect of these normal changes is influenced by the presence of pulmonary disease and prior fitness levels. Normal pulmonary changes of aging effects such as decreased activity tolerance must also be distinguished from pathologic changes that are more prevalent with aging and present with similar symptoms. (e.g., chronic lung disease, heart failure).

FIGURE 5-9 Breathing. The rising and falling of the chest wall through the contraction of intercostal muscles (muscles between the ribs), illustrating the bellows effect. Inspiration is assisted by the diaphragm, which

assumes a lower position in the chest. Like pulling a plunger back on a syringe, the rising of the chest wall and

the lowering of the diaphragm draw air into the lungs. Illustrations and X-rays showing the lungs in A full exhalation and B full inspiration. © S IU/Visuals Unlimited, Inc.

In contrast to inspiration, expiration is passive—not requiring muscle contraction. As the lungs fill with air, the diaphragm and intercostal muscles relax, returning to their previous position. Returning to their natural position decreases thoracic volume and increases intrapulmonary pressure. This greater pressure forces air out of the lungs. Elastic fibers in the lungs aid in passive expiration by causing the lungs to recoil. Expiration can also be active—that is, created by contracting the chest and abdominal muscles.

Muscle contraction and nerve impulses are not the only factors involved in air movement. Pressure gradients between the atmosphere and lungs must exist to facilitate air movement in and out of lungs and prevent collapse of the alveoli and lungs (FIGURE 5-10). Air moves from areas of high pressure to low pressure. There are three pressures that are important concerning breathing and maintenance of expanded lungs—atmospheric, intrapulmonary, and intrapleural. Atmospheric pressure is created by a mixture of gases, and at sea level, these gases exert a pressure of 760 mmHg. Intrapulmonary (within the lungs) pressure is created by the gases in the lungs and is influenced by lung volume (space). Pressure and volume are inversely proportional (e.g., when one goes up, the other goes down and vice versa).

FIGURE 5-10 Pressure changes during inspiration and expiration. A At the end of expiration, intrapulmonary pressure equals atmospheric pressure, and no movement of air occurs. B During inspiration, the volume of the pleural space increases, causing the pressure in the intrapulmonary spaces (alveoli) to decrease. Air then flows from the outside of the body, where the pressure is greater (760 mmHg), into the alveoli, where it is lower (759

mmHg). C At the end of inspiration, intrapulmonary pressure again equals atmospheric pressure, and no movement of air occurs. D During expiration, the volume of the pleural spaces decreases, causing the intrapulmonary pressure to increase (761 mmHg). Because the intrapulmonary pressure exceeds the

atmospheric pressure (760 mmHg), air flows out of the lungs.

As we inhale, lung volume expands, gases move in and have more space, so the pressure decreases slightly (e.g., -3 to 757 mmHg) in the lung. This decreased pressure is often referred to as negative pressure because some pressure is lost and not necessarily that there is a negative number (i.e., the 757 is not negative). Then, air from the atmosphere (higher pressure) comes into the lower pressure lungs. This air movement causes pressure in lung to go up because there are more gases (e.g., 760 mmHg) now in the lung.

Then we exhale and volume decreases, but we still have the gases in the lungs with less space for a moment, causing the pressure in the lungs to go up even a bit

higher (e.g., 763 mmHg). This increase is often referred to as positive pressure. Air then goes from the lung (higher pressure) back to the atmosphere, which at the time is lower, and then lung pressure drops to 760 mmHg. Inhalation occurs and the inspiratory–expiratory cycle starts all over.

One more pressure is the pressure between the lung and chest wall, which is known as the intrapleural pressure. The intrapulmonary pressure is greater than the intrapleural pressure, and this pressure keeps the parietal and visceral pleura clinging together and the lungs expanded. The pleura is the thin, serous membrane surrounding the lungs, which also lines the thoracic cavity. The pleura folds back onto itself to form the two-layered pleural sac. The pleural sac is filled with a watery fluid that protects the lungs and minimizes friction during breathing.

Air flow, both inspiratory and expiratory, can be measured to aid in diagnosis of respiratory disorders. Pulmonary function tests evaluate lung volumes and capacities (FIGURE 5-11). Tidal volume is the amount of air involved in one normal inhalation and exhalation. The average tidal volume is 500 milliliters but is smaller in shallow breathing. Minute respiratory volume is the amount inhaled and exhaled in 1 minute. This volume is calculated by multiplying the tidal volume by the number of respirations per minute; the average is 6 liters per minute. Inspiratory reserve volume is the amount of air beyond the tidal volume that can be taken in with the deepest inhalation. Inspiratory reserve volume averages 2–3 liters. Expiratory reserve volume is the amount of air beyond tidal volume that can be forcibly exhaled beyond the normal passive exhalation. The average expiratory reserve volume is 1– 1.5 liters. Vital capacity is the sum of the tidal volume and reserves. Some air is always present in the lungs, and this amount is called residual volume. Even after the most forceful exhalation, 1–1.5 liters of air remain in the lungs, which ensures efficient and consistent gas exchange. Forced expiratory volume in 1 second (FEV1) is compared to forced vital capacity to diagnose pulmonary disease (e.g., asthma).

FIGURE 5-11 Illustration of lung volumes and capacities. Tidal volume during resting conditions.

The medulla controls breathing through nerve cells that generate nerve impulses to the respiratory muscles. These impulses cease when the lungs are full, allowing the muscles to relax. Chemoreceptors inside the brain and arteries also regulate breathing. These receptors detect carbon dioxide levels and send messages to the medulla. Carbon dioxide levels, not oxygen levels, normally drive breathing (FIGURE 5-12). When these levels go up, respiration depth and rate increase to excrete the excess carbon dioxide, and vice versa. In some disease states, this drive becomes altered, and then oxygen levels drive breathing. Additionally, stretch receptors in the lungs aid in breathing by detecting when the lungs are full. In such a case, stretch receptors in the lungs send a message to the medulla to cease firing. This effect,

which is called the Hering-Breuer reflex, prevents overinflation of the lungs. The body also has oxygen receptors, but they are not sensitive. These receptors do not generate impulses until oxygen levels fall to a critical point. With aging, the chemoreceptors become less sensitive, further contributing to decreased activity tolerance.

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FIGURE 5-12 A Normal respiratory control and B hypoxic drive.

In addition to regulating oxygen and carbon dioxide levels, the lungs aid in regulating pH by altering breathing rate and depth. Carbon dioxide is a source of acid in the body. Increasing the respiratory rate and depth will lead to excretion of more carbon dioxide, making the blood less acidic (increasing pH). Conversely, decreasing the respiratory rate and depth will cause retention of more carbon dioxide, making the blood more acidic (decreasing pH). This compensatory mechanism allows for a quick fix of pH imbalances to reestablish homeostasis (see chapter 6 for further discussion of acid–base homeostasis).

Diagnostic Link

Pulse Oximetry ulse oximetry is a noninvasive method to measure arterial oxygen saturation (SaO2). A pulse oximeter is a sensor that is placed on a person’s finger that can rapidly detect the percentage of a person’s hemoglobin

that is carrying oxygen. Normal pulse oximetry readings of oxygen saturation is > 90%, which means 90% of the person’s hemoglobin is carrying oxygen. This reading is dependent on adequate circulation to the individual’s fingers. This reading can look high in times of decreased hemoglobin (e.g., anemia). In such cases, the reading may read 90–100% indicating 90–100% of that person’s hemoglobin is carrying oxygen, but the individual may not have enough hemoglobin to meet his or her needs.

Diagnostic Link

End-Tidal Carbon Dioxide Monitoring nd-tidal carbon dioxide (ETCO2) monitoring is a quick, noninvasive method to measure the amount of carbon dioxide (CO2) produced and exhaled during breathing. Various types of devices can be used in

intubated and nonintubated patients. The results can be numeric (capnometry) or waveforms (capnography). High ETCO2 values indicate effective ventilations, while lower numbers occur with poor ventilation and poor perfusion (there is less blood passing through the alveoli, so there is less gas exchange). Operating rooms and intensive care units have been the main areas using ETCO2 monitoring, but use now encompasses prehospital areas, outpatient surgical centers, and so forth. Clinical scenarios for use include verification of endotracheal placement, during sedation for procedures, or evaluating cardiopulmonary resuscitation.

Learning Points

Pregnancy Changes regnancy alters pulmonary function in several ways. Estrogen changes and increased blood volume stimulate the nasal passages to increase mucus secretion and become edematous and hyperemic. These

changes cause an increased feeling of nasal congestion and rhinitis. Dyspnea even at rest is common. The cause of the dyspnea is not well understood but may be due to an increased sensitivity to carbon dioxide and oxygen levels and increased progesterone levels. In response, minute ventilation increases, causing a sensation of dyspnea. Respiratory rate, however, is not significantly higher, and tachypnea may be a sign of a pulmonary disorder.

Understanding Conditions That Affect the Pulmonary System When considering alterations in the pulmonary system, it is best to organize them based on their basic underlying pathophysiology to increase understanding. Those pathophysiologic concepts include conditions that are infectious in nature, problems with ventilation, and issues with perfusion. Infectious conditions may involve either the upper respiratory tract or the lower respiratory tract. The pulmonary system requires both ventilation and perfusion to function properly. Problems in either of these areas will impair the pulmonary system’s ability to meet the body’s needs. Ventilation conditions result from problems with moving air into or out of the lungs. Ventilation disorders can further be described as obstructive or restrictive. Obstructive disorders are characterized by difficulty with exhaling, and restrictive disorders are characterized by difficulty with inhalation. Perfusion conditions result from problems that prevent gas exchange; many of these conditions are cardiovascular in nature (e.g., pulmonary embolism).

While this organization is intended to increase understanding, many of the alterations overlap and/or have other causes in addition to the causes under which they are categorized. For example, pneumonia is listed under infections; however, there are also noninfectious causes such as irritants. Additionally, pneumonias lead to problems with gas exchange.

Infectious Disorders Upper Respiratory Tract Infections The upper respiratory tract includes the mouth, nasal cavity, sinuses, pharynx, and larynx. Infections of these structures trigger the inflammatory response, which explains many of the symptoms associated with these conditions. Most of the upper respiratory tract infections (URIs) are interrelated and usually occur together, or one condition may lead to another. Viruses are frequently the causative organisms and the specific pathogen cannot be identified in most cases. Primary bacterial infections are the cause in approximately 25% of cases. In a small percentage of individuals, the breach in the physical and chemical barriers from a virus can lead to secondary bacterial infections.

Infectious Rhinitis Infectious rhinitis, also referred to as nasopharyngitis or the common cold, is a viral upper respiratory infection. Infectious rhinitis is a significant contributor to work and school absences, with adults averaging two to three colds per year and children having even more such infections (Centers for Disease Control and Prevention [CDC], 2016b). As with other infections, individuals who are younger or elderly or immunocompromised are at higher risk.

The most frequent causative organism is a rhinovirus, but many other viruses (e.g., parainfluenza, adenovirus, and coronavirus) can cause this illness. More than 200 organisms can cause infectious rhinitis, making it difficult to develop immunity. In infectious rhinitis, the infectious organism invades the epithelial lining of the nasal mucosa. Mild cellular inflammation leads to nasal discharge, mucus production, and shedding of the epithelial cells. The virus is highly contagious because it is shed in large numbers from the nasal mucosa and can survive for several hours outside the body. Close physical contact with the virus transmits the infection through exchanges with other people (e.g., shaking hands) and surfaces (e.g., doorknobs and telephones). Transmission may occur through inhalation. Despite popular misconceptions, wet and cold conditions do not cause or increase occurrences of infectious rhinitis. The apparent increase in occurrence of the infectious rhinitis during rainy and cold weather is due to increased congregation in confined spaces. Those persons in more frequent, closer contact with other people, such as children in day care centers, healthcare providers, and teachers, will be at higher risk for developing the infection. There are several other causes of rhinitis as allergens (allergic rhinitis), and nonallergic causes such medications (rhinitis medicamentosa), hormonal changes, and aging changes.

Clinical Manifestations

An individual who contracts infectious rhinitis usually experiences an incubation period between the invasion of the virus and the onset of symptoms, which is approximately 1–3 days. Clinical manifestations include clear nasal discharge that can become white, yellow, or green and causes rhinorrhea (runny nose). This discharge leads to sneezing and nasal congestion. The mucus drips down the pharynx, causing a pharyngitis, a subsequent sore throat, and usually a nonproductive cough. The virus can also affect the larynx and cause hoarseness (laryngitis). Due to the activation of the immune response, other systemic symptoms such as low-grade fever, chills, myalgia (muscle aching), and malaise may be present. A headache can be caused by inflammation of the mucus in the sinus cavities. During physical examination, nasal passages may be inflamed and erythematous, and mucus may be visualized. An external crease from a repeated upward wiping of the nose (nasal salute) may be present. The back of the throat may reveal mild increased erythema and increased lymphatic tissue (along the oropharynx) caused by the virus and mucus running down the back of the throat. Palatine and pharyngeal tonsils may be enlarged, along with lymph nodes in the neck. Conjunctivitis may be present with lacrimation (see chapter 14).

Diagnosis and Treatment Diagnosis of infectious rhinitis is primarily made based on the presence of signs and symptoms. URIs such as infectious rhinitis, pharyngitis, sinusitis, and bronchitis often have similar and at times nonspecific clinical manifestations, making it more challenging to determine if an etiology is viral or bacterial. In general, the diagnosis of infectious rhinitis is usually made when there is a lack of a localized or focused complaint or infection on one anatomic location such as the throat. The presence of purulence and fever is often considered bacterial; however, these manifestations can be present with viral infections.

Treatment is symptomatic. Most over-the-counter cold preparations are ineffective in shortening the course of the infection, but they can relieve symptoms. Cold preparations should be avoided in children younger than 4 years. Pharmacologic therapies that may be used include antipyretics (for fever), analgesics (for discomfort), decongestants (for nasal symptoms), cough suppressants, or expectorants. Humidifiers can liquefy secretions to aid in expectoration. Maintaining adequate hydration can also liquefy secretions and help manage fevers. Nasal saline can ease nasal discomfort. The benefit of vitamin C, echinacea, and zinc in prevention and treatment remains controversial. Most symptoms resolve within 7–10 days, although cough may take longer to resolve in pregnant women.

Proper hand washing remains the long-standing cornerstone of prevention because the hands are a significant source of transmission. Additional prevention measures include covering one’s mouth when coughing and sneezing, using tissue

or the upper sleeve of one’s shirt, and disposing of tissue immediately after use. Infectious rhinitis generally leads to no significant sequelae. However, the breach

in the physical and chemical barriers of the respiratory tract increases vulnerability of other parts of the head and/or respiratory system and may lead to secondary bacterial invasions. Infectious rhinitis can lead to otitis media, rhinosinusitis, bronchitis, and pneumonia, or secondary bacterial infections may be present in these same areas. The risk for secondary bacterial infections is increased in individuals who smoke because of the chronic damage done by smoke to the mucosa and cilia. Pregnant women have an increased risk for sinusitis and bronchitis because of normal hormonal changes that increase vascularity and swelling in the respiratory lining. As with viruses, the very young, elderly, and immunocompromised are at higher risk. Suspicions of secondary bacterial infection should occur when the illness is prolonged, the presentation is more severe, or when manifestations become more localized like in the sinuses.

Rhinosinusitis Sinusitis is an inflammation of one or more of the four paranasal sinuses. The maxillary is the most commonly affected, followed by the ethmoid. In children, the maxillary and ethmoid sinuses are present at birth, but the sphenoid sinus does open until the age of 5. The frontal sinus starts appearing at 7 and continues developing into adolescence. Sinusitis rarely occurs without concurrent rhinitis; therefore, rhinosinusitis is the more appropriate term. Rhinosinusitis affects all genders and ages and ethnicities equally.

Rhinosinusitis is most often caused by viruses that also produce infectious rhinitis (e.g., rhinovirus [30%], influenza, or adenovirus). Noninfectious causes include allergies, barotrauma, nasal/sinus tumors, and irritant exposure. Acute bacterial rhinosinusitis occurs in 2% of cases and is often preceded by a viral infection. Most common bacterial infections are caused by Streptococcus pneumoniae or Haemophilus influenzae in adults and Moraxella catarrhalis in children. In immunocompromised patients or those with diabetes, fungi (e.g., Aspergillus or Mucorales) may be the causative organisms. Fungal infection from molds and aspergilli are also implicated in atopic individuals who develop a type I hypersensitivity. In patients with cystic fibrosis or nosocomial sinus infections, the most common organisms are Staphylococcus aureus and Pseudomonas aeruginosa. Nosocomial infections are usually polymicrobial, resistant to therapies, and can also include Klebsiella pneumoniae, Serratia marcescens, and Enterobacter types. Increased risk for rhinosinusitis development includes environmental temperature changes or irritants such as smoke exposure and air pollutants; immunocompromised status such as HIV positivity; conditions that increase inflammation or mucus production such as cystic fibrosis, asthma, sarcoidosis, and

Wegener granulomatosis; nasal structural abnormalities such as nasal polyps; and dental abscesses with fistula development into the sinuses.

In rhinosinusitis, the inflammation and increased mucus prevents outflow of nasal secretions. These infectious secretions proliferate and cause damage to the ciliated pseudostratified lining in the sinus. The lack of secretion clearance and inflammation provide an environment for microbial growth. The basic underlying problem in all the etiologic and/or predisposing risk factors for sinusitis consists of the blockage of the sinus to nasal cavity openings and/or ciliary damage (FIGURE 5-13).

FIGURE 5-13 Blocked sinus. © Karan Bunjean/Shutterstock.

Sinusitis can present as several different types:

Acute, which lasts up to 4 weeks Subacute, which lasts 4–12 weeks

Chronic, which lasts more than 12 weeks and can continue for months or even years Recurrent, with several (four or more) attacks occurring within a year with remissions in between episodes.

Clinical Manifestations As exudate accumulates, pressure builds in the sinus cavity, which causes facial bone pain and headache usually of a throbbing and/or pressurelike quality. The location of pain can indicate which sinus is affected (FIGURE 5-14). Coughing, sudden movements, or anything that increases head pressure intensifies the pain. Lying down or bending forward increases pain in frontal sinusitis, while standing worsens maxillary sinus pain. Toothache may be present with maxillary sinusitis. Retro-orbital pressure and eye pain may be present with ethmoid sinusitis. Other clinical manifestations of rhinosinusitis include nasal congestion, purulent nasal discharge, hyposmia (reduced ability to smell), halitosis (foul-smelling breath), mouth breathing, fever, sore throat, nonproductive cough, and malaise. Facial pain without purulent discharge or vice versa are not consistent with rhinosinusitis. Objective findings include an edematous, erythematous nasal mucosa with purulent drainage from the middle meatus. If transillumination (shining a light) of the sinus is diminished, it may indicate sinusitis, although there are other reasons for a decrease. Ethmoid sinusitis will cause eye problems such as a conjunctival erythema, eyelid mucous membrane swelling (chemosis), eye protrusion (proptosis), and fixation, and eye muscle weakness and tremors. Palpation over an affected sinus may cause pain. Children often have accompanying otitis media (middle ear infection). Nosocomial sinusitis may often occur in the critically ill, particularly in those who are intubated without typical manifestations; therefore, this diagnosis should be considered when a fever is present in intubated patients.

FIGURE 5-14 Sinusitis. © Alila Medical Media/Shutterstock.

Diagnoses and Treatment Diagnostic procedures for rhinosinusitis are not necessary initially, and clinical manifestations will usually point to the diagnosis. Most cases of rhinosinusitis are viral, but bacterial infections are suspected when symptoms persist and do not improve after 10 days or when symptoms worsen when a person was improving. Complicated presentations such as fungal infections, intracranial extension, subacute/chronic cases, and complicated acute bacterial rhinosinusitis warrant further evaluation. Diagnostic tests may include nasal cultures and/or biopsies, sinus X-ray, and sinus CT, which is the radiography of choice. Treatment usually includes decongestants or nasal corticosteroid spray to shrink swollen nasal membranes; analgesics; and nasal irrigation with salt water until the sinuses begin draining. Bacterial infections require antibiotic therapy to resolve. Other measures may include humidifiers (to liquefy secretions and aid in drainage), warm compresses, adequate hydration, and avoidance of irritants (e.g., smoke, chemicals, and other allergens). Endoscopic sinus surgery or balloon sinuplasty may be necessary for chronic or recurrent rhinosinusitis. In children with recurrent sinusitis or other frequent upper respiratory infections, removing the adenoids may resolve the issue.

While not common, complications of acute bacterial sinusitis can include orbital abscess and cellulitis, meningitis, and brain abscess. Children are at higher risk for these complications than adults. Sinusitis from fungal infection are usually invasive

and cause life-threatening illness. Individuals with diabetes or who are immunocompromised (e.g., transplant, chronic steroid use) are at most risk. Acute cases can become subacute, and chronic cases are often thought to be caused by repeated infections (rather than persistent) that damage the mucociliary lining and ability for secretions to clear.

Pharyngitis/Tonsillitis Pharyngitis is an inflammation of the pharynx, which is simply known as a sore throat. Tonsillitis is an inflammation of the palatine tonsils. If the tonsils are predominantly affected, the diagnosis of tonsillitis is given; however, pharyngitis and tonsillitis often occur together, and the term pharyngitis will be used in reference to both. Pharyngitis is common among adults and children, and it is a frequent reason for seeking health care. Various infectious and noninfectious causes result in pharyngitis/tonsillitis. While many commonalities exist among the varying causes of pharyngitis, certain age groups have a higher prevalence of certain organisms. There are differences in pathogenesis, clinical manifestations, and treatments; therefore, viral pharyngitis, infectious mononucleosis, enterovirus oral infections (herpangina and hand-foot-and-mouth disease), and bacterial pharyngitis will be discussed individually.

Viral Pharyngitis As with other URIs, most cases of pharyngitis cases are infectious and caused by viruses (e.g., rhinovirus, coronavirus, influenza A and B, parainfluenza, respiratory syncytial virus (RSV). Pharyngitis is more prevalent in children overall. Most of these viruses create an inflammatory response, leading to erythema and edema. The main complaint is a sore throat described as soreness, irritation, or scratchiness. Since viral pharyngitis is often a part of a URI, clinical manifestations and treatment are similar.

Infectious Mononucleosis In about 2% of cases, pharyngitis is caused by the Epstein-Barr virus (also known as human herpesvirus 4). Epstein-Barr virus (EBV) is the most common cause of infectious mononucleosis. Many children contract EBV in childhood and remain asymptomatic, usually resulting in lifelong immunity. Adults can also get infected with EBV, have a mild disease, and never get diagnosed with mononucleosis. One in four adolescents and young adults infected with EBV, however, will get infectious mononucleosis. Other causes of infectious mononucleosis include cytomegalovirus (CMV), which is more common in adults between the age of 30 and 60. Once infected, the virus remains inactive (dormant), and while rare, it can be reactivated in

A

immunocompromised states. Transmission occurs via saliva and less frequently with other body fluids such as blood and semen.

EBV causes a lymphocytosis, and cytotoxic (CD8+) lymphocytes infect B lymphocytes. Lymphoid tissue in the throat, lymph nodes, and spleen can all be affected. In CMV mononucleosis, the macrophages are infected as opposed to the B cell. Both B lymphocyte and macrophage infection lead to T-lymphocyte reactivity.

EBV and CMV infection may be clinically silent. The incubation period is between 4 and 6 weeks. If symptomology occurs, both usually cause a fever, sore throat, myalgia, and malaise. Physical examination may reveal lymphadenopathy and an exudative pharyngitis, which is more severe with EBV. Splenomegaly and hepatomegaly are more common in EBV infection, although overall this finding is not common. EBV infection can cause hepatitis due to T lymphocytes releasing cytokines in the liver, which get trapped. Jaundice is more likely in adults over 30 with EBV or CMV infection. The classic EBV mononucleosis presentation is more common in the 12–25 age group and consists of fever, sore throat, and neck lymphadenopathy. CMV is usually associated with more severe fatigue, and duration is longer than EBV mononucleosis. Symptoms last about 2–4 weeks but fatigue can last much longer.

Diagnosis and Treatment Diagnosis is made based on the clinical presentation. EBV infection can be confirmed with several lab tests. A common, quick test is the monospot blood test. A complete blood count (CBC) may reveal increased bands, neutrophils, lymphocytes, reactive lymphocytes, and thrombocytopenia.

Diagnostic Link

Monospot ntibody testing for EBV is commonly evaluated with the monospot. This tests evaluates proteins in the blood known as heterophile antibodies produced in response to EBV. These antibodies peak around 2 to 6

weeks after infection and can present in low levels for about a year. This test does have a 25% false negative rate because children (usually < 2 years old) do not produce heterophile antibodies, and some people do not produce them at any age. The test may be negative if EBV is not the cause or if it is done too early. Other EBV antibody testing (e.g., viral capsid antigen) testing is available.

Treatment of infectious mononucleosis is focused on symptom management. Analgesics can be used for fever and myalgias. Short-term oral glucocorticoids may be useful in cases of grossly enlarged tonsils or if airway obstruction is a concern. Antivirals are not usually necessary as the symptoms are a result of the immune response as opposed to viral replications, but they can be considered in some situations like chronic EBV. Contact sports are to be avoided due to the risk of splenic rupture and should not be resumed until splenomegaly is resolved, which

occurs in a few weeks. Fatigue is common for up to two months but can continue for up to 6 months.

Complications of EBV mononucleosis can include splenic rupture. EBV infection is also a risk factor for the development of B cell lymphoma. Some complications of EBV and CMV infections include hemolytic anemia, thrombocytopenia, meningitis, myelitis, and Guillain-Barré syndrome and reactivation with immunosuppressive states. Prior CMV infection leads to the virus remaining latent in the body. The latent CMV is present in all solid organs, and the CMV infection can be reactivated when a transplantation occurs with subsequent immunosuppressive therapy.

Herpangina and Hand-Foot-and-Mouth Disease Enteroviruses, particularly the coxsackievirus, are implicated in two conditions known as herpangina and hand-foot-and-mouth disease, which are more common in children. Transmission occurs from contaminated hands, respiratory secretions, and fecal matter. The incubation period is 4–6 days. In hand-foot-and-mouth disease, vesicles (small blisters) that can ulcerate appear mainly on the buccal mucosa and tongue. The vesicles can also be on the palate, tonsils, hands, and feet. In herpangina, the lesions are more toward the back of the mouth on the soft palate, uvula, and tonsils. The lesions are grayish-white papulovesicular (raised and blistery) sores that ulcerate. Usually fever, malaise, and odynophagia (painful swallowing) is present. Treatment is geared toward symptom relief, and both diseases are self-limiting and resolve in 7–10 days.

Bacterial Pharyngitis Bacteria are another common cause of pharyngitis and usually result in an exudate on the tonsils and oropharynx. Streptococcus pyogenes is a group A beta- hemolytic (GABHS) bacteria that is responsible for up to 30% of pharyngitis cases in children and up to 15% in adults (CDC, 2016b). Other organisms such as Mycoplasma and Chlamydia species are also implicated in bacterial pharyngitis but are not as common. The peak prevalence is between the ages of 5 and 15 years. GABHS has an M protein on its cell surface, which resists phagocytosis. GABHS also has a polysaccharide capsule made of hyaluronic acid, which protects it from phagocytosis. Pharyngeal epithelial cells have CD4+, which is a hyaluronic acid- binding protein, and this protein is one reason why GABHS infections manifest on the throat. The GABHS capsule binds with CD44, leading to colonization (the presence of an organism without evidence of infection). Transmission occurs through saliva and nasal secretions from person to person. The highest risk for infection is close contact with someone who is infected. Some people can be carriers and not have symptoms. Carriers can still transmit the infection but not as commonly as

those with symptoms.

Clinical Manifestations The incubation period for GABHS pharyngitis is 2–5 days. Clinical manifestations include a sudden sore throat, painful swallowing, and fever (> 100.4°F). Cough is usually absent. Physical exam will reveal cervical lymphadenopathy (anterior more common); tonsillar erythema, hypertrophy, and exudates (may also be absent); and petechiae on the palate. A scarlatiniform rash can develop starting in the neck and chest and spreading throughout the body. The rash consists of numerous red papules.

The other less common causes of bacterial pharyngitis include Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum (syphilis), which are all sexually transmitted. Unvaccinated individuals can get pharyngitis from Corynebacterium diphtheriae. These bacteria will may cause different presentations. Diphtheria, for example, may cause the development of an adherent pseudomembrane that may appear grayish-green and bleeds when removal is attempted.

The diagnosis of bacterial pharyngitis is made clinically and can be confirmed with a rapid antigen detection test (RADT) or throat culture. These tests involve swabbing the throat. The results take about 20 minutes, and the cultures can take up to 48 hours. A throat culture should be completed if the results are negative, especially in children, because they have a higher likelihood of developing complications such as rheumatic fever and glomerulonephritis from GABHS.

Antibiotics are the mainstay of treatment in bacterial pharyngitis, and the choice is dependent on the organism (e.g., GABHS vs. gonorrhea). Infection can be self- limiting in GABHS, but antibiotics shorten the length of disease, reducing transmission and preventing complications from developing. Penicillin or amoxicillin is the first choice in GABHS. Other treatments are supportive (e.g., antipyretics, salt water gargles).

Epiglottitis Epiglottitis is a life-threatening condition of the epiglottis, the protective cartilage lid covering the trachea opening. Epiglottitis is also known as supraglottitis. In the past, Haemophilus influenzae type b (Hib) was the most common cause in the United States, but widespread use of the Hib vaccine has dramatically decreased the rate of Hib infections in recent years. Common culprits now include group A beta-hemolytic Streptococcus, Streptococcus pneumoniae, and Staphylococcus aureus. Other noninfectious causes include throat trauma from events such as drinking hot liquids, swallowing a foreign object, a direct blow to the throat, or smoking crack or heroin.

Regardless of the cause, the inflammatory response is triggered, causing, the

epiglottis (particularly the supraglottis) to quickly swell and block the air entering the trachea. The swelling and obstruction can lead to respiratory failure. The bacteria can also travel to the bloodstream, leading to life-threatening sepsis. Adults have an upper airway that is wider and more rigid than that of children and is, therefore, less predisposed to getting an obstruction with epiglottitis; however, obstruction can occur in adults and should not be overlooked.

Clinical Manifestations The onset of clinical manifestations is typically rapid in children, developing in a matter of hours, but it occurs more slowly in adults, over a few days. The manifestations include high fever, sore throat, muffled quality speech (“hot potato voice”), dysphagia (swallowing difficulty), drooling with an open mouth, inspiratory stridor, and subsequent hypoxemic signs such as central cyanosis, pallor, irritability, anxiety, and restlessness. A child may assume a forward-leaning sitting position in an attempt to facilitate breathing (tripod position). Respiratory distress and failure can follow. The throat should not be examined as it may precipitate laryngospasm and worsen the obstruction.

Diagnosis and Treatment If epiglottitis is suspected, maintaining the airway and stabilizing respiratory status is the priority before diagnostic procedures are performed. Efforts to preserve respiratory function include humidified oxygen therapy (likely delivered via mask), endotracheal intubation with mechanical ventilation, and tracheotomy. Additional efforts to minimize oxygen consumption should include keeping the patient calm and controlling fever (e.g., with antipyretics and hydration). Aerosolized epinephrine and systemic steroids (often treatments for croup) should be avoided because they may worsen the condition. Once the patient is stabilized, diagnostic procedures include visualization of the epiglottis through a fiber-optic camera, X-rays (neck and chest), cultures (throat and blood), arterial blood gases (ABGs), and a CBC. The neck X-ray on lateral view may have a “thumbprint sign,” which is created by the edematous epiglottis.

Intravenous antibiotics will be used to treat infections quickly. Hib vaccinations should be encouraged for children, the elderly, and immunocompromised persons so transmission rates will continue to be low. Other prevention strategies include proper hand washing, avoiding crowds, cleaning objects such as toys, and not sharing objects like pacifiers and bottles.

Peritonsillar Abscess One of the complications of a tonsillitis or pharyngeal infection is the development of an abscess (accumulation of pus). The abscesses can be in the peritonsillar,

retropharyngeal, and lateral pharyngeal areas. The infections are often polymicrobial (e.g., Staphylococcus aureus, Streptococcus pyogenes). Noninfectious causes include trauma from foreign body or procedures (e.g., intubation, endoscopy). Clinical manifestations are similar to other pharyngeal infections in the beginning with dysphagia (may be one side), odynophagia, drooling, fever, and voice quality changes. Airway obstruction is possible, and evaluating the respiratory status is a priority as an abscess can be difficult to distinguish from epiglottitis. Physical examination may be difficult due to trismus (jaw locking). If the throat can be examined, there will usually be a unilateral (rarely bilateral) swelling of the tonsil with exudate, asymmetry of the soft palate, and uvula displacement to the opposite side. If there is any concern that epiglottitis may be present, examination should not be conducted. Radiographic imaging or CT with contrast can aid in diagnosis. A CBC, electrolytes to evaluate hydration status, blood cultures, and ABG may be necessary.

In patients with airway compromise, management focuses on stabilizing the airway and may include intubation or tracheotomy. Intravenous antibiotics, hydration, and pain control are other treatment strategies. Incision and drainage of the abscess results in resolution in most cases. Drainage can be accomplished with topical anesthesia and a needle aspiration or with an incision. Either procedure should be done by an experienced clinician or otolaryngologist as hemorrhage and pus may accumulate in the airway, leading to respiratory compromise. Some patients such as young children may require drainage under general anesthesia. Tonsillectomy is another surgical alternative.

Laryngitis Laryngitis is an inflammation of the larynx. With laryngitis, the vocal cords become irritated and edematous and vibrate irregularly because of the inflammatory process. This inflammation distorts sounds, leading to hoarseness that is harsh and voice quality changes or aphonia (voice loss). Acute laryngitis is the most common cause of hoarseness and is usually the result of the same viral organisms (e.g., rhinovirus) that also cause other URIs. Occasionally, the airway can become blocked. Bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis can also cause laryngitis. Laryngitis can also be associated with croup and epiglottitis. Noninfectious causes of laryngitis include irritants (e.g., stomach acid, inhaled smoke, excessive alcohol use, or chemicals) or overuse (e.g., screaming, singing). These noninfectious causes can cause acute or chronic laryngitis.

BOX 5-1 Application to Practice Review the pharyngitis cases and answer the questions.

Case 1: Susan is a 16-year-old with sudden onset of severe sore throat for the past day. She feels like she had a fever but did not check her temperature (i.e., subjective fever). She states it is very painful to swallow, and she thinks she sees white spots on her throat. She denies cough, rhinorrhea, nausea, otalgia, shortness of breath, or headache. She reports no exposure to sick individuals.

Medications: none Allergies: none Social history: nonsmoker and drinks alcohol (two to three beers) one to two times a month.

Physical exam: Vital signs: temperature 101.0°F, pulse 100 per minute, respiration rate 18 per minute; blood pressure

110/66 mmHg. General: ill and tired appearance. Head, Eyes, Ears, Nose, and Throat unremarkable except for erythematous oropharynx with small

petechiae and white tonsillar exudates. Neck: anterior cervical lymphadenopathy; two on right, three on left; all small (< 0.5 cm) and tender. Cardiovascular, lungs, abdomen are unremarkable. What is the most likely diagnosis and pathogen causing this disorder and mode of transmission? Discuss data that support your decision. What diagnostic test, if any, should be done? Develop a treatment plan for this patient.

Case 2: Mr. Jones is a 54-year-old man with complaints of a scratchy, raw sore throat and painful swallowing, mild productive cough, and runny nose for the past 2 days. He says his sputum is whitish-yellow. His ears feel full, and he feels like he is getting a achy. He reports taking throat lozenges and denies nausea, fever, shortness of breath, chest pain, or headache. He states he teaches in a high school and a lot of his students have had colds.

Medications: none. Allergies: none. Social history: nonsmoker and does not drink alcohol.

Physical exam: Vital signs: temperature 99.0°F, pulse 84 per minute; respiratory rate 18 per minute; blood pressure 120/70

mmHg. General: cough during exam. HEENT: unremarkable except for mild erythematous oropharynx with no exudates; nares with mild

erythema and scant yellowish discharge. Neck, CV, lungs, abdomen are unremarkable. What is the most likely diagnosis and pathogen causing this disorder and mode of transmission? Discuss data that support your decision. What diagnostic test, if any, should be done? Develop a treatment plan for this patient. Compare the causes, clinical manifestations, diagnosis and treatment of pharyngitis in these two cases.

E

Clinical Manifestations Clinical manifestations of laryngitis can include hoarseness, a weak voice or aphonia, and a tickling sensation and raw feeling in the throat. The throat may feel dry and other symptoms of URI manifestations such as rhinorrhea and cough may be present. Laryngitis symptoms usually persist about a week longer than other URI symptoms.

Learning Points

Epiglottitis versus Croup piglottitis is often misdiagnosed as croup. One distinct difference in manifestations can assist healthcare providers in moving to appropriate life-saving treatment more quickly. With epiglottitis, patients look worse

than they sound. With croup, they sound worse than they look due to the seallike barking cough. Additionally, cough is not generally seen with epiglottitis. Although severe croup can cause complete airway obstruction, it is rarely life threatening. Picking up on these significant manifestations can save the patient’s life!

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Diagnosis and Treatment Diagnosis of acute laryngitis is based on clinical presentation, and diagnostic testing is not indicated. Treatment strategies aim to increase comfort or decrease the duration of the inflammation and includes resting the voice and warm humidification. Decongestants, antihistamines, and corticosteroids can dry out the mucous membranes and may lead to worsening of symptoms.

Acute laryngitis from viral infections or overuse is usually self-limiting. Lack of proper voice rest and shouting/singing; however, may lead to trauma and hemorrhage in the vocal cords or to the development of cysts and polyps during cases of laryngitis. Persistent laryngitis, usually beyond 2 weeks, or chronic hoarseness or voice quality changes may be indicative other disorders such as vocal cord cysts, polyps, granulomas, or ulcers. Smoking is a cause of laryngeal disorders and squamous cell laryngeal cancer and should be considered in evaluating laryngitis. Nodules on the vocal cords can develop in singers or with frequent screaming. The vocal cords can become paralyzed either unilaterally or bilaterally due to many causes such as vagal or laryngeal nerve damage from neck surgery. The cause of the paralysis could also be idiopathic. Laryngopharyngeal reflux caused by gastric acid can cause hoarseness, and it may be present with or without signs of gastroesophageal reflux (e.g., heartburn). All of these diseases require laryngoscopic evaluation. Management is based on the cause.

Laryngotracheobronchitis Laryngotracheobronchitis, or croup, is a common viral infection in children 3 months

to 3 years of age, but it can occur in older children and adults. The most common causes are parainfluenza viruses. Other viruses include adenoviruses and respiratory syncytial virus, and bacterial causes include Mycoplasma pneumoniae. Noninfectious causes include allergens and irritants (e.g., stomach acid, inhaled smoke, or chemicals). Outbreaks and epidemics occur in autumn and early winter coinciding with increased viral syndromes, but cases can occur sporadically year- round. Croup was once a deadly disease caused by diphtheria bacteria, but the introduction of antibiotics and immunizations have improved its prevention and treatment. Today, most cases of croup are mild. Nevertheless, this disease can still be dangerous as severe upper airway obstruction can occur.

Croup generally affects the larynx and trachea and leads to edema of the subglottic area and may extend to the bronchi. The subglottic tissue, as with other areas of the larynx, is looser, allowing for edema to develop readily. This edema leads to airway narrowing and obstruction.

Clinical Manifestations Croup usually begins as an upper respiratory infection with rhinorrhea, fever, and sore throat. Signs and symptoms, 1 to 2 days later, progress to hoarseness and a seallike barking cough because of laryngeal swelling. Inspiratory stridor, cyanosis, altered level of consciousness, impaired air entry, and retractions may be present. These five symptoms form part of the Westley score to determine the severity of croup. The worse these symptoms (e.g., stridor at rest, decreased air entry, severe retractions), the higher the score. Noninfectious causes of croup can present with similar symptoms but occur more suddenly, resolve quickly, and occur more often in older children.

Diagnosis and Treatment Diagnosis is usually made on clinical evaluation, and diagnostic tests are usually not necessary. If diagnostic testing is done, it may include a nasopharyngeal swab to determine viral antigen. Depending on presentation, other diagnostic tests may include a CBC, ABGs, and neck X-ray, which may reveal a narrowing of the upper trachea (often referred to as the steeple sign because the narrowing looks like a church steeple) in 50% of cases (FIGURE 5-15).

FIGURE 5-15 Steeple sign. Courtesy of Hugh Dainer, MD, PhD.

Croup is usually self-limiting, but if severe, cases can be life threatening without supportive therapy. Treatment strategies include cool humidity, corticosteroids to decrease edema, humidified oxygen (which can be administered via an oxygen tent over an infant’s crib), and hydration to combat fever, moisten the airway, and liquefy secretions. Aerosolized epinephrine’s (alpha and beta) adrenergic effects can reduce secretions and edema but epinephrine is usually reserved for severe cases. Heliox (a mixture of helium and oxygen) can also be used for cases of severe airway narrowing. Heliox decreases airway resistance, which reduces the work of breathing. Cool humidity may decrease edema, but no studies have supported this treatment. This intervention should be avoided in patients with asthma because it may trigger bronchial constriction. Cool humidity can be accomplished with a cool-mist humidifier, exposure to cool outside air especially at night, and exposure to a cold shower mist in a closed bathroom. Strategies to decrease oxygen consumption include keeping the patient calm and avoiding unnecessary procedures. Additionally, educating the public regarding diphtheria vaccination compliance is critical to manage this once life-threatening condition.

Influenza Influenza, or flu, is a viral infection that may affect the upper and lower respiratory tract. Influenza viruses are known as orthomyxoviruses, and three types are distinguished—A, B, and C.

Type A influenza, which includes several subtypes, is the most common type of influenza virus. This type is usually responsible for the most serious epidemics and global pandemics (worldwide epidemics), such as those that occurred in the United States in 1918, 1957, 1968, and 2009. A subgroup of type A is H1N1, colloquially referred to as the swine flu, which was responsible for a serious pandemic that started in the United States and Mexico in 2009. Type A influenza goes through continual antigenic changes. These changes make type A highly adaptive and constantly mutating, which in turn prevents the development of any long-term immune defense. Type B influenza outbreaks can also cause regional epidemics, but the disease is generally milder than that caused by type A. Type B can have antigenic change at times but to a lesser degree than A. Type C influenza causes sporadic cases and minor, local outbreaks. Type C has never been connected with a large epidemic. Type C is antigenically stable.

Type A influenza viruses are found in humans and many animals (e.g., ducks, chickens, pigs, and whales). Type B is isolated primarily in humans, whereas type C is found in humans, pigs, and dogs. Type A influenza has been found in aquatic birds for years without causing harm to them, but recently this frequently mutating flu virus has shown that it can jump the species barrier from wild birds to domesticated poultry and swine. Pigs can be infected by avian and human flu, especially in areas where human contact is frequent. If a pig becomes infected with the avian and human flu simultaneously, the two types may exchange genes. This exchange leads to a reassortment and what is termed an antigenic shift, which is abrupt and causes severe outbreaks. When infectivity occurs in the body, it does not recognize the animal component, so antibodies are not produced and immunity does not develop. The other human component allows replication. Immunity, therefore, does not occur. This lack of immunity development is usually how pandemics start. Since influenza B and C are primarily in humans, reassortment between species (e.g., humans and animals) does not occur, so the antigenic changes (i.e., antigenic drift) lead to new strains and spread occurs slowly. Reassorted flu can sometimes spread from pigs to humans and may cause a more or less severe strain. In 1997, scientists found that a form of avian H5N1 flu skipped the pig step and infected humans directly for the first time. Alarmed health officials feared a pandemic. Fortunately, the virus could not pass from person to person, so it did not spark an epidemic. As of July 2018, 860 human cases of the avian flu virus have been confirmed worldwide, which resulted in 454 deaths (World Health Organization [WHO], 2018a).

Millions of Americans contract the flu each year. The flu season (i.e., when the incidence is the highest) in the United States is typically between October and March. The virus is transmitted through the inhalation of or contact with respiratory droplets. Children are two to three times more likely than adults to contract the flu, and children frequently spread the virus to others. The 2015–2016 U.S. flu season saw mostly influenza type A (H1N1 and H3N2) (CDC, 2016a). The 2017–2018 flu season was less severe and did not reach the pandemic levels of the 2009–2010 season (CDC, 2018). The 2017–2018 season was the first season to be classified as high severity with mostly cases of type A (H3N2). The 2017–2018 flu season peaked close to levels seen in 2009, and the duration was longer than in other seasons (≥ 19 weeks). The 2017–2018 saw high levels of outpatient visits for influenza-like illness and rates of hospitalization. The number of reported deaths attributed to pneumonia and influenza was at or above epidemic levels compared with recent years, and the number of pediatric deaths was higher than in other years. Persons at greater risk for having negative outcomes because of the flu include children; elderly people; pregnant women; individual who are immunocompromised; those who are severely obese (with a body mass index of 40 or higher); and those with preexisting chronic diseases such as asthma, cardiovascular disease, diabetes mellitus, or kidney disease.

The antigen changes that occur with influenza and lead to the development of various subtypes of type A are categorized by two surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). Antibodies are directed mainly toward the HA, which is a protein continually evolving into new strains. On the surface of the virus, HA has large globules, and on these globules is a pocket, which is the viral attachment site. Antibodies are unable to penetrate this pocket. The NA glycoprotein is involved in the viral replication cycle by helping to release viral particles. NA may also help the virus penetrate the mucin in the respiratory tract, so it could then reach the epithelial cells.

The influenza virus is unique because of the continual antigenic changes of HA and NA. Other respiratory viruses do not display significant antigenic changes. The virus changes due to gene mutations that accumulate. The immune system allows these new antigen variants to flourish. This process eventually leads to a new strain.

Once a person is infected by the virus, replication occurs quickly as the virus shuts down the host cell protein synthesis for 3 hours. This short shutdown allows for viral proliferation. The influenza virus has an incubation period of 1–4 days, with peak transmission risk starting at approximately 1 day before onset of symptoms and lasting 4–7 days afterward in adults. The innate immune system releases interferon, which has an antiviral effect and is part of the recovery process. Acquired immunity (humoral/antibody and cell mediated) responses are not seen until 7–14 days after infection. Cytotoxic T lymphocytes attack the viral internal proteins and external glycoproteins. Children can be infectious for more than 10 days, and young children can spread the virus for 6 days before the onset of symptoms. Severely immunocompromised persons can spread the virus for weeks or months. Flu differs from infectious rhinitis (common cold) in that the flu usually has a sudden onset of symptoms (TABLE 5-2).

TABLE 5-2 Comparison of Infectious Rhinitis and Influenza Manifestations

Symptoms Infectious rhinitis Influenza

Fever Rare Usual; high (100°F to 102°F, but occasionally higher, especially in young children); lasts 3–4 days

Headache Rare Common

Myalgia Slight Usual; often severe

Malaise Sometimes Usual; can last up to 3 weeks

Exhaustion Never Usual; at the beginning of the illness

Stuffy nose Common Sometimes

Sneezing Usual Sometimes

Sore throat Common Sometimes

Chest discomfort, cough Mild to moderate, nonproductive cough

Common; can be severe

Modified from National Institutes of Allergy and Infectious Disease. (2008). Is it the cold or the flu? Retrieved from http://www.niaid.nih.gov/topics/Flu/Documents/sick.pdf

Clinical Manifestations Clinical manifestations occur as a result of the immune response (e.g., mononuclear infiltration, cytokine release). The signs and symptoms common with the flu include fever, chills, headache, myalgia, malaise, exhaustion, and a nonproductive cough with chest discomfort. Other clinical manifestations are similar to those found in infectious viral rhinitis but are not as common and include nasal congestion, sore throat, and watery rhinorrhea. Vomiting and diarrhea occur more often in children than adults. Typically, fever and body aches last 3–5 days, while rhinitis, cough, and fatigue may last for 2 or more weeks. Physical examination findings are usually similar to those in viral URIs (e.g., cervical lymphadenopathy and erythematous oropharynx and nasal passages).

Diagnosis and Treatment Diagnosis is usually made clinically, particularly if a patient has manifestations during the flu season and when there are known outbreaks. However, diagnostic tests may be important if diagnosis is questionable or if a patient is immunocompromised or has signs of a severe respiratory illness. There are several diagnostic tests used to evaluate for the influenza virus. These influenza tests can detect parts of the virus (i.e., antigen), or genetic testing of the virus (e.g., viral RNA, nucleic acid testing) can be done. Some tests can distinguish between types such as A or B. The test results can be ready within 30 minutes. Viral culture results can be obtained anywhere from 1–10 days after collection. Treatment is symptomatic and supportive unless a secondary bacterial infection is present. Antiviral medications such as amantadine or rimantadine are known as M2 ion inhibitors and are useful for type A influenza; however, these drugs are not recommended unless similar strains that were responsive return due to drug resistance. Zanamivir, oseltamivir (Tamiflu), and peramivir are NA inhibitors that can be used for type A or B to reduce the severity and duration of the symptoms. Resistance can occur and is more common in children. Baloxavir marboxil (Xofluza) is a newer category of medication for the flu that inhibits polymerase acidic endonuclease, which is necessary for viral reproduction. It prevents replication while NA inhibitors stop the release of the virus. Only one dose is necessary in comparison to oseltamivir, which requires at least 10 days of administration. Both are only effective if taken within 48 hours of exposure. Antivirals can be given on a postexposure basis as a preventive measure to decrease the likelihood of developing the flu. Other treatment strategies include increased fluid intake, adequate rest, antipyretics, and analgesics.

Complications can occur from the flu. The damaged respiratory epithelium is vulnerable to secondary bacterial pathogens such as staphylococci, streptococci, and Haemophilus influenzae as well as other viral pathogens. These pathogens invade the lower respiratory system, causing pneumonia. More commonly, the pneumonia is caused by a combination of a virus and bacteria. The staphylococcal bacteria split the HA glycoprotein, allowing for high levels of virus to infect the lungs. Deaths associated with the flu are often a result of secondary bacterial pneumonia. Although rare, influenza A and B can cause acute encephalopathy (Reye syndrome) in children and adolescents.

Prevention strategies are similar to those used to prevent the common cold (e.g., hand washing and avoiding crowds) but also include vaccinations. Currently, vaccinations exist for the seasonal flu and H1N1 flu (if warranted). Four types of seasonal flu vaccinations are produced—regular seasonal flu vaccine (the form most commonly administered to people 6 months and older), high-dose vaccine (for people age 65 and older), intradermal vaccine (for people age 18–64), and intranasal flu vaccine, which is approved for healthy, nonpregnant people age 2–49. The intranasal vaccine is attenuated (live), and the other types are inactivated. Prior to each flu season (usually before the previous season is over), the CDC develops a seasonal flu vaccine based on predictions of the likely strain to be encountered. In the United States, the seasonal flu vaccine should be administered each year in October, but it may be recommended to be administered again in February. The vaccine is recommended to everyone age 6 months and older, especially those in high-risk groups (e.g., persons with a chronic medical condition or who are immunocompromised persons age 50 years or older or those between 6 months to less than 5 years, those who are pregnant, persons living in a community setting, and those who are caregivers or have contact with anyone in any of these groups). When outbreaks of other types of the flu occur, as with the H1N1 influenza in 2009, the CDC develops vaccinations specific for those strains.

Myth Busters

A common misconception is that you can get the flu from the flu vaccine. What fuels this myth is that some people may experience very mild flulike symptoms (e.g., low-grade fever, aches, malaise) after receiving the vaccination. These symptoms do not occur because the individual has a mild case of the flu; rather, they are due to the process through which the immune system develops antibodies against the virus. An additional factor fueling this myth is the possibility that people may still have the flu even after receiving the vaccination. This infection is not caused by the flu vaccine; rather, it occurs because the person encountered a strain of the flu that was not covered by the vaccination. Remember, the

vaccination is based on predictions. Negative outcomes from the flu vaccine are rare and minimal. So get vaccinated and encourage others to do the same!

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Vaccine development can be a lengthy process. In many cases, the vaccines are grown in fertilized chicken eggs for approximately 10 months. Therefore, flu vaccines should not be administered to persons with egg allergies. Additionally, children younger than 6 months and people with a history of Guillain-Barré syndrome should not be vaccinated. People with an active febrile illness should wait to be vaccinated until after the illness resolves.

Lower Respiratory Tract Infections The lower respiratory tract includes the trachea, bronchi, bronchioles, and alveoli. Infections can have similar manifestations to upper respiratory tract infections. URIs can progress to lower respiratory tract infections. Lower respiratory tract infections can be life threatening such as with pneumonia. Laryngotracheobronchitis spans across the upper and lower tracts but is discussed in the Upper Respiratory Tract Infections section.

Acute Bronchitis Acute bronchitis is an inflammation of the tracheobronchial tree or large bronchi. This inflammation is most commonly caused by a wide range of viruses (e.g., influenza, rhinovirus, respiratory syncytial virus, and adenovirus). Bacterial invasions, which are not as common, can include Chlamydiae pneumoniae, Mycoplasma pneumoniae, and Bordetella pertussis. Secondary bacterial infections can occur after a viral infection and are usually caused by Streptococcus pneumoniae and Haemophilus influenzae. Secondary bacterial infections are more likely to occur in those with chronic obstructive pulmonary disease (COPD). In most cases, a pathogen cannot be identified. Noninfectious causes of acute bronchitis are less frequent and include irritant inhalation (e.g., smoke, marijuana, pollution, and ammonia) and allergic reactions. Young children, the elderly, and smokers are at the highest risk for developing acute bronchitis. In acute bronchitis, the bronchial lining becomes irritated, and the airways become narrowed due to the results of the inflammatory process (e.g., capillary dilation, edema, and exudate).

Clinical Manifestations Clinical manifestations of acute bronchitis are usually mild and resolve in 7–10 days, but coughing may linger for several weeks after the infection is resolved. Acute

bronchitis often begins with a nonproductive cough as the key complaint, but the cough can become productive. The cough is paroxysmal (sudden outburst), and musculoskeletal chest pain often occurs due to the coughing. The chest pain is usually retrosternal. Due to the inflammation, the airways may narrow and cause wheezing, which may be intermittent. Patients can have other symptoms similar to pneumonia such as fever, chills, malaise, and shortness of breath. Physical exam may reveal oropharynx erythema and neck lymphadenopathy. Wheezing may be present along with rhonchi and crackles; however, pulmonary consolidation signs (e.g., dullness to percussion) are absent. If consolidation signs are present, pneumonia is the probable diagnosis.

Diagnosis and Treatment Diagnosis of acute bronchitis is usually made based on clinical evaluation. Diagnostic tests such as a CBC and cultures (e.g., nasal secretions, sputum, blood) may be considered but are not necessary to confirm diagnosis. Chest X-ray findings will be normal and without evidence of an infiltrate or consolidation.

Acute bronchitis is generally self-limiting; therefore, treatment is supportive. Pharmacologic treatment may include antipyretics, analgesics, antihistamines, decongestants, cough suppressants, bronchodilators, and antibiotics in cases of bacterial infection. Cough suppressants should be used cautiously, as coughing mobilizes secretions and can prevent pneumonia. Other strategies include increasing fluid intake, avoiding smoke, and breathing humidified air.

Bronchiolitis Bronchiolitis refers to a common acute inflammation of the bronchioles that usually results from a viral infection. The most common virus is the respiratory syncytial virus (RSV). Other viruses include parainfluenza, influenza, adenoviruses, and metapneumoviruses (an emerging paramyxovirus). Bronchiolitis often occurs in children younger than 1 year of age, and the incidence increases in the fall and winter months. According to the CDC (2017c), 2.1 million children younger than the age of 5 years seek medical attention annually for RSV infection, and nearly all children will have an RSV infection by the time they are 2 years old.

When the virus infects the bronchioles, these small airways become inflamed and swollen. The cell mediated response to the antigens results in the mobilization of eosinophils, neutrophils, monocytes, and lymphokines (e.g., interleukin, interferon), which initiate the inflammatory process. As a result of the inflammatory process, cellular debris from destroyed epithelial cells and mucus collects in these small airways. Bronchospasm may further occlude the airways. The airway obstruction leads to trapping of air and hyperinflation. Atelectasis (collapse of the alveoli) and ventilation problems occur as expiration is impaired, all leading to increasing

breathing difficulties. Transmission of RSV occurs through contact with or inhalation of infected respiratory droplets. Factors contributing to the development of bronchiolitis include neonatal prematurity, asthma family history, and cigarette smoke exposure.

Clinical Manifestations Clinical manifestations of bronchiolitis vary in severity and include the following: rhinorrhea, cough, decreased appetite, malaise, and fever. Varying degrees of respiratory distress such as dyspnea, tachypnea, tachycardia, expiratory wheezing, rales or rhonchi, rapid shallow respirations, and labored breathing (e.g., retractions, nasal flaring, and grunting) may be present. Severe cases may alter chest structure by increasing the anterior–posterior diameter (like a barrel), and if there is significant swallowing of air, the abdomen can become distended.

Diagnosis and Treatment Diagnosis is usually made by clinical evaluation. Other diagnostic procedures may include a CBC and ABGs. Nasal specimens may be evaluated for RSV. A routine chest X-ray is also not necessary unless complications or comorbidities are suspected. Depending on the severity, the chest X-ray may reveal hyperexpansion (air gets trapped in lungs and they get overinflated) and infiltrates (accumulation of abnormal substances in interstitium or alveoli). Treatment strategies are geared towards symptoms as no specific therapy exists. These strategies include oxygen therapy, cool humidity, suctioning secretions, increased fluids (either by mouth or intravenously), keeping the patient calm, bronchodilators, and corticosteroids. Mild cases can be managed on an outpatient basis. Patients with severe cases or children at risk for decompensation (e.g., lung or heart disease, immunocompromise) will need to be hospitalized. Atelectasis and respiratory failure require more aggressive treatment and possible intubation with ventilator support.

Prevention strategies are the same as those previously discussed for other infectious respiratory conditions (e.g., hand washing). RSV has two glycoproteins—F glycoprotein, which attaches to the membrane of the target cell, and G glycoprotein, which targets the cilia in the airway. The vaccine palivizumab is a monoclonal antibody that binds to the F glycoprotein on RSV, preventing the virus from infecting the cells. This vaccine can be given to at-risk infants during RSV season to prevent and minimize infection. Other vaccines for RSV are in development but are not yet commercially available. Bronchiolitis may be linked to asthma development.

Pneumonia Pneumonia is an inflammatory process of the lung parenchyma. The parenchyma is the portion of the lungs where gas transfer occurs and includes the respiratory

bronchioles, alveolar ducts, and alveoli. Pneumonia is usually caused by infectious agents (e.g., bacteria, viruses, and fungi), but parenchymal injury with inflammation can occur through inhalation of chemicals such as smoke or from aspiration (e.g., stomach contents). According to the CDC (2017b), pneumonia accounts for 1.1 million hospitalizations and nearly 52,000 deaths in the United States annually.

Treatment decisions and prognosis are based on identification of the cause of pneumonia. The identification of specific causative pathogens in pneumonia can be challenging, and several categorizations of pneumonia exist. These categorizations include individual risk characteristics (e.g., immunocompromise, advanced age, underlying lung diseases, and alcoholism) and anatomic lung distribution involvement (e.g., lobar, bronchopneumonia, and interstitial pneumonia). Other categories include location of acquisition such as community-acquired pneumonia and hospital-acquired pneumonia [HAP]). The pathogen prevalent for each location, individual risks, and anatomic location can vary.

The gram-positive bacteria, Streptococcus pneumoniae (i.e., pneumococcal pneumonia) is responsible for most cases of community-acquired pneumonia. Other gram-positive organisms are Haemophilus influenzae and Staphylococcus aureus. Gram-negative bacilli include Klebsiella pneumoniae and Pseudomonas aeruginosa. Atypical pneumonia refers to infections with atypical organisms, which includes Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species. The term atypical is used clinically as the pneumonia from these pathogens may not respond to usual antibiotics, and symptoms and X-ray findings may be slightly different than pneumonia from typical pathogens. HAP is a pneumonia that occurs 48 hours after admission to a hospital, and another group is ventilator-associated pneumonia which develops 48 hours after intubation. HAP and ventilator-associated pneumonia causes are numerous and can be polymicrobial; the causes include organisms such S. aureus, P. aeruginosa, Klebsiella, and Enterobacter. Viruses can also be a common cause of pneumonia. Immunocompromised patients are at high risk for pneumonia from fungal infections.

Pathogens can enter the lung parenchyma as a result of aspirating oropharyngeal secretions or inhaling particles in the air through coughing, sneezing, or particles that have been aerosolized from equipment such as a respiratory mask. The introduction of devices such as endotracheal tubes and suction catheters can be a portal of entry for pathogens. Contiguous (adjacent) spread occurs when a site close to the lung is infected and causes a direct spread of the pathogen to the lung (e.g., amebic liver abscess). Another route for pathogens to enter the lungs is hematogenously (via bloodstream). The hematogenous mechanism is not as common but can occur with central line infection, urinary tract infection, endocarditis, or from any other bacteremic process.

Once the pathogen has entered the lungs, the innate immune defenses are activated. The first line of defense can become overwhelmed if the pathogen is

A

sufficiently virulent, is present in large numbers, and/or the person has risk factors such as smoking or preexisting lung disease (e.g., cystic fibrosis). The spongy character of the lung facilitates movement of pathogens. Some epithelial cells in the airway can recognize pathogens such as Pseudomonas aeruginosa or Staphylococcus and continue to mount a defense. The key defense cells, however, are the alveolar macrophages. These macrophages have pattern recognition receptors that can recognize a limited number of pathogens. This early detection leads to the activation of neutrophils, lymphocytes, platelets, and fibrinogen that travel to the site of infection. Macrophages, mast cells, and other cells release cytokines and chemokines (e.g., tumor necrosis factor-alpha, IL-1). Antigens are presented to the adaptive immune system (B and T cells) to further fight the infection. Neutrophils phagocytize pathogens and create a proteinlike mesh called a neutrophil extracellular trap in an attempt to trap bacteria. The inflammatory process ensues; bronchial, alveolar, and capillary membranes become damaged, and fluid goes into the interstitial space. A high-protein content exudate develops. The exudate and cell debris accumulate in the alveoli and bronchioles, impairing gas exchange and causing dyspnea and hypoxemia. The mixture of white blood cells, red blood cells, and fibrin fill areas of the lung affected by the infection and lead to a consolidation (inflamed, solid area). The consolidated area may be detected through physical exam (e.g., dullness to percussion) or chest X-ray.

Diagnostic Link

Chest X-Ray: Consolidation n X-ray involves the use of electromagnetic waves to create images. Different tissues absorb different amounts of radiation, and therefore the images are in shades of black and white. Tissue density refers to

the amount of radiation absorption, and objects with higher density are termed radiopaque and appear white while objects with lower density are radiolucent and appear black. In between are various shades of gray. Bones absorb more radiation and are dense and appear white (radiopaque). Fat and soft tissue are less dense and absorb less and have a gray appearance. Air absorbs the least amount of radiation and appears black (radiolucent). A consolidation on a chest X-ray refers to alveoli that have fluid, blood, pus, or other substances. Consolidations are dense and cause opacities (white areas). The opacities can be focal (lobar), diffuse, or multifocal. Pneumonia is the most common cause of consolidation, and different pathogens can produce different patterns (e.g., streptococcal pneumonia is lobar).

Legionnaires’ disease is a specific type of pneumonia that is caused by Legionella pneumophilia. These bacteria thrive in warm, moist environments (e.g., air-conditioning systems, standing fresh water, respiratory therapy equipment, and whirlpools), and most people acquire this type of pneumonia from inhaling the bacteria. Persons with a weakened immune system are at highest risk for developing legionnaires’ disease. Although most people with this type of pneumonia recover without incident, the disease can be fatal if untreated. Symptoms are similar to other types of pneumonia and usually appear 10–14 days postexposure. Additional

symptoms may include nausea, vomiting, and diarrhea. In addition to the usual pneumonia diagnostic procedures, a urine test can be performed to identify the presence of Legionella antigens. Legionnaires’ disease treatment is similar to that of other pneumonias.

Viral pneumonias can be caused directly by influenza virus, adenoviruses, paramyxovirus (e.g., metapneumovirus, RSV). Having other viral diseases such as varicella (chickenpox) or rubeola (measles) can lead to the development of viral pneumonia. Severe acute respiratory syndrome (SARS) is a respiratory illness that presents similarly to atypical pneumonia. SARS is caused by a coronavirus, SARS-CoV. First identified in China, its prevalence rates remain higher in Asian countries. Transmission occurs through inhalation of respiratory droplets or close contact, although oral–fecal contact may also be a mechanism of transmission. SARS has high mortality and morbidity rates. The incubation period for this disease is 2–7 days. The first stage presents as a flulike syndrome (e.g., fever, chills, headache, myalgia, anorexia, and diarrhea) that lasts 3–7 days. Several days later, a dry cough and dyspnea develop as the lungs become damaged and the patient moves into the second stage of the disease. Interstitial congestion and hypoxia progress rapidly. Additionally, liver damage can occur. If the patient continues to the third stage, severe and sometimes fatal respiratory distress can develop. Diagnostic procedures for SARS consist of a history, physical examination, and chest X-ray. Treatment focuses on maintaining oxygenation and respiratory status, with strategies including oxygen therapy, bronchodilators, and antiviral drugs. Endotracheal intubation with mechanical ventilation support may be required as hypoxia worsens.

An emerging illness in the same coronavirus family is Middle East respiratory syndrome (MERS-CoV). It was first reported in Saudi Arabia in 2012 and has since spread to several other countries, including the United States (CDC, 2017a). Between its discovery in April 2012 and May 2018, 2,200 cases and 790 deaths from this disease were reported worldwide (WHO, 2018b). The virus is currently isolated to four countries in the Arabian Peninsula. Dromedary camels are hosts, and there can be camel-to-human transmission and human-to-human transmission, but the CDC is still working on better understanding the virus (CDC, 2017c).

Most healthy people do not develop pneumonia from fungal exposure. Instead, many of these illnesses occur as opportunistic infections, which can be fatal in immunocompromised individuals (e.g., children and persons with AIDS or cancer). Pneumocystis jiroveci pneumonia, formerly known as Pneumocystis carinii pneumonia, is a specific type of pneumonia that is caused by yeastlike fungus. Diagnosis is accomplished through identification of the fungus through a sputum culture. Aggressive and early treatment will improve outcomes in these vulnerable patients. Other fungal-related pneumonias include histoplasmosis, coccidioidomycosis, and cryptococcal pneumonia.

In addition to previously discussed risk factors, persons at risk for developing

pneumonia from any cause and having serious complications include children, the elderly, immunocompromised individuals, those with existing chronic disease conditions, smokers, and alcoholics. Otherwise-healthy patients usually recover completely from pneumonia when treated properly. By comparison, high-risk persons are more likely to develop complications including septicemia, pulmonary edema, lung abscess, pleural effusion, and acute respiratory distress syndrome.

Irritating agents or events can also lead to pneumonia—for example, aspiration of gastric contents and inhalation of smoke or chemicals. Aspiration pneumonia frequently occurs when the gag reflex is impaired because of a brain injury or anesthesia. Aspiration can also occur because of impaired lower esophageal sphincter closure secondary to nasogastric tube placement or disease (e.g., gastroesophageal reflux disease). Additionally, inappropriate gastric tube placement can lead to tube-feeding formulas entering the lungs rather than the stomach. Gastric contents and tube-feeding formulas irritate the lung tissue, triggering the inflammatory response. The inflammatory response increases mucus production, which can in turn lead to atelectasis and pneumonia. Tube-feeding formulas also contain sugar and protein, creating a superior medium in which bacteria can grow and flourish. Finally, pneumonia can develop from stasis of pulmonary secretions. When these secretions become thick and stagnate, ciliary action cannot remove the bacteria-laden mucus, leading to pneumonia. Activities such as movement, talking, and coughing normally keep pulmonary secretions moving, and adequate hydrations keep secretions thin.

Pneumonia is classified based on the causative agents or events previously discussed and its location in the lung (TABLE 5-3). Lobar pneumonia is confined to a single lobe and is described based on the affected lobe (e.g., right upper lobe). Bronchopneumonia is the most frequent type and is a patchy pneumonia spread throughout several lobes. Interstitial pneumonia, or atypical pneumonia, occurs in the areas between the alveoli. Interstitial pneumonia is routinely caused by viruses (e.g., influenza type A and B) or by atypical bacteria (e.g., Legionella pneumophilia and Mycoplasma pneumoniae).

TABLE 5-3 Types of Pneumonia

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Clinical Manifestations Clinical manifestations of pneumonia may vary depending on type. General signs and symptoms include the following: productive or nonproductive cough, fatigue, pleuritic pain, dyspnea, fever, chills, crackles, consolidation signs (e.g., dullness to percussion), decreased breath sounds, pleural rub, tachypnea, and mental status changes (especially in the elderly). Viral pneumonia and bacterial pneumonia have some notable differences (TABLE 5-4). Viral pneumonia is usually mild and heals without intervention, but it can lead to virulent bacterial pneumonia.

TABLE 5-4 Comparison of Viral and Bacterial Pneumonia

Viral Bacterial

Cough Nonproductive Productive

Fever Low grade Higher

WBC Normal (low) Elevated

X-ray Minimal change Infiltrates

Severity Less More

Antibiotics No Yes

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Diagnosis and Treatment Early diagnosis and treatment of pneumonia are paramount to have positive

outcomes. A history and physical may be sufficient to diagnose pneumonia; however, a chest X-ray is an important diagnostic test as findings may aid in determining the pathogen, identifying pleural effusions, or detecting the development of cavities (walled hollow structures in the lungs). The information from the chest X- ray can then be used to choose efficacious treatments to expeditiously treat the pneumonia. Community-acquired pneumonia can be managed on an outpatient basis. Hospitalization (e.g., general or intensive care unit) may be necessary if illness is severe as manifested in degree of respiratory distress or septicemia. When deciding on place of treatment, either home or hospital, other factors that should be taken into consideration are ability to take and adhere to a medication regimen, self- care and cognitive abilities, and living situation (e.g., homelessness, distance from a hospital). Two clinical prediction scores can be used to determine need for admission—evaluation of confusion, blood urea nitrogen, respiratory rate, blood pressure, and age and this is commonly known by the acronym CURB-65. The second prediction score—the pneumonia severity index—uses multiple clinical data input such as age, gender, neoplastic disease, and congestive heart failure; a score is assigned for the multiple variables.

Additional diagnostic testing for pneumonia can include sputum cultures and gram staining, CBC, ABGs, and bronchoscopy. Managing respiratory distress is a priority, and endotracheal intubation may be necessary to provide ventilation support and maintain oxygenation. Antibiotics are required if bacterial infection is present. If treatment is empiric, antibiograms should be used to determine the most appropriate antibiotic. Antibiograms are created as part of infection control measures in an effort to promote antibiotic stewardship. Antibiograms are developed from institutional culture results to identify antibiotic susceptibility and resistance patterns. Additional treatment may include bronchodilators, corticosteroids, antipyretics, analgesics, humidified oxygen therapy, chest physiotherapy, increased fluids (either by mouth or intravenously), and rest. If aspiration is the cause of the pneumonia, additional treatment includes eliminating the causes and not giving the patient anything by mouth until swallowing studies can be performed. Pneumonia prevention strategies include hand washing, avoiding crowds, vaccinations (e.g., for pneumococcus, influenza, and Hib), mobilizing secretions (e.g., turning, coughing, deep breathing), and smoking cessation.

Tuberculosis Tuberculosis (TB), an ancient disease, is one of the world’s deadliest conditions. Although on the decline, TB remains a major cause of illness, with one-third of the world’s population being infected. According to the World Health Organization, TB was responsible for approximately 1.3 million deaths worldwide in 2017, and it is the leading cause of death for persons infected with HIV (WHO, 2018c). An additional

1.7 billion people are thought to have latent TB infection and are at risk for developing active TB (WHO, 2018c). In the United States, TB rates are highest among Asians at 18.0 per 100,000 persons, and the lowest rate is in White, non– Hispanic persons at 0.6 per 100,000 (CDC, 2018b).

TB is caused by Mycobacterium tuberculosis, a slow-growing aerobic bacillus that is somewhat resistant to the body’s immune efforts because it has a capsule composed of waxes and fatty substances. Other mycobacteria (e.g., M. bovis and M. africanum) are rare in the United States. Person-to-person transmission occurs through the inhalation of tiny infected aerosol droplets. Only people with active TB can spread the disease to others. The bacillus is capable of surviving in dried sputum for weeks, but ultraviolet light, heat, alcohol, glutaraldehyde, and formaldehyde destroy it. Many people contract TB but do not develop the disease because of an intact, healthy immune system or early treatment. Multidrug-resistant TB strains are relatively rare but account for 78 cases annually in the United States (CDC, 2018b); there are over 558,000 diagnosed cases worldwide (WHO, 2018c). Extensively drug-resistant TB is extremely rare in the United States, with only one known case occurring in 2016; in contrast, extensively drug-resistant TB is a global threat that has been linked to cases in more than 100 countries. TB is often considered an opportunistic infection because it is more likely to become active in someone with a weakened immune system. At-risk persons include those with immune deficiency (e.g., AIDS and cancer), malnutrition, diabetes mellitus, and alcoholism. Poverty, overcrowding, homelessness, and drug abuse also increase the risk for acquiring TB. Young children (less than 2 years old) and adolescents are also at greater risk than adults.

BOX 5-2 Application to Practice Review the pulmonary infection cases and discuss whether the diagnosis is infectious rhinitis, influenza, acute bronchitis, acute bronchiolitis, or pneumonia.

Case 1: Jack is a 21-year-old complaining of a sudden onset of myalgia with his body aching all over and headache for the past day. He feels tired and has the chills, and his temperature was 100°F. He has a mild nonproductive cough. He denies rhinorrhea, sinus pain, nausea, otalgia, or shortness of breath. He reports exposure to sick contacts in his dorm, stating, “Everyone seems to be coughing and catching a cold or the flu.”

Medications: none. Allergies: penicillin. Past medical history: healthy. Social history: college student, lives in a dormitory. Nonsmoker and drinks alcohol once a week, about two

or three beers.

Physical exam: Vital signs: temperature 100.5°F, pulse 98 per minute, respiratory rate 18 per minute, blood pressure

110/70 mmHg pulse oximeter 98%. General: ill and tired appearance. Head, Eyes, Ears, Neck, Throat: unremarkable. Neck: no lymphadenopathy; negative Kernig sign, negative Brudzinski sign. Cardiovascular: lungs, abdomen are unremarkable. What is the most likely diagnosis and pathogen causing this disorder? Discuss the mode of transmission

and discuss the data that supports your decision. What diagnostic test, if any, should be done? Develop a treatment plan for this patient.

Case 2: Mr. Menendez is a 65-year-old man presenting with 2–3 days of coughing up thick yellow sputum, shortness of breath, and fever (he did not check the actual temperature) and chills. He states his chest hurts when he breathes. He denies headache, rhinorrhea, sinus pain, and nausea. He reports no exposure to sick individuals.

Medications: lisinopril 10 mg a day by mouth. Allergies: no known drug allergies. Past medical history: hypertension Social history: smokes 1 pack of cigarettes per day (has done so for 30 years); denies alcohol use; works

as a landscaper.

Physical exam: Vital signs: temperature 101°F, pulse 98 per minute; respiratory rate 22 per minute, blood pressure 140/86

mmHg, pulse oximeter 93%. General: ill and tired appearance, coughing during visit with thick yellow sputum noted. HEENT: unremarkable. Neck: small anterior and posterior cervical nodes. CV: unremarkable. Lungs: right basilar crackles with dullness to percussion in right lower lobe. Abdomen: unremarkable. What is the most likely diagnosis and pathogen causing this disorder? Discuss the mode of transmission.

Discuss the data that support your decision. What diagnostic test, if any, should be done? Develop a treatment plan for this patient.

Case 3: Jamie is a 1- year-old girl who is coughing and has had rhinorrhea with yellowish discharge for the past day. Her father says today he felt like she had a fever and has not been eating or playing; she has been mostly sleeping. Her 5-year-old sibling has had a cold for a week.

Medications: none. Allergies: no known drug allergies. Vaccinations: up to date for age. Social history: in day care; lives with mother and father and 5-year-old sibling.

Physical exam: Vital signs: temperature 101.5°F, pulse 120 per minute, respiratory rate 34 per minute; blood pressure

100/60 mmHg, pulse oximeter 92%. General: sitting in father’s lap; ill, lethargic appearance, and coughing. HEENT: nasal flaring, nasal mucus yellowish bilaterally; oropharynx with mild erythema. Neck: small anterior and posterior cervical nodes. CV: unremarkable. Lungs: intercostal retractions, expiratory wheezing. Abdomen: unremarkable. What is the most likely diagnosis and pathogen causing this disorder? Discuss the mode of transmission

and discuss data that supports your decision. What diagnostic test, if any, should be done?

Develop a treatment plan for this patient.

There are two stages of TB pathogenesis—primary and secondary infection. Primary TB infection occurs when the bacillus first enters the body. In this phase, macrophages engulf the microbe, causing a local inflammatory response that is different from the usual inflammatory response. The macrophages are unable to phagocytize the bacteria. Some bacilli are carried to the lymph nodes and around the lungs, activating the type IV hypersensitivity reaction. Cell mediated immunity is the main mechanism by which the body fights the tubercle bacillus and starts a few weeks after infection. Lymphocytes (helper T and cytotoxic T) and macrophages congregate to form a granuloma (an epithelial nodule). The granuloma contains some live bacilli, forming a tubercle. Caseous necrosis, a cottage cheese–like material, develops in the center of the tubercle. This complex of cells and necrosis is called a caseating granuloma, which stimulates a granulomatous inflammation. An intact immune system can resist this development, so the lesions—referred to as Ghon complexes (FIGURE 5-16)—remain small, become walled off by fibrous tissue, and calcify. The bacilli can remain dormant and viable in the tubercle for years as long as the immune system is intact. In this phase, the individual has been infected by the bacilli and remains asymptomatic. At this time, the person is said to have latent tuberculosis infection (LTBI). Transmission to others does not occur even though there are organisms in the granuloma. However, any time the immune system is compromised the disease may reactivate and cause pulmonary TB disease.

FIGURE 5-16 Ghon complexes. Courtesy of Benjamin M. Marais.

In about 10% of infected people, the initial exposure leads to active primary tuberculosis. In other words, upon initial infection 90% develop LTBI and 10% go on to develop active primary tuberculosis. Primary active tuberculosis development after initial exposure is more likely if there is a large inhalation of the tubercle or if the person is immunocompromised. The remaining 90% of cases of active pulmonary tuberculosis occurs because of reactivation of latent TB, and at this point, the TB is a secondary infection. The reactivation can occur at any time, even years after the infection occurred. Reinfection with TB can also occur. During the active phase, whether from primary infection at initial exposure or reactivation of latent TB, the bacillus spreads throughout the lungs, and hematogenous spread can infect other organs and tissues (e.g., kidney, brain, and bone marrow). The infected solid organs look like millet seeds due to the multiple foci, and, hence, disseminated TB is called miliary tuberculosis. Even when the pulmonary infection has healed, progression to extrapulmonary organs can proceed.

Clinical Manifestations Latent TB does not produce any symptoms and is not considered infectious. With development of the disease, whether from primary active infection (i.e., disease after first exposure) or latent infection that reactivates, the manifestations tend to appear gradually. Manifestations are a result of chronic infection and the immune process and include productive cough, night sweats, fever, chills, fatigue, unexplained weight loss, and anorexia. Hemoptysis may occur when granulomas erode into the pulmonary vasculature. Other symptomatology may be present depending on other organ involvement (e.g., bone pain, neurologic symptoms).

Diagnosis and Treatment Diagnostic procedures for TB are multifaceted, usually beginning with a tuberculin skin test (TST) (also known as the Mantoux test) or a blood test called interferon gamma release assays (IGRAs). For the TST, a small amount of a purified protein- derivative tuberculin is injected just below the dermis. If the person has been infected by the bacilli, a local reaction (e.g., redness and induration) will occur. The degree of induration is measured to determine if the person is positive or negative (see TABLE 5-5). Persons will test positive once the bacilli trigger the inflammatory response. A history of bacillus Calmette-Guérin (BCG) vaccination will produce a false-positive reaction. Additionally, previously treated TB will generate a false- positive reaction. Conversely, persons with immature immune systems (e.g., children) or immunocompromise may not generate enough of a response to test positive. The two IGRAs include the QuantiFERON TB Gold in-tube and the T-SPOT, which measure CD4+ T cells’ interferon gamma concentration in response. The IGRAs are not affected by the BCG vaccine, and, therefore, are more accurate in those previously vaccinated. The TST or the IGRAs do not help to differentiate between latent and active TB. Because of the uncertainty that the TB skin test creates, chest X-rays and sputum for stained smears and cultures (most definitive) are used after a positive TST is noted (either to confirm an original case or to assess reinfection). A computed tomography (CT) scan can also be used to visualize TB lesions, as this imaging modality is more sensitive than an X-ray. Nucleic acid amplification may be performed on the sputum to detect the presence of resistant strains. Extrapulmonary manifestations will require collection of specimens from the areas of infection (e.g., pericardium, bone).

TABLE 5-5 Classification of the Tuberculin Skin Test Reaction

An induration of 5 or more millimeters is considered positive in: HIV-infected persons A recent contact of a person with TB disease Persons with fibrotic changes on chest radiograph consistent with prior TB Patients with organ transplants

Persons who are immunosuppressed for other reasons (e.g., taking high dose prednisone for 1 month)

An induration of 10 or more millimeters is considered positive in: Recent immigrants (< 5 years) from high-prevalence countries Injection drug users Residents and employees of high-risk congregate settings Mycobacteriology laboratory personnel Persons with clinical conditions that place them at high risk Children < 4 years of age Infants, children, and adolescents exposed to adults in high-risk categories

An induration of 15 or more millimeters is considered positive in: Any person, including person with no known risk factors for TB

Centers for Disease Control and Prevention, October 2011.

TB is often successfully treated in the home setting; however, it takes diligence to eradicate the disease. Treatment requires an average of 6–9 months of antimicrobial therapy. The goal of treatment is to cure the patient and prevent transmission. Combination therapy (consisting of two or more drugs) is recommended to prevent the emergence of resistant strains. The slow-growing bacilli have a high mutation rate, with those mutations often appearing when the pathogen is exposed to monotherapy. Because TB is a public health risk, antituberculin medications are provided free of charge by the U.S. Public Health Service. In some states, therapy noncompliance is unlawful, and imprisonment may be used to ensure adherence when other measures (e.g., direct observed therapy) fail. Compliance is a common problem in treating TB because of the length of therapy and the medication side effects (e.g., nausea, paresthesias, discolored bodily secretions). Patient education, including an emphasis on taking the entire regimen of drugs as ordered, is crucial to maximize therapy success and prevent resistance. People with LTBI should also be treated as they still have organisms even though they do not spread the infection. Treating LTBI reduces the probability of having TB reactivate and cause a secondary infection in the future.

Strategies to prevent the transmission of TB include respiratory precautions (e.g., TB-approved masks, covering one’s mouth when coughing, and disposing of tissues), adequate ventilation (if the patient is at home), and placing the patient in a negative-pressure isolation room (if hospitalized). The bacillus Calmette-Guérin vaccination is primarily used in children in countries with a high rate of Mycobacterium tuberculosis.

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BOX 5-3 Application to Practice The CDC (2018b) recommends that certain people who are at higher risk for becoming infected with tuberculosis (TB) get tested. Those individuals include:

Those who have had exposure/time spent with someone who has TB disease Infants, children, and adolescents exposed to adults who are at increased risk for latent tuberculosis infection or TB disease Persons who are living or traveling from a country where TB disease is more common (most countries in Latin America, the Caribbean, Africa, Asia, Eastern Europe, and Russia) Persons who are living or working in high-risk settings such as correctional facilities, long-term care facilities or nursing homes, and homeless shelters) Healthcare workers who care for patients at increased risk for TB disease

The recommended frequency of testing for healthcare workers varies on the risk of exposure classification (e.g., low, medium, or ongoing). The TST may also be conducted using two-step testing. The two steps occur as follows:

First step: TST administered

If positive, the person probably has TB infection If negative, retest done 1–3 weeks later

Second step: TST administered 1–3 weeks after initial test

If positive, it is considered a boosted reaction from latent infection that occurred at some time prior (usually years)

If negative, the person probably does not have TB

Review the following TB testing cases. Interpret the findings and identify a diagnosis. Develop a management plan.

Case 1: 45-year-old registered nurse who works on a medical surgical unit. TST is 10 mm.

Case 2: 35-year-old man with HIV. TST is 4 mm.

Case 3: 25-year-old woman who is an international student (from Peru, South America) who has been studying in the United States for the past year. TST is 11 mm.

Case 4: 3-year-old boy who just moved from Asia to the United States. TST is 10 mm.

Case 5: 20-year-old-woman. TST is 11 mm.

Case 6: 50-year-old man with a history of BCG vaccination. TST 11 mm.

Alterations in Ventilation Asthma—Obstructive Asthma is a chronic pulmonary disease that is characterized by chronic airway inflammation and bronchial hyperresponsiveness (FIGURE 5-17). Asthma is one of the most common noncommunicable chronic illnesses globally and in children in the United States. Most cases (approximately 50%) of asthma are diagnosed in childhood with a peak prevalence at the age of 3 years old. Adults who develop asthma (about 33%) are usually diagnosed by the age of 40 years. Women are more likely to have asthma than men, but in children, boys are more likely to have asthma than girls. Persons of multiple races/ethnicities and Black adults and children are more likely to have asthma than White adults and children.

FIGURE 5-17 Asthma. A Location of the lungs and airways in the body. B Cross-section of a normal airway. C Cross-section of an airway during asthma symptoms.

Many mechanisms underlie asthma development, and there is increasing recognition that asthma may be a syndrome rather than one disease entity. Over 100 genes are implicated in the development of asthma. The genetic predisposition coupled with environmental factors further enhance the likelihood of asthma development. Asthma development is thought to be polygenic with multiple genes interacting to then cause the variable phenotype (observable expression) of asthma. Genetic alterations are not only implicated in disease development but also in modifying asthma severity and response to treatment.

Various theoretical propositions explain the development of asthma. The most

well-known and clear association is between asthma and atopy. Atopy is a genetic predisposition to producing a usually exaggerated IgE response to allergens or irritants. Determining if atopic and asthma genetic alterations are the same or different is difficult. For example, people with asthma often have other atopic diseases such as allergic rhinitis and eczema; however, not all people with atopic diseases develop asthma. Atopic diseases and asthma share genetic alterations that lead to genetic immune dysregulation. Other factors such as smoking, pollen, and other environmental factors also contribute to this immune dysregulation.

Key characteristics of asthma are chronic airway inflammation and bronchial hyperresponsiveness with intermittent, reversible airway obstruction. Exposure to an antigen or irritant in a sensitized individual triggers a cascade of innate and adaptive immune responses. The result is bronchoconstriction, bronchospasm, bronchiole edema, and mucus production.

An episode of asthma (asthma flare-up or attack) is characterized by two phases —an early response and a late response. The early response phase is primarily related to bronchospasm and bronchoconstriction and is usually signaled by coughing. Peaking within 30 minutes and resolving usually in less than 3 hours, the inflammatory mediators released as a result of mast cell degranulation include leukotrienes, histamine, and prostaglandins. Mast cell degranulation also results in release of tumor necrosis factor, which causes recruitment and activation of inflammatory cells.

The dendritic cells present the antigen, and Th2 (T helper) lymphocytes release several cytokines (interleukin: 3, 4, 5, 8, 9, 13, 17, 22 and granulocyte macrophage- stimulating factor). The cytokines cause B cell activation, mast cell proliferation, eosinophil production and survival, neutrophil release, basophil survival, and T cell recruitment and differentiation into Th2 cells. The cytokine effects and/or specific interleukins cause tissue injury, release of toxic chemicals, an enhanced inflammatory response, an impaired mucociliary response, increased fibroblasts, and airway remodeling.

A few hours after the acute event a late response can occur. Neutrophils, lymphocytes, and eosinophils can further release many of the same mediators from the acute phase. The late response peaks within 6 hours of symptom onset. This phase is a result of airway edema and mucus production. Leukotrienes are synthesized, causing smooth muscle contraction. The alveolar hyperinflation causes air trapping. The airways start scarring, and bronchial hyperresponsiveness continues, leading to impaired clearing of mucus and the formation of mucous plugs (glycoproteins). The mucous plugs are secreted by goblet cells in the airways. Leaky bronchial vessels also release plasma proteins contributing to mucous plug development. Without treatment, irreversible changes develop, which include fibrosis under the epithelial layer and hypertrophy of smooth muscle and mucous glands. These changes are termed airway remodeling.

The polygenic and environmentally mediated nature of asthma is evident in the various phenotypes. Asthma genetics is complex. For example, different people can have different genes and yet have one type of asthma expression. Genetic alterations cause development of asthma but also influence severity and response to treatment. In addition to the atopic asthma (i.e., eosinophilic asthma), several other phenotypes include exercise-induced asthma, aspirin-induced asthma, and intrinsic asthma. Asthma may occur independent of atopy.

In general, asthma severity remains relatively constant within an individual. This consistency means that a person with mild asthma will usually continue to have mild asthma throughout their life, and those who develop severe asthma were likely to have had severe asthma around the time of diagnosis and will continue to have a severe disease expression.

The onset of asthma during childhood is usually due to atopy and allergies. Adult- onset asthma is highly variable. Atopy is a more common cause in those with mild- to-moderate disease (approximately 50%); however, atopy is not a likely cause in adult-onset asthma in patients who have severe disease (TABLE 5-6).

TABLE 5-6 Classification of Asthma Severity

* Classification is based on symptoms and lung function before treatment. Patients should be assigned to the most severe step in which any feature occurs. ** Percentage of predicted function. PEF = peak expiratory flow (rate); FEV1 = forced expiratory volume in 1 second.

Modified from National Heart, Lung, and Blood Institute. (2007). National Asthma Education and Prevention Program, Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. NIH Publication Number 08-5846. Retrieved from https://www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf

Nonatopic asthma, which is more common in adults, has been linked to individuals with high eosinophil levels. Eosinophils are often associated with atopy (production of IgE in response to allergens) but those individuals with eosinophilic asthma do not necessarily have allergies. Another nonatopic asthma is that associated with chronic rhinosinusitis, nasal polyposis, and reaction to aspirin. The asthma is called aspirin-exacerbated respiratory disease. These nonatopic disorders can coexist, and both are considered severe asthma phenotypes. The mechanism of

aspirin sensitivity occurs because under normal circumstances aspirin and other drugs such as nonsteroidal anti-inflammatory drugs block enzymes called cyclooxygenase that lead to arachidonic acid conversion to prostaglandins, which stimulates leukotriene release—a powerful bronchoconstrictor. Consequently, there is arachidonic dysregulation and an overproduction of leukotrienes with subsequent bronchoconstriction and promotion of airway inflammation in cases of aspirin sensitivity. Other types of asthma phenotypes include exposure to occupational allergens such as plant proteins or animal proteins (e.g., farmers) or other chemicals (e.g., plastic or formaldehyde), which has been implicated in the development of asthma independent of atopy. Symptoms develop over time, worsen with each exposure, and improve when away from work (e.g., on weekends or during vacations).

In individuals with severe adult-onset asthma, there is variability in response to glucocorticoids. Some individuals have little to no response (resistance) while others require high doses (dependence). Children with severe asthma have also demonstrated resistance to glucocorticoids. Another example of genetic variations and medication response in asthma is evident in those with a polymorphism of the beta-adrenergic receptor gene, which is known as the Arg16Arg genotype. Long- acting beta agonists (LABA) often used in the management of asthma increase bronchospasm in those with the genetic polymorphism.

Exercise-induced asthma is more common in childhood. The hyperventilation that occurs with exercise is thought to lead to airway fluid lining changes and mast cell mediator release. With exercise-induced asthma, the attack usually occurs 10–15 minutes after physical activity ends. Symptoms can linger for an hour with this type of asthma. The airways can become cool and dry during exercise, and asthmatic symptoms may be a compensatory mechanism to warm and moisten the airways. Following each episode of exercise-induced asthma, a refractory (symptom-free) period begins within 30 minutes and can last 90 minutes. During this time, little or no bronchospasm can be induced even if the person is rechallenged with vigorous exercise. Athletes often take advantage of this fact by warming up vigorously to induce a refractory period prior to competition. Weather changes such as cold air or hot weather can trigger asthma symptoms in the same manner as exercise.

Several other factors trigger or influence asthma manifestations. Some women report a premenstrual worsening of their asthma, demonstrating that hormonal changes can be a trigger. Stress can induce asthma symptoms through a cholinergic reflex pathway. In addition to aspirin and nonsteroidal anti-inflammatory drugs previously discussed, medications such as beta blockers can trigger asthma. Some people with asthma have worsening symptoms at night. This nocturnal trigger usually occurs between 3:00 and 7:00 a.m. and is thought to be related to circadian rhythms. At night, cortisol and epinephrine levels decrease, while histamine levels increase. Changes in these naturally occurring substances lead to

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bronchoconstriction. Individuals who are obese (body mass index ≥ 30 kg/m2) have a higher incidence of asthma, and this increased risk is possibly related to fat stores having adipokines (cytokines secreted by adipose tissues) that are proinflammatory and have less anti-inflammatory capacity. The roles of obesity and asthma, however, are still not clear. Several other factors such as diet, in utero smoke exposure, acetaminophen ingestion in childhood, and so forth continue to be evaluated for association and causality.

Learning Points

Hygiene Hypothesis and Asthma nother theory, referred to as the hygiene hypothesis, suggests that the modern Western lifestyle’s focus on hygiene and sanitation limits early childhood allergen and infection exposure. Childhood microbial

exposure normally leads to a proinflammatory Th1 response, which does not involve IgE production and confers immune protection in a different manner. The lack of exposure, however, leads instead to a Th2 immune response with interleukin release and an IgE and eosinophil activation. This Th2 response renders individuals more vulnerable to the development of asthma. Another way to think of the hygiene hypothesis is that the lack of exposure to microbes does not allow the immune system to develop and teach the immune system how to react. The hygiene theory has been disputed as there are several instances where asthma incidence is high in less hygienic environments.

Clinical Manifestations Asthma is usually classified by its severity (intermittent, mild persistent, moderate persistent, and severe persistent) (Table 5-5). Clinical manifestations of asthma include expiratory wheezing, dyspnea, chest tightness, cough, anxiety, tachypnea, and tachycardia. The expiratory phase is prolonged. The work of breathing will increase, wheezing may be heard during inspiration but is commonly heard on expiration, and accessory muscles use becomes evident if the asthma attack is not treated or not responding to treatment. The increased work of breathing leads to hypoxemia.

Status asthmaticus is a life-threatening, prolonged asthma attack that does not respond to usual treatment. Maintaining a patent airway is critical in such cases, and endotracheal intubation with ventilation support may be necessary. In addition, acid– base imbalances—specifically respiratory alkalosis from expelling too much carbon dioxide because of tachypnea and hypoxemia, can develop early in the attack. Eventually, respiratory muscles fatigue as the obstruction of airflow and hyperinflation continues, causing CO2 retention and respiratory acidosis.

Diagnosis and Treatment Diagnosis is made with a thorough history and physical examination along with pulmonary function tests (Figure 5-11). Pulmonary function findings consistent with

C

asthma include FEV1 decreases, which are reversible. Other tests include chest X- ray, ABGs, CBC, challenge testing (i.e., bronchoprovocation), and allergen testing to search for underlying causes and triggers. Although airflow obstruction is usually reversible, some individuals can develop irreversible airflow limitation.

Asthma cannot be cured, but its symptoms can be controlled. Unless treated promptly, asthma attacks can lead to impaired gas exchange and death. Left untreated, long-term asthma can result in bronchial damage and scarring. The goals of treatment are to minimize the occurrence and severity of asthma attacks. Pharmacologic treatment for all patients with asthma at any classification includes a short-acting beta agonist (SABA), which relaxes bronchial smooth muscle and causes bronchodilation. These SABAs are commonly called rescue inhalers. Other medications for acute attacks can include anticholinergics and corticosteroids. Long- term management is guided by the use of the stepwise approach from the 2007 National Heart, Lung, and Blood Institute and National Institutes of Health expert panel report. Medication choice is dependent on the frequency of symptoms, SABA use, nighttime awakenings, interference with normal daily activities, and peak flow measurements. The step a person is deemed to be at and the level of control will guide the use of various other pharmacotherapeutics such as inhaled and systemic corticosteroids, long-acting beta-2 agonists (LABA), leukotriene modifiers, mast cell stabilizers, methylxanthines, anticholinergics, and immunotherapy. These agents can be delivered orally, by inhalation, and/or intravenously. Biologics are the newest category of medications approved for severe asthma. These medications are humanized monoclonal antibodies that are categorized as anti-IgE antibodies (e.g., omalizumab) or interleukin-5 antagonists (e.g., reslizumab, mepolizumab). Additional strategies include developing an asthma plan and teaching it to all caregivers. This plan will include the avoidance of triggers, environmental cleanliness such as air filters and hypoallergenic sheets and pillowcases, maintaining a healthy immune system by exercising, proper nutrition, and receiving vaccines.

Learning Points

Cough Diagnostic Tips ough is an important protective mechanism but can become a bother and harmful. Coughing occurs because of irritation of cough receptors (afferent) located in the respiratory tract (larynx, trachea, bronchi,

pleura), ear canal and eardrum, pericardium, esophagus, stomach, and diaphragm. The receptor stimulation travels through the vagus nerve to the cough center in the medulla. The result is a corresponding spinal, phrenic, and vagus effector response of cough. Coughing is a common symptom for which people seek health care. Clinicians, at some point in time, will care for someone with a cough. Classifying cough by duration can be useful in determining likely diagnostic possibilities. Acute cough is defined as one that exists for less than 3 weeks. Acute coughs are usually due to a respiratory tract infection. Subacute cough exists for 3–8 weeks. Subacute cough is often postinfectious even with resolution of other infectious symptoms (e.g., myalgia, fever) or due to upper airway cough syndrome (i.e., postnasal drip cough). Chronic cough is one that exists for greater than 8 weeks. The three most common causes (up to 90% of cases of nonsmokers or those not taking angiotensin-converting enzymes) of chronic cough are postnasal drip cough, asthma, or gastroesophageal

reflux. Postnasal drip cough is most likely due to allergic and nonallergic rhinitis or sinusitis. While patients may complain of heartburn or sour taste in the mouth with reflux disease, cough may be the only symptom in up to 40% of cases.

Chronic Obstructive Pulmonary Disease Chronic obstructive pulmonary disease (COPD) describes a group of chronic respiratory disorders characterized by recurrent respiratory symptoms and airway obstruction that are attributed to irreversible airway and/or alveolar abnormalities (FIGURE 5-18). The irreversible nature of COPD is in contrast to asthma, where airway obstruction is reversible despite underlying chronic inflammation. Asthma is predominantly viewed as an allergic IgE phenomenon with different mediators and inflammatory cells (e.g., more eosinophils) while COPD is caused by smoking with a subsequent different inflammatory response and damage. Individuals, however, can have coexisting asthma and COPD. The limitation in airflow with COPD causes persistent respiratory symptoms (e.g., dyspnea, cough, and sputum production). COPD can impair an individual’s ability to work and function independently and leads to premature death. Severe hypoxia and hypercapnia can lead to respiratory failure. The chronic hypercapnia shifts the normal breathing drive from the need to expel excess carbon dioxide to the need to raise oxygen levels (Figure 5-12).

FIGURE 5-18 Chronic obstructive pulmonary disease (COPD) is often one disease or a mixture of two diseases —chronic bronchitis and emphysema.

Prevalence rates for COPD are likely underestimated because this disease is often asymptomatic in its early stages, is masked by smoking symptoms, or is underreported. According to the CDC (2015a), COPD was the third leading cause of

death in the United States in 2011 and the fourth leading cause of death worldwide. Fifteen million Americans are currently diagnosed with COPD. Symptoms usually present around 60 years of age. A rare familial type of COPD (emphysema only) is due to alpha-1 antitrypsin deficiency (AATD). AATD presents much earlier—in the 30s or 40s. Groups at higher risk of developing COPD include Whites, individuals of lower socioeconomic status, and persons with a history of asthma. It was considered that men had a higher incidence, but the incidence of smoking has increased in women making the disease equally prevalent in men and women (Global Initiative for Chronic Obstructive Lung Disease, 2019).

The most significant contributing factor to developing COPD is cigarette smoking. Other contributing factors include the inhalation of pollution and chemical irritants as well as a variety of host factors. The chronic inflammation from smoking affects the large airways, small airways (e.g. bronchioles), and parenchyma. Emphysema is a destruction of the alveoli, and although it is often used as a clinical diagnosis, it is just reflective of one of the pathologic changes that occurs in COPD. Chronic bronchitis, conversely, is a clinical diagnosis as opposed to the description of a structural lung change as in emphysema. COPD is often a mixture of two diseases— chronic bronchitis and emphysema (FIGURE 5-18). Chronic bronchitis is defined as an obstructive respiratory disorder characterized by inflammation of the bronchi, a productive cough, and excessive mucus production that occurs for at least 3 months of the year and for at least 2 consecutive years.

Smoking and other pollutant sources, such as using wood to cook and burning garbage, cause chronic airway irritation and trigger the inflammatory process. Large airway changes due to smoking include an increase in size and number of goblet cells and submucosal glands, which increases mucus production. These changes lead to a chronic productive cough, which characterizes chronic bronchitis. The large airway changes, however, are not reasons for the airflow limitation in COPD. The airflow limitation is caused by small airway (e.g., bronchioles) and alveolar or alveolar duct damage (emphysema). COPD as a combination of chronic bronchitis and emphysema has variability in presentations. As an example, not everyone with chronic bronchitis has airflow limitation (e.g., small airway and alveolar damage), and not everyone with COPD has increased mucus secretion (e.g., large airway damage).

The inflammatory response that is triggered during COPD is heightened in comparison to other inflammatory responses to insults. Neutrophils, macrophages, and lymphocytes release inflammatory mediators and oxidants, which infiltrate the airway. The inflammatory mediators attract more inflammatory cells from the circulation, enhance the inflammatory response, and start the process of structural lung changes. Fibrosis then ensues, leading to small airway damage and subsequent airflow limitation.

Normally, a balance between proteases (enzymes like elastase) and

antiproteases (alpha antitrypsin) keeps elastin in lung connective tissue from being destroyed. Inflammatory and epithelial cells increase the level of the destructive proteases, causing parenchymal damage. The alveoli turn into large, irregular pockets with gaping holes with air spaces (termed bullae). Gas exchange becomes ineffective. Blebs (smaller than bullae)—air spaces near the pleura—also develop and contribute to the reduced gas exchange. The result is a limitation of oxygen entering the bloodstream. The elastic fibers and surfactant that normally keep the alveoli open are slowly destroyed. The loss of elastic recoil and small airway limitations causes the airway to collapse during expiration, causing trapping of gas during expiration. Hyperinflation from this gas trapping leads to respiratory muscle impairment and increased work of breathing during inspiration and expiration. Hypercapnia and hypoxemia occur due to ventilation and perfusion abnormalities.

Emphysema (i.e., alveolar damage) can occur throughout the lung. When the destruction is in the upper lobes, with alveoli distal to the bronchioles remaining intact, the term is centriacinar (centrilobular) emphysema. When the lower lobe (distal) alveoli are involved, the term is panacinar (panlobular) emphysema. The latter is more common in older adults and those individuals with AATD. Genetics also plays a role in COPD development. Alpha-1 antitrypsin is an enzyme that prevents elastase from attacking the lungs’ structural fibers; therefore, the enzyme acts as an antielastase. With AATD, alveolar destruction ensues in smokers as well as nonsmokers. Symptoms of AATD appear at a younger age (e.g., early 30s–40s) and accounts for about 3% of COPD cases. Other genes are being evaluated in relation to COPD.

Lung underdevelopment, whether due to gestational issues (e.g., maternal smoking during pregnancy), birth issues such as low birthweight, or environmental exposure such as secondhand smoke, can also influence the development of COPD in adult life. Older age is also associated with COPD development. The normal aging lung demonstrates evidence of structural airway and alveolar changes similar to those seen in COPD. These normal aging changes include a decrease in total lung capacity (TLC) and an increase in residual volume (RV) (Figure 5-11). FEV1 can slowly decrease every year. In addition to normal aging structural changes, older adults have a lifetime of environmental exposure to substances that can affect the lungs. These factors contribute to COPD development. People with asthma or airway hyperresponsiveness (without asthma) have an increased risk of developing COPD.

Clinical Manifestations Patients with COPD typically first start complaining of a cough, which is often referred to as a smoker’s cough. The cough may be productive or nonproductive and varies greatly. At times, patients may swallow the mucus rather than expectorate it.

Chest tightness and wheezing is another complaint. Wheezing, cough, and sputum production can be intermittent. Airflow limitation may be present without cough. Dyspnea is a key clinical complaint in those with COPD. At first, the dyspnea manifests with activity and patients will complain of decreased activity tolerance, and as the disease progresses, the dyspnea occurs at rest. The description of dyspnea is subjective, and objective findings may not be present. The description of dyspnea varies among patients and can be described as a sense of gasping for air or chest heaviness.

Airway resistance results in hypoventilation, hypoxemia, and hypercapnia. In response to the hypoxemia, erythropoietin stimulates increased red blood cell production leading to secondary polycythemia, clubbing of fingers, cyanosis, and dyspnea at rest. Patients will complain of malaise, fatigue, and lack of appetite with weight loss. Anxiety and depression may be present. Physical abnormalities early in the course of the disease may not be present. As the disease progresses, findings may include intermittent inspiratory and expiratory wheezing as well as prolonged expiration (longer than 3 seconds). A barrel chest occasionally is evident, although it is more common when there is emphysematous damage. Hypoxemia eventually leads to pulmonary hypertension, which increases right-sided heart filling pressures, leading to right ventricular structural changes (e.g., hypertrophy) and right-sided heart failure (cor pulmonale). Cor pulmonale may manifest as weight gain and edema. See chapter 4 for a discussion of cor pulmonale.

Acute exacerbations of COPD are common and manifest as worsening respiratory status. Exacerbations can be triggered by various stimuli such as pollutant exposure or viral and bacterial infections. With COPD, the impaired pulmonary defenses (e.g., cilia damage and decreased phagocytic activity) result in frequent respiratory infections, further injuring the airway. In some cases, respiratory failure occurs. Exacerbations worsen the inflammation and heighten respiratory symptoms (e.g., dyspnea, hypoxemia). Infections can also present with fever, increased sputum volume, and purulent sputum, which are more consistent with a bacterial infection. The most common reason for an exacerbation, however, is a rhinovirus infection (i.e., common cold). Patients who recover slowly from their exacerbations (requiring more than 10 days) and/or have more frequent episodes tend to have a worse prognosis. Common comorbidities with COPD are usually due to smoking and aging and include cardiovascular disease (e.g., hypertension, ischemic heart disease), diabetes mellitus, normocytic anemia, and osteoporosis.

Diagnosis and Treatment Spirometry is the diagnostic test used to evaluate COPD. Confirmatory diagnostic criteria include a postbronchodilator FEV1/Forced Vital Capacity of < 0.70%, which is evidence of airflow limitation (Figure 5-11) and presence of risk for COPD (e.g.,

smoking, poor lung development). COPD should be suspected in anyone with persistent and progressive dyspnea and dyspnea associated with activity, chronic cough with or without sputum or wheezing, or chronic sputum production.

Bronchodilators used for testing include a short-acting beta-2 agonist (SABA) and/or a short-acting anticholinergic. Patients with COPD may be evaluated for AATD even if they are older as the diagnosis may have been missed when they were younger. Chest X-rays are used to evaluate for other diagnoses that may present with similar symptoms. Findings on X-ray that are caused by COPD include a flat diaphragm, more air retrosternally due to hyperinflation, and hyperlucency (increased air, decreased density). Pulse oximetry and ABGs can be used to evaluate oxygenation status. During exacerbations, sputum cultures may be helpful, but waiting for results should not delay treatment for those suspected of bacterial infections (e.g., purulent sputum with dyspnea and/or increased sputum volume). Procalcitonin, if available, is a peptide biomarker that is released during bacterial infections and may be used to guide antibiotic administration.

Management strategies include smoking cessation, which is paramount in changing the course of COPD. Common medications for COPD include bronchodilators that are short- and long-acting beta-2 agonists (i.e., SABA and LABA) and short- and long-acting anticholinergic inhalers. Anticholinergic agents are also known as antimuscarinic (muscarine is a type of acetylcholine receptor). These agents act by relaxing bronchial smooth muscle. Other medications that can be considered are methylxanthines, which cause bronchodilation. Inhaled corticosteroids for maintenance and oral glucocorticoids have anti-inflammatory effects and can be used for acute exacerbations. Phosphodiesterase 4 inhibitors (e.g., roflumilast) reduce inflammation without bronchodilation and can decrease exacerbations as well as improve lung function. Mucolytics can be used to help with mucus clearance. Alpha-1 antitrypsin augmentation therapy is useful for those with deficiencies. Pulmonary rehabilitation, which includes exercise and self-management education, is beneficial for reducing dyspnea, enhancing exercise tolerance, and improving overall health status. Oxygen therapy can increase survival in patients with hypoxemia and is used during exercise for others. Ventilation support can be provided noninvasively with a variety of devices such as nasal, face, or mouth mask during exacerbations and respiratory failure. Invasive and surgical interventions for COPD can include bullectomy, lung volume reduction surgery, or lung transplantation.

Antibiotics are used during bacterial infections. Common pathogens include Streptococcus pneumoniae and Haemophilus influenzae; therefore, prescribed antibiotics should provide coverage for these organisms. Antibiotic selection is also guided by local resistance patterns and susceptibility to Pseudomonas aeruginosa. Hospitalization is indicated when hypoxemia and dyspnea are worsening, respiratory rate is high, and signs of altered mental status such as confusion and lethargy are

present. These signs may be manifestations of acute respiratory failure or an exacerbation that is nonresponsive to treatment. Patients with heart failure, arrhythmias, or other serious comorbidities, as well as those who are not in environments where they can receive support may need to be hospitalized. Management in the hospital will be similar to the therapies previously described, such as increasing short-acting bronchodilator frequency and dose and short-term oral steroids. Oxygen therapy is administered while monitoring saturation with arterial or venous blood gases. Caution should be taken not give too much oxygen and knock out the newly oxygen-centered respiratory drive. Intubation or tracheostomy may be necessary for unstable patients (e.g., those with PaO2 40 mmHg, respiratory acidosis, tachycardia, tachypnea, or hypotension). Patients with COPD should receive pneumococcal and influenza vaccines.

Sleep Apnea—Obstructive Sleep apnea is characterized by the recurrent cessation or limitation of airflow through the mouth and nose despite continuing breathing efforts. The result is hypercapnia, hypoxemia, and fragmented sleep. Sleep apnea, a sleep-related breathing disorder, is categorized as obstructive (OSA) or central (CSA) in origin. OSA is associated with episodes of hypopnea (decreased depth and rate of breathing)—not solely apnea—and is also termed OSA-hypopnea. Of the two types, OSA is common and CSA is rare. OSA affects approximately 25 million Americans adults (Peppard et al., 2013). The incidence of OSA is on the rise due to the association and higher rates of obesity; men are affected at twice the rate of women. Risk factors include older age, obesity, and craniofacial or upper airway abnormalities. A higher prevalence of OSA is seen in people with chronic disorders such as heart failure, end-stage renal disease, and chronic lung disorders. OSA is more likely in smokers, during pregnancy, and in menopausal women. Asthma and prematurity are additional risk factors noted in children.

During sleep, there is a normal loss of muscle tone and reduced muscle activity in the upper airways, particularly during the phase of rapid eye movement. Usually there are no consequences to these physiologic changes; however, upper airway collapse, obstruction, and narrowing can occur in those predisposed to OSA. Anatomic or neuromuscular factors are associated with the predisposition to develop OSA. This collapse and the obstruction are recurrent. The obstruction is usually at the level of the soft palate/nasopharynx (i.e., velopharyngeal) or the tongue (i.e., oropharynx). (FIGURE 5-19).

FIGURE 5-19 Apnea.

Anatomic variations, specifically those involving craniofacial, soft tissue, and vascular factors, can cause a decrease in size of the upper airway and an increase in pressure. Enlargement of the tonsils, tongue, or oral structures (e.g., soft tissue, pharyngeal wall, long soft palate or long uvula) contribute to OSA development. Enlargement of these structures often occurs with obesity; however, they can also be independent of body mass index. Enlarged tonsils and adenoids are a particular risk factor and cause of OSA in children. Craniofacial and upper airway variations that contribute to OSA can include abnormal maxillary size, short mandible size, or a lower jaw that is set farther back than the upper jaw (like an overbite). Some of these structural variations are a cause in Asians who have OSA independent of obesity. Increased vascular volume in the neck may also contribute to OSA, and this increase is more likely in patients with volume overload states such as heart failure and end-stage renal disease. Although risk factors are known, there are many instances when the exact pathophysiologic mechanism is unclear.

CSA is not as common as OSA and is more likely the result of input from inhibitory respiratory center in the brain exceeding excitatory signals. The result is a lack or decreased respiratory effort and subsequent episodes of cessation or decreased airflow (i.e., apnea-hypopnea). CSA is often associated with heart or brain abnormalities. Cheyne-Stokes respirations, which occur with stroke and heart failure, are associated with CSA. Cheyne-Stokes is a pattern of breathing characterized by deep and fast breathing followed a decrease and slow or absent breathing, so Cheyne-Stokes breathing includes cycles of hyperpnea and apnea. Drug abuse, particularly opioids, can also cause CSA.

Learning Points

Snoring

S noring is created by vibration of tissue in the upper airway during sleep. Snoring occurs during inhalation. Almost everyone snores at some time, but some people snore habitually. Men do so more than women. Snoring is more likely with aging. Habitual snoring is a sign of airway resistance and collapse. Snoring is

caused by many of the same factors that lead to OSA, such as obesity, craniofacial abnormalities, and tonsillar hypertrophy. Snoring may be associated with sleep disruption or without sleep disruption. If airway resistance increases secondary to weight gain or other factors, respiratory effort increases as a compensatory mechanism and may start to cause sleep disturbances. Persistent airway resistance can then lead to OSA. In summary, snoring may or may not be associated with OSA. The main reason for evaluating causes of snoring, in addition to sleep alteration, is to identify OSA. Treatment of snoring is similar to OSA and includes weight loss, smoking cessation, reduction of alcohol consumption particularly just prior to bedtime, and sleeping on one’s side; and several devices such as nasal dilators can be beneficial.

Clinical Manifestations Clinical manifestations include:

Snoring that is habitual, often loud, and frequent Periods of silence in breathing or apnea (witnessed by bed partner or another person) Sleep characterized by nighttime choking, gasping, or breath holding Nonrestorative sleep with daytime sleepiness, fatigue, poor concentration, and irritability

Other symptoms that are nonspecific and may be present include nocturia and morning headaches.

Diagnosis and Treatment Diagnosis is based on history and physical examination and a sleep study (i.e., polysomnography) as the first-line diagnostic study. Criteria for diagnosis includes:

Five or more obstructive respiratory events (e.g., apnea, hypopnea, increased respiratory effort) per hour of sleep with one or more of the bulleted clinical manifestations discussed and/or a diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, heart failure, atrial fibrillation, or type 2 diabetes mellitus Fifteen or more obstructive respiratory events per hour of sleep regardless of the presence of comorbidities

The sleep study can be done in a laboratory or home setting. The laboratory setting is preferred if there are comorbidities as additional parameters such as seizure activity or limb movement can be measured.

The treatments for sleep apnea include weight loss, behavioral measures, and the delivery of continuous positive airway pressure (CPAP). Behavioral modification includes nonsupine sleeping position and avoidance of alcohol or sedating

medications, particularly at night. Daytime reduction of alcohol and sedating medications may also decrease the incidence, improve sleep, and promote weight loss. Various oral and nasal appliances such as a nasal splint or tongue retaining apparatuses may be beneficial. CPAP is the cornerstone of therapy; however, there are other modes of positive pressure administration such as bilevel positive airway pressure and auto-titrating positive airway pressure. CPAP is the simplest as well as the most clinically studied and used. The principle of CPAP therapy involves the delivery of pharyngeal pressure so that it exceeds surrounding pressure, which in turn prevents collapse.

Cystic Fibrosis—Obstructive Cystic fibrosis (CF) is a common inherited respiratory disorder that causes severe lung damage and nutritional deficits. Approximately 1,000 new patients are diagnosed each year in the United States (Cystic Fibrosis Foundation, n.d.). Whites are more likely to develop cystic fibrosis than other ethnic groups, followed by Latinos and American Indians. Most children (66%) are diagnosed by the age of 1 year and of newly diagnosed patients 58% are detected by newborn screening. (CF Registry, 2017).

The genetic defect that leads to cystic fibrosis is a mutation in the gene that makes transmembrane conductance regulator (CFTR) protein. In CF, there are CFTR defects in production, processing, regulation, or conduction.The mutated gene has been isolated to chromosome 7, and transmission follows an autosomal recessive pattern. Over 1,700 mutations in the defective CFTR gene are possible, but only some of the mutations are disease causing. One mutation known as the F508del is a common cause of many CF symptoms. Out of the 1,480 amino acids that make up the CFTR protein, the F508del mutation causes one single amino acid to develop into an abnormal shape and an inability for the CFTR protein to function properly. More than 10 million Americans (1 in 31) are carriers of this faulty gene, and many do not know they are carriers.

CFTR defects cause problems with chloride movement across the cell membrane, also causing imbalances in sodium and water transport. Cystic fibrosis changes the cells that produce mucus, sweat, saliva, and digestive secretions. The number and size of goblet cells increases resulting in more mucus production. The lungs and pancreas are primarily affected, but other organs can also be involved (e.g., liver, intestines, sinuses, and reproductive organs). In CF, normally thin secretions become thick and tenacious as a result of defects in chloride secretion and excess sodium reabsorption. In the respiratory tract, the secretions occlude airways, ducts, and passageways instead of providing normal lubrication. Occlusions also occur in cilia fluid layer is reduced and the cilia become ineffective in clearing the excess mucus.

Neutrophils are abundant in the airways of those with CF and contribute to the

lung damage by releasing various oxidants. Neutrophil elastase damages elastin, promotes inflammation, and further stimulates mucus secretion. Antioxidants, as part of the defense mechanisms, are not able to cross the defective channels, rendering defense mechanisms ineffective. Immunoglobulin G is also destroyed by neutrophil elastase, further insulting the immune system. Atelectasis develops as airways are obstructed, leading to permanent damage (FIGURE 5-20). Mucus stagnates, becoming a prime medium for bacterial growth. Pseudomonas aeruginosa is commonly present in the airway of those with CF. Infections are recurrent and, combined with the cycle of impaired mucus clearance and chronic airway inflammation, progressive lung destruction ensues. Bronchiectasis (permanent abnormal dilatation and destruction of bronchial walls) and emphysema-like changes are common as fibrosis and obstructions advance. Abscesses and bullae may develop. The bullae can burst and lead to pneumothorax. The vascular changes in the lung lead to pulmonary hypertension and cor pulmonale. Respiratory failure is the most common cause of death in people who have cystic fibrosis.

FIGURE 5-20 Cystic fibrosis.

In the digestive tract, the mucus blocks the intestines, producing a meconium ileus in the newborn. Mucus also blocks pancreatic ducts, leading to damaged acinar cells that are not able to produce and transport pancreatic enzymes. Without these digestive enzymes, malabsorption and malnutrition develop. The trapped digestive enzymes damage pancreatic tissue by causing autodigestion. Additionally, the acinar cells become atrophic. These changes contribute to the development of diabetes mellitus and osteoporosis. Blocked bile ducts add to the malabsorption issues and increase risk for developing cirrhosis.

Salivary glands are only mildly affected by blockages. Sweat glands produce

sweat high in sodium chloride, which can cause electrolyte imbalances in times of excessive loss (e.g., during exercise or hot weather). Obstructions in the reproductive system can lead to sterility and infertility.

Clinical Manifestations Clinical manifestations of cystic fibrosis may appear at birth and progressively worsen throughout the life span. Lung function often starts declining in early childhood. The severity of the disease varies even with the same mutations, and genetic variants also influence disease progression and survival. Some mutations are more commonly associated with gastrointestinal instead of lung symptoms, but awareness of the type of mutation is not always consistent with presentation or severity.

Meconium ileus in the newborn may occur. Parents may notice their baby’s skin tastes salty when they kiss their child. Respiratory manifestations include frequent respiratory infections, chronic cough with tenacious sputum, dyspnea, fatigue, and activity intolerance. Digital clubbing, wheezing, rhonchi, chronic sinus infections, and nasal polyps may also be present. Thoracic changes such as a barrel chest appear later in the disease. Hemoptysis is a sign of damage to the vascular system due to bronchiectasis. Gastrointestinal manifestations include steatorrhea (fatty, foul- smelling stools) and fat-soluble vitamin deficiency (vitamins A, D, E, and K). Despite a voracious appetite, weight is difficult to maintain, and growth may be delayed or impaired. Various complications can develop, and manifestations will vary for each. Manifestations could include chronic bronchitis, failure to thrive, cardiomegaly, diabetes mellitus, pancreatitis, rectal prolapse, liver disease, cholelithiasis, osteoporosis, hyponatremia, metabolic alkalosis, and infertility.

Diagnosis and Treatment Diagnosis of cystic fibrosis can be accomplished prenatally when family history warrants testing. In the United States, all newborns are screened for cystic fibrosis regardless of family history. This screening involves analysis of the newborn’s blood for higher than normal levels of immunoreactive trypsinogen (IRT), a chemical released by the pancreas. IRT level may be elevated because of prematurity or a stressful delivery; therefore, other tests are used to confirm the diagnosis. Sweat analysis (i.e., sweat chloride test) is the standard for diagnosing CF. The test can be conducted as soon as the infant is 48 hours old or as long as enough sweat can be produced. Sweat analysis is used to detect sweat chloride concentration. A level of greater than 60 mmol/L is diagnostic. The delta F508 test can identify the chromosome 7 mutation, and it is often used if a false-negative sweat test is suspected or to identify carrier status of siblings. Genotyping for the CFTR mutation is done to evaluate for CF. Stool can be evaluated for the presence of pancreatic

(e.g., fecal elastase) content. Other tests that assess lung function include chest X- rays, pulmonary function tests, and ABGs.

Cystic fibrosis treatment requires diligent family involvement and an interdisciplinary approach because of the progressive, multisystem nature of the disease. Treatment regimens have improved the life expectancy for patients who have cystic fibrosis, with some people living into their 40s or 50s. Treatment often requires a multidisciplinary team including cystic fibrosis specialists, respiratory therapists, dietitians, and psychological counselors. Strategies are focused on respiratory care and infection control. Airway clearance therapy is important to facilitate the expectoration of mucus. These therapies include intensive chest physiotherapy either manually or with a mechanical percussor, postural drainage, and coughing and breathing exercises. Regular, moderate aerobic exercises can improve pulmonary health. Adequate hydration, humidified air, and avoidance of respiratory irritants such as smoke, pollution, and allergens or contact with infectious people are also part of respiratory care. Good hand washing and maintaining clean respiratory equipment can reduce infections. Categories of medications for pulmonary health include aerosol therapy, antibiotics, anti-inflammatory drugs, and CFTR modulators. Aerosol therapies can include beta-2 agonists and anticholinergics. Mucolytics, such as dornase alfa or hypertonic saline, improve mucociliary clearance. Inhaled or oral corticosteroids are not recommended and are considered harmful, but other anti-inflammatories such as ibuprofen, glutathione, N- acetyl cysteine, leukotriene modifiers or azithromycin may be beneficial in reducing inflammation. Antibiotics can be considered for maintenance and treatment of pulmonary infections. Various studies are underway to evaluate the best choice of antibiotics, method of delivery, and duration of treatment. CFTR modulators are medications that target the underlying genetic mutation and correct the malfunctioning protein. These medications are categorized as potentiators, correctors, and amplifiers and include such medications as ivacaftor or ivacaftor/lumacaftor. Gene therapy is under investigation.

Nutritional and gastrointestinal guidelines include pancreatic enzyme, bile salt, and fat-soluble vitamin replacement. A well-balanced, high-protein, low-fat, high- sodium diet is recommended. Enteral tube feedings may be necessary if a patient has an inadequate oral intake. Lung transplantation may be considered for severe lung disease. Even if the transplant is successful, other areas (e.g., gastrointestinal) are still affected by CF. Management of comorbidities is essential.

Lung Cancer Lung cancer is the second most often diagnosed cancer in men and women and the leading cause of cancer in the United States (American Cancer Society, 2018). Primary lung cancers (e.g., bronchogenic carcinoma) arise from the epithelial cells that line the bronchi or bronchioles. After increasing for decades, lung cancer

incidence and mortality rates are now decreasing in parallel with decreases in rates of cigarette smoking in this country. Frequently, other cancers—such as breast, bladder, and colon—metastasize to the lung tissue causing secondary lung cancer.

Smoking contributes to the majority (80–90%) of lung cancer cases. The more than 4,000 chemicals in cigarette smoke include carcinogens and chemicals that paralyze cilia. The risk for developing lung cancer is directly related to the length of time a person smokes and the number of cigarettes smoked. Secondhand smoke can also be a significant contributing factor. Smoking cessation or removing the smoke exposure will gradually decrease risk. Inhalation of other chemicals (e.g., asbestos, radon gas, tar, and pollution) and chronic lung disease can also increase risk (FIGURE 5-21).

FIGURE 5-21 Lung cancer.

The lungs provide an optimal environment for tumor development and growth. Carcinogens can seek refuge in the many nooks and crannies of the air passages. Upon exposure to the carcinogen, irreversible oncogene DNA mutations and inactivation of tumor suppressor genes occur in the epithelial stem cells. The cells are unable to grow or differentiate properly and rather become metaplastic and eventually progress to invasive carcinoma. Inherited genetic predispositions contribute to lung cancer development. Epidermal growth factor and inflammatory mediators promote tumor growth. The scores of blood vessels supplying the lungs serve as entrance points for distant cancer cells to gain access, and those vessels furnish the cancer with a rich blood source to facilitate its growth.

There are different categorizations of lung cancers, but generally, they can be divided into two types—small cell and non–small cell carcinomas (FIGURE 5-22). Small cell carcinoma is often referred to as oat cell carcinoma and is considered a neuroendocrine tumor. Other neuroendocrine tumors include large cell neuroendocrine and typical and atypical carcinoid tumors. Small cell carcinoma occurs almost exclusively in heavy smokers and is less frequent than non–small cell cancers. Prognosis is poor as the tumors grow rapidly and metastasis occurs early in the disease. Non–small cell carcinoma is the most common type of malignant lung cancer, accounting for 85% of all cases of lung cancer. Non–small cell carcinoma is classified into several subgroups—squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma. Adenocarcinoma is the most prevalent of all lung tumors. Other lung cancer tumors (e.g., mesothelioma) exist, but they are considered to be rare.

FIGURE 5-22 Cancer of the lung. A Small cell (oat cell) carcinoma. B Squamous cell carcinoma. C Adenocarcinoma. D Large cell carcinoma.

Tumors in the lungs lead to several issues including airway obstruction and inflammatory changes, which cause a cough and contribute to infections. Fluid can accumulate in the pleural space, leading to an effusion, hemothorax, or pneumothorax. Some tumors cause an endocrine dysfunction associated with secretion of hormones and cause a paraneoplastic syndrome.

Clinical Manifestations Clinical manifestations of lung cancer are insidious because they mimic signs of smoking (e.g., cough). Manifestations can include a persistent cough or a change in usual cough, dyspnea, hemoptysis, and frequent respiratory infections. Chest pain and hoarseness may be present. Anorexia, anemia, and weight loss accompany symptoms. Other symptoms specific to the site(s) of metastasis, such as bone pain, should be evaluated. Paraneoplastic syndromes can be manifested in multiple systems (e.g., endocrine, neurologic, dermatologic). Syndrome of inappropriate antidiuretic hormone and hypercalcemia are some common signs (see chapter 10 for more on endocrine function and chapter 6 for more on fluid and electrolyte homeostasis).

Diagnosis and Treatment Diagnostic procedures for lung cancer include a history, physical examination, chest X-ray, CT, MRI, bronchoscopy, sputum studies, biopsy, positron emission tomography, bone scans, and pulmonary function tests. Treatment is based on staging and can include usual cancer treatment—that is, chemotherapy, surgery, and radiation (TABLE 5-7; TABLE 5-8). The treatment is generally palliative because the tumor rarely responds favorably to treatment. Early diagnosis and treatment may improve this prognosis. Other strategies include those to maintain optimal respiratory function—oxygen therapy, bronchodilators, and antibiotics (if bacterial infections are present).

TABLE 5-7 Staging and Treatment of Non–Small Cell Lung Cancer

Stage Description Usual treatment plan

Stage I Cancer has invaded the underlying lung tissue but has not spread to the lymph nodes.

Surgery

Stage II Cancer has spread to neighboring lymph nodes or invaded the chest wall.

Surgery, radiation, and chemotherapy

Stage IIIA Cancer has spread from the lung to lymph nodes in the center of the chest.

Combined chemotherapy and radiation, sometimes surgery based on results of treatment

Stage IIIB Cancer has spread locally to areas such as the heart, blood vessels, trachea, and esophagus—all within the

Chemotherapy, sometimes radiation

A

chest—or to lymph nodes in the area of the collarbone or to the tissue that surrounds the lungs within the rib cage (pleura).

Stage IV Cancer has spread to other parts of the body, such as the liver, bones, or brain.

Chemotherapy, targeted drug therapy, clinical trials, supportive care

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

TABLE 5-8 Staging and Treatment of Small Cell Lung Cancer

Stage Description Usual treatment plan

Limited Cancer is confined to one lung and to its neighboring lymph nodes.

Combined chemotherapy and radiation, sometimes surgery

Extensive Cancer has spread beyond one lung and nearby lymph nodes and may have invaded both lungs, more remote lymph nodes, or other organs.

Chemotherapy, clinical trials, supportive care

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Pleural Effusion A pleural effusion is the accumulation of excess fluid in the pleural cavity. Normally, a small amount of fluid (approximately 20 mL.) drained from the lymphatic system is present in this space to lubricate the constantly moving lungs. Effusions develop because there is either excess pleural fluid formed or decreased lymphatic removal. Excessive fluid in the pleural cavity can compress the lung and limit expansion during inhalation. Effusions vary in nature and may affect both lungs or one lung.

Diagnostic Link

Lung Cancer Screening with Computed Tomography Scanning nnual screening with low-dose CT scanning was found to reduce overall mortality by 20% (National Lung Screening Trial, 2011). Therefore, screening is recommended for all adults age 55–74 years (United States

Preventive Task Force recommends up to 80) who:

Currently smoke or have quit within the past 15 years; and Have at least a 30 pack-year smoking history; and Receive evidence-based smoking cessation counseling, if they are current smokers; and Have undergone a process of informed/shared decision making that included information about the potential benefits, limitations, and harms of screening with low-dose CT; and Have access to a high-volume, high-quality lung cancer screening and treatment center.

Effusions are categorized by whether they are transudative or exudative. Identifying the cause of the effusion is facilitated by categorization. Transudative

effusions are caused by systemic processes, such as heart failure, cirrhosis, or kidney disease. Transudates result because of changes in hydrostatic and osmotic pressure that shift fluid into the pleural space. In heart failure, the excess fluid in the interstitial space increases hydrostatic pressure, causing fluid to enter the pleural space. Hypoproteinemia, which can occur with cirrhosis or kidney disease, causes a reduction in oncotic pressure drawing water out of the capillaries and into the pleural space. Exudative effusions can be more difficult to diagnose as there are a variety of mechanisms. In general, exudative effusions occur when there is a localized lung or pleural alteration such as inflammation or decreased lymphatic drainage. The inflammatory process occurs in disorders such as pneumonia, lung abscesses, or bronchiectasis that increase capillary membrane permeability causing shifting of fluid into the pleural space. Impairment in lymphatic drainage results in an accumulation of pleural fluid due to decreased removal. Some exudates have observable characteristics. Grossly purulent effusions are termed empyema. An effusion known as a hemothorax (blood in the pleural space) is usually due to trauma. Another type of effusion is a chylothorax (an accumulation of a milky white fluid composed of fat droplets and lymph) that can also occur due to trauma or alterations in the lymph system. Lymphoma, lung, and breast cancers are the three most common tumors (75%) that cause a malignancy-associated pleural effusion, and the type is usually exudative.

Pleurisy, or pleuritis, can precede or follow the effusion, or it may occur independently. Pleurisy comprises inflammation of the pleural membranes, which leads to swollen and irregular tissue. This inflammation is often associated with pneumonia and creates friction in the pleural membranes.

Clinical Manifestations Clinical manifestations and consequences of pleural effusion depends on its type, location, amount, and fluid accumulation rate. Patients may have few to no symptoms with small effusions and/or complain of dyspnea and chest pain (usually sharp and worsens with inhalation). Physical examination findings can include tachypnea, tachycardia, pleural friction rub (pleurisy), and diminished or absent lung sounds over the effusion. Dullness to percussion may be elicited over the effusion. Large effusions can cause the pleural membranes to separate, preventing their cohesion during inhalation (FIGURE 5-23; FIGURE 5-24). This lack of cohesion impedes full expansion, leading to atelectasis and a pneumothorax. Large effusions can impair venous return in the inferior vena cava and cardiac filling by exerting pressure on those structures, causing a mediastinal shift (heart, esophagus, trachea) to the unaffected side. A shift can cause cardiopulmonary compromise, which can be life threatening.

FIGURE 5-23 Pleural effusion is a buildup of fluid in the lining of the lungs.

FIGURE 5-24 X-ray of pleural effusion. Courtesy of Michael-Joseph F. Agbayani.

Diagnosis and Treatment Diagnostic procedures for pleural effusion include a history, physical examination, chest X-ray, CT, ABGs, and CBC. Thoracentesis (needle aspiration of fluid) with subsequent examination to distinguish between transudative versus exudative effusions is indicated when there is a new pleural effusion. If the effusion is small or the diagnosis is clear, such as heart failure, thoracentesis may be postponed. Pleural fluid analysis starts with gross appearance (e.g., hemothorax) and evaluation of cells (e.g., eosinophils, lymphocytes), pH, protein (e.g., levels are low in transudative

effusion), lactic dehydrogenase, and glucose levels. Additional tests of the fluid, such as acid-fast bacillus staining for tuberculosis, may be warranted depending on clinical suspicion.

Treatment focuses on addressing the underlying cause. Regardless of etiology, removal of the fluid is necessary to promote full expansion of the lungs. Strategies to do so may include thoracentesis, placement of a chest drainage tube, and antibiotics. However, small effusions can cause minimal symptoms and resolve with just the correction of the underlying problem (e.g., heart failure).

Pneumothorax Pneumothorax refers to air in the pleural cavity. The presence of atmospheric air in the pleural cavity and the separation of pleural membranes can lead to a partial or complete collapse of a lung (FIGURE 5-25 and FIGURE 5-26). The air enters in one of two ways. Damage to the visceral pleura surrounding the lung causes air to escape from the lungs to the intrapleural space. The visceral pleura can be damaged due to pulmonary disease or lung injury. Air can also enter when the parietal pleura that lines the chest wall or the chest wall itself is injured and atmospheric air enters the intrapleural space. A small pneumothorax causes mild symptoms and may heal on its own. A larger pneumothorax generally requires aggressive treatment to remove the air and reestablish pulmonary negative pressure. Risk factors for developing pneumothorax include smoking, tall stature, and history of lung disease or previous pneumothorax.

FIGURE 5-25 Serous membranes showing how a pneumothorax occurs when air leaks into the pleural space between the parietal and visceral pleura. The lung collapses as air fills the pleural space and the two pleural

membranes are no longer in contact with each other.

FIGURE 5-26 X-ray of a pneumothorax. Courtesy of Leonard V. Crowley, MD, Century College.

Several types of pneumothoraces are distinguished, based on their cause. Pneumothoraces can be categorized as spontaneous or traumatic. A spontaneous (nontraumatic) pneumothorax occurs in the absence of trauma. The pneumothorax develops when air enters the pleural cavity from an opening in the internal airways. Primary spontaneous pneumothorax occurs when a small air blister on the top of the lung (bleb) ruptures. Blebs cause a weakness in the lung tissue. Bleb development without other lung disease is more common in tall, thin healthy men between the ages of 20 and 40 years. The bleb may rupture, often for no apparent reason, and cause a spontaneous pneumothorax. Mutations in the folliculin gene have been linked to the incidence of spontaneous pneumothorax in families. Rupture can also occur from changes in air pressure, such as occur when scuba diving, flying, mountain climbing, or listening to extremely loud music. Additionally, a spontaneous pneumothorax may happen while smoking marijuana—a deep inhalation, followed by slowly breathing out against partially closed lips, forces the smoke deeper into the lungs. Primary spontaneous pneumothoraces tend to be milder with less serious consequences than other types of pneumothoraces.

O

Spontaneous pneumothoraces can develop in people with preexisting lung disease (e.g., emphysema, pneumonia, cystic fibrosis, or lung cancer). A pneumothorax from prior lung disease can also be termed secondary pneumothorax. In these cases, the pneumothorax occurs because the diseased lung tissue is weakened, and usually air blisters within the lung tissue (bullae) and/or on top (blebs) rupture (similar to primary pneumothoraces). A pneumothorax from preexisting disease can be more severe and even life threatening because diseased tissue can create a larger opening in the lung, allowing more air to enter the pleural space. Additionally, pulmonary disease reduces lung reserves, making any further reduction in lung function more serious. Chronic obstructive lung disease is a common cause of spontaneous pneumothorax.

A traumatic pneumothorax defines the mechanism by which a pneumothorax occurs (i.e., traumatically) and can stem from blunt trauma (e.g., vehicle air bag deployment) or penetrating injury (e.g., knife or gunshot wounds) to the chest. Traumatic pneumothoraces can inadvertently occur during certain medical procedures, such as chest tube insertion or removal, cardiopulmonary resuscitation, and lung or liver biopsy; this is termed iatrogenic pneumothorax. Mechanical ventilation is another cause of traumatic pneumothorax. Mechanical ventilation can increase alveolar pressures and cause alveolar rupture (barotrauma), leading to air escaping outside the alveolar space. Overdistention of the lungs from mechanical ventilation (volutrauma) can cause a pneumothorax. Using high levels of positive end-expiratory pressure (PEEP) and tidal volume during mechanical ventilation increases the risk of pneumothorax. Pneumothorax can also be categorized as open or closed. When the chest wall is intact, the term used is closed pneumothorax; causes include traumatic nonpenetrating injuries such as blunt trauma, rib fractures, or spontaneous bleb rupture from COPD. An open pneumothorax involves a breach in the chest wall whether iatrogenic or traumatic.

Learning Points

PEEP ne of the settings on a mechanical ventilator is PEEP. Mechanical ventilation causes inactivation of the normal surfactant that keeps alveoli from collapsing. During mechanical ventilation, alveolar capillary

membrane permeability is increased, causing frequent alveolar opening and collapsing with resulting increased pressure to reopen the alveoli. The use of applied PEEP from the ventilator provides an external pressure to avoid alveoli collapse at the end of expiration so that more alveoli (recruitment) remain available for gas exchange. While PEEP can be used therapeutically such as with acute respiratory distress syndrome (ARDS), there are negative consequences with high delivered pressures (e.g., pneumothorax, decreased cardiac output, increased intracranial pressure).

A tension pneumothorax is the most serious consequence of a pneumothorax; it occurs when the pressure in the pleural space is greater than the atmospheric pressure (Figure 5-10). The increased pressure rises due to air getting trapped in the

pleural space during inspiration, but the air cannot escape during expiration. The force of the trapped air can cause the affected lung to collapse completely and shift the heart toward the uncollapsed lung (called mediastinal shift), compressing the unaffected lung and the heart (FIGURE 5-27). Tension pneumothorax progresses rapidly and is fatal if not treated quickly. Tension pneumothorax can occur from open penetrating trauma or even if the chest is closed, as with positive pressure mechanical ventilation or after chest tube removal.

FIGURE 5-27 Tension pneumothorax. A one-way valve from a penetrating injury allows air into the pleural space during inspiration, but not out during expiration.

Clinical Manifestations Clinical manifestations vary in severity depending on the type of pneumothorax. These manifestations include the following signs and symptoms: sudden chest pain over the affected lung, chest tightness, anxiety, and dyspnea. Physical findings can include tachypnea, tachycardia, and decreased breath sounds as well as hyperresonance over the affected area. Chest expansion may be asymmetrical. A pneumothorax, particularly a tension pneumothorax, can lead to a deviated trachea and mediastinal shift, hypotension, and rapid deterioration and cardiovascular collapse if not corrected.

Diagnostic procedures for pneumothorax consist of a history, physical

examination, chest X-ray, CT, and ABGs. Treatment usually involves removal of the air and reestablishment of negative pressure, allowing for full expansion of the lungs. Such strategies may include thoracentesis and placement of a chest drainage tube with suction, which removes fluid and reestablishes negative pressure. Surgery may be required in some cases to correct and prevent future episodes. During surgery, the leak is repaired, and a chemical may be used to scar the area (pleurodesis). Blebs can be removed when there is recurrence or other situations. To reduce the incidence of mechanical ventilation–induced pneumothorax, pressures and volumes should be titrated (usually lowered), taking into consideration therapeutic benefit versus risk of pulmonary compromise.

Acute Respiratory Distress Syndrome—Restrictive Acute respiratory distress syndrome (ARDS) is a sudden failure of the respiratory system due to massive alveolar capillary membrane injury and acute lung inflammation. ARDS has many other names, such as shock lung, wet lung, stiff lung, and noncardiogenic pulmonary edema. Multiple conditions can precipitate ARDS, including prolonged shock, burns, aspiration, and smoke inhalation. This condition involves an acute hypoxemic event that is cardiac in origin resulting from an indirect systemic event, a direct pulmonary event, or a combination. An indirect systemic event could be a trauma, septicemia, acute pancreatitis, a drug overdose, a cardiopulmonary bypass, or a transfusion reaction. A direct pulmonary event could involve illicit drug and toxic gas inhalation, pneumonia, RSV infection, gastric acid aspiration, near drowning, or fat embolism. Pneumonia with sepsis would be an example of both. ARDS develops rapidly, often within 90 minutes of a systemic inflammatory response or within 48 hours of a lung injury. Risk factors include the presence of a chronic lung disease (e.g., emphysema, chronic bronchitis, and asthma), alcoholism, age greater than 65 years, and severe illness on presentation.

Multiple blood transfusions can cause a type of ARDS known as transfusion- related acute lung injury, which is one of the main causes of death due to transfusion. Sepsis is a common cause of ARDS. Varying criteria and definition of ARDS over the years and advances in management have led to various statistics pertaining to incidence and mortality. In general, ARDS is fatal in approximately one- third of cases. Individuals who survive will fully recover; however, it may take as long as a year for them to regain complete lung function, and they can have neurocognitive changes for up to 5 years.

ARDS progresses through phases that have varying and overlapping clinical and pathologic changes. These three phases are the exudative, proliferative, and fibrotic phases. The exudative phase is early in the course of ARDS and begins within 4 hours of the causative event and can last up to 7 days. Injury to the alveolar epithelial cell (i.e., type I pneumocytes) and the capillary endothelial cell membranes leads to the release of chemical inflammatory mediators (e.g., interleukin 1 and 8,

tumor necrosis factor) (FIGURE 5-28; FIGURE 5-29). These mediators increase capillary permeability, promote fluid and protein accumulation in the alveoli and interstitial spaces, and damage surfactant-producing cells (type II pneumocytes). Lung damage progresses as neutrophils migrate to the site, releasing proteases and other mediators, further damaging the alveolar capillary membrane and causing further leaking of fluid, proteins, and blood into the interstitium and alveoli. A hyaline membrane (a thin layer of tissue) forms in the alveoli and causes them to become stiff. Increased platelet aggregation and complement activation promotes microemboli development, further injuring the pulmonary vasculature. These events result in decreased gas exchange with severe hypoxemia and hypercapnia, reduced pulmonary blood flow, and limited lung expansion. Diffuse atelectasis and reduced lung capacity ensue.

FIGURE 5-28 Acute respiratory distress syndrome pathogenesis.

FIGURE 5-29 Acute respiratory distress syndrome.

The proliferative phase lasts up to 21 days, and signs of resolution begin with pulmonary edema resolving. Type II pneumocytes begin making more surfactant along the alveolar wall and become type I pneumocytes for gas exchange. While some people recover during this phase, others continue to have lung injury and begin to develop fibrosis. During the fibrotic phase, the alveoli and interstitium are fibrotic with emphysematous changes and bullae development. The fibrotic processes damage pulmonary circulation leading to pulmonary hypertension. Pneumothorax can occur along with acute respiratory failure. If the patient survives, scattered necrosis and fibrosis are apparent throughout the lungs. ARDS is similar in pathogenesis to disseminated intravascular coagulation (see chapter 3 for more on hematopoietic function).

Clinical Manifestations

Clinical manifestations of ARDS can develop suddenly or insidiously. Early signs such as tachypnea, dyspnea, and tachycardia can be subtle or a sign of many other illnesses. As lung injury continues, respiratory efforts worsen with evident accessory muscle use, anxiety, restlessness, and hypoxemia. Lung sounds, which are initially normal, begin to reflect the edema, and coarse crackles can be heard. In ARDS, supplemental oxygen delivery is usually not effective, and arterial oxygen saturation (SaO2) decreases. If damage continues, mental status becomes altered. Bowel sounds decrease, generalized edema sets in, and progression continues with symptoms of multiple organ dysfunction syndrome. Other systemic changes are often occurring simultaneously with ARDS as the chemical mediators affect more than just the lung. The inflammatory activation is initially protective but becomes detrimental and leads to what is termed systemic inflammatory response syndrome. This syndrome occurs often with ARDS and also leads to multiple organ dysfunction syndrome. Systemic inflammatory response syndrome criteria include tachypnea (> 20 breaths/minute), tachycardia (> 90 beats/minute), PaCO2 of less than 32 mmHg, and temperature decrease (< 38°C) or increase (> 38°C) with a white blood cell count that is either low (< 4,000 cell/mm3) or high (> 12,000 cell/mm3) or higher than 10% bands.

Diagnosis and Treatment Diagnostic procedures for ARDS consist of ABGs, chest X-ray, CT, and CBC and other tests such as blood cultures to identify the cause. Chest X-rays in the early stages may be normal, and blood gases may reveal a respiratory alkalosis. As time progresses, chest X-rays may reveal bilateral infiltrates and fluid in the alveoli (air bronchogram). Respiratory and metabolic acidosis become evident. The Berlin criteria were developed to predict ARDS prognosis and to define diagnostic criteria. For ARDS to be diagnosed respiratory symptoms must have begun within 1 week of injury/insult. To diagnose ARDS, opacities on chest X-ray or CT scanning and clinical findings must not be explained by other diseases (e.g., lung collapse or pleural effusion), and oxygenation must be low with three categories (i.e., mild, moderate, or severe) determined by PaO2/FiO2 and PEEP or CPAP settings (e.g., moderate is 100 < PaO2/FiO2 ≤ 200 with PEEP ≥ 5 cm H2O). The mild Berlin category is now the term used instead of acute lung injury.

The main goal of treatment is to maintain adequate oxygenation and respiratory status. Such strategies include mechanical ventilation. To prevent ventilator-induced lung injury, recommendations are to use low tidal volumes (< 6 mL/kg of predicted body weight) with PEEP (10–15 cm H2O) to counterbalance the use of high oxygen administration (FiO2). Extracorporeal membrane oxygenation, which is useful in neonatal respiratory distress might be beneficial in certain cases. Extracorporeal

membrane oxygenation, as opposed to a ventilator, facilitates the process of gas exchange through an artificial membrane lung. Pharmacologic therapy may include antibiotics empirically (not prophylactically), bronchodilators, mucolytics, and sedatives. Cardiovascular status must be carefully monitored. Other strategies include nutritional support (e.g., enteral feedings), conservative fluid therapy, and stress ulcer and deep vein thrombosis prophylaxis and other supportive therapies in critically ill patients. Appropriate treatment of underlying causes is key to treating ARDS.

Alterations in Ventilation and Perfusion Atelectasis—Restrictive Atelectasis refers to incomplete alveolar expansion or collapse of the alveoli. It occurs when the walls of the alveoli stick together. Atelectasis may be caused by the following conditions:

Surfactant deficiencies Bronchus obstruction (e.g., foreign objects, mucous plugs, and tumors) Lung tissue compression (e.g., tumor, pneumothorax, pleural effusion, and abdominal distention) Increased surface tension (e.g., pulmonary edema) Lung fibrosis (e.g., emphysema)

When alveoli are not filled with air, they shrivel—much like raisins. This ventilation issue can, in turn, impair blood flow through the lung. The ineffective ventilation and perfusion then impair gas exchange. Surgery and immobility increase the risk for developing atelectasis for this reason.

Atelectasis can occur in either small or large areas. If only a small area is affected, the respiratory rate will increase to improve the excretion of carbon dioxide and control the carbon dioxide levels. The larger the area affected, the more severe the symptoms experienced. Necrosis, infection (e.g., pneumonia), and permanent lung damage can occur if the alveoli are not reinflated quickly.

Clinical Manifestations The clinical manifestations of atelectasis are due to impaired ventilation and perfusion and include dyspnea, cough, anxiety, and restlessness. Physical exam findings include diminished breath sounds, asymmetrical chest expansion, tachypnea, tachycardia, and fever.

Diagnosis and Treatment Diagnostic procedures for atelectasis include determining a cause and may include a chest X-ray (FIGURE 5-30), CT, bronchoscopy, ABGs, and CBC. A high white blood cell count can occur with atelectasis. Treatment focuses on remedying the underlying causes (e.g., antibiotics for infections, thoracentesis for fluid accumulation) and reinflating the alveoli. Incentive spirometry (a device to promote ventilation) is effective in reinflating the alveoli. For severe cases, noninvasive ventilation with use of various modes such as continuous positive airway pressure or endotracheal intubation may be necessary for ventilation support. Prevention strategies include increasing mobility (e.g., turning and ambulating), coughing, and

deep breathing exercises (e.g., incentive spirometry) every 1 to 2 hours. Effective pain management and postoperative incisional splinting increase the likelihood that these interventions will be performed adequately.

FIGURE 5-30 X-ray of atelectasis. A Normal lung. B Lung with atelectasis (whiter area on right). Courtesy of Leonard V. Crowley, MD, Century College.

Acute Respiratory Failure Acute respiratory failure (ARF) is a life-threatening condition that can result from a variety of disorders, including COPD, asthma, ARDS, amyotrophic lateral sclerosis, alcohol or drug overdose, and spinal cord injury. Normally, oxygen levels are in the range of 80–100 mmHg, and carbon dioxide levels are in the range of 35–45 mmHg. In ARF, oxygen levels (PaO2) become dangerously low (less than 50 mmHg) or carbon dioxide levels (PaCO2) become dangerously high (greater than 50 mmHg). The low oxygen levels observed in ARF are not sufficient to meet the body’s metabolic needs, and the nervous system quickly becomes affected by the shortage of oxygen. The oxygen level becomes progressively worse as the patient’s condition worsens. Respiratory acidosis develops as the carbon dioxide levels rise. The hypoxia and acidosis trigger a reflex pulmonary vasoconstriction, further impairing

•

• • •

gas exchange and increasing cardiac workload. The heart decompensates from the lack of oxygen, which could lead to cardiac arrest. Respiratory arrest may occur as the respiratory system ceases all activity from the strain. See chapter 6 for discussion of respiratory acidosis.

Clinical Manifestations Clinical manifestations are usually evident and result from the impaired gas exchange. Shallow respirations, tachycardia, dysrhythmias, altered mental status, and other signs of hypoxemia may be present with ARF.

BOX 5-4 Application to Practice Now that we have learned what can go wrong in the pulmonary system, let us put that knowledge into practice. While working in the emergency department, the following patients need to be triaged.

A 2-year-old with a history of asthma with a fever, lethargy, and multiple uses of short-acting beta agonist treatments prior to arrival A 25-year-old male with nasal drainage and hoarseness A 40-year-old female with fever, severe body aches, and nasal congestion A 59-year-old male with stage III bronchogenic carcinoma who reports increased shortness of breath

Which patient would have the highest priority? Explain why. What are possible diagnoses in each scenario? What clinical manifestations would be consistent with each

possible diagnosis?

Modified from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

BOX 5-5 Application to Practice Case 1: A 25-year-man was playing basketball and develops sudden chest pain and shortness of breath. He is healthy. His body mass index is 20. History is negative for smoking and drug use. He presents to the emergency department and a chest X-ray reveals a pneumothorax. He asks why this happened. Explain the cause of pneumothorax in this young man.

1. a. b. c. d.

2.

a. b. c. d.

3.

Case 2: Thomas Jones, a 15-year-old who has a history of asthma, is complaining of increasing asthma symptoms (wheezing, shortness of breath) for the past 3–4 months. He states he has been using his short- acting bronchodilator 3–4 times a week and feels his symptoms have been flaring up. He has been waking up at night about 2 times a month. His vital signs are temperature: 98.6°F, pulse 84 beats per minute, respiratory rate 18 per minute, and blood pressure 110/70 mmHg. His pulse oximeter reading is 96%. Upon examination, he is awake, alert, talking in full sentences, and is in no acute distress. Lung auscultation reveals mild expiratory wheezing throughout. The remainder of the clinical examination reveals no other abnormalities.

What asthma step/classification would Thomas fall into? Intermittent Mild persistent Moderate persistent Severe persistent

A pulmonary function test is conducted. What two results would be consistent with the classification Thomas is in?

Increased peak expiratory flow Decreased residual volume Increased total lung capacity Decreased forced expiratory volume in 1 second

An inhaled corticosteroid is prescribed for Thomas. Describe the effects of a corticosteroid on asthma pathophysiology and symptomatology.

Case 3: Mrs. Garcia brings her 5-year-old, Manuel, to the emergency department with high fever, irritability, sore throat, and inspiratory stridor. She reports that he has had croup several times in the past and has required hospitalization for treatment twice. You see that Manuel is anxious and is sitting on his mother’s lap leaning forward. She says he has had trouble swallowing because of his sore throat, and he is drooling a lot. She is concerned he has croup again, but he is not coughing like before.

The healthcare provider suspects acute epiglottitis. Describe epiglottitis causes and compare to croup causes.

Which of the manifestations in this case are consistent with epiglottitis in comparison to croup?

Modified from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Diagnosis and Treatment Diagnostic procedures for ARF consist of ABGs, chest X-ray, electrocardiogram, and CBC. Treatment focuses on resolving the cause and maintaining adequate respiratory status. Strategies include oxygen therapy, support of ventilation with a noninvasive positive pressure ventilation, or invasive mechanical ventilation. Treatment for underlying causes may include bronchodilators, antibiotics (if bacterial infection is present), corticosteroids, and treatment of emboli (e.g., embolectomy and anticoagulants). Cardiac support such as cardiopulmonary resuscitation, sympathomimetic medications, or inotropic agents are usually inevitable as the heart arrests under the strain.

C H A P T E R S U M M A R Y

The pulmonary system plays a crucial role by supplying the oxygen essential for cellular metabolism and excreting the carbon dioxide waste product of that metabolism. Because of this vital function, pulmonary disorders can cause extensive and devastating problems throughout the body. Often the healthcare team has a limited amount of time to identify and respond to some of these pulmonary disorders to control their negative consequences. Additionally, many of these diseases are preventable; therefore, identifying those persons at increased risk and implementing prevention strategies can limit the severity or halt the development of these debilitating conditions. Prevention, early detection, early diagnosis, and prompt treatment will improve outcomes of patients with these conditions.

R E F E R E N C E S A N D R E S O U R C E S

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T

C H A P T E R 6

Fluid, Electrolyte, and Acid–Base Homeostasis

L E A R N I N G O B J E C T I V E S

Discuss normal fluid composition and distribution. Discuss fluid and electrolyte movement and regulation. Discuss acid–base regulation and compensatory mechanisms. Analyze arterial blood gases. Determine cause and effect of fluid, electrolyte, and acid–base imbalances. Summarize the interrelationship of electrolytes and components in fluids. Apply understanding of fluid, electrolyte, and acid–base imbalances when describing various disorders associated with imbalances. Develop diagnostic and treatment considerations for various fluid, electrolyte, and acid–base imbalances.

he human body requires a delicate balance, or homeostasis, to function optimally. The body continuously employs strategies to maintain this balance. Fluids, electrolytes, and pH all play critical roles in sustaining homeostasis.

Fluids are distributed in various body compartments and move among these compartments to preserve equilibrium. Electrolytes are vital for cellular function, and they work with the various fluids to maintain stability. Acid–base balance is critical for health and is achieved through a complex buffer system. Fluids, electrolytes, and pH have a dynamic relationship in which imbalances in one area can cause imbalances in the other two. Additionally, the other areas can serve to compensate for those imbalances. Often fluid, electrolyte, and pH imbalances are a consequence of multiple disorders. Compensatory mechanisms may fail to reestablish homeostasis affecting many bodily functions. Serious consequences are reflected systemically. In such a case, interventions will be necessary to reestablish stability.

Fluid and Electrolyte Balance Distribution Body fluid is made of water (i.e., solvent) and solutes (e.g., Na+, Cl−). Water is the medium within which metabolic reactions and other processes occur. Water carries nutrients into the cells, waste products out of the cells, enzymes in digestive secretions, and blood cells around the body. Fluid also facilitates movement of body parts (e.g., the joints, lungs, and heart). Fluid found inside the cells is referred to as intracellular fluid (ICF) and fluid found outside the cells is referred to as extracellular fluid (ECF) ECF is further divided into interstitial (between the cells), intravascular (inside the blood vessels), and transcellular (between epithelial lined spaces) compartments. The transcellular compartment includes fluid in the peritoneal, pleural, and pericardial cavities, cerebrospinal fluid, and fluid in the joint spaces, lymph system, eyes and gastrointestinal tract. The cell membrane serves as a barrier that substances and water must pass through to move to or from the intracellular compartment (i.e., between ECF and ICF. Collectively, the ICF accounts for approximately two-thirds of the body’s water (weight 40% of total body weight).

The ICF is rich in potassium, magnesium, phosphates, and proteins. The remaining one third of the body fluid makes up the ECF (20% of total body weight). Approximately three fourths of the ECF (i.e., 15% of total body weight) is found in the interstitial compartment, and the remaining one fourth (i.e., 5% of total body weight) is found in the intravascular and transcellular compartment. The ECF is rich in sodium, chloride, and bicarbonate. The intravascular space is composed of plasma. Blood (serum) electrolyte tests examine only intravascular electrolytes, but inferences from these tests can be made as to what is occurring in the other compartments. Despite the intravascular fluid only being a small portion of total body fluids, it is this fluid that contributes to blood pressure. See chapter 3 for a discussion of hematopoietic function.

The summary of body weight (adult man) is as follows:

Body weight: 100% = Solids 40% + total body fluids 60% Total body fluids Weight: 60% = intracellular 40% + extracellular 20% (15% interstitial + 5% intravascular/transcellular)

The distribution of fluid varies based on gender and age. The weight and percentages discussed describe a healthy adult male (FIGURE 6-1). A newborn and infant have less body fat and, therefore, the amount of water in the body is higher (i.e., 70–80%). As a child matures, the body water amount decreases until puberty, when adult ratios are reached. Men have more muscle and less fat and, therefore, have a higher amount of body water than women. Women have higher body fat (adipose cells do not store water) and, therefore, a lower total body water than men.

Regardless of the gender, the higher the muscle mass, the more body water, and the higher the fat composition, the lower the body water. Obesity, whether in childhood or adulthood (male or female), results in lower body water. Those who are obese, very young, or very old are more susceptible to the effects of fluid imbalances such as dehydration and hypovolemia when body water is lost. Even though newborns and infants have a high amount of body water, it is a significantly large amount in comparison to their total body size. Infants’ compensatory mechanism to manage imbalances are less mature. Due to these factors, body water loss such as from diarrhea in or vomiting by newborns and infants can result in serious consequences. With aging, muscle mass decreases and fat increases resulting in decreased body water. The elderly are also prone to severe consequences due to fluid losses because their compensatory mechanisms (e.g., kidneys), while mature, decline in function with age.

FIGURE 6-1 Fluid compartments of the body.

Fluid Movement Fluids are constantly circulating throughout the body and moving among compartments to maintain homeostasis. The body exchanges solutes (e.g., ions) and water between compartments to compensate for conditions that increase or decrease losses. This movement between compartments is primarily accomplished through osmosis, the movement of fluid (specifically water) across a semipermeable membrane from an area of lower solute concentration to an area of higher solute concentration. Water moves across the semipermeable membrane until equilibrium is achieved, at which point there is an equal ECF and ICF osmolality. See chapter 1 for a discussion of cellular function.

Because water moves freely across cell membranes, this equilibrium is usually easy to achieve. The movement of water depends on hydrostatic (push) and osmotic (pull) pressures (FIGURE 6-2). The ability of the solutes, proteins, and electrolytes to attract water is what determines the osmotic pressure of a fluid (FIGURE 6-3). In other words, solute concentration is what determines osmotic pressure. Sodium (Na+), chloride (Cl−), and bicarbonate (HCO3-) are the main (95%) determinants of osmotic pressure in the ECF with minor (5%) contributions from urea and glucose. Potassium (K+), adenosine triphosphate (ATP), phosphate (PO4-), and phospholipids are key determinants of osmotic pressure in the ICF. A pressure opposing osmotic pressure is hydrostatic pressure which is created by the water pushing against the cell membrane. Colloid osmotic pressure, which is known as oncotic pressure, is created mainly by the protein albumin. Water is pulled in with higher oncotic pressures. To summarize, the osmotic pressure created by solute concentration and oncotic pressure created by albumin pull or attract water to the compartments of highest concentration. Hydrostatic pressure created by water pushes water away. These pressures are usually in balance.

FIGURE 6-2 Pressures that control fluid balance.

FIGURE 6-3 Osmotic pressure.

Pressures (e.g., hydrostatic, oncotic) vary along the capillary. At the arteriolar end of the capillary, the blood net hydrostatic pressure (blood pressure) is higher than the net oncotic pressure, moving (pushing) fluid out of the intravascular compartment and into the interstitial compartment to meet cellular needs. At the venous end of the capillary, the net oncotic (colloid osmotic) pressure is higher than hydrostatic pressure, moving (pulling) fluid from the interstitial compartment to the intravascular compartment to aid in the exchange of waste products to be excreted. The higher pressure at the venous end is due to the hydrostatic pressure decreasing rather than the oncotic pressure increasing because the proteins, such as albumin, do not cross the semipermeable membrane. Most of the movement of water is dependent on the pressures intravascularly as interstitial pressures are very low. To be an effective osmole (i.e., create pressure/attract water), the solute must not be able to pass passively through a semipermeable membrane (e.g., Na+, protein). Urea can create pressure, but urea moves freely across the membrane and is, therefore, an ineffective osmole.

The effect of the osmotic pressure or tension on the cell is termed tonicity. Tonicity is determined by the osmotic pressure of two solutions (i.e., solvent and solute) separated by a semipermeable membrane and the concentration relative to one and other on each side of the membrane (i.e., intracellular and extracellular). These two terms can be complex to understand, so it is helpful to review differences between the two. Osmotic pressure is created by several solutes such as sodium, which is an effective osmole, and ineffective osmoles, such as urea or other toxins. Osmotic activity is described as the osmolarity or osmolality of a solution. Osmolality is the preferred term when referring to fluids inside the body. Osmolarity (e.g., intravenous fluids) is best used to describe fluids outside the body. Tonicity, on the other hand, only takes into account osmotic pressure created by effective osmoles (e.g., sodium, glucose) and not the ineffective ones. Tonicity is always discussed in reference to two sides of a membrane.

Tonicity is often used to describe the cell’s response to an external solution (FIGURE 6-4). In health care, the external solution described in relation to tonicity consists of intravenous (IV) solutions, specifically those containing electrolytes (e.g., Na+, K+) and nonelectrolytes (e.g., glucose). These solutions are termed crystalloids and are used to treat a variety of patient conditions (e.g., dehydration and shock). These solutions are classified based on their tonicity prior to infusion and in relationship to the intravascular plasma and there are three categories—isotonic, hypotonic, and hypertonic. IV solutions are administered with the intention to therapeutically alter the fluid dynamics between the ECF and ICF. Isotonic solutions (e.g., 0.9% saline, lactated Ringer’s solution, 5% dextrose in water solution) have concentrations of solutes equal to those in the intravascular

compartment. As a result of these equivalent solute concentrations (i.e., equal in the IV solution and plasma), isotonic solutions allow fluid to move equally between compartments and do not cause notable shifts in fluid volume. Hypotonic solutions (e.g., 0.45% saline) have a lower concentration of solutes (i.e., lower osmotic pressure) than those in the intravascular compartment. Hypotonic solutions cause fluid to shift from the intravascular compartment to the intracellular space. Hypertonic solutions (e.g., 5% dextrose in 0.9% saline, 3% saline, 10% dextrose in water) have a higher concentration of solutes (i.e., higher osmotic pressure) than those in the intravascular compartment. Hypertonic solutions cause fluid to shift from the intracellular compartment to the intravascular space.

FIGURE 6-4 Cellular response to tonicity. Courtesy of Mariana Ruiz Villarreal.

Tonicity is also a way to classify sodium and water imbalances. For example, these imbalances can be isotonic, hypotonic, and hypertonic. When discussing tonicity from this perspective, the imbalance is between the various fluid compartments.

In addition to fluid moving between compartments, fluid is added to the body through the ingestion of food and fluids, and a small amount is replenished as an internal cellular by-product. Approximately 100 mL of water is needed per 100 calories (i.e., energy) ingested to help with metabolism (i.e., the bodily processes of catabolism and anabolism) and waste elimination. As an example, a person who expends 1,500 calories in a day will require 1,500 mL of water for proper metabolism. Water ingestion is, therefore, critical for proper metabolism. Fluid is

primarily lost in the urine and feces, but additional insensible (immeasurable) losses occur through the skin (e.g., perspiration) and the respiratory tract (e.g., breathing, coughing, talking, and mechanical ventilation). A small amount is even lost in vaginal secretions. The minimum urine output for proper elimination of waste products is termed the obligatory urine output, and in adults this is approximately 500 mL. Formulas that incorporate kilograms are used to calculate the minimum in adults and children (see chapter 7 for a discussion of urinary function).

Fluid Regulation Body fluid intake and output balance is maintained through several mechanisms. Water balance is closely related to sodium balance. Sodium is responsible for most of the osmotic force in the ECF and serum sodium concentration is determined by water balance (ECF volume). Water balance (volume) is determined by the serum sodium concentration (osmolality). For purposes of simplicity and understanding fluid regulation, water balance is equated with volume and sodium serum concentration is equated with osmolality or tonicity.

Many of the compensatory mechanisms that maintain fluid balance involve the suppression or excretion of hormones that influence sodium and water. The osmoreceptor cells, for example, sense intravascular osmolality. Increased osmolality triggers the thirst mechanism in the hypothalamus to increase oral intake. The thirst sensation occurs with even the smallest water losses and is one of the best regulators to prevent water loss. This thirst sensation can decrease with aging (a phenomenon called hypodipsia). Changes in osmolality will also trigger antidiuretic hormone (ADH), also known as vasopressin which is the primary regulator of water excretion. Released from the pituitary gland in times of increased osmolality, ADH promotes reabsorption of water into the blood from the renal tubules. ADH suppression will conversely lead to water loss. So thirst is the mechanism to protect against water loss through ingestion while ADH suppression is the mechanism to regulate water through excretion (increased or decreased). While water balance changes occurred in response to osmolality (i.e., created by sodium concentration), the sodium balance changes occur in response to volume. Changes in volume activate kidney, heart, and vascular receptors to then increase or decrease sodium excretion. Decreased volume leads to decreased perfusion to the kidneys causing activation of the renin-angiotensin-aldosterone- system (see chapter 4 for more on cardiovascular function). Renin ultimately leads to development of angiotensin II which directly stimulates aldosterone and causes aldosterone release from the adrenal cortex. The hormone aldosterone when stimulated increases reabsorption of sodium, and subsequently water in the renal tubules. There are also volume sensors in the heart. Atrial natriuretic peptide from the atria, and brain natriuretic peptide from the ventricles, are released when the chambers of the myocardium become overstretched, indicating increased fluid volume. This peptide

stimulates renal vasodilation, thereby increasing urinary excretion of urinary sodium. Additionally, natriuretic peptides suppress aldosterone secretion, further increasing urinary output. Pressure receptors in the vascular system, particularly the aorta and carotids sense changes in volume. Decreases in volume activate the receptors which activate the sympathetic nervous system leading to renin activation, norepinephrine release and vasoconstriction and sodium retention.

Electrolytes Electrolytes play a crucial role in homeostasis. Electrolytes are minerals with electrical charges found in the blood, urine, and other body fluids. Electrolytes in the body include sodium, chloride, potassium, calcium, magnesium, and phosphorus (TABLE 6-1). Cations are positively charged, whereas anions are negatively charged. Cations and anions are attracted to each other, so a cation like sodium will be attracted to an anion like chloride or bicarbonate (i.e., NaCl, NaHCO3). The main extracellular electrolytes are sodium, chloride, and bicarbonate. The intracellular electrolytes are potassium, calcium, and magnesium. The charge on each side of the membrane is relatively neutral, so cation and anion charges are equal. Electrolytes are important in muscle and neural activity and in acid–base and fluid balance. The purpose and regulation of each electrolyte are discussed with each respective imbalance. Bicarbonate plays an important role in acid–base balance and is discussed in the Acid–Base Balance section.

TABLE 6-1 Normal Serum Values of the Major Electrolytes*

Electrolyte Normal range

Sodium (Na+) 135–145 mEq/L

Chloride (Cl−) 98–108 mEq/L

Potassium (K+) 3.5–5 mEq/L

Calcium (Ca++) 8.8–10.3 mg/dL

Phosphorus (P) 2.5–4.5 mg/dL

Magnesium (Mg++) 1.8–2.4 mEq/L

Bicarbonate (HCO3 −) 24–31 mEq/L

*Values may vary slightly. Modified from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Fluid and Electrolyte Imbalances Imbalances in fluid and electrolytes are usually related to disorders of intake (excessive or inadequate) or impairment in elimination (increased or decreased). Disorders often occur when an imbalances exceed the body’s ability to compensate for them. The kidney is the primary organ regulating electrolyte and fluid balance. Despite the kidneys’ key role, the catalyst for the imbalance can be another system. These systems can include disorders in the neurologic system (e.g., pituitary issues), cardiovascular system (e.g., heart failure), or the liver (e.g., cirrhosis). Fluid and electrolyte imbalances are a reflection of an underlying disorder and require further investigation to identify the cause. A fluid or electrolyte imbalance rarely occurs in isolation and is often just one piece of the puzzle in determining a disorder. Imbalances constantly fluctuate, meaning an imbalance is a reflection of a certain point in time in the trajectory of a disorder, so repeat measurements and evaluations may reveal a different result. While some imbalances are transient and inconsequential, some, such as potassium and sodium shifts, can be life threatening.

Water, Sodium, and Chloride Relationship Water and sodium balances are intricately linked. Chloride is attracted to sodium, so changes in sodium cause the same changes in chloride (e.g., decreased sodium, decreased chloride). The body is made up of approximately 60% fluids (this varies by weight, age, and gender), and most of that fluid is water with sodium as the most abundant solute in the ECF. Serum sodium concentration is the major determinant of the volume (i.e., water) of the ECF. Whenever an imbalance occurs there is either a problem with sodium, water or both. Imbalances in sodium (an effective osmole) will alter the tonicity (i.e., change in concentration between two cell membranes) within the ECF and between the ECF and ICF. These alterations in tonicity may cause intravascular water shifting. These changes in tonicity are classified as isotonic, hypertonic, or hypotonic (see Figure 6-4). Isotonic fluid shifts occur when water and sodium are lost proportionately (i.e., relatively equal amounts). No changes in osmolality occur with isotonic shifts, so the fluid between the ICF and ECF does not move and the cell is not affected. The shifts occur in the ECF compartments between interstitial and intravascular. Hypertonic shifts are mainly due to excess sodium (i.e., hypernatremia) with insufficient water. Osmolality increases due to the hypernatremia, so water shifts from the ICF to the high-sodium ECF. Because water leaves the cells, hypertonic shifts cause the cells to shrivel. Hypotonic shifts are mainly due to inadequate sodium (i.e., hyponatremia) with excessive water. Osmolality decreases due to the hyponatremia, so water shifts from the ECF to the ICF. Hypotonic water shifts are opposite of hypertonic shifts because water enters the cell with hypotonic shifts and causes the cell to burst (i.e., lysis).

To review, isotonic imbalances are water shifts from the intravascular to interstitial

spaces (both ECF compartments), while hypertonic imbalances are water shifts from ICF to the ECF. Hypotonic imbalances cause shifts from the ECF to the ICF. Volume (i.e., water) imbalances are generally in reference to the intravascular compartment. Volumes may shift as a result of changes in tonicity as just described. These volume shifts may be categorized as euvolemic (normal intravascular volume), hypervolemia (increased intravascular volume), and hypovolemia (decreased intravascular volume). Hypervolemia is at times used interchangeably with edema; however, edema is a result of fluid shifts from interstitial and intracellular and may also occur with hypovolemia.

Several disorders can cause sodium and/or water imbalances, which can present challenges in determining the cause. In general, volume disorders (excess or deficits) are due to altered sodium control, and ECF sodium concentration disorders are usually due to altered water control. Some imbalances are rare or unlikely which can also help in determining the cause. As an example, hypernatremia with hypervolemia is rare. Likewise, sodium excess from too much intake (oral or IV) is not too common. People do not usually ingest salts in amounts sufficient to cause hypernatremia because they would usually become thirsty and drink water to counterbalance. Some other disorders that cause sodium and water imbalances, such as Cushing syndrome, are rare in the overall population. Determining the cause of imbalances will guide treatment decisions. Imbalances are managed with fluid replacement, which involves determining the type of fluid (e.g., isotonic, hypertonic, or hypotonic crystalloids), the amount, the rate, and the route. Fluid management can also include withholding of fluids or removal of fluids and electrolytes with pharmacotherapeutics (e.g., diuretics) or dialysis.

Fluid Excess Ideally, fluid intake should be equal to the amount of loss. As previously discussed, fluid excesses are usually due to problems with sodium control as opposed to water control. A common issue with fluid excesses is too much sodium with water being retained, specifically in the ECF. The excess usually occurs because of inadequate water and sodium elimination and less commonly due to an excessive amount of sodium or water intake. Various disorders lead to fluid excess (TABLE 6-2). The fluid excess causes hypervolemia and edema. Usually hypernatremia or hyponatremia results depending on the causes of the fluid excess. As previously discussed, hypervolemia is the term used for shifts into the intravascular space rather than edema. Edema describes fluid shifts into the interstitial or intracellular spaces. The concepts of hypervolemia and edema are often used interchangeably by clinicians. Clinicians often refer to hypervolemia also as “fluid overload” and edema is considered the clinical manifestation of the overload. While hypervolemia can cause edema, hypervolemia can also occur without edema. Likewise, edema can occur without hypervolemia.

TABLE 6-2 Disorders of Fluid Excess and Deficit

Fluid excess—hypervolemia/edema; hyponatremia or hypernatremia

Fluid deficit—hypovolemia/dehydration- hyponatremia or hypernatremia

Excessive sodium*—excessive intake or decreased elimination

Excess hypertonic solutions: D10W, Hypertonic 3% saline, enteral feedings Excess dietary intake (e.g., processed foods, sodas, and certain seasonings)—a rare cause in a healthy person Corticosteroid disorders Cushing syndrome (glucocorticoid disorder)—e.g., adrenal gland or medication Hyperaldosteronism (mineralocorticoid disorder)— increase sodium retention Near-drowning in salt water

Deficient sodium*—decreased intake or increased elimination

Inadequate intake Excessive diuretic use (e.g., thiazide) Low aldosterone—hypoaldosteronism, Addison disease

Excessive water*—excessive intake or decreased elimination

Psychogenic polydipsia (excessive water ingestion) Free water (pure) intake Syndrome of inappropriate antidiuretic hormone (excessive ADH levels, which increases water retention) Hypotonic intravenous saline (0.45% saline) Cardiac disorders (e.g., heart failure) (see chapter 4) Renal disorders (e.g., renal water retention) can cause excess or deficit (see chapter 7)

Deficient water*—inadequate intake or excessive elimination

Inadequate intake—impaired ability to communicate (e.g., confusion, stroke, dementia); altered thirst (hypodipsia, adipsia) Inadequate replacement Gastrointestinal losses—watery diarrhea, vomiting, nasogastric suctioning Excessive insensible losses—excessive diaphoresis, prolonged hyperventilation Excessive diuresis—diuretics Diabetes insipidus—insufficient ADH (an inability to concentrate urine, leading to excess water loss) Hyperglycemia (e.g., uncontrolled diabetes mellitus, mannitol infusion) leads to glucose excretion and, in turn, water losses Massive fluid losses—burns, hemorrhaging, open wounds Renal disorders (e.g., nephrosis, which causes excess protein and water loss) can cause excess or deficit (see chapter 7)

* Excessive and deficient states are not necessarily reflected in serum plasma as several factors, particularly the underlying disorder, degree of alteration, and other losses that affect fluid balance such as potassium and glucose, which are not reflected in this table, can contribute to imbalances.

Fluid excesses in the interstitial compartment is edema. Intracellular fluid excesses are a result of water intoxication. Significant daily gains or losses do not usually occur in the transcellular compartments. Transcellular increases may occur with certain physiologic conditions or traumatic events such as pericarditis, pleurisy, and ascites. Significant fluid increases in the transcellular compartment are often referred to as third spacing because fluid is not easily exchanged among the other extracellular fluids. The concept of third spacing can also refer to the massive movement of fluid from the intravascular into the interstitial space, as occurs with

E

burns. Edema is a problem of fluid distribution. In other words, the fluids are in the

wrong place. Edema occurs when hydrostatic forces are greater than osmotic forces, causing the movement of fluid from the intravascular compartment to the interstitial space. The lymphatic system, which normally removes fluid, is unable to keep up with the excess. The venous system usually transports about 80% of fluid from the interstitial spaces while the lymphatic system accounts for approximately 20%. The arterial end of the capillary can tolerate changes in pressure, but the venous end of the capillary does not tolerate pressure changes well. Any increase in volume or obstruction in the venous system can increase capillary hydrostatic pressure and lead to edema. Disorders that cause sodium and water retention under circumstances that the body is unable to accommodate such volume increases, such as heart or renal failure, will lead to increased venous pressure and edema. Although the sodium is retained, the sodium plasma levels may actually be low (dilutional hyponatremia) as there is a proportionate amount of water retained. Venous pressure can also increase when the fluid return system is affected, which occurs with cardiac pump failure. Other causes of increased venous pressure not related to sodium or water imbalances are venous insufficiency (the veins are unable to return blood), being in a prolonged or chronic dependent position such as lying, and inadequate calf muscle pump activity that can occur with paralysis or gait issues. Deep vein thrombosis causes venous obstruction, increasing venous pressure. Medications can also cause edema. Medications, such as calcium channel blockers or pregabalin (e.g., Lyrica), cause edema through a slightly different mechanism. These medications cause arteriolar dilatation with subsequent increased capillary pressure with fluid extravasation. The edema that occurs with calcium channel blockers and pregabalin is usually in the lower extremities and mild. Some patients will discontinue the medication due to edema development. The edema from calcium channel blockers is an effect of dihydropyridines (e.g., amlodipine, nifedipine) and does not occur with nondihydropyridines (e.g., verapamil, diltiazem). Therefore, evaluating possible medications as the cause of the edema is an important component of diagnosis.

Learning Points

Albumin-Related Edema dema can occur due to a decreased colloid osmotic pressure (i.e., oncotic pressure). Hypoalbuminemia leads to a decrease in plasma oncotic pressure (pulling force) and fluid shifts from the intravascular to the

interstitial space. Proteins (e.g., albumin), in a sense, attract water. Low albumin levels can occur with nephrotic syndrome or gastrointestinal disorders (excess loss) or liver disease (decreased production). Vascular injury can cause increased capillary permeability, resulting in a loss of albumin and a shift of fluid into the interstitial space. Vascular injury can occur with many conditions such as burns, trauma, and infection.

Fluid excess can also occur in the intracellular space, a condition known as water intoxication. Water intoxication occurs as a result of ingesting large amounts of water faster than it can be eliminated. The high intravascular water concentration and dilutional hyponatremia (hypotonic) causes water to shift into ICF causing the cells to burst. Water intoxication can occur if someone drinks an excessive amount of water in a short period of time. Thirst triggers increased water ingestion, but healthy kidneys can only excrete up to 1 liter of fluid per hour. During rehydration, individuals should keep this in mind. Men on average need 3 liters of fluid per day while women need 2 liters per day. However, many factors influence the actual fluid needs such as climate, exercise, age, and health status. Psychogenic polydipsia is a disorder characterized by compulsive water drinking and occurs in patients with mental health disorders such as schizophrenia. Patients with this disorder can drink up to 10 liters per day, which can lead to water intoxication. ICF excess can lead to the rupture, or lysis, of the cells. Cerebral cells are the most sensitive to lysis, and cerebral edema can also be present.

Edema may be localized to one area (e.g., the feet, around the eye, or scrotum) and can be unilateral or bilateral. Edema can be acute or chronic, as with nephrotic syndrome or chronic venous insufficiency, respectively. Edema may be in dependent or nondependent areas. Dependent refers to areas most affected by gravity (e.g., the lower body). Nondependent refers to areas less affected by gravity (e.g., upper body). Bilateral edema in dependent areas (e.g., feet, legs, sacrum) is often due to systemic problems such as heart failure. Nondependent edema such as that in the face or arms can be caused by albumin disorders, as this fluid is throughout the body. The most common cause of unilateral edema is deep vein thrombosis. Weeks to months after the the thrombus is resolved the affected extremity can develop intermittent or persistent edema. This edema after a blood clot is known as post- thrombotic syndrome. The disorder occurs as a result of damage to the venous valves leading to valvular incompetence and increased venous pressure as a result of the clot. Unilateral edema can also be due to infections like cellulitis or muscular injury like an ankle sprain. Edema that is pitting (FIGURE 6-5) is caused by excess interstitial fluid. Nonpitting edema is usually either caused by a lymphatic disorder or a thyroid disorder. Generalized severe edema throughout the body, referred to as anasarca, is usually the result of liver cirrhosis or renal failure.

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FIGURE 6-5 Pitting edema. © Jones & Bartlett Learning. Photographed by Kimberly Potvin.

Learning Points

Lymphedema, Lipoedema, and Myxedema ymphedema is a type of edema that occurs when there is a blockage in lymphatic channels (e.g., tumor) or removal of lymph nodes (e.g., breast cancer). Lymphedema differs from other causes of edema (e.g.,

sodium imbalances) as the lymphatic system is structurally altered. Lymphedema is thought to occur due to a combination of increased capillary protein permeability and polysaccharides binding to excess proteins, preventing the lymphatics from effective removal of fluids.

Lipoedema is a type of edema caused by excess deposition of fat cells in an irregular and disproportional manner and not fluid shifts. The fat deposition is usually in the legs, thighs, and buttocks but can go to the arms. The legs will look like block columns. Lipoedema occurs mostly in women and rarely in men. It can occur with or without obesity. Eventually, lipoedema can cause venous and lymphatic problems.

Myxedema is another type of edema not related to fluid shifts. Myxedema refers to a thick nonpitting edema caused by deposits of mucopolysaccharides in the skin as a consequence of thyroid disorders.

Clinical Manifestations Clinical manifestations of fluid excess can include edema. If the disorder causing the edema is a systemic problem (e.g., heart failure), then the edema is more likely to be peripheral, bilateral, dependent (e.g., ankle, feet, sacrum), and pitting (Figure 6-5). Edema can be generalized (anasarca) or localized periorbital (e.g., nephrotic syndrome). Cerebral edema can cause headache, confusion, irritability, anxiety,

nausea, and vomiting. Other signs of fluid excess include dyspnea, bounding pulse, tachycardia, hypertension, jugular vein distention, crackles, and bulging fontanelles in infants. Fluid excesses can also be manifested as pleural effusions, pulmonary edema, or ascites. Rapid weight gain (3 pounds in a week or 1–2 pounds in a day; 1 pound approximately equals 500 mL of fluid) may be noted. Localized edema from disorders such as cellulitis or focal trauma (e.g., sprained ankle) will generally not cause systemic manifestations.

Diagnosis and Treatment Diagnosis of fluid excess is based on physical examination. The diagnostic procedures for fluid excess are focused on determining the cause, and the history and physical findings are the starting point. The choice of procedures will be determined by clinical suspicion. As an example, suspected deep vein thrombosis will require evaluation with a venous duplex Doppler ultrasound. Suspicion for heart failure will warrant a chest X-ray, echocardiogram, and other tests. The appropriate and recommended diagnostic procedures are discussed in other chapters in the text for each respective disorder—cardiovascular, endocrine, urinary, and so forth.

Management of fluid excess focuses on identifying and treating the underlying cause. Strategies may consist of wearing compression stockings and administering diuretics, as well as restricting sodium and fluids. Fluid administration, although counterintuitive, may be necessary and include the administration of colloids or crystalloids to shift fluids from the interstitial to intravascular space. Any fluid administration must be monitored carefully as use of fluids may worsen the excess, causing further compromise.

BOX 6-1 Application to Practice The following activity includes several case presentations of edema. Make a diagnosis for each case, remembering the following questions:

Is the edema acute/sudden or chronic (e.g., duration, progression)? Is it unilateral or bilateral? Is the edema generalized or localized? Is it pitting or nonpitting? Is it dependent? In addition to edema, what other characteristics are associated with the edema (e.g., redness, pain)? What is the pertinent past or coexisting medical history? What medications is the patient taking? You may want to refer to chapter 3 and chapter 4 to help determine the diagnosis.

Activity: Identify the probable diagnosis and what data support your decision. Describe the pathogenesis for the diagnosis. What data are inconsistent with your diagnosis? What diagnostic tests would you order, if any, and how would you treat this patient? Note: Assume history and exam is normal if not listed.

Case 1: 45-year-old Mrs. Rodriguez is complaining of intermittent mild bilateral feet/ankle swelling for the past 2 months, but it is worse on her right leg. She denies leg pain, but she does describe her legs as feeling heavy at times and reports standing for long periods worsens the swelling. She notes her veins are getting larger in her legs. For the past 8 months, she has been experiencing intermittent numbness in her feet and reports her left knee has been achy. She is a server at a busy restaurant and sometimes works 10-hour days. She denies any fever, warmth, erythema, or trauma.

Past medical history: obesity (BMI 31); type 2 diabetes mellitus. Medications: metformin. Physical examination: vital signs are within normal limits; exam is unremarkable except for bilateral tortuous

veins in both lower extremities, which are worse on the right leg, and decreased sensation in both feet.

Case 2: 68-year-old Mr. Quincy is complaining of left leg swelling for the past 2 weeks. The swelling started while he was on a cruise. The swelling is intermittent and below the knee to his foot. He describes a cramplike pain in his left calf. Lately, both legs have been cramping while walking, but it resolves when he sits. He denies any fever, warmth, erythema, or trauma.

Past medical history: iliofemoral deep vein thrombosis of his left leg after he had left hip replacement for osteoarthritis 9 months ago; treated with rivaroxaban for 6 months; stable angina; obesity (BMI 31); dyslipidemia.

Social history: quit smoking 4 years ago but resumed one-fourth pack per day 1 year ago. Medications: simvastatin; aspirin; metoprolol. Physical examination: vital signs are within normal limits; right leg is within normal limits except hairless,

shiny skin; left leg has 1+ pitting edema in the pretibial area and foot; mild pain with left calf compression and one small tortuous vein on the medial aspect of his calf; left leg is also hairless and shiny.

A venous duplex Doppler ultrasound of his left leg was done and reveals no deep vein thrombosis.

Case 3: 85-year-old Mrs. Delaney has bilateral ankle and foot swelling for the past 3 weeks; she states her feet hurt and her shoes feel tight and describes this swelling as the first occurrence; she denies fever, erythema, warmth, or trauma.

Past medical history: aortic valve replacement; hypertension; dyslipidemia; osteoporosis. Medications: amlodipine; benazepril; atorvastatin; alendronate sodium; aspirin. Physical examination: vital signs within normal limits; exam unremarkable except for grade 1 systolic

ejection murmur at the left sternal border, second intercostal space with no radiation, and mild (< 1+) pitting edema bilateral ankles and feet.

Case 4: 78-year-old Mr. Smith is complaining of increased swelling in his lower legs for the past 3 weeks. He states it worsens when his legs are hanging down and gets a bit better when he elevates them. The swelling started about a week after he left the hospital for an episode of pneumonia. He states his legs occasionally swell, especially when he eats too much salt, and the last time it happened was about 8 months ago. He reports taking a water pill for a while but not lately. He noted that he feels like he has put on a few pounds this week and feels a bit more tired and short of breath. He has had to sleep propped up with two pillows. He denies leg pain, fever, warmth, or trauma.

Past medical history: anterior wall myocardial infarction 2 years ago; hypertension; heart failure with reduced ejection fraction; dyslipidemia.

Social history: one pack a day smoker for 30 years—quit 2 years ago. Medications: sacubitril/valsartan; metoprolol; rosuvastatin; aspirin (which he forgets to take). Physical examination: temperature 98.5°F, pulse 70 beats/minute, respirations 22 breaths/minute, blood

pressure 150/80 mmHg; pulse oximeter 96%; weight increase of 5 pounds in 1 month; cardiovascular exam remarkable for an S3 gallop; lungs with bibasilar fine inspiratory crackles; bilateral lower extremities pretibial to feet with 2+ pitting edema and mild pain when depressing skin.

Case 5: 40-year-old Mr. Jason is complaining of right leg swelling, pain, erythema, and warmth for the past 2 days. The swelling started after he accidentally cut the front of his leg with a pocket knife while fishing.

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Past medical history: hypertension. Medications: amlodipine. Social history: drinks four to five beers on the weekends and has smoked one or two cigarettes a day for

the last 15 years (he states he is trying to quit). Physical examination: temperature 100°F, pulse 88 beats/minute, respirations 18 breaths/minute; blood

pressure 140/92 mmHg; exam unremarkable except for edematous anterior right leg with open linear wound approximately 1-inch long; wound with scant purulent drainage; area is warm and tender with blanching erythema that extends 3 inches around the wound.

Fluid Deficit Fluid deficit occurs when total body fluid levels are insufficient to meet the body’s needs. As with excesses, fluid deficits are usually due to problems with sodium control as opposed to water control. The most common issue in fluid deficit is too little sodium with an inability to retain water (see Table 6-2). The deficits usually occur because of excessive water and sodium elimination, but inadequate water and sodium intake can also be present. Fluid deficit may be referred to as dehydration or hypovolemia. Hypovolemia is a fluid deficit in the intravascular compartment as a result of total volume loss (sodium and water). Dehydration refers to water loss alone, which results in hypernatremia. The terms are often used interchangeably. Dehydration causes a hypertonic state which leads cell shriveling (Figure 6-4) as fluid shifts from the ICF to ECF. This ICF cell dehydration often affects brain (neurons) cells (edema also affects neurons) with subsequent neurologic manifestations. Fluid deficit can occur independently or with electrolyte imbalances, such as hypernatremia or hyponatremia. Sodium alterations are dependent on how much sodium is in the fluid that is lost. As an example, diarrhea or vomiting may cause a significant loss in relation to the water. If sodium loss is greater than water loss (e.g., as with thiazide diuretics), then plasma sodium levels fall. Sodium, along with levels of other blood solutes (e.g., blood cells and electrolytes), increases if water loss is greater than sodium losses because of hemoconcentration. If sodium loss and water loss are relatively equal, plasma sodium levels may not be altered. Fluid volume deficits can cause hypotension and orthostasis.

Learning Points

Rule of Threes: Survival luid deficits can happen in healthy people; however, deficits are usually due to lack of water being accessible. The rule of threes is a good way to remember how long a person can survive without water and

other basics of life. A person can survive approximately 3 minutes without oxygen, 3 days without water, 9 days without sleep (multiple of 3), and 3 weeks without food. Water ranks high in the basic needs.

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BOX 6-2 Application to Practice An example of osmotic diuresis can be seen in a tragic case in which a newborn was fed concentrated formula by mistake. Often, tube feeding and baby formulas are high in glucose and other electrolytes. Many times, these formulas come concentrated for shipping purposes. The newborn’s father was unaware that the formula required dilution prior to feeding it to his child. The high concentrations of glucose caused excessive urination, and the baby died because of hypertonic dehydration.

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Learning Points

Fluid Balance: Elimination hile imbalances can occur due to excessive or inadequate intake of sodium or water, the usual culprit is elimination (i.e., loss). Intake issues are not as likely to occur. For example, excessive water intake to the

point of illness is not likely. Decreased water intake issues are probably more prevalent in comparison to excess water intake, but the balance can be restored with an intact thirst mechanism unless a person has no access (e.g., running out of water in extreme conditions). Likewise, excessive salt intake causing imbalance by itself is not too common as salt alone is not very palatable. Even drinks with electrolytes are often more sugar and, therefore, water retaining, so they balance out the excess salt. There are situations where even reasonable amounts of salt intake can be an issue, such as with heart failure and other disorders. Even under those circumstances, the issue is the that salt intake causes water retention (problem with elimination). Inadequate pumping decreases renal perfusion and decreased elimination. Clinicians should be aware of the side effects of hypotonic or hypertonic administrations, whether parenteral or gastric, and adjustments should be made (e.g., enteral feeds with water boluses or continuously). Even disorders that cause retention of water or sodium or both are not common in the general population, so elimination is the most common issue with either too much sodium or water eliminated or too much sodium or water retained (see chapter 7 for further details on urinary function).

Clinical Manifestations Clinical manifestations of fluid deficits include thirst and altered level of consciousness. Hypovolemia may cause hypotension or orthostatic symptoms (e.g., dizziness) with compensatory tachycardia. As volume continues to decrease, the pulses become weak and thready. Signs opposite of edema (fluid excess) such as flat jugular veins, sunken fontanelles in infants, decreased skin turgor, dry mucous membranes, oliguria, and weight loss can occur.

Diagnosis and Treatment Diagnosis of fluid deficit is based on physical examination. The diagnostic procedures for fluid deficit are focused on determining the cause, and the history and

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physical findings are the starting point. The choice of procedures will be determined by clinical suspicion. As an example, diagnostic tests may include a complete blood count (CBC), chemistry profile, stool samples (to test for Clostridium difficile), and others if a person has hypotension with excessive vomiting and diarrhea. The appropriate and recommended diagnostic procedures are discussed in other chapters in the text for each respective disorder—gastrointestinal, urinary, and so forth.

Management focuses on identifying and treating the underlying cause of the fluid deficit. Strategies include fluid replacement—oral fluids for mild losses and intravenous fluids (IVFs) for greater losses, usually isotonic. Prompt management and awareness of fluid deficits are aimed at avoiding hypovolemic shock (see chapter 4).

Learning Points

Glucose and Fluid Balance lucose normally has a minor contribution to osmotic pressure in comparison to sodium. Glucose, like sodium, is an effective osmole as it does not freely cross the cell membrane and needs to be transported

by insulin. So, excess glucose (hyperglycemia) in the ECF, specifically intravascular fluid, increases osmotic pressure and hypertonicity, causing water to be drawn out of the ICF (cells). The cells become dehydrated. The kidneys compensate by eliminating the excess glucose and water, causing what is termed an osmotic diuresis. Potassium follows glucose out of the cell with resulting hyperkalemia (in the intravascular compartment). However, other electrolytes like sodium get diluted due to the excess water. For every 100 mg/dL of serum glucose above normal, sodium decreases about 1.6 mEq/L. Hyperglycemia can cause a fluid deficit due to water being pulled out of the cell and compensatory diuresis. A high glucose solution like mannitol is used for cerebral edema or increased intracranial pressure with the intent that water moves out of the cells.

Sodium Sodium is considered the most significant cation. The most prevalent electrolyte within the ECF, sodium’s primary function is to control serum osmolality and water balance. Sodium accounts for most of the extracellular osmolality, so sodium changes, in turn, alter osmolality. There are negligible amounts of sodium in the ICF and the sodium in the interstitial space is bound and osmotically inactive. Sodium has an affinity for chloride and helps maintain acid–base balance when combined with another anion, bicarbonate (HCO3-).

Sodium concentration is determined by the volume (i.e., water) status. Mechanisms to increase or decrease sodium are regulated by the kidneys as well as aldosterone produced by the adrenal cortex. When aldosterone is released the kidneys retain sodium. The sympathetic nervous system assists the kidneys in sodium regulation by changing the glomerular filtration rate, which is a reflection of renal blood flow. Increasing the glomerular filtration rate increases sodium excretion; decreasing the glomerular filtration rate decreases sodium excretion. The renin–

angiotensin–aldosterone mechanism also manipulates sodium in the kidneys; this mechanism is triggered in times of decreased renal perfusion (e.g., hypovolemia and hypotension). Renin, a protein, converts angiotensinogen to angiotensin I; subsequently, angiotensin I is converted to angiotensin II in the lungs. Angiotensin II causes the kidneys to retain sodium (also causes release of aldosterone) and, in turn, water. Volume and pressure receptor activation can lead to sodium retention or excretion.

The cellular membrane is permeable to sodium, but it is dependent on the sodium–potassium pump to transport these ions. Sodium facilitates muscle and nerve impulses through the pump. As sodium moves into the cell, potassium shifts out of the cell, resulting in depolarization (increasing the membrane potential or excitability) of the cell membrane. When sodium shifts out of the cell, potassium moves back into the cell, resulting in repolarization (restoring the resting potential) of the cell membrane.

Sodium is primarily brought into the body through dietary intake and a common type ingested is sodium chloride (i.e., table salt). Many other types of sodium are in food products such as sodium bicarbonate (i.e., baking soda). The key is to look for the word sodium in the ingredients (e.g., monosodium glutamate, sodium phosphate). The recommended dietary allowance (RDA) of sodium is 2–4 grams. This electrolyte can be found in many sources, such as table salt (1 teaspoon contains more than 2 grams of sodium), processed or prepackaged foods (e.g., canned foods and deli meats), snack foods (e.g., chips), condiments (e.g., ketchup and hot sauce), and certain cooking seasonings (e.g., garlic salt and seasoned salt).

Normally, sodium losses occur in the kidneys. Excessive losses can occur through the gastrointestinal tract through vomiting, diarrhea, and nasogastric suctioning. Extensive burns can also cause sodium losses through the skin. Finally, sodium losses can occur with excessive sweating (e.g., fever and strenuous exercise).

Hypernatremia is defined as a high serum sodium levels (greater than 145 mEq/L). The excessive sodium levels generally lead to high serum osmolality (greater than 295 mOsm/kg) because of the imbalance between sodium and water. As sodium levels rise, hypertonicity occurs, and water shifts out of the intracellular space and into the intravascular compartment. This shift leads to intracellular dehydration, shrinking the cells (Figure 6-4). Hypernatremia usually results from water imbalances due to excessive loss without adequate replacement as opposed to actual sodium excess issues (e.g., rapid ingestion without water or hypertonic solution administration). Inadequate water replacement occurs as a result of impairment in thirst or lack of access to water. Excessive water losses can be categorized as extrarenal or renal losses. Extrarenal losses can occur as a result of gastrointestinal losses (e.g., severe diarrhea, vomiting) or profuse sweating and insensible losses from mechanical ventilation. Renal water loss is a result of the

kidneys’ inability to retain water. Conditions that cause an osmotic diuresis such as hyperglycemia from poorly controlled diabetes mellitus or mannitol infusion will initially lead to hyponatremia with hypertonicity but water losses become progressive and ultimately hypernatremia ensues. Administration of hyperalimentation whether enteral or parenteral with high protein (causes increased urea) can also cause an osmotic diuresis. Diabetes insipidus is a disorder that results in ADH deficiency or an unresponsiveness of the kidneys to ADH (see chapter 10 for more on endocrine function). Diabetes insipidus will cause water loss. Usually two clinical scenarios occur with hypernatremia—either 1) a loss of sodium with even greater amounts of water loss causing hypovolemia, or 2) excessive water loss relative to sodium loss (i.e., hemoconcentration) (Table 6-2).

Hyponatremia is defined as low serum sodium levels (less than 135 mEq/L). Serum osmolality levels also fall below 280 mOsm. As sodium levels decrease, hypotonicity occurs and water shifts from the ECF into the ICF. The cells swell with water, causing intracellular edema. The brain is particularly susceptible to hyponatremia as water moves into brain cells, causing cerebral edema. Additionally, nerve conduction becomes impaired as the sodium levels fall. Hyponatremia occurs due to excessive water usually from inadequate renal water excretion (water intake must still be present). Therefore, to determine the cause of hyponatremia, it is important to figure out why the kidneys are unable to excrete the water and also determine all the water sources (is there an excess taken in beyond the kidney capacity). Often there is impaired ADH suppression; but there can also be increased ADH secretion both situations will lead to with water retention. ADH suppression may however be intact. Hyponatremia is generally associated with hypotonic states. Disorders that lead to decreased water excretion and therefore hyponatremia include:

Renal failure—the lack of ability of the kidneys to filter causes an inability to excrete. Severe volume depletion—usually from gastric losses (e.g., vomiting and diarrhea) leads to ADH release (water retained with hyponatremia). Diuretics—particularly thiazides impair water excretion and increased sodium excretion. Syndrome of inappropriate antidiuretic hormone—abnormal ADH secretion (see chapter 10 for more on endocrine function). Adrenal insufficiency or failure—impaired adrenocorticotropic hormone leads to inability to suppress ADH (water retained) and aldosterone deficiency leads to release of ADH (water retained). Lack of sodium intake or too much water ingestion—such as can occur with psychogenic polydipsia, excessive beer drinking (beer is dilute and has little solute), dietary sodium restriction, prolonged exercise can increase ADH

secretion (water retained). Decompensated heart failure, liver failure, or nephrotic syndrome—leads to water retention.

Hyponatremia can be associated with hypertonic states although this is not as common. As an example, there is hyponatremia with hyperglycemia, as the glucose creates a hypertonic state and water shifts from the ICF to the ECF. Mannitol, a type of glucose infusion, will create a hyponatremia with hypertonic state. Extremely high triglycerides (generally in the 1000s when normal range is less than 150 mg/dL) or high proteins as can occur with multiple myeloma can also act as effective osmoles. These are other circumstances causing hyponatremia with hypertonicity.

Clinical Manifestations Sodium imbalances generally result in neuromuscular clinical manifestations. Manifestations of hypernatremia can range from subtle to serious, depending on the severity of the hypernatremia itself. Manifestations include lethargy, headache, confusion and irritability, seizures, and coma (i.e., usually greater than 158 mEq/L). Hypernatremia usually causes hypovolemia, and manifestations can include hypotension, dry mucous membranes, thirst, and decreased urine output.

Manifestations of hyponatremia can also cause similar neuromuscular manifestations (e.g., headache, lethargy, confusion, seizures, and coma) and are likely to be present with extremely low levels (i.e., less than 125 mEq/L). Levels of 130 mEq/L generally cause gastrointestinal symptoms such as nausea, vomiting, and diarrhea. Signs of hyponatremia with hypovolemia will be similar to fluid deficits such as hypotension. Hyponatremia with hypervolemia will cause fluid excess signs such as edema.

Diagnosis and Treatment Diagnoses of sodium imbalances are made based on serum levels. Diagnostic procedures for hypernatremia and hyponatremia include a history, physical examination, blood chemistry, and urine analysis. Other diagnostic tests are conducted to identify the cause. Generally, serum osmolality will be increased with hypernatremia and decreased with hyponatremia Urine sodium and osmolality evaluation can aid in determining the underlying disorder.

Management of hypernatremia focuses on treating the underlying cause. If the cause is related to water loss, treatment begins with replacing water and remedying any electrolyte deficits. Glucose-electrolyte solutions (e.g., sports drinks) are given orally for less severe cases. Electrolyte solutions are also available for infants and young children. More severe cases can be corrected with IV hypotonic (e.g., 5% dextrose in water or 0.45% saline) solutions. The healthcare professional must use

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caution to avoid correcting the hypernatremia too rapidly. The brain can become accustomed to the high levels of sodium; as the levels drop with the treatment of hypernatremia, water moves into cerebral cells, causing cerebral edema. Generally, hypernatremia should initially be reduced no faster than 1 mEq/L per hour, however, the total reduction in 24 hours should be no greater than 12 mEq/L. Additionally, seizure precautions (e.g., low lighting and decreased stimuli) and neurologic checks should be part of the patient’s plan of care.

Diagnostic Link

Urine: Specific Gravity and Urine Osmolality rine osmolality and specific gravity are reflections of urine concentration and reflect hydration (volume) status and kidney functioning. These tests are used in conjunction with serum values (i.e., electrolytes,

osmolality) to identify causes of alterations in urine output or serum electrolyte imbalances. Specific gravity is determined by the number and size of the solutes in the urine as opposed to urine osmolality witch is determined by the number of solutes in the urine. Specific gravity, therefore can be less accurate. Osmolality in urine is determined by the same solutes as in serum such as sodium, chloride, urea, potassium, and glucose. The higher the solutes, the higher the urine osmolality. The osmolality is considered more accurate than urine specific gravity as large molecules (e.g., glucose, proteins) invalidate results with specific gravity. A high urine osmolality means there are increased solutes with decreased water in the urine (e.g., dehydration). A low urine osmolality means there are decreased solutes with increased water in the urine (e.g., diabetes insipidus indicates inadequate ADH). The normal urine-to-serum osmolality ratio is 3:1. As an example, if urine osmolality is 855, then serum osmolality is 285 under normal circumstances. Alterations in the ratio can occur with concentrated urine (increased solutes, inadequate water), which will cause a high ratio. Poorly concentrated urine (decreased solutes, too much water), which will cause a low ratio.

Management of hyponatremia focuses on treating the underlying cause (e.g., administering corticosteroids for Addison disease; discontinue medication if it is causing syndrome of inappropriate antidiuretic hormone). In cases caused by excessive water, intake may be limited, whether orally or IV (i.e., avoid hypotonic solutions). Diuretics or dialysis may be necessary to remove excess free water. In cases caused by deficient sodium, intake may be increased either orally or with hypertonic solutions. Correction of sodium levels should be done slowly as with hypernatremia. Rapid correction can cause fluid to shift into the intravascular space and overload the heart. Rapid correction may also cause cerebral cellular volume changes with serious neurologic consequences and death. With hyponatremia, patients should be on seizure precaution (e.g., low lighting and decreased stimuli) and neurologic checks should be part of the patient’s plan of care.

Chloride Chloride is a mineral electrolyte and the major extracellular anion. Chloride assists in fluid distribution by attaching to sodium or water. Because of its negative charge, chloride can bind and travel with positively charged ions such as sodium, potassium, or calcium. This electrolyte is found in gastric secretions, pancreatic juices, and bile.

In the stomach, it unites with hydrogen to form hydrochloric acid. Chloride is abundant in cerebrospinal fluid, where it binds with sodium. When bound to sodium, it behaves just like sodium in regard to water balance. When bound to hydrogen, chloride plays an important role in acid–base balance.

Diet is the main source of chloride. The chloride RDA is 3–9 grams. Chloride is easily obtained through consumption of a balanced diet. Common sources of chloride include table salt, fruits, vegetables, cheese, milk, eggs, fish, canned foods, and processed meats. The kidneys are primarily responsible for chloride excretion, but some chloride is also lost through sweating. Hyperchloremia is an excess amount of chloride in the blood (greater than 108 mEq/L). Hyperchloremia is usually a result of an underlying condition; it does not have its own clinical manifestations, but the companion condition may cause signs and symptoms (e.g., metabolic acidosis). Hypochloremia occurs when chloride levels fall below 98 mEq/L. Hypochloremia rarely occurs in the absence of other abnormalities (e.g., metabolic alkalosis), so as with hyperchloremia, it does not have its own set of clinical manifestations. Cystic fibrosis is caused by a mutation in the gene that makes transmembrane conductance regulator protein, and defects in this protein cause problems with chloride movement across the cell membrane, which, in turn, causes imbalances in sodium and water transport. Chloride imbalances are often due to the same disorders that affect sodium and water balance (Table 6-2). Metabolic acidosis and hyperparathyroidism can cause hyperchloremia (excess calcium attracts chloride), and metabolic alkalosis and hypothyroidism cause hypochloremia.

Diagnostic procedures include a history, physical examination, blood chemistry, urine analysis, and measurement of arterial blood gases (ABGs). Management of hyperchloremia and hypochloremia focuses on treating the underlying cause. With hyperchloremia, administering diuretics to assist in eliminating sodium will, in turn, assist in the removal of chloride. Administering bicarbonate can correct acidosis if present. Some strategies for treating hypochloremia include increasing oral sodium intake and administering sodium-containing IV solutions. Additionally, ammonium chloride can be given with caution to raise chloride levels. Saline solutions can also be used to irrigate gastric tubes.

Potassium Potassium is the primary intracellular cation. It plays a crucial role in electrical conduction throughout the body (e.g., nerves, skeletal system, and cardiac system), acid–base balance, and metabolism of carbohydrate, protein, and glucose. Potassium is present in huge quantities in the intracellular space (98% of total body potassium)—a store that can be utilized if serum levels drop. However, certain circumstances such as lysis cause excessive amounts of potassium to shift to the intravascular space, which can be dangerous (especially within the heart). Serum potassium cannot fluctuate much—either up or down—without causing serious

issues. The sodium–potassium pump regulates ICF and ECF potassium exchange and the exchange ratio is 3 sodium ions for 2 potassium ions. The kidneys regulate levels through retention or elimination. Potassium along with ATP, phosphate, and phospholipids maintain intracellular osmotic pressure. Potassium levels in the ICF, which are not measured clinically, are approximately 140–150 mEq/L. Serum potassium, which is clinically measured, is 3.5–5.0 mEq/L. Insulin and catecholamines, particularly beta-2 adrenergic receptors, cause activation of the sodium–potassium pump with potassium shifting back into cells. Acid–base balance through hydrogen also influences shifts. Hydrogen and potassium exchanges occur between the ICF and ECF when pH is altered. For example, hydrogen increases in the blood with metabolic alkalosis (increased pH); therefore, potassium does not shift out of the cell, resulting in hypokalemia (low potassium levels in the serum). Aldosterone promotes retention of sodium but regulates potassium by promoting excretion (see chapter 7 for more on urinary function).

Dietary intake (e.g., cantaloupes, raisins, bananas, oranges, green leafy vegetables, and lentils) is the primary source of potassium. The RDA for potassium is 40–60 mEq as the average adult stores are about 50 mEq/kg (the amount varies with weight and muscle mass). Most potassium (about 90%) is excreted in the kidneys, but some potassium is lost through the gastrointestinal tract (i.e., in the stool) and some in sweat.

Hyperkalemia refers to serum potassium levels greater than 5 mEq/L. Hyperkalemia is unusual in the healthy individual. Hyperkalemia may be a medical emergency. Generally, the most common causes of hyperkalemia are conditions that decrease excretion. Conditions that increase intake or release potassium out of the cells can cause hyperkalemia. Hypokalemia occurs when potassium levels drop below 3.5 mEq/L. Hypokalemia typically results from opposite causes of hyperkalemia; this includes excessive loss, decreased intake, or increased potassium cellular uptake (TABLE 6-3).

TABLE 6-3 Hyperkalemia and Hypokalemia Causes and Mechanisms

Hyperkalemia causes and mechanisms Hypokalemia causes and mechanisms

Decreased excretion—renal Renal failure Addison disease—decreased aldosterone (reducing excretion) Medications: potassium-sparing diuretics (e.g., spironolactone), nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme, angiotensin receptor blockers decrease response or production of aldosterone Gordon syndrome—rare genetic disorder in which the kidneys are unable to respond to aldosterone

Excessive loss—renal and gastrointestinal Renal losses

Potassium-losing diuretics (e.g., thiazide, loop) Renal failure—diuretic phase Corticosteroid elevations—decreases sodium excretion and increases potassium excretion (e.g., in hyperaldosteronism, Cushing syndrome, medications, stress-related trauma, surgery)

Gastrointestinal losses Vomiting and diarrhea (e.g., with illness, excessive laxative use) Nasogastric suctioning

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Gastrointestinal fistula

Increased intake Oral/enteral—excessive supplements, salt substitutes (potassium chloride) more common with renal disease Rapid intravenous administration—undiluted potassium can be lethal even with normal kidney function

Decreased intake Deficient diet (e.g., malnutrition, extreme dieting, alcoholism) Intake inability/difficulties—chewing, swallowing (e.g., in the elderly) Inadequate potassium replacement with intravenous solution

Release from cells to ECF Acidosis—increased hydrogen-potassium shifts out Deficient insulin (diabetic ketoacidosis)—potassium not transported back into cell Blood transfusions—can cause blood lysis with increased potassium Burns, tissue trauma, extreme activity or seizures

Increased cellular uptake from ECF Alkalosis—decreased hydrogen-potassium shifts into cell Insulin excesses—transports potassium back into the cell (e.g., used during diabetic ketoacidosis)

Diagnostic Link

Pseudohyperkalemia any reports of hyperkalemia are not due to actual body imbalances but rather occur due to errors in the handling of the serum sample prior to the analysis. The factors leading to a pseudohyperkalemia include

errors in obtaining a sample that include applying the tourniquet too tightly, leaving the tourniquet on for longer than 1 minute, fist clenching, traumatic venipuncture, the wrong needle diameter, or excessive force when withdrawing. After the sample is obtained, errors that can cause pseudohyperkalemia include excessive force with transferring to the vacutainer and vigorous mixing, whether by hand or by centrifuge. Delays in processing and cold temperature storage are other considerations. When hyperkalemia is seen on a report, go back to your patient to evaluate if the result makes sense—a potassium of 6.5 mEq/L in a person who is awake, alert, and has no concerns does not make sense. Even in the critically ill, go back and evaluate the likelihood that potassium would go up so high. Evaluate the patient first, then treat while keeping in mind the possibility of pseudohyperkalemia due to serum sample errors.

Clinical Manifestations Hyperkalemia and hypokalemia can affect several body systems in which potassium plays key functions, including the nervous, cardiac, respiratory, and gastrointestinal systems (TABLE 6-4; FIGURE 6-6; FIGURE 6-7). The severity of these effects depends on the extent of the hyperkalemia and hypokalemia. A bit of an oversimplified way to remember differences between manifestations is: Hyperkalemia makes things excitable, while hypokalemia depresses or slows things down.

FIGURE 6-6 Hyperkalemic effects on the electrocardiogram.

FIGURE 6-7 Hypokalemic effects on the electrocardiogram.

TABLE 6-4 Clinical Manifestations of Hyperkalemia and Hypokalemia

Hyperkalemia* Hypokalemia*

Neuromuscular Paresthesias Muscle cramps Weakness/fatigue Hyperreflexia Flaccid paralysis (later) Anxiety

Paresthesias Muscle cramps Weakness/fatigue Hyporeflexia Flaccid paralysis Confusion/depression

Cardiovascular Electrocardiogram (EKG) changes and dysrhythmias (delayed conduction—bradyarrhythmias/asystole) Cardiac arrest

Hypotension Weak, irregular pulse EKG changes and dysrhythmias (Ventricular fibrillation) Cardiac arrest

Respiratory Respiratory depression/arrest—diaphragm weakness

Gastrointestinal Nausea/vomiting Diarrhea Cramping

Nausea/vomiting Constipation Distention and ileus

* Bold indicates differential manifestations

Diagnosis and Treatment A chemistry panel, which includes potassium levels, is a common diagnostic test in most clinical settings. Potassium imbalance is determined by serum levels (remember laboratory errors). The next step is determining the reason for the alteration by conducting a history and physical examination. Imbalances can cause severe consequences, so the evaluation should be conducted rapidly, with the extreme values (e.g., 2.5 mEq/L or 6.0 mEq/L) considered an emergency. When looking for a cause, the most common reasons should be evaluated initially, such as renal disease for hyperkalemia. A 12-lead EKG is a common diagnostic test conducted to identify the potential cardiac disturbances (e.g., dysrhythmias, slowed conduction). An ABG is done to check for acid–base imbalances.

Emergent management of hyperkalemia includes methods to increase excretion. These methods include dialysis, sodium polystyrene sulfonate (Kayexalate), and insulin with IV dextrose to prevent hypoglycemia. Sodium polystyrene sulfonate induces gastrointestinal potassium excretion. Acidosis, if present, is treated prior to the hyperkalemia so that potassium can shift back into the cells and a true potassium level can be obtained. Calcium gluconate may be administered to minimize dysrhythmias. Hyperkalemia due to excess dietary intake will necessitate discussing reduction of foods high in potassium. Medications such as angiotensin- converting enzymes that can cause hyperkalemia may have to be discontinued, or if the elevation is minor, close serial potassium evaluation will be necessary.

Management strategies of hypokalemia are directed at increasing the amount of potassium available to the body. Oral potassium is administered for mild cases, while

IV potassium that is diluted is administered for more severe deficits. For rapid replacement, patients will usually be in an intensive care unit to monitor for potentially life-threatening cardiac side effects (e.g., ventricular tachycardia, asystole). Rapid infusions need to be delivered using a central line as the amounts that can be safely administered peripherally are lower. Administering potassium IV can be caustic to the veins, which is another reason that potassium must be given diluted and slowly. Once the potassium gets to a safe level with IV infusion, then a transition to oral replacement over days is done.

Calcium Most of the body’s calcium is found in the bones and teeth (99%). Most of the remaining amount (1%) is found in the blood. Ionized (unbound or free) can be used for several physiologic processes—for example, blood clotting, hormone secretion, receptor functions, nerve transmission, and muscular (e.g., skeletal and cardiac) contraction. The other form of calcium in the blood is mostly bound to albumin, and a small amount is bound (chelated) with phosphate, citrate, and sulfur. Calcium has an inverse relationship with phosphorus and a synergistic relationship with magnesium. When calcium levels go up, phosphorus goes down, and vice versa. Calcium needs magnesium to fully function as well as balance its effects.

Calcium is brought into the body through the absorption of dietary sources in the gastrointestinal tract, specifically the small intestines; therefore, conditions affecting intestinal absorption or surgical procedures that change the gastrointestinal tract (e.g., gastric bypass) can alter calcium absorption. Vitamin D aids in calcium absorption; it is primarily obtained through sun exposure and from fortified dairy products. Vitamin K also plays an important role in calcium regulation and bone formation (vitamin K binds to calcium in the bone); it is primarily found in green leafy vegetables. Calcium is found in large amounts in dairy products, salmon, sardines, green leafy vegetables, pinto beans, almonds, and figs, among other sources. The RDA of calcium is 800–1,200 mg/day; however, individuals’ daily needs vary with certain conditions (e.g., pregnancy, childhood, and osteoporosis). The RDA of vitamin D is 400–600 international units/day up to the age of 70 and then 800 international units/day after 70 years of age.

Calcium is excreted in the urine and stool. Levels of this electrolyte are regulated by the parathyroid hormones and calcitonin (a thyroid hormone). When serum calcium levels are low, parathyroid hormone quickly mobilizes the bone calcium and pulls it into the bloodstream and also increases renal reabsorption. To compensate for this shift, parathyroid hormone replaces this calcium by activating vitamin D, which promotes intestinal absorption and renal reabsorption, and increases elimination of phosphorus. Parathyroid hormone secretion is influenced by magnesium levels. When magnesium levels are low, parathyroid is inhibited, and calcium levels decrease. Calcitonin, in contrast, regulates elevated calcium levels by

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pushing the excess calcium into the bone, decreasing intestinal absorption and increasing renal excretion.

Normal total adult serum calcium levels are between 8.8 and 10.3 mg/dL. Hypercalcemia occurs with levels that are above 10.3 mg/dL, and hypocalcemia occurs below 8.8 mg/dL. Values vary slightly for children. Hypercalcemia may result from excessive calcium intake or calcium release from the bone as well as from inadequate excretion. Hypocalcemia may occur as a result of increased losses or decreased intake of calcium (TABLE 6-5).

TABLE 6-5 Hypercalcemia and Hypocalcemia Causes and Mechanisms

Hypercalcemia causes and mechanisms Hypocalcemia causes and mechanisms

Decreased excretion—renal Renal failure Thiazide diuretics—increase renal reabsorption

Excessive loss—renal and gastrointestinal and serum active loss due to increased binding

Renal failure Alkalosis—serum hydrogen decreases and unbinds from albumin leading to more albumin bound to calcium (i.e., less free) Medications (e.g., diuretics, calcitonin, and gentamicin) Hyperphosphatemia—phosphate binds the calcium (i.e., less free) Diarrhea Pancreatitis (decreases intestinal absorption of fat; calcium binds to fat and is excreted)

Increased intake/absorption (gastrointestinal) or increased bone resorption

Cancer (e.g., breast, lung, multiple myeloma) Excess intake—diet, antacids (e.g., Tums), supplements Excess vitamin D Parathyroid hormone abnormalities (e.g., hyperparathyroidism) Prolonged immobility Medications (e.g., corticosteroids) Hypophosphatemia

Decreased intake/absorption or decreased bone release

Deficient diet (e.g., malnutrition, extreme dieting, alcoholism) Absorption disorders (e.g., Crohn disease) Vitamin D deficiency (e.g., kidney disease) Excessive laxative use (e.g., increased phosphate causing decreased absorption) Parathyroid hormone abnormalities (e.g., hypomagnesemia, hypoparathyroidism) impair release from bone

Diagnostic Link

Vitamin D hen vitamin D is absorbed from the sun and small amounts from food, it must undergo processes in the liver and kidney to become activated. Serum measures include 25-hydroxyvitamin D2 and 25-

hydroxyvitamin D3, and these two metabolites are part of 25-hydroxyvitamin D [25(OH)D], which is clinically used when evaluating overall body status. The two measures of 25-hydroxyvitamin D include nanomoles per liter (nmol/L) or nanograms per milliliter (ng/mL). Levels consistent with deficiency are < 30 nmol/L (i.e., < 12 ng/mL). These low levels can be associated with bone diseases such as rickets and osteomalacia. Optimal levels are > 50 nmol/L (> 20 ng/mL); however, controversy exists regarding appropriate levels due varied laboratory measurement standards. Efforts are being made to adopt an international gold standard for

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measurement.

Diagnostic Link

Calcium and Albumin Levels erum calcium measurements are often done to evaluate several disorders such as kidney disease and parathyroid disorders. Total serum calcium levels consist of the three stores: 1) active (free, unbound,

ionized), 2) bound mainly to albumin, and 3) bound to anions such as phosphate. The bound forms are metabolically inactive. The active ionized level is regulated by hormones such as parathyroid hormone and is the more clinically relevant value. The report may only contain the total serum calcium levels; however, the total levels can be misleading as they also reflect inactive bound levels. Therefore, the total is affected by albumin levels (high or low). In cases where the calcium and albumin are abnormal, a corrected level should be calculated or an active ionized calcium serum level should be obtained to get a real reflection of the active calcium level. For example, the total calcium may be abnormal, but it might be because there is hypo- or hyperalbuminemia where the active ionized level is normal. Before a clinical decision is made about a high or low total calcium, take a look at the albumin level. The most common unit of measure for calcium in the United States are mg/dL, and other units of measure include mEq/L and mmol/L.

Clinical Manifestations Calcium is involved in cell membrane depolarization and repolarization, and imbalances are often a reflection of increased or decreased cell excitability. Clinical manifestations of hypercalcemia reflect decreased cell membrane excitability and renal effects. Hypocalcemia increases cell membrane excitability (TABLE 6-6). Manifestations are often nonspecific. The cardiac, nervous, musculoskeletal, gastrointestinal systems, can all be affected by high or low calcium levels. Hypercalcemia can also affect the renal system while hypocalcemia can affect the respiratory and hematologic systems. Tetany describes spasms of the skeletal muscle that are specific to hypocalcemia. Two clinical examinations can be used to evaluate hypocalcemia facial and carpopedal spasms—Trousseau and Chvostek signs. To test for Trousseau sign, arterial blood flow is occluded by using an inflated blood pressure cuff. The cuff is placed on the upper arm and inflated above the individual’s usual systolic pressure measurement. The inflated cuff is left in place for approximately 3 minutes. The test is considered positive for increased neuromuscular irritability if it elicits a carpal spasm (flexed wrist and metacarpophalangeal joints, extended interphalangeal joints, and adducted thumb) (FIGURE 6-8). To test the Chvostek sign, the patient’s facial nerve in front of the ear is tapped. A spasm or brief contraction of the corner of the mouth, nose, eye, and muscles in the cheek is considered a positive sign and indicates increased neuromuscular irritability (FIGURE 6-9).

FIGURE 6-8 Trousseau sign. © Jones & Bartlett Learning. Photographed by Carolyn Arcabascio.

FIGURE 6-9 Chvostek sign. © Jones & Bartlett Learning. Photographed by Carolyn Arcabascio.

TABLE 6-6 Clinical Manifestations of Hypercalcemia and Hypocalcemia

System Hypercalcemia Hypocalcemia

Neuromuscular Personality changes and behavior changes: confusion, memory changes, psychosis Headache Lethargy/stupor/coma Muscle weakness/atrophy Decreased deep tendon reflexes Osteopenia/osteoporosis

Anxiety Confusion Depression Irritability Fatigue Lethargy Paresthesia Muscle spasms/tetany—positive Chvostek and/or Trousseau signs Laryngeal spasms Tremors/seizures Increased deep tendon reflexes

Cardiovascular EKG changes and dysrhythmias—short QT interval; atrioventricular blocks Hypertension Cardiac arrest—hypercalcemic crisis (acute

EKG changes and dysrhythmias— prolonged QT interval with risk for ventricular dysrhythmias; heart blocks Hypotension

increase)

Renal Renal calculi Renal insufficiency Polyuria/polydipsia (hypercalcemia interferes with ADH, resulting in increased water excretion) Dehydration

Gastrointestinal Anorexia Nausea/vomiting Constipation Abdominal pain Pancreatitis (e.g., stones in pancreatic duct)

Increased bowel sounds Abdominal cramping/spasms

Hematologic Increased bleeding tendency (e.g., bruising, petechiae)

Diagnosis and Treatment Diagnostic procedures include a history, physical examination, blood chemistry, and 12-lead EKG. Management focuses on identification (e.g., renal failure, parathyroid disorders) and treatment of the underlying cause (e.g., dialysis). For hypercalcemia, several medications, including oral bisphosphonate preparations and calcitonin, can inhibit osteoclastic activity, reducing the amount of calcium released from the bone. Increasing mobility can also prevent resorption. Other medications, such as corticosteroids or mithramycin (antineoplastic), reduce resorption and are used with cancer-associated hypercalcemia. Increasing hydration with IVF administration can increase renal excretion of calcium. Loop diuretics may be necessary to enhance this excretion further. Thiazide diuretics are usually avoided as they can increase calcium levels.

Hypocalcemia is often treated with oral supplements in mild deficiencies and IV calcium gluconate or calcium chloride in moderate to severe deficiencies. Vitamin D supplements can increase intestinal calcium absorption. Additionally, phosphorus intake may be decreased to bring calcium levels up. Supplemental parathyroid hormone can be administered for hypoparathyroidism.

Phosphorus Most of the body’s phosphorus, or phosphate, is found in the bones, with smaller quantities in the cells (organic phosphate) and in even smaller amounts circulating in the intravascular space (inorganic phosphate). Serum levels are slightly higher in children due to the higher levels of growth hormone. As previously mentioned, phosphorus has an inverse relationship with calcium. Phosphorus plays a key role in bone and tooth mineralization, cellular metabolism, acid–base balance, and cell membrane formation, among other functions.

Phosphorus primarily enters the body through dietary sources, and its elimination

mainly occurs in the urine. Foods with high phosphorus concentrations include dairy products, protein sources (e.g., chicken, beef, fish, and nuts), grains, and carbonated sodas. The RDA of phosphorus is approximately 1,000 mg/day. Absorption of phosphorus is decreased when it is ingested with foods containing calcium, magnesium, and aluminum—all of which bind with phosphorus. Phosphate levels are regulated by the kidneys. When serum levels are high, more is excreted, and when levels are low, more is reabsorbed by the kidneys. Parathyroid hormone influences renal reabsorption.

Hyperphosphatemia in adults occurs when phosphorus levels are above 4.5 mg/dL. It usually results from decreased excretion, increased intake, or redistribution from ICF to ECF phosphorus (TABLE 6-7). Hypophosphatemia occurs when phosphorus levels drop below 2.5 mg/dL. This imbalance is usually caused by increased excretion or decreased intake, decreased absorption, or redistribution of phosphorus. More than one mechanism can be causing phosphorus imbalances, such as increased excretion with intracellular shifting (hypophosphatemia).

TABLE 6-7 Hyperphosphatemia and Hypophosphatemia Cause and Mechanism

Hyperphosphatemia causes and mechanisms Hypophosphatemia causes and mechanisms

Decreased excretion—renal Renal failure Hypoparathyroidism (decreases renal excretion) Adrenal insufficiency Hypothyroidism

Increased excretion Renal failure/renal tubular defects Hyperparathyroidism (increases renal excretion)

Increased intake/absorption and ICF to ECF shifts Laxatives, especially those containing phosphorus (decrease calcium levels, which increases phosphorus levels) Cellular damage (e.g., burn, trauma, rhabdomyolysis, and chemotherapy) Seizures Potassium deficiency Hypocalcemia Acidosis (increased phosphorus shifts from the intracellular compartment to the intravascular compartment)

Decreased intake/absorption and ECF to ICF shifts Malabsorption Vitamin D deficiency Magnesium, aluminum, and calcium antacids Alcoholism Decreased dietary intake (rare) Alkalosis (increased amounts of phosphorus shift from the intravascular compartment to the intracellular compartment as well as increased renal excretion)

Clinical Manifestations Clinical manifestations of hyperphosphatemia are similar to those observed with hypocalcemia and are rarely seen alone. Clinical manifestations for hypophosphatemia are similar to those associated with hypercalcemia (Table 6-6).

Diagnosis and Treatment

Diagnostic procedures for phosphate imbalances consist of a history, physical examination, and blood chemistry. Management includes identification and treatment of the underlying cause (e.g., dialysis for renal failure). Aluminum hydroxide and aluminum carbonate can bind to phosphorus and increase intestinal excretion and, therefore, is used as a treatment for hyperphosphatemia. Additionally, treatment of hypocalcemia may be necessary.

Hypophosphatemia can be treated with the administration of oral supplements (in mild deficiencies) and IV potassium phosphate (in moderate to severe deficiencies). However, supplementation with phosphate in certain disorders causing hypophosphatemia (e.g., hyperparathyroidism) can increase the risk for development of extracellular calcifications.

Magnesium Magnesium is an intracellular cation (second most abundant) that is mostly stored in the bone and muscle (approximately 50% in bone and muscle and 50% in cells). Only small amounts (e.g., 1%) of magnesium are in the intravascular space, and it is protein bound. This electrolyte helps maintain normal muscle and nerve function, regular cardiac rhythm, a healthy immune system, bone strength, blood glucose levels, and normal blood pressure; it is also involved in energy metabolism (i.e., ATP from ADP) and protein synthesis (i.e., DNA and RNA processes). Magnesium has a direct relationship with calcium and an inverse relationship with phosphorus. Parathyroid hormone requires magnesium, and calcium levels will not be balanced without it. Magnesium also blocks potassium movement out of cells, and potassium can leave the cell if magnesium is low, decreasing intracellular potassium.

Magnesium is obtained through dietary intake, absorbed in the intestines, and excreted through the kidneys. Foods with a high magnesium content include green vegetables, legumes, nuts, seeds, and whole grains. The RDA for magnesium is approximately 400 mg per day. Magnesium balance is regulated by the kidneys excreting more or less magnesium in response to serum magnesium levels. Various hormones (e.g., parathyroid hormone and calcitonin) may also alter magnesium balances, and their roles in homeostasis are unclear.

Hypermagnesemia occurs when magnesium levels increase above 2.4 mEq/L. This imbalance is rare. It usually results from renal failure, as the kidneys are the only regulators of magnesium levels, or from excessive intake as with parenteral administration for eclampsia or excessive ingestion of magnesium-containing preparations (e.g., enemas, laxatives, Epsom salts). Because of magnesium’s synergistic relationship with calcium, hypercalcemia is often seen with hypermagnesemia, and hypophosphatemia may be present due to calcium’s inverse relationship with phosphorous.

Hypomagnesemia results when magnesium levels drop below 1.8 mEq/L. Hypomagnesemia is more common than hypermagnesemia because the levels can

fall quickly as bone magnesium does not rapidly exchange in the circulation. Mobilization from the bone can take many weeks. Low levels can result from inadequate intake (e.g., chronic alcoholism, malnutrition) or decreased absorption. More commonly, the cause is increased loss from the gastrointestinal or renal systems (e.g., diuretics, diarrhea, renal tubular disorders). Because of magnesium’s synergistic relationship with calcium, hypocalcemia is often seen with hypomagnesemia, and hyperphosphatemia may be present due to calcium’s inverse relationship with phosphorous. Additionally, low levels of magnesium may increase potassium renal excretion, so hypokalemia may be present.

Clinical Manifestations Clinical manifestations of magnesium imbalances are due to the neuromuscular and cardiovascular system effects. Hypermagnesemia causes decreased neuromuscular function with resulting decreased deep tendon reflexes, confusion, and lethargy. The cardiovascular effects of hypermagnesemia are due to magnesium-blocking calcium channels, causing a shortened QT interval. Hypermagnesemia manifestations are often masked by the manifestations of hypercalcemia. Because hypomagnesemia is usually accompanied by hypocalcemia and hypokalemia, clinical manifestations are similar to those imbalances such as neuromuscular excitability with tremor, tetany, and QRS widening.

Diagnosis and Treatment Diagnostic procedures include a history, physical examination, and blood chemistry. Treatment strategies for hypermagnesemia consist of diuretics and IVF administration to promote renal excretion and dialysis if magnesium levels do not decrease. Additionally, administering IV calcium can be used to directly antagonize the neuromuscular and cardiac effects of magnesium. Treatment strategies for hypomagnesemia include magnesium oral supplements for mild deficits and IV magnesium for more severe cases.

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Acid–Base Balance Acid–base stability is crucial to sustain life and maintain health. Acid–base balance is achieved through a variety of buffer systems and compensatory mechanisms. Body fluids, the kidneys, and the lungs all play pivotal roles in maintaining this balance. Acid–base balance is measured by examining pH, which is the concentration of hydrogen (H+) ions and has a narrow safety margin (serum pH of 7.35–7.45). Acid–base imbalances can vary in severity based on the degree of pH change. Death can occur if serum pH levels fall below 6.8 or rise above 7.8. Changes in pH may be caused by a variety of conditions, including infection, organ failure, or trauma. In many cases, the acid–base fluctuations can cause more negative effects than the causative condition; therefore, the resulting acid–base imbalance is often corrected before treating the underlying condition.

Learning Points

Relationships Between Ions nderstanding ions’ relationships with other ions can help you understand what is happening in the body. In general:

Sodium and potassium have an inverse relationship; thus, when one goes up, the other goes down. Calcium and phosphorus have an inverse relationship. Calcium and magnesium have a synergistic relationship, so one enhances the other.

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

pH Regulation One way to measure serum hydrogen is by pH, which reflects acid–base status. The pH measure is a negative logarithm that reflects the hydrogen (H+) concentration; the higher the H+ concentration, the lower the pH number (FIGURE 6-10). Hydrogen is necessary for maintaining the cellular membranes and for enzyme activities. Acids are produced as a by-product of protein, carbohydrate, and fat metabolism. Three key types of acids in the body are critical to be balanced: 1) CO2 and carbonic acid, 2) organic acids, and 3) nonvolatile acids. The acidic by-products are found in body fluids as volatile acids, such as carbonic acid (H2CO3), and nonvolatile acids, such as hydrochloric, sulfuric, lactic, and phosphoric acids. Carbonic acid breaks down into H+ and bicarbonate HCO3- (base). Additionally, an acidic volatile gas is produced as a by-product of cellular respiration, such as carbon dioxide (CO2). Carbon dioxide combines with water to become carbonic acid (FIGURE 6-11). There are two acids, carbonic acid and carbon dioxide, in the extracellular space that must remain in balance. The balance is maintained because carbon dioxide is expelled through breathing, regulating carbonic acid level. The nonvolatile acids, such as sulfuric

acids (by-products of amino acids containing sulfur), are managed by the kidneys by excreting it in urine or the kidneys adding more bicarbonate to the extracellular supply. Several organic nonvolatile acids, such as lactic acid and citric acid, are the result of normal metabolic reactions and are neutralized into other substances such as glucose and water. Balance of the body’s acids is maintained by three systems that work together—the buffers, respiratory system, and renal system.

FIGURE 6-10 The pH scale. Acids release hydrogen ions (lower pH), while bases accept or combine with hydrogen ions (higher pH).

FIGURE 6-11 Acid–base balance.

Buffers Buffers are the chemicals that combine with an acid or a base to change pH. Buffering is an immediate reaction to counteract pH variations until compensation is initiated. Acids and bases are paired together just like cations and anions are paired together. During buffering processes, acid and bases are exchanging with other acids and bases (e.g., weak acid/conjugate base for a strong acid/conjugate base). The body has several chemical buffer mechanisms—the bicarbonate–carbonic acid system, the protein system, the phosphate system, and hydrogen-potassium exchange.

The bicarbonate–carbonic acid system is the most significant buffering mechanism in the extracellular fluid. Carbonic acid and bicarbonate (base) are the key players in this system. Carbon dioxide (acid) is a by-product of cellular metabolism. Once produced, it diffuses into the interstitial fluid and blood, where it reacts with water to form carbonic acid. The carbonic acid decomposes immediately, because of the presence of the enzyme carbonic anhydrase, to form hydrogen ions and bicarbonate (Figure 6-11). Carbonic anhydrase is present at many sites in the

body, including the lungs and kidneys. In the lungs, this reaction is reversed so that carbon dioxide can be expired along with water—a process that decreases the amount of carbonic acid. In the kidneys, the reaction forms hydrogen ions that are then excreted in the urine and bicarbonate that is returned to the blood.

Several proteins, both intracellular and extracellular, form part of a large buffering mechanism. Proteins can act as either an acid or a base by binding to or releasing hydrogen, respectively. Proteins exist in the intracellular and extracellular fluids but are most abundant inside the cells. Albumin and other plasma proteins are the primary buffers in the intravascular space. Hydrogen and carbon dioxide diffuse across the cell membrane to bind with proteins inside the cells. The protein hemoglobin, found in the erythrocytes, works as a buffer by binding to or releasing hydrogen and carbon dioxide. When combined with oxygen, hemoglobin tends to release hydrogen. Exposing hemoglobin to acid and lower oxygen concentrations in the capillaries causes it to release the oxygen that is bound to it. Hemoglobin then becomes a weaker acid, taking up extra hydrogen. This change maintains the pH in the capillaries. The opposite change occurs when hemoglobin is exposed to the higher oxygen concentrations found in the lungs. As hemoglobin binds with oxygen, it becomes more acidic (more prone to release hydrogen). Hydrogen reacts with bicarbonate to form carbonic acid, which is then converted to carbon dioxide and released into the alveoli.

The phosphate system acts much like the bicarbonate–carbonic acid system. Phosphates are found in high concentrations in the intracellular fluid. Some of these phosphates act as weak acids, whereas others act as weak bases. Buffering in this system primarily takes place in the kidneys by accepting or donating hydrogen.

In addition to these systems, two positively charged ions—potassium and hydrogen—move in opposite directions in and out of the cell to maintain the pH balance. With extracellular excess of hydrogen, hydrogen moves inside the cell for buffering purposes; in exchange, potassium moves out of the cell. With extracellular deficit of hydrogen, these ions move in the opposite directions. As previously mentioned, potassium imbalances can lead to acid–base imbalances, and acid–base imbalances can lead to potassium imbalances.

Respiratory Regulation The respiratory system manages pH deviations by changing carbon dioxide (acid) excretion. Increasing ventilation will lead to excretion of more carbon dioxide, thereby decreasing acidity (increasing pH). Decreasing ventilation will lead to excretion of less carbon dioxide, thereby increasing acidity (decreasing pH). Chemoreceptors that sense pH and PCO2 fluctuations trigger this change in breathing pattern. The only way the lungs can remove acids is through the elimination of carbon dioxide from carbonic acid—the lungs cannot remove other acids. The respiratory system is also a mechanism that can respond quickly to pH

imbalances, although it cannot bring it back a normal baseline. The quick action of the respiratory system is generally short lived. The respiratory system reaches its maximum response in 12–24 hours but can maintain the changes in breathing pattern for only a limited time before becoming fatigued.

Renal Regulation The renal system is the slowest mechanism to react to pH changes, taking hours to days to achieve its buffering effect, but it is the longest lasting. The kidneys respond to alterations in pH by changing the excretion or retention of hydrogen (acid) or bicarbonate (base). The renal system acts to balance pH levels by permanently removing hydrogen from the body. The kidneys are the only organs that can remove hydrogen ions. When carbonic acid is catalyzed into hydrogen and bicarbonate, the hydrogen combines with urinary buffers to be excreted. These buffers are necessary for the kidneys to eliminate hydrogen. Two important urinary buffers are phosphate and ammonia. These buffers attach to the hydrogen ions, which are then excreted in the urine. The kidneys maintain pH balance by reabsorbing bicarbonate. The kidneys correct pH imbalances by regenerating bicarbonate from the reabsorbed carbon dioxide. The kidneys also excrete nonvolatile acids like sulfate, phosphate, and chloride that are buffered (e.g., body proteins or bicarbonate).

Compensation To maintain homeostasis, the body will take actions to compensate for the pH changes. The body never overcompensates; rather, the pH is adjusted so that it remains just within the normal range. The pH is a ratio of bicarbonate and carbon dioxide. There is an attempt to maintain the ratio with imbalances, and the cause of the imbalance often determines the compensatory change FIGURE 6-12. For instance, the renal system will kick in to compensate if the pH is becoming more acidic because of lung disease that limits gas exchange, such as emphysema, by releasing more bicarbonate and excreting more hydrogen. The kidneys will compensate if a lung disease is increasing carbon dioxide excretion (e.g., it is causing hyperventilation), which will increase pH, by decreasing bicarbonate production and decreasing hydrogen excretion. In contrast, the lungs can compensate for problems that originate outside the lungs. For example, the lungs will decrease the rate and depth of respirations to retain more carbon dioxide (acid) when a condition increases the loss of acids such as by vomiting. The lungs will increase the rate and depth of respirations to excrete more carbon dioxide (acid) if a condition increases the loss of bases, perhaps from diarrhea, and, in turn. If the kidneys and lungs cannot compensate to restore the pH levels to normal range, cellular activities are affected, leading to disease states. The degree of compensation is determined by the severity of the imbalance. The expected

compensatory responses have been derived from experimental studies. The expected responses are most accurate when a baseline of the patient’s acid–base balance is known prior to the imbalance occurring (TABLE 6-8). If compensatory mechanisms are not appropriate (e.g., more or less of a response) the compensating system may be affected. As an example, if a patient is in metabolic acidosis, lack of a respiratory response may indicate disorder in the respiratory system. Compensation mechanisms for respiratory alkalosis or mild to moderate respiratory acidosis may be sufficient to return the pH to normal. However, compensatory mechanisms are generally inadequate to return the pH to normal for metabolic acidosis or alkalosis or severe respiratory acidosis. As previously discussed, pulmonary system compensation for metabolic derangements is not as effective as kidney compensation.

FIGURE 6-12 A. Acidosis and compensatory mechanisms. B. Alkalosis and compensatory mechanisms.

TABLE 6-8 Compensatory Responses in Acid–Base Imbalances

↓ = decreases; ↑ = increases.

Metabolic Acidosis Metabolic acidosis results from a deficiency of bicarbonate (base) or an excess of hydrogen (acid) due to increased production or decreased excretion (TABLE 6-9). These conditions drop the pH below 7.35. Causes of metabolic acidosis include the following:

TABLE 6-9 Acid–Base Imbalances

Acidosis Alkalosis

Respiratory System

Causes Slow, shallow respirations Respiratory congestion

Hyperventilation

Effect Increased PaCO2 Decreased PaCO2

Compensatory mechanism Kidneys excrete more hydrogen and reabsorb more bicarbonate

Kidneys excrete less hydrogen and reabsorb less bicarbonate

Diagnostic findings High PaCO2 High bicarbonate Compensated: pH = 7.35–7.4 Decompensated: pH < 7.33

Low PaCO2 Low bicarbonate Compensated: pH = 7.4–7.45 Decompensated: pH > 7.47

Metabolic System

Causes Diarrhea Renal failure Diabetic ketoacidosis Tissue hypoxia

Vomiting Excessive antacid use

Effect Decreased bicarbonate Increased bicarbonate

Compensatory mechanism Rapid, deep respirations Slow, shallow respirations

Kidneys excrete more hydrogen and increase bicarbonate absorption (when not involved)

Kidneys excrete less hydrogen and decrease bicarbonate absorption (when not involved)

Diagnostic findings Low bicarbonate Low PaCO2 Compensated: pH = 7.35 – 7.4 Decompensated: pH < 7.33

High bicarbonate High PaCO2 Compensated: pH = 7.4–7.45 Decompensated: pH > 7.47

PaCO2 = partial pressure of carbon dioxide; PO2 = partial pressure of oxygen.

Modified from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Bicarbonate deficit, including that caused by the following: Intestinal losses (e.g., diarrhea and fistulas) Renal losses (e.g., those caused by early renal failure, renal tubular acidosis)

Acid excess (i.e., increased production or decreased renal excretion), including that caused by the following: Tissue hypoxia resulting in lactic acid accumulation (e.g., shock and cardiac arrest) Ketoacidosis (caused by uncontrolled diabetes, excessive alcohol consumption, starvation, and extreme dieting) Drugs and toxins (e.g., antifreeze, aspirin, and hyperalimentation) Renal retention—uremia (e.g., renal failure)

Clinical Manifestations Metabolic acidosis occurs when the bicarbonate and pH levels are lower than normal (TABLE 6-10). Metabolic acidosis results from an existing problem; therefore, the characteristics of that condition are manifested along with the acidosis. Clinical manifestations of metabolic acidosis are often neurologic in nature, but the gastrointestinal, cardiac, and respiratory systems can also be affected. These manifestations include the following signs and symptoms: headache, malaise, weakness, fatigue that progresses to lethargy, confusion, and coma. The severity of the manifestations reflects the severity of the acidosis. Gastrointestinal symptoms include nausea, vomiting, and anorexia. Cardiovascular symptoms include hypotension, dysrhythmias, and shock. Kussmaul respirations are deep, rapid respirations that develop in an attempt to eliminate excess acid by exhaling more carbon dioxide.

TABLE 6-10 Normal Serum Arterial Blood Gas Values*

Blood gas Normal range

pH 7.35–7.45

A

C

PaO2 95–100 mmHg

PaCO2 35–45 mmHg

Bicarbonate (HCO3 -) 22–26 mEq/L

Base excess −2.4 to +2.5 mEq/L

Arterial O2 saturation 96–98%

*Values may vary slightly. PaO2 = partial pressure of oxygen; PaCO2 = partial pressure of carbon dioxide.

Modified from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Diagnostic Link

Blood Gases: Arterial and Venous rterial blood gases sampling can be difficult and painful to obtain unless the patient has an arterial line. Venous blood gases are an alternative way of evaluating carbon dioxide and pH. Venous samples can be

obtained peripherally or via a central venous catheter. Blood gases from a central venous catheter are the most understood and correlated with arterial blood gases, so they are preferred over peripheral venous sampling. The venous sample measures all the same components as arterial sampling (e.g., oxygen, carbon dioxide). The values are labeled with a subscript v for venous (e.g., PvCO2). The oxygen value is not useful as most of the oxygen has been extracted. The venous sampling does provide one additional measure, which is the oxyhemoglobin saturation (SvO2). The SvO2 is a reflection of the amount of oxygen actually used by the tissue. Arterial and venous blood gas values are slightly different; therefore, for interpretation correlation and reference ranges need to be used.

Learning Points

Acid-Base Compensation ompensation can be a challenge to understand. First, make sure you understand acids and bases. Carbon dioxide and hydrogen are acids; bicarbonate is a base. The body will increase or decrease the excretion of

these substances in an attempt to restore pH balance. If the body excretes more acid or produces more base, then the pH will become more alkaline. If the body retains more acid or produces less base, then the pH will become more acidic.

Two body systems can compensate for pH imbalances—the renal and respiratory systems. If the cause of the imbalance originates within one of those systems, then the other system will have to perform the role of the primary compensatory mechanism. The system that is the source of the pH imbalance will not be able to resolve its own problem. Thus, the kidneys will manage problems that originate in the lungs. If the problem originates outside the lungs, the lungs will manage it.

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Diagnosis and Treatment Diagnostic procedures for metabolic acidosis include a history, physical examination, ABGs, blood chemistry, and CBC. As previously mentioned, the pH will be low and bicarbonate from the blood gas or serum will be low with metabolic acidosis.

Evaluation of the anion gap is often used to determine the cause of the metabolic acidosis (FIGURE 6-13). The anion gap is used to identify the anions that are not usually measured, such as albumin, sulfates, and phosphates. Conditions that cause metabolic acidosis because of excess acid, whether from increased production or decreased excretion, will increase the anion gap; otherwise, the anion gap will remain normal. These disorders of acid are termed high anion gap metabolic acidoses. With metabolic acidosis caused by loss of bicarbonate, anion gap will remain normal and this is also termed nonanion gap metabolic acidosis. Chloride is retained when bicarbonate is lost as a way of maintaining balance, so normal anion gap acidosis is also called hyperchloremic metabolic acidosis. Under normal conditions, the sum of cations is approximately equal to the sum of anions in the extracellular fluid. Sodium is the most plentiful cation in the extracellular fluid, while bicarbonate and chloride are the most abundant anions. To determine the anion gap, the bicarbonate and chloride results are added together and subtracted from the sodium (sodium−[bicarbonate + chloride]). A normal anion gap is 3–10 mEq/L. Each laboratory may have a different range for an anion gap, and clinically, it is best to follow trends rather than ranges. As an example, if an anion gap is 3 mEq/L at first, and subsequent measurement is 10 mEq/L, this is considered significant even though the anion gap is within the normal range. Different anion gap formulas that include potassium with sodium are available. Albumin is a key anion that affects the gap, and a corrected measure must be calculated if the albumin is low. Electrolyte imbalances such as hyperkalemia, hypercalcemia, and hypermagnesemia will reduce an anion gap by approximately 2 mEq/L.

FIGURE 6-13 Anion gap with metabolic acidosis.

UA− = unmeasured anion

HCO3 = Bicarbonate

Cl− = Chloride

Na+ = sodium

H+ = hydrogen

Identifying and treating the causative condition (e.g., antidiarrheal agents or dialysis) is vital to achieve successful patient outcomes. Treatment to correct the acidosis merely stabilizes the patient until the causative condition can be managed. Strategies to correct the acidosis may include the administration of IV sodium bicarbonate, particularly when the pH is below 7.1. Indications for sodium bicarbonate administration are controversial. Other strategies include correcting electrolyte disturbances such as hyperkalemia (e.g., administering IV insulin for diabetic ketoacidosis) and improving oxygenation (e.g., oxygen therapy, mechanical ventilation).

Metabolic Alkalosis Metabolic alkalosis results from excess bicarbonate because of increased intake or retention, deficient acid, or both (Table 6-9). These conditions cause the pH to rise above 7.45. The most common causes are due to the loss of acids, usually from the gastrointestinal tract. Causes of metabolic alkalosis include the following:

Excess bicarbonate, such as that caused by the following: Excessive antacid use Use of bicarbonate-containing fluids (e.g., lactated Ringer’s solution) Hypochloremia (increases bicarbonate reabsorption)

Deficient acid, such as that caused by the following: Gastrointestinal loss (e.g., vomiting or nasogastric suction) Hypokalemia (low potassium levels cause hydrogen to shift inside the cells) Renal loss (e.g., renal failure or diuretics) Hypovolemia (decreases renal perfusion) Hyperaldosteronism (excessive aldosterone increases renal excretion of hydrogen)

Clinical Manifestations Metabolic alkalosis exists when the bicarbonate and the pH levels rise to greater than normal (Table 6-10). Much like metabolic acidosis, metabolic alkalosis manifestations generally occur in combination with the manifestations of the causative conditions (e.g., hypovolemia, hypokalemia). Patients can also be asymptomatic. Clinical manifestations of metabolic alkalosis are mostly neuromuscular in nature. Alkalosis causes calcium to bind, so manifestations are similar to hypocalcemia (e.g., paresthesias, tetany, seizures, mental confusion, and increased deep tendon reflexes). Bicarbonate alterations causes fewer alterations in pH in the intracellular compartment and blood–brain barrier, so symptoms do not occur as quickly as with other acid–base imbalances (e.g., such as in respiratory alkalosis where CO2 shifts are transmitted immediately). With metabolic alkalosis, respirations will decrease in an attempt to retain more carbon dioxide. Dysrhythmias may also occur.

Diagnosis and Treatment Diagnostic procedures for metabolic alkalosis include a history, physical examination, ABGs, blood chemistry, and CBC. Identifying and treating the causative condition (e.g., antiemetics or fluid replacement) is vital to achieve successful patient outcomes. Treatment to correct the alkalosis merely stabilizes the patient until the causative condition can be managed. Strategies to correct the alkalosis include adequate fluid replacement. Electrolyte imbalances such as hyponatremia, hypokalemia, and hypochloremia can be present as they are also lost in gastric secretions with such as occurs with vomiting and suctioning. Chloride can be replaced by administering arginine hydrochloride or a weak hydrochloric acid solution. Potassium chloride will correct two deficits.

Respiratory Acidosis Respiratory acidosis results from carbon dioxide retention, which increases the amount of carbonic acid present and, in turn, decreases the pH level (Table 6-9). This increase in carbon dioxide usually follows a state of hypoventilation or decreased gas exchange in the lungs. Many conditions can cause hypoventilation and/or impair gas exchange, including:

Respiratory center depression (e.g., brain trauma, oversedation, drug overdose) Thoracic cage/muscle disorders (e.g., flail chest, respiratory muscle paralysis) Lung parenchyma disorders (e.g., chronic obstructive pulmonary disease, pneumonia, pulmonary edema)

Respiratory acidosis can occur acutely, such as in narcotic overdose, or it can be chronic, such as occurs in patients with chronic obstructive lung disease. The medullary center usually responds to carbon dioxide levels to control breathing. In patients with chronic obstructive lung disease, the chronic high carbon dioxide level causes the medullary center to adapt. The stimulus to breathe becomes low oxygen levels as opposed to the high carbon dioxide levels. The chronically high carbon dioxide also causes bicarbonate reabsorption to maintain the pH balance.

Clinical Manifestations Respiratory acidosis exists when the carbon dioxide levels rise (i.e., hypercapnia occurs) and the pH levels fall below normal (Table 6-10). Manifestations generally occur in combination with the signs and symptoms of the causative condition (e.g., pneumonia). Manifestations are also dependent on whether the acidosis is acute or chronic. Acute acidosis is often accompanied by hypoxemia, causing symptoms such as dyspnea and cyanosis. Carbon dioxide easily diffuses across the blood– brain barrier, causing the neurologic manifestations. These manifestations occur due to the dilation of the cerebral blood vessels, increased intracranial pressure, and neurologic depression. Patients will complain of headache, blurred vision, and irritability. With progression of the acidosis, behavioral changes can include lethargy, confusion, and disorientation. Musculoskeletal tremors, twitching, and paralysis may occur. Cerebrospinal pressure and coma can ensue in severe cases. Cardiovascular depression can occur with arrhythmias, hypotension, or fluctuations in blood pressure. The elevated carbon dioxide levels may cause warm and flushed skin with diaphoresis unless hypoxemia is present.

Diagnosis and Treatment Diagnostic procedures for respiratory acidosis include a history, physical

examination, ABGs, blood chemistry, CBC, and chest X-ray. Treatment centers on improving respiratory status by relieving hypoxia and hypercapnia. Strategies may include oxygen therapy, optimizing ventilation with positioning, and bronchial hygiene measures (e.g., coughing, deep breathing, and chest physiotherapy). Mechanical ventilation may be necessary. Other strategies center on treatment of causative conditions such as antibiotics for pneumonia. Some patients with chronic obstructive lung disease may develop worsening hypercapnia with the administration of oxygen, so the patient should be monitored for respiratory depression.

Respiratory Alkalosis Respiratory alkalosis results from excess exhalation of carbon dioxide, which leads to carbonic acid deficits and increased pH (Table 6-9). Respiratory alkalosis generally occurs because of conditions that cause hyperventilation and/or stimulation of the medullary respiratory center, including:

Acute anxiety Pain Fever (which causes excessive oxygen utilization, increasing respirations) Hypoxia (e.g., oxygen deprivation and high altitudes) Gram-negative septicemia (which triggers the respiratory centers in the brain to increase respirations) Aspirin overdose (also triggers the medulla to increase respirations) Excessive mechanical ventilation Hypermetabolic states such as hyperthyroidism (which causes excessive oxygen utilization, increasing respirations)

Clinical Manifestations Respiratory alkalosis exists when the carbon dioxide levels fall and the pH levels rise above normal (Table 6-10). Clinical manifestations reflect central nervous system irritability and decreased cerebral blood flow. Manifestations of hypocalcemia may be present secondary to calcium binding to protein as a result of alkalosis. Clinical manifestations of respiratory alkalosis include paresthesia, dizziness, syncope, and neuronal hyperexcitability causing twitching, tetany, and seizures. The patient may complain of dyspnea, dry mouth, and feelings of panic and anxiety.

Diagnosis and Treatment Diagnostic procedures for respiratory alkalosis include a history, physical examination, ABGs, blood chemistry, CBC, and chest X-ray. Treatment of the underlying cause and increasing carbon dioxide levels is crucial to improve patient

outcomes. Often the solution is as simple as breathing into a paper bag—an intervention that allows carbon dioxide to be recirculated back to the lungs. Strategies that are more aggressive may be needed if the patient is unable to follow directions or is unconscious. They may include controlled mechanical ventilation and anxiety-reduction interventions (e.g., sedatives and therapeutic communication).

Mixed Disorders Mixed disorders occur when respiratory and metabolic disorders result in an acidotic or alkalotic state. Such an outcome occurs when both the respiratory and renal systems demonstrate an imbalance of acid or base. The severity of the pH imbalance depends on the degree of acid and base disturbances. Suspicion of a mixed acid–base disorder can be evaluated by the history and determination of whether the compensatory response of the kidneys and respiratory system are not as expected (e.g., too high or too low). Many conditions can create this synergistic effect (FIGURE 6-14). Such mixed disorders are common in patients with comorbid conditions (e.g., renal and respiratory disease) and in those who are critically ill. Mixed disorders can be complex to manage.

FIGURE 6-14 Mixed acid–base disorders.

Arterial Blood Gas Interpretation Arterial blood gases (ABGs) have traditionally been, and remain today, the principal diagnostic tool for evaluating acid–base balance (Table 6-9). ABG interpretation can

be confusing particularly in determining whether the values are due to compensation or a mixed disorder. Additionally, it is important to keep in mind that an ABG is a single point in time, and serial measurements must often be undertaken to determine what is occurring. Through simple steps, the ABG riddle can be solved and interpreted in context of the clinical evaluation so the patient can receive appropriate care. First, the following descriptions of the results found on an ABG, some of which have already been discussed, should be reviewed again:

The pH measures the hydrogen concentration in the plasma. PaCO2 (the partial pressure of carbon dioxide) indicates the adequacy of pulmonary ventilation. HCO3- (bicarbonate) indicates the activity in the kidneys to retain or excrete bicarbonate. PaO2 (the partial pressure of oxygen) indicates the concentration of oxygen in the arterial blood. Base excess/deficit indicates the concentration of buffer—in particular, bicarbonate. Positive values indicate an excess of base or a deficit of acid. Negative values indicate a deficit of base or an excess of acid.

When interpreting an ABG result, focus on the pH, PaCO2, and HCO3-. Interpreting ABGs involves looking for patterns and understanding what those patterns indicate, keeping in mind the patient’s total clinical picture. Recall that PaCO2 is an acid and HCO3- is a base. More acid will lower the pH, whereas less acid will raise the pH. More base will raise the pH, whereas less base will lower the pH.

Turning to the ABG results, use a systematic approach when examining them (TABLE 6-11). Make note of the patient’s pH, PaCO2, and HCO3- on a piece of paper. Start by examining the pH. Is it high, low, or normal? The pH is half of the puzzle. The pH will identify whether the condition is acidosis or alkalosis. If it is high, write a B for basic beside it. If the pH is low, write an A for acidic. If it is normal, which side of normal is it? For results less than 7.4, write an A; for results greater than 7.4, write a B.

TABLE 6-11 Arterial Blood Gas Interpretation

Reproduced from Story, L. (2017). Pathophysiology: A Practical Approach, 3rd Edition. Burlington, MA: Jones & Bartlett Learning.

Next, check the PaCO2. Is it high, low, or normal? In respiratory disturbances, pH and CO2 move in opposite directions. If the CO2 goes up, the pH goes down, and vice versa. Because CO2 is an acidic influence, write an A if it is high and a B if it is low. If it is within normal range, write an N beside it.

Next, examine the HCO3. Is it high, low, or normal? With metabolic disturbances, the pH and HCO3- move in the same direction. Because HCO3- is a base influence, write a B if it is high and an A if it is low. If it is within normal range, write an N beside it.

At this point, you should have three letters written down beside your patient’s ABG results. Now you just match up the As and Bs you have written down to the disturbance. Finally, determine if the body has been able to compensate. The results with the paired A or B are the primary changes. The third unpaired result indicates the compensation. If the unpaired result is still normal, then it is uncompensated. If the unpaired result has changed to the opposite letter of the pairs and the pH is still abnormal, then it is partially compensated; if the pH has returned to normal, then it is fully compensated.

To review, these are the steps in ABGs interpretation:

1. Is the pH high, low, or normal? a. If pH > 7.4, write a B beside it for basic. b. If pH < 7.4, write an A beside it for acidic. c. Make note if pH is within normal limits (7.35–7.45).

2. Is the PaCO2 high, low, or normal? a. If PaCO2 is between 35 and 45 mmHg, write an N beside it for normal. b. If PaCO2 > 45 mmHg, write an A beside it for acidic. c. If PaCO2 < 35 mmHg, write a B beside it for basic.

3. Is the HCO3 high, low, or normal? a. If HCO3 is between 22 and 26, write an N beside it for normal. b. If HCO3 > 26 mEq/L, write a B beside it for basic. c. If HCO3 < 22 mEq/L, write an A beside it for acidic.

4. Look for patterns: a. Two As indicate acidosis. If one of the As is CO2, then the disorder is

respiratory. If one of the As is HCO3-, then the disorder is metabolic. In both cases, the other A is the pH.

b. Two Bs indicate alkalosis. If one of the Bs is CO2, then the disorder is respiratory. If one of the Bs is HCO3, then the disorder is metabolic. In both cases, the other B is the pH.

c. Three As or Bs indicate a mixed disorder. All As indicate mixed respiratory and metabolic acidosis. All Bs indicate mixed respiratory and metabolic alkalosis.

5. Determine compensation and whether the compensation is appropriate: a. If the unpaired result is within normal range, then the disturbance is

uncompensated. b. If the unpaired result is the opposite letter of the pairs but the pH is still

abnormal, then the disturbance is partially compensated. c. If the unpaired result is the opposite letter and the pH has returned to normal

range, then the disturbance is fully compensated. 6. Determine the anion gap, particularly for metabolic acidosis. 7. Determine a cause or causes of the disorder.

Practice Arterial Blood Gas Interpretation

Practice 1 pH: 7.32 A PaCO2: 37 mmHg Normal HCO3-: 14 mEq/L A

Practice 2 pH: 7.50 B PaCO2: 30 mmHg B HCO3-: 24 mEq/L Normal

Practice 3 pH: 7.33 A PaCO2: 55 mmHg A HCO3-: 28 mEq/L B

Practice 4 pH: 7.47 B PaCO2: 48 mmHg A HCO3-: 29 mEq/L B

Practice 5 pH: 7.38 A (but within normal limits) PaCO2: 48 mmHg A HCO3-: 29 mEq/L B

Practice 6 pH: 7.44 B (but within normal limits) PaCO2: 49 mmHg A HCO3-: 29 mEq/L B

Practice 7 pH: 7.30 A PaCO2: 50 mmHg A HCO3-: 19 mEq/L A

Practice 8 pH: 7.49 B PaCO2: 32 mmHg B HCO3-: 30 mEq/L B

Reproduced from Story, L. (2017). Pathophysiology: A practical approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

BOX 6-3 Application to Practice A 70-year-old woman was recently treated for pneumonia with antibiotics. After 1 week on antibiotics, she started developing severe diarrhea of 6–7 loose, watery stools per day. The diarrhea has been present for 3 days. She also has a decreased appetite, feels nauseous, and has not been drinking a lot of fluids. She feels very weak and dizzy. She lives alone, so she called 911 and was brought to the emergency department. She is diagnosed with diarrhea, presumptive Clostridium difficile.

Patient medical history: Clostridium difficile 2 years prior. Physical exam: temperature 99.0°F, pulse 100 beats/minute, respirations 24 breaths/minute, and blood

pressure 90/50 mmHg, which dropped to 70/40 when seated. Exam unremarkable except for dry mucous membranes and generalized mild abdominal tenderness with

palpation. Laboratory findings reveal: Chemistry panel: sodium 135 mEq/L; potassium 3.4 mEq/L; chloride 100 mmol/L; HCO3- 12 mEq/L; blood

urea nitrogen 40 mg/dL. Creatinine: 1.2 mg/dL.

ABG: pH 7.22, PaO2 85 mmHg, PaCO2 20 mmHg, HCO3- 12 mEq/L.

Analyze the ABG and determine the acid–base disturbance. Calculate the compensation response and determine if it is appropriate. Calculate and interpret the anion gap. Discuss the diagnosis and reasons for the acid-base disturbance. Develop a treatment plan.

C H A P T E R S U M M A R Y

Fluid, electrolytes, bases, and acids are constantly moving among body compartments. This movement is influenced by intake, output, cellular metabolism, and pathologic states. The body is equipped with numerous mechanisms to maintain fluid, electrolyte, and pH homeostasis among these compartments. When these mechanisms fail, conditions that threaten the individual’s well-being arise. Imbalances are generally a reflection of an underlying disorder and early identification and action are crucial to improve the prognosis of the person encountering these conditions.

R E F E R E N C E S A N D R E S O U R C E S

Baumberger-Henry, M. (2008). Fluid and electrolytes (2nd ed.). Sudbury, MA: Jones and Bartlett Publishers. Chiras, D. (2015). Human biology (8th ed.). Burlington, MA: Jones & Bartlett Learning. Clark, R. K. (2006). Anatomy and physiology: Understanding the human body. Sudbury, MA: Jones and Bartlett Publishers.

Crawford, A., & Harris, H. (2011). I.V. fluids: What nurses need to know. Nursing2015, 41(5), 30–38. doi: 10.1097/01.NURSE.0000396282.43928.40

Elling, B., Elling, K., & Rothenberg, M. (2004). Anatomy and physiology. Sudbury, MA: Jones and Bartlett Publishers.

Emmett, M., & Palmer, B. F. (2019). Simple and mixed acid–base disorders. T. W. Post (Ed.). Uptodate. Waltham, MA: UpToDate, Inc. Retrieved from https://uptodate.com

Gould, B. (2015). Pathophysiology for the health professions (5th ed.). Philadelphia, PA: Elsevier. Madara, B., & Pomarico-Denino, V. (2008). Pathophysiology (2nd ed.). Sudbury, MA: Jones and Bartlett Publishers.

Preston, R. A. (2018). Acid-base, fluids, and electrolytes made ridiculously simple (3rd ed.). Miami, FL: MedMaster, Inc.

T

C H A P T E R 7

Urinary Function

L E A R N I N G O B J E C T I V E S

Discuss normal urinary anatomy and physiology. Differentiate renal alterations that alter urinary elimination. Differentiate renal alterations that result in impaired renal function. Describe the correlation of systemic disorders such as hypertension and diabetes with kidney disease development. Explain how various urinary disorders cause and/or worsen chronic kidney disease and failure. Summarize how various disorders cause impaired urinary elimination and renal function. Explain the clinical consequences of impaired urinary elimination and renal function. Apply understanding of urinary system alterations in describing various common disorders such as urinary incontinence, infections, tumors, malignancy, glomerular disorders, and kidney disease. Develop diagnostic and treatment considerations for various urinary disorders.

he urinary system plays a pivotal role in homeostasis. Structures of the urinary system include the kidneys, ureters, bladder, and urethra (FIGURE 7-1). This system regulates fluid volume, blood pressure, metabolic waste and drug

excretion, vitamin D conversion, pH regulation, and hormone synthesis. This chapter focuses on normal and abnormal states of the urinary system. Disorders of this system can create imbalances in homeostasis quickly. Hence, these disorders require a prompt response to restore the body’s delicate balance.

FIGURE 7-1 The urinary system. A Anterior view showing the relationship of the kidneys, ureters, urinary bladder, and urethra. B A cross-section of the human kidney showing the cortex, medulla, and renal pelvis.

Anatomy and Physiology Structure and Function The urinary system regulates fluid volume, blood pressure, metabolic waste and drug excretion, vitamin D conversion, pH balance, and hormone synthesis. It includes the kidneys, ureters, bladder, and urethra. See chapter 6 for a discussion of fluids and pH balance.

The kidneys are bean-shaped organs about the size of a person’s fists; they are positioned on either side of the vertebrae in the retroperitoneal space. Connective tissue called the renal capsule surrounds each kidney. The area immediately beneath the capsule is known as the renal cortex; it contains the functional units of the kidney, the nephrons, and blood vessels. The inner layer is called the medulla, which contains the renal pyramid. The renal artery supplies each kidney with blood. The renal hilum is the opening in the kidney through which the renal artery and nerves enter and the renal vein and ureter exit. The hilum opens medially into a cavity called the renal sinus. The central portions of the renal sinuses enlarge to form the renal pelvis. Urine drains in a manner similarly to a funnel into the renal pelvis through tubes called calyces. The calyces drain urine into the ureters, which transport the urine using peristaltic actions to the bladder for storage. Urine then leaves the body through the urethra and urinary meatus.

The kidneys are the primary site for carrying out the urinary system’s functions. One kidney contains 1 million to 2 million microscopic filtering units, or nephrons, to accomplish its functions (Figure 7-1 and FIGURE 7-2). Each nephron is similar to a funnel with a long stem (i.e., renal tubules). The tubules are connected to the circulatory and the urinary systems. The tubules contain multiple sections including the loop of Henle, proximal convoluted tubule, and distal convoluted tubule, and each of these sections is responsible for secreting substances from the blood into the filtrate or reabsorbing specific substances from the filtrate back into the blood (TABLE 7-1). The proximal convoluted tubule of the kidney enlarges into a double- membrane chamber called the Bowman capsule (i.e., glomerular capsule). The capsule contains an inner visceral layer and an outer parietal layer, and the space in between these two layers, called the Bowman space, is where the filtrate that will become urine is created. Most of the nephron structures are in the cortex with parts of the loops dipping into the medulla, and these nephrons are termed cortical nephrons. About 20% of the nephrons are in the cortex, but their tubules’ longer lengths go through the entire medulla, and these nephrons are termed juxtamedullary nephrons (i.e., they are in the cortex but next to the medulla). The juxtamedullary nephrons have a key role in concentrating urine. The Bowman capsule surrounds a cluster of capillaries referred to as the glomerulus. Blood enters the glomerulus through an afferent arteriole and exits through an efferent arteriole (FIGURE 7-3). The efferent arteriole connects to peritubular capillaries that are

found throughout the cortex and medulla and bring reabsorbed substances back to the blood through the renal vein.

FIGURE 7-2 Nephrons of the kidney. Part of the nephron is located in the cortex, and part is located in the medulla. The electron micrograph to the left of the illustration is of a glomerulus from a human nephron.

Courtesy of Kenjiro Kimura, MD, PhD.

FIGURE 7-3 The glomerulus of the kidneys. The nephron carries out three processes: glomerular filtration, tubular reabsorption, and tubular secretion. All three processes contribute to the filtering of the blood.

TABLE 7-1 Components of the Nephron and Their Functions

Component Function

Glomerulus Mechanically filters the blood

Bowman capsule Mechanically filters the blood

Proximal convoluted tubule Reabsorbs 75%* of the water, sodium,** glucose, potassium, bicarbonate, phosphate, urea, and amino acids Secretion of hydrogen, other substances (e.g., medications)

Loop of Henle Participates in countercurrent exchange, which maintains the concentration gradient Reabsorption of water and sodium Secretion of urea

Distal convoluted tubule Reabsorption of sodium, water, and bicarbonate Secretion of hydrogen, potassium, urea, ammonia and certain drugs

* approximate; % varies by molecule. **chloride follows sodium. Modified from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Urine Formation and Elimination The human body can excrete waste through the kidneys, skin, liver, and intestines, with the kidneys being the primary site for excretion. Urine formation is dependent on renal blood flow, tubular reabsorption, and secretion functions. Blood goes to the glomerulus (afferent arteriole) where a protein-free filtrate (i.e., ultrafiltrate) is created, and the filtrate goes through the tubules where substances are reabsorbed into the blood or secreted into the filtrate to be excreted (i.e., urine).

Approximately 25% of cardiac output is directed toward kidney perfusion. For example, a cardiac output of 5 liters (5,000 mL) per minute would translate into 1,250 mL/min of blood flow to the kidneys (25% of 5,000 mL). This amount of blood supply to the glomerulus is needed to maintain proper waste elimination. Of that amount, an average of 125 mL/min (greater than 90 mL/min is considered normal) is filtered in the glomerulus and goes to the Bowman capsule. The speed at which the blood moves through the glomerulus is called the glomerular filtration rate (GFR). GFR is the best measure of renal functioning and can be calculated using a formula that incorporates serum creatinine levels, age, gender, and ethnicity. While an average 125 mL/min of filtrate is produced, that is not the amount of urine output. Only 1–2 mL/min ends up in urine, and the remainder is reabsorbed back into the tubules and then the circulation. The exchange mechanism between the glomerulus and the Bowman capsule is influenced by the same factors influencing capillary exchange such as oncotic pressure and capillary permeability. Approximately 90% of

blood flowing through the kidney goes through the cortex, while the remaining 10% passes through the medulla. During times of decreased renal perfusion (e.g., decreased cardiac output, shock), blood is shunted to the medulla so that urine concentration is maintained.

Renal blood flow is affected by the same factors affecting blood pressure. The renin–angiotensin–aldosterone system is a key regulator of renal blood flow. The mechanisms that cause vasoconstriction and a decrease in renal blood flow include sympathetic nervous system stimulation with release of catecholamines, angiotensin II, antidiuretic hormone (ADH), and endothelins. Substances causing vasodilation include dopamine, prostaglandins, and nitric oxide. Natriuretic peptides (e.g., atrial, brain) respond to increases in blood volume (e.g., heart failure) and cause afferent arteriole dilation and efferent arteriole constriction, both which increase urine formation. Urodilatin, a natriuretic peptide, is produced in the distal tubule and collecting duct. Urodilatin also responds to volume increases by inhibiting water and sodium reabsorption and causing vasodilation and diuresis. See chapter 4 for a discussion of cardiovascular function.

In addition to the neural and hormonal mechanisms, intrinsic renal mechanisms maintain renal blood flow. One of these intrinsic mechanisms is known as the juxtaglomerular complex (i.e., juxtaglomerular apparatus). The complex is a group of specialized cells located next to the blood vessels (afferent and efferent arterioles) and the distal tubule that regulate blood flow and produce renin. This complex senses systemic arterial blood pressure changes, particularly sodium levels in the distal tubule, and pressure changes in the afferent arteriole. Decreases in GFR and sodium stimulate the complex, leading to dilation of the afferent arteriole and renin release, which causes efferent arteriole vasoconstriction with a resulting increased GFR. If there is an increase in GFR and sodium, then the reverse happens with afferent arteriole constriction and efferent arteriole dilation, which results in a decreased GFR. Several renal vascular disorders can affect renal blood flow, such as renal artery stenosis and renal vein thrombosis. The renal vasculature serves as another intrinsic mechanism by directly dilating and constricting in response to solute, water, and blood volume changes. This vasoactive capacity can maintain renal blood flow independent of systemic blood pressure changes.

Cells continuously produce waste products as they carry out their internal processes (TABLE 7-2). The body removes these waste products to maintain homeostasis through urine formation. The tubules of the kidneys are the site of reabsorption and secretion of water, electrolytes, and nutrients (Table 7-1; FIGURE 7-4). The kidneys regulate the concentration of water and electrolytes by increasing or decreasing their excretion to maintain stability within the body. Mechanisms of exchange of water, electrolytes, and other substances in the tubular structure are similar to other exchange mechanisms throughout the body (e.g., active and passive transport, osmosis). The ultrafiltrate, which is protein free, enters the proximal

convoluted tubule and contains plasma substances such as sodium, potassium, creatinine, urea, glucose, and amino acids. The proximal convoluted tubule reabsorbs (back into the blood) most of the filtrate components and is also a site of secretion (blood to filtrate). In addition to water, urea is a significant component of urine. Approximately 50% of urea is reabsorbed in the proximal convoluted tubule, and the remainder moves through the tubule and is excreted in the urine. Urea is derived from ammonia, which is a highly toxic chemical that results from the breakdown of amino acids in the liver. Amino acid breakdown generally occurs in the presence of an excess of protein or a deficit of carbohydrates in the diet; however, carbohydrate deficits are rare in industrialized countries except in persons on high- protein diets. When amino acids are broken down, the amino groups are stripped from the molecules in a process called deamination. These amino groups are converted to ammonia following deamination. Most of this ammonia is then converted to urea in the liver, which is then excreted in the urine. Liver disease can impair this process, leading to extremely high levels of ammonia. Uric acid is another metabolism by-product produced by the liver. Uric acid results from the breakdown of nucleotides, the building blocks of deoxyribonucleic acid (DNA). Excess uric acid levels in the serum can lead to gout, which results in uric acid crystal deposits in the joints. See chapter 6 for a discussion of fluid, electrolyte, and acid–base homeostasis. See chapter 9 for a discussion of gastrointestinal function. See chapter 12 for a discussion of musculoskeletal function.

FIGURE 7-4 The steps in urine formation in successive parts of a nephron are filtration, reabsorption, and secretion.

TABLE 7-2 Important Metabolic Wastes and Substances Excreted from the Body

Chemical Source Organ of excretion

Ammonia Deamination (removal of amine group) of amino acids in liver

Kidneys

Urea Derived from ammonia Kidneys and skin

Uric acid Nucleotide breakdown in the liver Kidneys

Bile pigments Hemoglobin breakdown in the liver Liver (into the small intestine)

Urochrome Hemoglobin breakdown in the liver Kidneys

Carbon dioxide Breakdown of glucose in cells Lungs

Water Food and water; breakdown of glucose Kidneys, skin, and lungs

Inorganic ions* Food and water Kidneys and sweat glands

* Ions are not a metabolic waste product like the other substances shown in this table. Nonetheless, ions are excreted to maintain constant levels in the body. Modified from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

Some molecules (e.g., glucose, creatinine) need a carrier molecule to cross the membrane. A limited number of carriers is available, and the excess molecules get excreted in urine (i.e., transport maximum). A classic example is the glycosuria that occurs when serum glucose levels are high (e.g., 180 mg/dL).

The filtrate passes from the proximal convoluted tubule to the loop of Henle, which is the site of countercurrent exchange and urine concentration. The cortical nephron loops dip into the medulla, but the juxtamedullary nephrons are longer and dip further into the medulla. The further into the medulla, the greater the concentration gradient and fluid exchanges between the vasa recta (i.e., capillaries around loops in the medulla) and the loop. Sodium, along with chloride, potassium, and water move back and forth as osmolality between the tubule and interstitium varies. The epithelial lining of the loop of Henle produces a protein known as uromodulin (i.e., Tamm-Horsfall protein). This protein is thought to have protective functions against uropathogens by binding and sequestering organisms as well as preventing kidney stone formation, but the role in kidney injury is unclear. Uromodulin is being evaluated as a potential marker of kidney function in addition to GFR.

The filtrate entering the distal convoluted tubule is more dilute (hypotonic). Hormones, such as ADH and aldosterone, alter this rate of excretion of sodium and water in the distal convoluted tubule (FIGURE 7-5). In part, this mechanism of water and electrolyte regulation aids in blood pressure management and, simultaneously, renal blood flow. The kidneys regulate acid–base balance through the secretion of hydrogen ions, which bind with base buffers, such as ammonia and phosphate, and are excreted in the urine. See chapter 6 for more on acid–base balance.

FIGURE 7-5 Effects of antidiuretic hormone and aldosterone on the kidneys.

The kidneys have two other important functions with systemic effects—vitamin D conversion into its active form and erythropoietin production. The inactive form of vitamin D is produced by the action of ultraviolet rays on cholesterol in the skin or is ingested. The active form of vitamin D created by conversion aids in calcium and phosphorus absorption. The reabsorption of calcium and phosphorus occurs mainly in the proximal convoluted tubule. People with renal disease will have issues converting vitamin D into its active form. Most (95%) of the hormone erythropoietin is produced by the kidneys and is released in response to decreased oxygen delivery to the kidneys. Erythropoietin increases red blood cell production in the bone marrow. See chapter 3 for a discussion of hematopoietic function.

Urine is mainly composed of water (approximately 95%) and dissolved waste products by the time it is excreted. The next most abundant component is urea (approximately 2%), then sodium chloride (approximately 1%), and the remainder includes many other dissolved organic wastes (e.g., creatinine and uric acid). Ions in urine include potassium, calcium, magnesium, ammonia, sulfates, and phosphates. Many other substances are present in urine including carbohydrates, hormones, and enzymes.

Urine leaves the collecting duct once it is formed, traveling to the renal pelvis and funneling into the ureters to the bladder. The uroepithelium is the protective lining from the renal pelvis to the urethra. The ureters enter the bladder at an angle, and the bladder pushes against the ureters when it contracts to prevent urine backflow (FIGURE 7-6). The muscular bladder serves as a reservoir for urine until it can be excreted. As the volume of urine in the bladder increases, the urine exerts pressure on the two bladder sphincters (internal and external) and stretch receptors in the bladder. A pressure of 200 to 300 mL on the sphincters and receptors sends nerve impulses to the brain, triggering the urge to urinate (FIGURE 7-7). The amount of urine the bladder can store varies depending on age. An adult can store approximately 300–600 mL of urine. In children between the ages of 2 and 16 years old, the formula is estimated bladder capacity (mL) = (age of the patient in years + 2) × (30 mL).

FIGURE 7-6 A Male urinary bladder and B female urinary bladder and related structures.

FIGURE 7-7 Urination.

Urination, or micturition, is a voluntary act. When urination is initiated, the bladder contracts and the internal and external sphincter relax, forcing urine out through the urethra. The external sphincter is able to stay closed despite high pressures and is able to close to stop urination once initiated. The urethra is approximately 1.5 inches

V

long in women and 6–8 inches long in men. The shorter urethra in women, in combination with use of a sitting position for urination, increases women’s risk for developing urinary tract infections. The muscles of the pelvic floor maintain bladder placement and contribute to urination control.

The minimum urine output for proper elimination of waste products is termed the obligatory urine output, and this output is approximately 500 mL/day in adults. Formulas incorporate kilograms of body weight to calculate the minimum urine output in adults and children, including:

Adult: 0.5 mL/kg/hr Child (> 1 year old): 1.0 mL/kg/hr Neonate/infant (< 1 year old): 2.0 mL/kg/hr

With aging, the kidneys begin functioning less efficiently. Renal blood flow decreases due to decreased arterial elasticity and increased stiffness. The decreased blood flow results in decreased number of nephrons, and the glomeruli enlarge as a compensatory mechanism. The glomeruli become hypertrophic and sclerosed. The nephrons cannot regenerate. Every decade after 40 an average of 10% of nephrons are lost, which means by age 80 up to 40% of nephrons may be lost. The kidneys, however, despite the decreased number of nephrons are able to function adequately. The tubular structures shorten, lose mass, and atrophy. These tubular changes result in concentration difficulties, fluid imbalances, and acid–base and electrolyte imbalances. This decreased functioning can be further exacerbated by the presence of chronic conditions (e.g., diabetes mellitus, hypertension, and arteriosclerosis). Additionally, renal-related complications are common with aging changes (e.g., anemia, hypertension, and osteoporosis). Aging persons may require alternative medication dosing (usually a smaller dose or doses spaced farther apart) to prevent drug toxicity because of this impaired filtration. Also, several micturition issues such as incontinence from menopause or obstruction from an enlarged prostate can occur with aging.

Diagnostic Link

Blood Urea Nitrogen and Serum Creatinine arious diagnostic serum laboratory tests are commonly used to evaluate renal function. The most common are blood urea nitrogen (BUN), serum creatinine, and GFR. Ammonia is converted in the liver to urea,

which is the end product of protein metabolism. Urea is excreted entirely by the kidneys; therefore, BUN is an indication of liver and kidney function. Creatinine forms when creatine phosphate is used in skeletal muscle contractions and from dietary meat intake. The serum creatinine level is also an indication of renal function because it is entirely excreted by the kidneys. The creatinine level is not affected by hepatic function, so it is a more precise indication of renal function than is BUN. Creatinine levels double when there is a 50% reduction in GFR. However, creatinine fluctuates with dietary protein intake or supplements and decreases with malnutrition, muscle wasting, and amputation.

T

T

Diagnostic Link

Estimating GFR he glomerular filtration rate (GFR) is the best measure of renal function, but it can only be estimated and not measured directly. There are two common methods to estimate GFR. One calculation uses the serum

creatinine and incorporates age, sex, and race; this calculation is reported as estimated GFR (eGFR). Another calculation uses the serum creatinine and a 24-hour urine sample; this calculation is reported as the creatinine clearance. The creatinine clearance is the rate that creatinine is cleared from the blood by the kidneys in 24 hours.

Diagnostic Link

Urinalysis Components he urinalysis is a commonly used laboratory test to evaluate for many disorders (e.g., urinary tract infections, kidney stones). The test consists of three parts: 1) a visual examination for color and clarity; 2) a

chemical examination for variables such as pH, specific gravity, blood, protein, glucose, bilirubin, urobilinogen, nitrite, leukocyte esterase, and ketones; and 3) a microscopic examination for red blood cells, white blood cells, epithelial cells, casts, crystals, and organisms (e.g., bacteria). Electrolytes such as sodium, potassium, and calcium can be measured but are not part of a routine urinalysis. The urine sample can also be used to screen for substances such as cocaine, marijuana, and amphetamines.

Understanding Conditions That Affect the Urinary System When considering alterations in the urinary system, organize them based on their basic underlying pathophysiology to increase understanding. Those pathophysiologic concepts include those conditions that alter urinary elimination and impair renal function. Conditions that alter urination may include infections, structural barriers, or problems with the act of urination). Infections could include cystitis or pyelonephritis; a structural barrier might be nephrolithiasis, a congenital disorder, or a tumor; and a problem with the act of urination could be incontinence. These conditions require interventions to promote urination (e.g., antibiotics, catheterization, bladder training, or surgery). Conditions that impair renal function can be life threatening (e.g., acute kidney injury) and include those disorders that prevent the kidneys from regulating fluid and electrolytes as well as excreting waste products and other substances. These conditions require prompt recognition and treatment (e.g., dialysis) to restore and maintain homeostasis and avoid progressive kidney disease.

Conditions Resulting in Altered Urinary Elimination The act of urination requires 1) a functioning bladder with stretch receptors that can sense the filling of the bladder with urine, 2) an intact parasympathetic pelvic nerve to transmit the signal for emptying, and 3) working detrusor muscles to initiate bladder contractions to expel the urine (Figure 7-7). The sympathetic nerve innervations to the detrusor muscle cause detrusor relaxation and internal urethral sphincter contraction, which then lead to urine storage (see Figure 7-6). Somatic neurons (which provide voluntary control) cause external sphincter relaxation when inhibited and contraction when stimulated. Upper motor impulses can delay voiding by tightening the urethral sphincter. Although urination is mostly a voluntary act, voiding can be delayed only to a certain point. If the urge to void is ignored too long, bladder contractions take over the neural delaying mechanism and involuntary urination occurs.

Incontinence Urination is a reflex in very young children, but it is controlled consciously in older children and adults. In children up to 3 years of age, urination is completely reflexive. Once the bladder expands, it empties. As children grow older, they learn to control urination. In older children and adults, the external sphincter is under conscious control—it will not relax until deliberately allowed to do so.

Older children and adults sometimes lose control over urination, resulting in a condition referred to as urinary incontinence (Figure 7-7). Urinary incontinence is a common and often embarrassing problem that has many causes. Incontinence is more common with aging, and women are more affected than men. There are four main types of incontinence—stress, urge/overactive bladder, overflow, and mixed (FIGURE 7-8). Other terms to describe incontinence include functional, gross total, and transient incontinence. In children, incontinence is divided into nighttime incontinence (i.e., enuresis) or daytime incontinence.

FIGURE 7-8 Types of incontinence.

Stress incontinence describes loss of urine from increased intraabdominal pressure (stress) exerted on the bladder by coughing, sneezing, laughing, exercising, or lifting something heavy without any bladder contraction. Stress incontinence occurs when the urethra becomes hypermobile. The pelvic floor muscles and vaginal connective tissue normally support the urethra and bladder neck, and when support is lost, the urethra and bladder shift and no longer close by pushing against the anterior vaginal wall. The lack of connective and muscular support usually occurs in women due to physical changes resulting from pregnancy, childbirth, and obesity. Another cause of stress incontinence is intrinsic sphincter deficiency, causing an inability of the sphincter to close properly. Additionally, women may develop a cystocele (bulging of the bladder through the vaginal wall) because of these physical changes (lack of support), which can also increase their risk for stress incontinence. In men, prostate removal is the most common cause of stress incontinence. Other causes in men can include pelvic or neurologic trauma. Additional factors contributing to stress incontinence in both genders include obesity and chronic coughing. Chronic coughing such as that caused by smoking and lung disease can increase stress on the urinary sphincter. Congenital (e.g., meningomyelocele) and neurologic disorders can also cause stress incontinence due to structural abnormalities or deficits. See chapter 8 for a discussion of reproductive function.

Urge incontinence is a sudden, intense urge to urinate, preceding or occurring simultaneously with an involuntary loss of urine. Overactive bladder is a term that is

often used interchangeably with urge incontinence as they often coexist. Overactive bladder is involuntary contractions with dysuria, urgency, and nocturia with or without incontinence. In urge incontinence, the detrusor muscle contracts involuntarily while the bladder is filling and may give the individual only a few seconds’ to a minute’s warning before voiding. With urge incontinence, the need to urinate is felt often, including throughout the night. The causes can be due central nervous system disorders altering inhibition of voiding, thereby, resulting in overactivity. Central nervous system disorders causing urge incontinence include stroke, Parkinson disease, and multiple sclerosis. Urge incontinence can also be the result of muscle changes in the bladder due to nerve-ending damage or detrusor muscle changes from aging. Urinary tract infections, bladder irritants, bowel conditions, and smoking may all cause urge incontinence.

Overflow incontinence is the result of an inability to empty the bladder, or retention. The bladder does not empty properly because the detrusor contractility is impaired due to aging, muscle damage and fibrosis, neuropathy, spinal detrusor efferent nerve disorders (e.g., multiple sclerosis), or low estrogen (e.g., menopause). Retention is usually due to an obstruction of the urethra, such as in prostate enlargement or a uterine fibroid compressing the urethra. Indications of overflow incontinence include dribbling urine and a weak urine stream. Chronic overdistention, also colloquially called nurse’s bladder and teacher’s bladder, occurs because of a perceived inability to interrupt work to void. This chronic avoidance of emptying the bladder results in detrusor muscle areflexia and overflow incontinence.

Mixed incontinence occurs when symptoms of more than one type of urinary incontinence are experienced. With functional incontinence, there are no urinary system disorders, but rather a physical or mental impairment prevents toileting in time. Functional incontinence occurs in many older adults, especially in people in nursing homes. For example, a person with severe arthritis may not be able to undress quickly enough to prevent incontinence.

Gross total incontinence refers to a continuous leaking of urine, day and night, or the periodic uncontrollable leaking of large volumes of urine. In these cases, the bladder has no storage capacity. This type of incontinence can occur because of anatomic defects, spinal cord or urinary system injuries, or a fistula (abnormal opening) between the bladder and an adjacent structure, such as the vagina.

Transient incontinence refers to urinary incontinence resulting from a temporary condition. Such conditions include delirium, infection, atrophic vaginitis, use of certain medications (e.g., diuretics and sedatives), psychological factors (e.g., depression and anxiety), high urine output (e.g., from overhydration), restricted mobility, fecal impaction, alcohol, and caffeine.

Incontinence in children can be divided into daytime or nighttime incontinence (i.e., enuresis). Incontinence in children is the involuntary urination by a child after 4– 5 years of age, when bladder control is expected; however, nighttime bladder control

may be achieved later (by 5–7 years old) than daytime control. Most children have only nocturnal enuresis, or bed-wetting, and no other symptoms (i.e., monosymptomatic enuresis). If a child never achieved nighttime dryness, then the enuresis is primary, but if they were not bedwetting for greater than 6 months and then start wetting, it is termed secondary enuresis. Enuresis is more common in boys than girls. Possible causes of primary enuresis include nighttime polyuria due to increased fluids taken at night or reduced ADH response or decreased ADH secretion (ADH follows a circadian pattern and normally increases at night), detrusor overactivity, and sleeping disorders. The relationship of ADH and enuresis are unclear. There may even be a genetic predisposition to enuresis as children who are bed wetters often have parents who were bed wetters. Enuresis may be due to a delay in the normal maturation of the central nervous system or small bladder capacity. Secondary enuresis may occur with an impactful event occurring in a child’s life, such as parental divorce, and can be associated with poor bowel and voiding habits (e.g., constipation, holding urine). Most cases of enuresis resolve spontaneously.

If a child has enuresis as well as other urinary tract symptoms such as urgency, hesitance, or daytime incontinence, the condition is termed nonmonosymptomatic enuresis. Those children with enuresis and daytime incontinence are more likely to have urinary tract dysfunction, such as frequent urinary tract infections or neurologic disorders. Daytime incontinence can also occur without enuresis and can be caused by various disorders such as an overactive bladder or spinal cord disorders (e.g., spina bifida). Daytime incontinence can occur because children hold their urine. Over time, holding urine causes the bladder to become distended, and the detrusor muscle overstretches and becomes hypoactive. Bladder contractions become ineffective.

Generally, risk factors for developing urinary incontinence include the following conditions:

Being female: Women are more likely than men are to have stress incontinence. Pregnancy, childbirth (particularly vaginal delivery), menopause, and normal female anatomy account for this difference. However, men with prostate conditions are at increased risk for urge and overflow incontinence. Advancing age: The muscles of the bladder and urethra lose some of their strength with age. Changes with age may also reduce bladder capacity and increase the risk of involuntary urination. However, incontinence is not inevitable with age, and incontinence is not normal at any age, except during infancy. Being overweight: Being obese or overweight increases the pressure on the bladder and surrounding muscles, weakening them and allowing urine to leak out under stress (e.g., stress caused by coughing or sneezing). Smoking: Chronic coughing associated with smoking can cause episodes of

incontinence or aggravate incontinence that has other causes. Constant coughing puts stress on the urinary sphincter, leading to stress incontinence. Smokers are also at risk of developing overactive bladder. Other diseases: Renal disease or diabetes mellitus may increase the risk for incontinence because of changes in renal function and nerve innervations.

Urinary incontinence can lead to complications ranging from minor to severe in nature. Skin problems (e.g., rashes, skin infections, and ulcers) can result from the presence of constant moisture. Recurrent urinary tract infections can develop from incomplete emptying of the bladder. Additionally, urinary incontinence can negatively affect psychological health and quality of life (e.g., it can cause poor self-image, embarrassment, sexual dysfunction, anxiety, and depression), and changes can occur in the individual’s usual activities (e.g., work and exercise).

Diagnosis and Treatment Diagnostic procedures for urinary incontinence include a history, physical examination, urinalysis, and urine cultures, if indicated. Bladder diaries (e.g., kept for 24–72 hours) can be completed to establish how often and when the incontinence occurs. Bladder stress testing in women can be done to evaluate for stress incontinence. This test involves having the patient vigorously cough or perform a Valsalva maneuver (i.e., forced exhalation with nose pinched and mouth closed) in a lithotomy and/or standing position while the examiner visualizes the urethra for urine leakage. Postvoid residual measurement can assess for bladder and bladder outlet activity and can be evaluated with a bladder ultrasound or catheterization. A normal postvoid residual is usually less than 50 mL and up to 100 mL in older adults, but norms vary by age. Postvoid residuals are particularly useful for evaluating retention and overflow issues but can be used for other concerns. Other urinary system diagnostic tests include a cystourethrogram (X-ray of the bladder and urethra while the bladder is full and during urination), cystoscopy (visualization of the bladder with a small, lighted instrument), pelvic ultrasound, and urodynamic testing (which measures pressures and flow rate in the bladder). A prostate specific antigen test should be done for men. If there is suspicion of spinal cord disorder, then neurologic imaging (e.g., magnetic resonance imaging [MRI]) is indicated. Treatment for urinary incontinence depends on the type, underlying cause, and severity. Treatment and management strategies range from conservative to aggressive and include:

Bladder training Scheduled toileting Fluid and diet management (e.g., avoiding alcohol, caffeine, or acidic foods; reducing liquid consumption; losing weight; or increasing physical activity) Pelvic floor muscle exercises (e.g., Kegel exercises)

Electric stimulation (electrodes are temporarily inserted into the rectum or vagina to strengthen pelvic floor muscles through gentle electric stimulation) Medications (e.g., anticholinergics or estrogen replacement) Urethral inserts (small, tampon-like disposable devices or plugs inserted into the urethra) Pessary (a stiff ring inserted into the vagina to hold up the bladder) Radiofrequency therapy (a nonsurgical procedure that uses radiofrequency energy to heat tissue in the lower urinary tract, causing it to become firmer) Botulinum toxin type A (BOTOX) injections into the bladder muscle Bulking material injections (e.g., collagen, carbon-coated zirconium beads, Coaptite) into tissue surrounding the urethra Sacral nerve stimulator (an implanted device that emits painless electrical impulses that stimulate the sacral nerve) Artificial urinary sphincter (a fluid-filled ring implanted around the neck of the bladder that is controlled by a manual subcutaneous valve) Sling procedures (a surgically constructed pelvic sling or hammock around the bladder neck and urethra created by using strips of tissue, synthetic material, or mesh) Bladder neck suspension (a surgical procedure to raise and support the bladder in a more normal anatomic position) Absorbent pads and protective garments Urinary catheter (usually as an intermittent self-catheterization) Increased perineal hygiene Skin barrier creams Safety measures (e.g., moving any rugs or furniture out of path to the restroom, providing adequate lighting, widening the bathroom doorway, and installing an elevated toilet seat) Acupuncture Hypnotherapy Herbal remedies (e.g., Crataeva nurvala, horsetail [Equisetum], aloe vera extract) Coping strategies and support

For children with enuresis, additional strategies and treatments are available (e.g., motivation, support, and alarm systems). Desmopressin is a synthetic version of ADH that can be used for children with enuresis who have not responded to behavioral strategies. Other treatment strategies are centered on the cause, if known. Incontinence can resolve with time with or without treatment.

Neurogenic Bladder Neurogenic bladder (FIGURE 7-9) refers to all bladder dysfunction caused by an interruption of normal bladder nerve innervation along any part of the peripheral or

central nervous system. The bladder either becomes spastic and incapable of urine storage or flaccid with an inability to empty properly. A combined dysfunction in storage and emptying may also be present. Spastic issues generally occur with upper motor lesions that alter central nervous system control (i.e., brain or spinal cord) centers. Under these circumstances, micturition reflexes continue to function and control the bladder. With a spastic bladder, detrusor hyperreflexia with or without sphincter dyssynergia (uncoordinated) may be presented. If the disease is above the micturition center in the pons, then the bladder and the external urinary sphincter function in coordination (i.e., the bladder fills, the sphincter relaxes, and the bladder empties). Examples of disorders associated with a spastic bladder with detrusor hyperreflexia are brain injury, stroke, and multiple sclerosis. If the injury is below the micturition center of the pons but above the micturition center of the sacral area (between cervical level 2 and sacral level 1), then coordination between the bladder contraction and the external sphincter is absent, and they both contract together, leading to an obstructive problem. The result is hyperactive bladder that does not relax (i.e., it is spastic) and cannot store much urine, bladder pressures rise easily, and symptoms of an overactive bladder occur. Disorders causing this detrusor- sphincter dyssynergia include Guillain-Barré syndrome, multiple sclerosis, and intervertebral disc problems.

FIGURE 7-9 Neurogenic bladder.

Flaccid bladder issues are a result of interruption in sacral area or peripheral nerve conduction (sensory or motor) from the bladder and the spinal cord (i.e., the lower motor neuron) while the central nervous system remains intact. This results in detrusor areflexia with a hypotonic or atonic bladder with a loss of sensation. Examples of disorders associated with a flaccid bladder are congenital anomalies such as meningomyelocele, cauda equina syndrome (damage to the bundle of nerves in the lumbosacral area), and peripheral nerve neuropathies (e.g., those

H

involving the pelvic nerve or herpes zoster).

Learning Points

Urinary Incontinence ere is an easy acronym to remember the causes of acute urinary incontinence.

DRIPS

D delirium, dehydration, diapers R retention, restricted mobility I impaction, infection, inflammation P pharmaceuticals (opiates and calcium antagonists cause urinary retention and

constipation; anticholinergics cause retention; alpha-adrenergic antagonists cause reduced urethral resistance in women; diuretics increase urine production), psychological problems (e.g., depression, neurosis, or anxiety)

S stool impaction (constipation) (Resnick & Yalla, 1998, p. 1045)

Clinical Manifestations Clinical manifestations of neurogenic bladder include symptoms of a spastic overactive bladder such as frequency, urgency, and urge incontinence. Symptoms of a flaccid underactive bladder include urinary retention as well as distention with stress and overflow incontinence. If sensation is intact, the patient may feel a full bladder but contractions for emptying will not occur.

Diagnosis and Treatment Diagnostic procedures for neurogenic bladder consist of a history, physical examination, bladder diary, urinalysis, urine cultures, cystourethrogram, cystoscopy, pelvic ultrasound, postvoid residual measurement, and urodynamic testing. Additional procedures (e.g., computed tomography [CT], MRI) may be performed to determine the underlying cause. Treatment strategies depend on the etiology and include those therapies previously discussed for incontinence.

Painful Bladder Syndrome/Interstitial Cystitis Painful bladder syndrome, often referred to as interstitial cystitis, is a syndrome manifested by chronic bladder pain without an apparent cause for the pain. Despite the term cystitis, bladder inflammation is usually absent; however, the term continues to be used in the literature and by clinicians. The syndrome is five times more prevalent in women than men, and the highest incidence occurs in the 30s and 40s. Psychosocial factors and quality of life are often impacted with painful bladder

syndrome due to difficulty with sleep and sexual dysfunction. The urinary symptoms can also impact work and social life.

The pathogenesis is poorly understood, but the diagnosis is often associated with other pain syndromes such as fibromyalgia, vulvodynia (vulvar pain of an unknown cause), and irritable bowel syndrome. Painful bladder syndrome is considered part of a group of hypersensitivity disorders that affect multiple organ systems because of the association with other pain syndromes. The disorder was originally associated with the development of visible ulcers known as Hunner lesions on cystoscopy. However, the lesions are only present in a small number (i.e., < 10%) of those with the disorder. In these patients, evidence of inflammation with accompanying mast cells and development of fibrosis is present. These findings are not present in the remainder of patients. Theories that continue to be explored are related to changes in the urothelial lining of the bladder and altered nerve sensitivity noted in those with painful bladder syndrome. A loss of integrity in the glycosaminoglycan (GAG) lining (a coating of urothelial cells) allows for increased permeability to irritants. The loss of urothelial integrity leads to activation of nerve and muscle tissue in the bladder, further perpetuating damage. Autoimmunity has been proposed as a mechanism. Bladder neuron sensitivity and central sensitization are increased, which is a result of abnormal brain processing of sensory input. Central sensitization results in more pain with less stimuli.

Clinical Manifestations The key characteristic of painful bladder syndrome is suprapubic bladder pain, pressure, or discomfort with bladder fullness. The pain improves with urination. The pain is also usually in the pelvis but can be in the lower back and abdomen. Pain can worsen with ingestion of certain foods (e.g., tomatoes, spicy foods) or fluids (e.g., caffeine, alcohol). Frequency and urgency are common, but these manifestations are also present in other disorders such as overactive bladder or urinary tract infections. The symptoms must be present for more than six weeks with no other causes that explain the symptoms (e.g., urinary tract infection, malignancy).

Diagnosis and Treatment Painful bladder syndrome diagnosis is made by conducting a history and physical examination. Diagnostic tests are done to exclude other disorders causing the symptoms. Cystoscopy and urodynamic evaluation are recommended when diagnosis is in doubt or complications are present. Treatment is geared toward symptom control. Treatment should be initiated in a stepwise approach, starting with conservative measures. Treatment should also be instituted individually so that an evaluation can be made regarding the effectiveness. Treatments initially include measures such as relaxation, behavioral modification like bladder training and

avoiding bladder irritants, and urinary pain analgesics (e.g., phenazopyridine). Other treatments include physical therapy, oral medications (e.g., amitriptyline, instillation of medications in the bladder [e.g., glycosaminoglycan]), intradetrusor botulinum toxin, sacral neuromodulation, and surgical urinary diversion, in this order.

Congenital Disorders Abnormalities of the urinary and reproductive systems are the most common congenital defects. Because of these systems’ close proximity and intertwined structure, an abnormality in one system will often lead to an abnormality in the other. Numerous congenital disorders of the urinary system are possible, most of which are structural problems. Some defects cause no symptoms (e.g., both ureters draining one kidney and abnormal kidney positioning), whereas others are life threatening (e.g., renal agenesis [failure of an organ to develop in utero]). Problems with kidney development can be the most severe. The kidneys begin to develop in approximately the fifth week of gestation. Urine formation begins at 9–12 weeks’ gestation. Urine is the main component of amniotic fluid, which is vital for normal fetal development.

Urinary Tract Infections—Cystitis and Pyelonephritis Urinary tract infections (UTIs) are very common and include any infections that begin in the urinary tract. Infections can be categorized as upper urinary tract, which include the kidneys (i.e., pyelonephritis), or lower urinary tract, which include the bladder (i.e., cystitis) and the urethra (i.e., urethritis). The lower urinary tract is the most frequent site for infection. UTIs can be further divided into acute uncomplicated (e.g., simple cystitis) and acute complicated (e.g., pyelonephritis). UTIs can also be recurrent or chronic.

UTIs are caused by a direct invasion of the urinary tract by bacteria. Urine is an excellent medium for microorganism growth because of its protein content. Most bacteria that enter the urinary tract are quickly removed by the body before they cause symptoms. Notably, the urinary system contains several mechanisms to prevent infection, including one-way valves where the ureters attach to the bladder; urination, which washes microbes out of the body; the bladder lining, which has a barrier against bacteria; prostate secretions that slow bacterial growth in men; periurethral flora of Lactobacillus that prevents colonization in women; and the general functions of the immune system. Occasionally, the bacteria resist the body’s defenses and cause infection. Due to the high concentration of bacteria, most infections invade the urethra from the meatus from microorganisms in the perineal area. The microorganism can then ascend through the urethra to the bladder, causing a cystitis, and then can move along the ureters to the kidneys, causing a pyelonephritis. Occasionally, microorganisms may invade the kidneys from the blood (hematogenous spread); this pathogenesis is more likely in the very young or

immunocompromised. Pyelonephritis is more common in those persons who require frequent medical attention, experience recurrent UTIs, or have contracted an antibiotic-resistant bacterial strain.

UTIs are most often caused by Escherichia coli, which is part of the normal intestinal flora. Virulent forms of E. coli can avoid being washed away during urination by attaching to the mucosa along the urinary tract. E. coli can gain access to the urinary tract due to the anus’ proximity to the urinary meatus, especially in women. In addition to this proximity, women are more vulnerable to developing UTIs for the following reasons:

Women have shorter urethras, so the microorganisms have a shorter distance to travel. Women usually urinate in a sitting position, which prevents full emptying of the bladder. Women may experience increased perineal tissue irritation from sexual activity, tampons, bubble baths, bathing suits, tight-fitting pants, and deodorants as well as nylon, lace, and thong underwear. Women who are postmenopausal have a change in the periurethral flora, which increases the risk of urethral colonization. Women are more predisposed to urethrovesical reflux when doing any activities that involve bearing down, such as coughing and squatting. The pressure from bearing down pushes urine into the urethra, and it flows backwards in the bladder when pressure decreases.

Other organisms implicated in UTIs are Enterobacteriaceae species (e.g., Klebsiella pneumoniae, Proteus mirabilis) and Staphylococcus saprophyticus. Healthcare-associated urinary infections (whether from exposure or instrumentation), the recent use of antibiotics, and travel to areas with multidrug-resistant organisms may reveal the presence of other UTI-causing organisms. These other causes include species such as Pseudomonas or methicillin-sensitive or -resistant Staphylococcus aureus.

Although men are less likely than women to experience a UTI, when they do develop a UTI they are likely to have a recurrent UTI because the bacteria can hide deep inside prostate tissue. Recurrence in men is uncommon and defined as the return of symptoms within a few weeks after treatment. Recurrence in men is suspect for underlying disorders such as prostatitis or anatomic abnormalities. Urologic evaluation is usually warranted in men with recurrent UTI. In contrast to men, recurrent simple cystitis in women is defined as more than two infections in 6 months or more than three infections in 1 year. Most of the recurrences are due to reinfection rather than relapse. Relapses are considered when an infection occurs shortly after completion of a treatment (e.g., < 2 weeks) and the organism is the same. Relapses may require further evaluation or different management option such

as long-term antibiotics. Children with recurrent UTIs need to be evaluated for vesicoureteral reflux

(VUR), which is the backward flow of urine from the bladder into the upper urinary tract. The most common cause of VUR is a defect in the closure of ureterovesical junction (FIGURE 7-10). In VUR, the ureter is congenitally short, and part of the ureter is embedded abnormally into the bladder wall. High bladder pressures as a result of anatomic defects or obstruction (e.g., neurogenic bladder) may also cause recurrent UTIs in children, and the condition can also be hereditary. Because the urine is flowing backwards, there is incomplete emptying with a predisposition to infections. The infected urine can then travel to the kidneys, causing pyelonephritis. The recurrent infections can lead to renal scarring and kidney failure. VUR can be detected by ultrasound prenatally when hydronephrosis is present. A child will usually have fever along with recurrent UTIs. There can be spontaneous resolution of a VUR depending on the characteristic of the reflux (e.g., whether it is unilateral or less severe).

FIGURE 7-10 Primary vesicoureteral reflux.

Vesicoureteral Reflux (VUR), National Institute of Diabetes and Digestive and Kidney Diseases, Retrieved from https://www.niddk.nih.gov/health-information/urologic-diseases/urine-blockage-newborns/vesicoureteral-reflux.

Other risk factors for developing UTIs include the following:

Benign prostatic hypertrophy (causes urinary obstruction/retention or decreased bactericidal prostatic activity with aging) Congenital urinary tract abnormalities (can alter urinary flow) Immobility (prevents complete bladder emptying, leading to urinary stasis) Urinary or bowel incontinence (can increase the potential for contamination of the urinary meatus) Renal calculi (obstruct urine output, leading to urinary stasis) Decreased cognition (increases the risk for incontinence and toileting issues) Pregnancy (the growing uterus puts pressure on the bladder, impairing urinary flow) Impaired immune response (e.g., diabetes mellitus) Impaired nerve innervations or neurogenic bladder (e.g., spinal cord injuries) Urinary catheterization and instrumentation (provides a direct pathway to the urinary system; the most common source of nosocomial infections, particularly gram-negative septicemia) Improper personal hygiene (increases the number of microorganisms) Using a diaphragm or spermicide for birth control (increases bacterial growth) Using unlubricated condoms (increases irritation)

Clinical Manifestations For acute simple cystitis, clinical manifestations include urgency, dysuria, frequency, suprapubic pain, hematuria, bacteriuria, and cloudy, foul-smelling urine. Acute UTI symptoms when accompanied by fever (> 99.9° F/37.7° C), systemic manifestations (e.g., significant fatigue, chills, rigor), flank pain, and costovertebral angle tenderness more likely indicate pyelonephritis or an infection beyond the bladder (i.e., prostatitis). In men, the presence of pelvic or perineal pain is suggestive of a complicated UTI (i.e., prostatitis). In the elderly and frail, a UTI may present with nonspecific findings such as confusion or change in mental status, falls, or other functional impairments. Systemic infectious manifestations in the elderly tend to be subtle (e.g., less fever). Most instances of simple acute cystitis resolve without sequelae.

With pyelonephritis, the kidneys become grossly edematous, and structures fill with exudate and can compress the renal artery. Abscesses (e.g., corticomedullary, perinephric) and necrosis can develop, impairing renal function and causing permanent damage.

Diagnosis and Treatment A diagnosis of UTI can often be made by history and physical examination. A urinalysis can be done to confirm the diagnosis or is useful when manifestations are not classic or questionable. A urinalysis and urine culture and sensitivity should be done in men even with a simple case of cystitis. The urinalysis can be done with a urine dipstick or by microscopy. Urinalysis will reveal pyuria (white blood cells in the urine). Leukocyte esterase is an enzyme in the urine that is released by white blood cells; the presence of leukocyte esterase in the urine reflects pyuria and is consistent with the presence of a UTI. Nitrites in urine are reflective of infection with Enterobacteriaceae (e.g., E. coli). These organisms convert nitrate to nitrite. A positive nitrite test suggests significant bacteriuria. However, urine dipsticks can yield false-negative nitrite results when the urine has not been in the bladder long enough to allow the conversion of nitrate to nitrite. Some organisms do not cause nitrate conversion (e.g., Enterococcus faecalis). A low urine pH (e.g., such as with cranberry juice ingestion) may cause a false-negative nitrite reading. Despite a negative nitrite reading, treatment should be provided if the history is suggestive of a UTI. Substances that make the urine turn red, such as beets or the use of phenazopyridine (e.g., bladder analgesic), will cause a false-positive nitrite test. White blood cell casts indicate kidney inflammation and are present in acute pyelonephritis.

A UTI is usually treated by targeting the most common causative organism (e.g., E. coli). A urine culture and sensitivity test can further provide information regarding the organism and antibiotic susceptibility (i.e., sensitivity). A culture and sensitivity test should be done on those patients with complicated infection (e.g., pyelonephritis, urosepsis), atypical presentation, failure to respond to therapy, and recurrent symptoms. Blood cultures are necessary for those patients with urosepsis.

Asymptomatic bacteriuria is the term used when urine contains bacteria (i.e., ≥ 105 colony-forming units/mL, with or without pyuria and without symptoms of a UTI. The reasons for the lack of symptoms may be related to the pathogen (e.g., less virulent strains) or patient factors. Most cases of asymptomatic bacteriuria will not progress, so treatment is not necessary. Potential for an adverse drug event with antibiotics is considered riskier in comparison to the presence of benign bacteriuria. Treatment may also cause a higher chance of antibiotic resistance. In certain groups, however, treatment of asymptomatic bacteriuria is warranted, including pregnant women, those undergoing urologic intervention (e.g., prostate resection), and renal transplant patients.

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BOX 7-1 Application to Practice Review the following urinary infection cases and determine the most likely cause, including pathogen and mode of transmission. Discuss data that supports your decision and treatment strategies.

Case 1: A 50-year-old woman presented complaining of burning sensation when urinating and feeling like she has to go every hour for the last day. She denies fever and suprapubic or back pain.

Past medical history: dyslipidemia and hypertension. Medications: atorvastatin. Allergies: sulfa. Physical examination: temperature 98.5° F; pulse 80 beats per minute; respiration rate 18 breaths per min;

blood pressure 110/66 mmHg; examination unremarkable; no suprapubic or costovertebral angle tenderness; urine dipstick reveals moderate leukocytes and positive nitrites, with all other values within normal limits.

What is the most likely diagnosis and pathogen causing this disorder and mode of transmission? Discuss data that support your decision. What diagnostic test, if any, should be done? What diagnostic test findings would support your diagnosis? Develop a treatment plan for this patient.

Case 2: A 65-year-old woman with no urinary system complaints had a routine urinalysis with the results shown in the table.

What is the most likely diagnosis and pathogen causing this disorder and mode of transmission? Discuss data that support your decision. What diagnostic test, if any, should be done? Develop a treatment plan for this patient.

Case 3: A 45-year-old woman is complaining of urgency and dysuria for the past 2 days. Yesterday, she started getting chills, feels she is getting a fever, and her back hurts.

Past medical history: UTI 1 year ago. Medications: none. Allergies: no known drug allergy (NKDA). Physical examination: temperature 100° F, pulse 86; respiration rate 18 per min; blood pressure 110/70

mmHg; positive costovertebral angle and suprapubic tenderness, otherwise unremarkable; urine dipstick reveals positive leukocytes but negative for nitrites and blood.

What is the most likely diagnosis and pathogen causing this disorder and mode of transmission? Discuss data that support your decision. What diagnostic test, if any, should be done? What diagnostic test findings would support your diagnosis? Develop a treatment plan for this patient.

Urinalysis, complete Result Reference range

Color Dark yellow Yellow

Appearance Cloudy Clear

Specific gravity 1.022 1.001–1.035

pH ≤ 5.0 5.0–8.0

Glucose Negative Negative

A

Bilirubin Negative Negative

Ketones Negative Negative

Occult blood Negative Negative

Protein Negative Negative

Nitrite Negative Negative

Leukocyte esterase Moderate Negative

White blood cells 5–10 WBC/HPF ≤ 5 /HPF

Red blood cells 0–2 RBC/HPF ≤ 2 /HPF

Squamous epithelial cells 6–10 HPF ≤ 5 /HPF

Bacteria None seen None seen/HPF

Hyaline casts None seen None seen/HPF

HPF = high-power field.

Diagnostic Link

Urine Culture and Sensitivity urine culture can confirm the presence of bacteriuria and provide antibiotic susceptibility information. The optimal urine sample should be a clean-catch midstream specimen (i.e., discard initial urine). When

obtaining a specimen, females should spread the labia and uncircumcised males should retract their foreskin. A positive culture is defined as ≥ 105 colony-forming units/mL. However, lower bacterial counts with pyuria and symptoms of UTI may still be diagnostic for a UTI. A lower bacterial count with a UTI is more common in men (contamination is rare), with organisms other than E. coli, or with concurrent antibiotic therapy. Lower bacterial counts without pyuria may be indicative of contamination. Sensitivity reports will include information classifying the organism’s expected antibiotic effect into one of the three categories—susceptible, intermediate, or resistant.

Other diagnostic tests can evaluate for causes, particularly if a UTI is recurrent, relapsing, chronic, or complicated and include a cystoscopy, cystourethrogram, and imaging of the kidneys, ureters, and bladder (e.g., ultrasound, X-ray, CT, MRI). Not all complicated UTIs require imaging, particularly if there is a prompt response and improvement with antibiotic treatment. UTI treatment focuses on eradicating the microorganism with antibiotics. Length of antibiotic therapy can vary from 3 days for acute, simple cystitis to 14 days for pyelonephritis. Patients with pyelonephritis may need to be treated in a hospital if there are manifestations of critical illness (e.g., septicemia), an inability to remain hydrated, or an intolerance of oral medications. Additional strategies concentrate on prevention of UTIs:

Increasing hydration, especially consumption of water and juices (increases flushing of the urinary tract) Avoiding irritants (e.g., bubble bath and deodorants) Performing proper perineal hygiene (women should clean from front to back, and uncircumcised men should retract the foreskin to clean the penis) Wearing cotton underwear Wearing loose-fitting clothing Not delaying urination Adequately emptying the bladder, especially after intercourse Providing appropriate catheter care (when present) Probiotics (reestablish normal flora)

Urinary Tract Obstructions The urinary system is similar to the basic plumbing in any house. Blockages in any part of the plumbing system prevent the flow of the liquid, causing the system to back up. Many opportunities for blockages to occur exist throughout the urinary system, making urinary obstructions common (FIGURE 7-11). These blockages may stem from functional and/or anatomic abnormalities and be as simple as particulates collecting and forming stones to being as complex as the growth of tumors. Areas proximal to the obstruction are affected as pressure builds up and structures dilate (e.g., hydroureter, hydronephrosis). Urinary tract obstructions can cause urinary infections, and unless the obstruction is resolved, renal scarring and damage can occur. Obstructions can be acute or chronic as well as cause a complete or partial blockage. The blockage can be unilateral or bilateral (e.g., enlarged prostate).

FIGURE 7-11 Urinary tract obstruction and hydronephrosis. (a) Causes of urinary tract obstruction. Terms in italics are normal structures. (b) Hydronephrosis, marked dilation of renal pelvis and calyces with thinning of

parenchyma.

Nephrolithiasis Nephrolithiasis refers to the presence of renal calculi (kidney stones). Calculi are hard masses of crystals composed of minerals that the kidneys normally excrete (FIGURE 7-12). These stones, which can vary in size from as small as a grain of sand to as large as a golf ball, are the most common cause of urinary obstruction. Nephrolithiasis is more common in men and Whites. Adults are more commonly affected than children. Generally, the calculi form in the renal pelvis, ureters, and bladder. Urolithiasis is a general term used for a stone located or formed anywhere in the urinary system such as the bladder, while nephrolithiasis refers to those stones located or formed in the kidneys. The renal medullary interstitium is probably the site of most stone formation.

FIGURE 7-12 Renal calculi. © Eskimo71/Dreamstime.com.

Calculi may contain various combinations of chemicals (TABLE 7-3). The most frequently encountered type of calculi (about 80%) contains calcium in combination with either oxalate (80% of calcium stones) or phosphate (5% of calcium stones).

Other types of calculi include struvite or infection stones, uric acid stones, and cystine or xanthine stones. The calculi may be smooth or jagged, and they are usually yellow or brown.

TABLE 7-3 Types of Renal Calculi

Type Causes Treatment

Calcium Increased absorption of calcium from the small bowel Hyperparathyroidism Inability of renal tubules to reabsorb calcium Dietary excess of calcium Chronic bowel disease that results in steatorrhea; fat then combines with calcium and renders the calcium unable to bind to oxalate, causing stone formation Alkaline urine High urine calcium, high urine oxalate, or low urine citrate Low urine volume

Cellulose phosphate or thiazide diuretics to decrease dietary absorption of calcium Surgical resection of the parathyroid gland to reduce hyperparathyroidism Thiazide diuretic therapy to correct renal tubular defects, resulting in the inability to reabsorb calcium Purine dietary restrictions to reduce uric acid production Increased fluid intake and treatment of chronic diarrhea

Struvite (magnesium ammonium phosphate)

Urase-producing bacteria Urinary pH around 7.2 Usually large in size (e.g., staghorn calculi) Texture is relatively soft Associated with frequent UTI More common in women (due to increased UTI) UTI is a common cause in children

Prevention of UTI Percutaneous nephrolithotomy

Uric acid Excess uric acid excretion (e.g., gout) Urine pH lower than 5.5 encourages insoluble urate salt formation Rapid and dramatic weight loss Some malignancies

Dissolution of large calculi by increasing the urine pH above 6.5 with potassium citrate (the solubility of urate salt is then increased) Purine dietary restrictions to reduce uric acid production

Cystine or xanthine Genetic disorder causing abnormal excretion of cystine or xanthine (amino acids), ornithine lysine, and arginine

Prevention: increase fluid intake and increase urine pH above 7.5

Modified from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

In a healthy individual, urine contains chemicals that prevent crystals from forming. Once the minerals begin to precipitate, they grow like a snowball being rolled in the snow. Calcium crystals can form in the interstitium of the kidney and cause a small plaque (i.e., Randall plaque). Subsequently, crystal deposition occurs in this plaque with stone formation. Conditions that increase the likelihood of the crystals forming include urine pH changes (whether alkaline or acidic), excessive concentration (e.g., as with dehydration, bone disease, gout, renal disease, and

dietary increases) of insoluble salts in the urine in relation to volume, and urinary stasis (e.g., from immobility or anatomic abnormalities). Several inhibitors of stone formation act as natural protectors, such as citrate, magnesium, and pyrophosphate. Low levels of these inhibitors can increase risk for nephrolithiasis. Citrate is considered one of the key inhibitors and acts by forming a complex with calcium in the urine. A reduction in urine citrate (i.e., hypocitraturia) can be due to factors such as high animal protein diet or chronic metabolic acidosis. Additional risk factors for developing nephrolithiasis include family history, obesity, hypertension, and diet (high-protein, high-sodium, or low-calcium diet). A low calcium diet may contribute to stone formation. Usually calcium binds to oxalate and when there is insufficient calcium there is less binding. Therefore, the increased oxalate results increased tendency to stone formation.

Clinical Manifestations Calculi usually cause symptoms only when they obstruct urine flow. This obstruction can lead to hydronephrosis (enlargement of renal pelvis and calyces). The movement of calculi through the urinary system (i.e., renal pelvis to the ureter) can be quite painful and cause irritation of the urinary mucosa, increasing the risk for a UTI. Clinical manifestations of nephrolithiasis include the following signs and symptoms:

Colicky pain (pain that fluctuates in intensity, with periods of pain lasting 20–60 minutes; often severe, this pain is due to the calculi scraping the ureter wall, and it is colicky due to ureter spasms that occur in an attempt to move the calculi along; the pain is located in the flank area for upper ureteral or renal pelvic obstruction while pain with radiation to the lower abdomen and groin area (ipsilateral testicle or the labia) occurs with lower ureteral obstruction Hematuria, gross or microscopic (at least three RBCs per HPF; almost always present) Dysuria, frequency, and urgency with calculi in the distal ureter Nausea and vomiting Fever and chills (if an infection is present)

Some patients have asymptomatic nephrolithiasis, and stones are found incidentally when imaging is done for another purpose.

Diagnosis and Treatment Diagnosis of nephrolithiasis is accomplished with a history and physical examination along with a urinalysis. The urinalysis may reveal hematuria. The stone should be analyzed at least one time to determine the type and/or if treatments are not effective. A noncontrast, low-dose CT scan of the abdomen and pelvis (standard

contrast dose can be alternative) is the preferred diagnostic exam. The CT can detect stone size, location, and presence of hydronephrosis. The second option is an ultrasound of the kidneys and bladder (i.e., renal ultrasound) if CT technology is not available or if there is concern regarding radiation exposure (e.g., pregnancy). The ultrasound detects hydronephrosis but is less reliable in detecting stones and less accurate in stone measurement or location. Other procedures may include an abdominal X-ray, which detects stones but with less accuracy and does not detect hydronephrosis. An MRI is rarely used as stones are relatively invisible.

If hyperparathyroidism is suspected as a cause of stone formation, then a parathyroid hormone level should be evaluated. Serum studies can include calcium, uric acid, and phosphate levels.

The acute treatment of nephrolithiasis often includes pain management. Nonsteroidal anti-inflammatory agents (e.g., ketorolac) will help with pain reduction and decrease ureteral spasms. Opioids are another pharmacologic pain management option. Treatment of nephrolithiasis is specific to the type of calculi present (Table 7-3); therefore, determining the type of calculi is crucial to resolve the current calculi and prevent future calculus development. To determine the type of calculi, all urine is strained to capture any passed calculi. Small stones (< 5 mm) can pass through the urinary system, and the likelihood of spontaneous passage decreases as stones get larger (e.g., those stones > 4 mm). Stones ≥ 10 mm rarely pass. If there is underlying ureteral dilation, some larger stones may pass. Patients with uric acid stones may report passing gravel rather than a stone. Strategies to assist the passing of these calculi include engaging in physical activity (if possible) and increasing fluid intake to 2.5–3.5 L throughout the day to achieve a urine output of 2.5 L per day. The increased presence of fluid in the urinary system will expand the diameter of the ureters and urethra, easing the passage of the calculi. Two pharmacotherapeutic agents can be used as medical expulsive therapy—tamsulosin (alpha blocker) and nifedipine (calcium channel blocker)—particularly if the stone is within the 5–10-mm range. Larger calculi can be broken up to allow for passing of the smaller pieces. Procedures to disintegrate these calculi include extracorporeal shock wave lithotripsy (high-frequency sound waves are directed at the calculi to pulverize them), percutaneous nephrolithotomy (a laser is directed at a calculus with a fiber-optic scope), and ureteroscopy (a forceps is used to grab a calculus and remove it through a fiber-optic scope). Surgical removal of the calculi may be indicated in the following situations:

The calculi do not pass after a reasonable period of time and cause constant pain. A calculus is too large to pass on its own or is lodged in a difficult location. The calculi obstruct urinary flow. The calculi cause ongoing UTIs, renal damage, or constant bleeding.

R

The calculi have enlarged.

Treating the underlying cause (e.g., with antibiotics, antigout agents, or urine pH– modifying agents) of the calculi and pain management will also be necessary.

Recurrence is common with nephrolithiasis. However, the lapse between episodes can be years (e.g., 15% incidence 1 year after passage of the first stone and 50% incidence 10 years after passage of the first stone), so prevention strategies are essential. Dietary changes are the mainstay of prevention, with the changes implemented being specific to the type of calculi (Table 7-3). Additional prevention strategies include adequate fluid intake (2–2.5 L per day) and physical activity.

Diagnostic Link

Urinary Imaging enal ultrasound (US) is useful in evaluation of urinary tract obstruction and hydronephrosis. Kidney stones may be obscured by the bowel in the lower abdomen/pelvis; therefore, a pelvic ultrasound may

also be necessary. Due to its safety (no contrast media or invasiveness), renal US is commonly recommended and used for renal disorders of unknown cause. A renal US may identify renal masses (e.g., tumors or simple or complex cysts); however, CT is more sensitive. Doppler US can be used to evaluate renal flow and is indicated in disorders such as renal artery stenosis, renal vein thrombosis, and renal infarction. The renal US can be used to guide placement of needles or catheters. Abdominal and pelvis CT is the test of choice for nephrolithiasis (noncontrast low dose). The CT is more useful than renal US for location of obstruction and stone size. The CT with contrast is best for evaluation of masses and for identifying abscesses. The concern with a CT is the exposure to radiation. The intravenous pyelogram is infrequently used due to the need to administer intravenous contrast, high-radiation exposure, and other tests such as the US and CT that are safer and can provide the same information.

Hydronephrosis Hydronephrosis is an abnormal dilation of the renal pelvis and the calyces of one or both kidneys that occurs secondary to a disease (FIGURE 7-13). Diseases that obstruct urine flow are commonly associated with this condition, including nephrolithiasis, tumors, benign prostatic hyperplasia, strictures, and stenosis. Congenital urologic defects can also cause hydronephrosis, including reflux nephropathy, a congenital condition that causes backflow of urine into the kidneys. Unilateral renal involvement indicates an obstruction in one of the ureters, and bilateral renal involvement indicates an obstruction in the urethra.

FIGURE 7-13 Hydronephrosis. Courtesy of Leonard V. Crowley, MD, Century College.

Because urine is continuously forming, the presence and severity of clinical manifestations depend on the degree of urinary obstruction. Partial obstructions with mild hydronephrosis may not produce any initial symptoms. Complete obstruction with severe hydronephrosis, by comparison, applies direct pressure and compresses tissue and blood vessels, leading to atrophy, necrosis, and glomerular filtration cessation. When present, clinical manifestations include the following signs and symptoms:

Colicky flank pain or pressure Bloody, cloudy, or foul-smelling urine Dysuria Decreased urine output Frequency Urgency Nausea and vomiting Abdominal distention

UTIs

Diagnostic procedures for hydronephrosis include a history, physical examination, urinalysis, renal ultrasound, CT, intravenous pyelogram, and MRI. Prognosis depends on the severity of the hydronephrosis and early treatment. Treatment focuses on resolving the underlying cause, and facilitating urine flow will be necessary if UTIs develop. If the hydronephrosis is prolonged, permanent renal damage can occur to one or both kidneys.

Tumors and Cysts Bladder or renal masses can be cystic or solid (i.e., tumor). The masses can also be benign (adenomas, papillomas) or malignant (e.g., renal cell carcinoma). Cysts are the most common type of masses found on the kidneys. Most cysts are benign; however, most urinary tumors are malignant. These tumors can occur at any point along the urinary system. Regardless of their location, tumors can obstruct urine flow and impair renal function in addition to leading to the consequences of cancer (e.g., metastasis, pain, and weight loss).

Wilms Tumor Wilms tumor, or nephroblastoma, is a rare kidney cancer that primarily affects children. According to the National Cancer Institute (2016), 500 new cases of Wilms tumor are diagnosed each year. The peak incidence of Wilms tumor occurs around the age of 3–4 years (American Cancer Society, 2016). This tumor usually occurs in one kidney, but it can affect both (in 4–5% of cases). A second tumor may appear later in the remaining kidney. Wilms tumor usually grows as a solitary mass that can become quite large (FIGURE 7-14). In some cases (10%), there are multiple tumors in one kidney.

FIGURE 7-14 Wilms tumor. © University of Alabama at Birmingham Department of Pathology PEIR Digital Library (http://peir.net).

The exact cause of Wilms tumor is unknown, but it is thought to arise in utero when the cells that normally form the kidneys fail to develop properly. This development issue usually occurs due to spontaneous and sporadic genetic mutations. Notably, Wilms tumor has been associated with genetic mutations, such as tumor suppressor loss of function on chromosome 11 (e.g., WT1, WT2 genes), chromosome 17 (p53), as well as on the X chromosome. Despite awareness of various genetic mutations, the correlation and development of Wilms tumor is still unclear. Wilms tumors occur in conjunction with several congenital defects (about 10% of cases) and is termed WAGR syndrome. The defects include aniridia (absence of the iris of the eye), genitourinary anomalies (e.g., cryptorchidism and hypospadias), and intellectual disability. Disorders such as Denys-Drash syndrome includes hemihypertrophy, renal disease, and Wilms tumor. Wilms tumor is rarely familial, with only up to 2% of cases having a family history. The mode of transmission is autosomal dominant. The risk of developing this tumor also seems to be higher in females and Blacks. In contrast, Asian Americans have a lower risk of developing Wilms tumor than other ethnic groups.

Clinical Manifestations Because of improved diagnostic procedures, Wilms tumor can now be detected

early, leading to an improved prognosis for children affected by this disease. The long-term survival rate is excellent with early detection and treatment. Unfortunately, Wilms tumor may sometimes go undetected early because the tumor can grow quite large without causing pain; nevertheless, most of these tumors are diagnosed before they have metastasized.

Patients with Wilms tumor usually present with an abdominal mass or swelling with pain (up to 40%) or without pain. Accompanying manifestations include hematuria in up to 25% of cases with fever and hypertension in another 25% of cases. Other manifestations may be present if Wilms tumor is associated with other congenital syndromes, such as in Denys-Drash syndrome (e.g., hemihypertrophy) or WAGR syndrome (e.g., genitourinary anomalies). On physical examination, the abdominal mass is usually firm and nontender, and it does not usually cross the midline.

Diagnosis and Treatment Diagnostic procedures for Wilms tumor include a history and physical examination, as well as an abdominal ultrasound as the usual first diagnostic test. The renal tumor will then be further evaluated with doppler ultrasound and abdominal CT with contrast or abdominal MRI. A biopsy is necessary for histologic confirmation. Evaluation of the chest (e.g., chest CT and X-ray) will be conducted to evaluate for metastasis. Laboratory analysis will include a BUN, creatinine, creatinine clearance, complete blood count, liver function tests, serum calcium, coagulation studies, and urinalysis. Once diagnosed, two staging systems guide treatment. One staging system, used prior to chemotherapy, is the National Wilms Tumor Study (NWTS) system. The NWTS system includes the following stages:

Stage I: The cancer is in only one kidney and generally can be completely removed with surgery. Stage II: The cancer has metastasized to the tissues and structures near the kidney, but it can still be completely removed by surgery. Stage III: The cancer has metastasized beyond the kidney area to nearby lymph nodes or other structures within the abdomen and may not be completely removed by surgery. Stage IV: The cancer has metastasized to distant structures, such as the lungs, liver, or brain. Stage V: Cancer cells are found in both kidneys.

The standard treatment for Wilms tumor is surgery (e.g., simple, partial, or radical nephrectomy) and chemotherapy, but radiation therapy may be used if warranted by tumor histology. The 5-year survival rate can be as high as 90% with the administration of multiple treatments. Recurrence is dependent of the type of tumor

histology, and rates can be as low as 15% and as high as 50%. Coping strategies and support interventions (e.g., allowing play time and local support groups) will be beneficial for the family and child. Additionally, once the patient is diagnosed, subsequent palpation of the abdomen should be avoided because the renal capsule may rupture, and the cancer may spread.

Renal Cysts Cystic masses, particularly simple cysts, are found in normal kidneys and increased incidence occurs with aging. Simple renal cysts, which are considered benign, are the most common type of masses found in the kidneys. Cysts on kidneys are often found incidentally on imaging (e.g., ultrasound, CT) done for other purposes. Most cysts cause no symptoms, result in no sequalae, and require no treatment. However, some cysts are complex and associated with the risk of malignancy. If a cyst is detected on ultrasound, then a CT scan is generally indicated. The radiologic system known as the Bosniak classification uses contrast CT scan findings to evaluate cysts and categorize them from I to IV based on the cyst appearance. The Bosniak classification is useful in determining the diagnosis, treatment, and follow-up for renal cysts (TABLE 7-4).

TABLE 7-4 Bosniak Classification for Renal Cysts

Bosniak classification Description Treatment/malignancy potential

Type I Benign simple cyst— imperceptible cell wall, round

Further evaluation and treatment not necessary; repeat US (e.g., 6–12 months) may be done to confirm stability Malignancy potential: < 1%

Type II Minimally complex, benign cysts that are well marginated and with a few thin septa, thin calcifications, and nonenhancement

Further evaluation and treatment not necessary; repeat US (e.g., 6–12 months) may be done to confirm stability Malignancy potential: < 1%

Type IIF Minimally complex cysts that have suspicious features in comparison to II such as thicker calcification, multiple septa, and perceived enhancement

Further evaluation with CT or MRI with contrast (preferred) Malignancy potential 5%

Type III Indeterminate are thick, nodular septa and show enhancement

Further evaluation and treatment include fine-needle biopsy, partial nephrectomy, and radiofrequency ablation Malignancy potential 55%

Type IV Malignant cysts that are solid mass with necrosis

Further evaluation and treatment include partial or total nephrectomy Malignancy potential 85–100%

In additional to the incidental finding of renal cysts, there are several diseases associated with the development of cysts such as polycystic kidney disease, as well as medullary and cortical kidney diseases. Cysts can form as a consequence of chronic kidney disease. A few of these disorders will be discussed elsewhere.

Renal Cell Carcinoma Renal cell carcinoma is the most frequently occurring kidney cancer in adults (most common in those 50–70 years of age). The National Cancer Institute (2018b) estimated that nearly 65,340 new cases of renal cancer would be diagnosed in 2018, with more than 14,000 deaths attributed to this cancer. Most cases (approximately 85%) of renal cell carcinoma are primary tumors arising from the renal cortex (FIGURE 7-15). The remaining renal cell carcinomas (approximately 8%) arise from the renal pelvis (i.e., transitional or urothelial cell carcinoma). Other tumors, such as renal sarcoma and renal medullary carcinoma, occur infrequently. Its exact cause is unknown. Risk factors for developing this type of cancer include being male, obesity, advanced kidney disease particularly those requiring dialysis treatment, family history, hypertension, other kidney disease (e.g., horseshoe kidney and polycystic kidney disease), toxin exposure (e.g., asbestos), prolonged analgesic use (e.g., aspirin, acetaminophen), chronic hepatitis C infection, kidney stones, and smoking. Metastasis to the liver, lungs, bone, or nervous system is common at the time of diagnosis.

FIGURE 7-15 Renal cell carcinoma. Courtesy of Dr. Edwin P. Ewing, Jr./CDC.

Clinical Manifestations Renal cell carcinoma (i.e., renal adenocarcinoma) is typically asymptomatic in its early stages. When present, the most common clinical manifestations include the following signs and symptoms: hematuria, an abdominal renal mass that is firm, abdominal flank pain described as dull and achy, and unexplained weight loss. Other symptoms may include scrotal varicoceles. If the inferior vena cava is affected, then manifestations can include edema, ascites, and hepatic problems. Patients can present with manifestations of metastasis. Patients can develop paraneoplastic syndromes, such as anemia with erythropoietin suppression or polycythemia with tumors that secrete erythropoietin or erythropoietin-like substances. Fever is usually intermittent with night sweats and fatigue. Hypertension may occur due to high renin levels. Hypercalcemia (due to ectopic parathyroid hormone production by the tumor or bone metastasis) or Cushing syndrome (increased adrenocorticotropic hormone) are other paraneoplastic syndromes.

Diagnosis and Treatment Diagnosis is often made incidentally, but unexplained hematuria should be evaluated for possible renal cell carcinoma. Renal cell carcinoma should be considered with

the presence of clinical manifestations. Initial imaging evaluation is usually with an abdominal CT; however, an abdominal ultrasound can be used. Further diagnostic procedures will include a biopsy, and the abdominal CT can be used for staging. Other diagnostic procedures are to determine whether metastasis has occurred and can include a bone scan, MRI, positron emission tomography scan, and chest CT. Laboratory analysis will include a liver function panel, complete blood count, and blood chemistry. The tumor, node, metastasis staging system is used for staging renal cell carcinoma.

Interestingly, renal cell carcinoma is one of the few tumors where the tumor can regress spontaneously in the absence of therapy, but this is very rare and may not lead to long-term survival (National Cancer Institute, 2018b). Partial or complete surgical nephrectomy is recommended because the cancer is generally unresponsive to radiation or chemotherapy, although some newer chemotherapy agents (e.g., multikinase inhibitors) have shown promise in this indication. Surgery is considered curative if there is no metastasis. Hormone therapy and immunotherapy may have modest effects in shrinking the tumor. Prognosis is better when the condition is diagnosed prior to metastasis of the cancer.

Bladder Cancer Bladder cancer refers to any cancer that forms in the tissue of the bladder. Most bladder cancers (90%) are urothelial (transitional)) cell carcinomas (cancer beginning in the cells that make up the inner bladder lining). The urothelial cells also line the ureters, urethra, and renal pelvis, but the cancerous cells usually arise from the bladder. Urothelial bladder cancer is most commonly caused by chemical carcinogenesis, particularly smoking. Other less common types of bladder cancer are termed nonurothelial and include squamous cell carcinoma (cancer beginning in thin, flat cells), adenocarcinoma (cancer beginning in the cells that make and release mucus and other fluids), and small cell tumors. The cells that form squamous cell carcinoma and adenocarcinoma develop in the inner lining of the bladder because of chronic irritation and inflammation usually from infection. This type of cancer usually evolves as multiple invasive tumors that extend through the bladder wall and surrounding structures. Metastasis to the pelvic lymph nodes, liver, and bone is common. Benign tumors can arise in the bladder (e.g., urothelial papilloma, inverted papilloma) and usually have a low rate of recurrence and progression.

The National Cancer Institute (2018a) estimated that nearly 81,190 new cases of bladder cancer would be diagnosed in 2018, with more than 17,000 deaths being attributed to this cancer. Although bladder cancer most frequently occurs in older adults, it can occur at any age, and it is more common in men and Whites. The median age at diagnosis is 69–71 years. Smoking is the most common risk factor and is associated with almost half of all bladder cancers. Other persons at increased

risk include those who work with chemicals (e.g., dye, rubber, hairdressing chemicals, and aluminum), have excessive use of analgesics, experience recurrent UTIs, have long-term catheter placement, family history, and received chemotherapy or radiation. Genetic mutations of the RAS and tumor suppressor genes are associated with bladder cancer. See chapter 1 for more about cellular function.

Clinical Manifestations The initial clinical manifestation of bladder cancer is painless hematuria that is gross (i.e., visible) or microscopic. The hematuria is intermittent and occurs throughout all of micturition as opposed to just the beginning. Irritative symptoms such as frequency, urgency, and dysuria may be present and occur due to detrusor overactivity, obstruction, or decrease in bladder capacity. Flank or abdominal pain (e.g., suprapubic) are usually signs of more advanced cancer. Other general symptoms such as fatigue, weight loss, or anorexia are also manifestations of more advanced disease. Physical examination findings may reveal the presence of a pelvic or abdominal mass (if advanced) and prostate induration.

Diagnosis and Treatment As with renal cell carcinoma, unexplained hematuria (e.g., not from renal calculi or UTI) needs an evaluation for possible bladder cancer particularly in individuals over the age of 40. A urine evaluation can be conducted with a dipstick and microscopy, which will confirm the presence of blood. Urine dipsticks can sometimes be positive for blood even when there are no red blood cells (RBCs) upon microscopy. This finding may be caused by myoglobin (muscle injury) rather than hemoglobin. Clinically significant hematuria consists of more than three RBCs/HPF on microscopic examination. The morphology of RBCs in bladder cancer is usually normal, and the presence of abnormal shapes or RBC casts usually indicates intrinsic (intrarenal) renal disease. A cystoscopy is the diagnostic test of choice for diagnosing and staging bladder cancer. A urinalysis, urine cytology, and urine-based markers that identify tumor-related proteins can supplement cystoscopy findings. After cystoscopy, staging is also done with a transurethral resection of bladder tumor that is performed under anesthesia. The resected tumor histology and depth of invasion are then determined. Stage I lesions are confined to the submucosa; stage II includes invasion into the muscle; stage III is beyond the muscle and into the fat, possibly beyond the bladder; and stage IV lesions have metastasized. A CT scan with and without contrast of the abdomen and pelvis or an MRI are diagnostic procedures that can further evaluate metastatic disease. Other procedures to evaluate for metastasis can include a chest X-ray, chest CT scan, bone scan, and positron emission tomography scan. Even with early diagnosis and treatment, bladder cancer often reoccurs. Treatment strategies are based on staging and include surgical removal of the tumor, generally for nonmuscle invasive bladder

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cancer. Intravesical chemotherapy is infused during the resection and administered for maintenance therapy. Patients with stage II disease generally require a cystectomy, and those with muscle-invasive disease (stage III and above) will have a radical cystectomy which includes removal of adjacent organs and lymph nodes. A patient with a cystectomy will need to undergo a urinary diversion procedure. The diversion procedure may include the creation of an ileal conduit (in which urine flows from the ureter through the ileum and then a skin stoma) or creation of an orthoptic neobladder where a piece of intestine is created into a new bladder. The new bladder is attached to the ureters and urethra allowing for a normal urine flow pattern. Other therapies can include radiation and immunologic agents.

Diagnostic Link

Cystoscopy and Ureteroscopy cystoscopy is a common diagnostic test used for evaluating the lower urinary tract. The procedure can be done in an office. A flexible or rigid scope is inserted in the urethra after application of local anesthesia.

Either water or saline is infused into the bladder for better visualization. A ureteroscopy can also be performed through insertion of a flexible or rigid scope to view the ureters and kidneys. Renal calculi can be removed during ureteroscopy, and ureter stents can be placed.

Diagnostic Link

Hematuria ematuria is the presence of urine in the blood. Gross hematuria is visible to the naked eye, and the urine may be brown or red. As little as 1 mL of blood per 1 L of urine can cause a change in color. Hematuria

with clots is more likely with a lower urinary tract disorder. Hematuria may only be detected microscopically with a urinalysis or a urine dipstick. Urine dipsticks can detect 1–2 RBCs per HPF. Myoglobin (e.g., seen with rhabdomyolysis) and hemoglobin (e.g., with hemolytic disorders) will cause a false positive on the urine dipstick, and there will be few to no RBCs. Additionally, menstrual blood may contaminate a urine specimen (i.e., dipstick or urinalysis). Drugs such as phenazopyridine (a urinary analgesic) or phenytoin can cause a false urine blood result. When a urinalysis report is positive for blood, the next step is evaluation of the number of RBCs present. Abnormal hematuria is defined as the presence of three or more RBCs per HPF. The presence abnormal RBC morphology or red blood cell casts is generally indicative of an upper urinary tract disorder (i.e., kidney) as opposed to the bladder.

BOX 7-2 Application to Practice Review the following case and urinalysis report.

A 46-year-old woman is asymptomatic and has a routine urinalysis as part of her annual physical. The urinalysis with microscopy report is shown in the table.

Describe the urinalysis findings and determine possible reasons for the findings and follow-up, if necessary.

Urinalysis, complete Result Reference range

Color Dark yellow Yellow

Appearance Cloudy Clear

Specific gravity 1.022 1.001–1.035

pH ≤ 5.0 5.0–8.0

Glucose Negative Negative

Bilirubin Negative Negative

Ketones Negative Negative

Occult blood 1+ Negative

Protein Negative Negative

Nitrite Negative Negative

Leukocyte esterase Negative Negative

White blood cells None seen ≤ 5 /HPF

Red blood cells 0–2 ≤ 2 /HPF

Squamous epithelial cells 6–10 ≤ 5 /HPF

Bacteria None seen None seen/HPF

Hyaline casts 0–5 None seen/HPF

HPF = high-power field.

Benign Prostatic Hyperplasia Although the prostate is a structure of the male reproductive system, diseases of the prostate can cause significant issues in the lower urinary system because of its close proximity to those structures (FIGURE 7-16). Benign prostatic hyperplasia (BPH), also called benign prostatic hypertrophy, is a common, nonmalignant enlargement of the prostate gland that occurs as men age, usually appearing by age 50. Its exact cause is unknown, but multiple factors that cause prostatic stromal cell proliferation are implicated. This increase in proliferation enlarges the prostate gland. Hormones such as testosterone, dihydrotestosterone (DHT), and estrogen seem to be involved

in BPH development, but their contribution is not clear. Testosterone levels decrease with aging; however, DHT (the active form of testosterone) remains at a relatively normal amount in the stromal tissue of the prostate. DHT, which is reduced by the enzyme 5α-reductase from testosterone, is one of the hormones necessary for normal prostatic growth. Inhibitors of 5α-reductase are used to treat BPH. With aging, there is an increased ratio of estrogen to androgen. Estrogen may contribute to BPH development by making the prostate tissue susceptible to hypertrophy. A second theory postulates that stem cells in the prostate do not mature and die as they are programmed to do (apoptosis). The resulting imbalance between dying cells and reproducing cells enlarges the prostate over time. As the prostate expands, it presses against the urethra like a clamp on a hose. Clamping the urethra obstructs urine flow, leading to urinary stasis and UTIs. The bladder wall becomes thick and irritated as urine overfills this organ. The bladder begins to contract with even small amounts of urine, and, over time, it loses its ability to empty completely.

FIGURE 7-16 Urethra and prostate gland.

Clinical Manifestations Lower urinary tract symptoms (LUTS) are the clinical manifestations of BPH. By age 50, approximately half of men with BPH will have symptoms, and by age 80, the incidence of LUTS increases to 80% of men with BPH. Manifestations are usually

slow and insidious. The size of the prostate is not correlated with the presence and severity of symptoms. LUTS can be divided into storage symptoms and voiding symptoms.

Storage symptoms are also known as irritative symptoms and include daytime frequency, nocturia, urgency, and incontinence. Voiding symptoms are also known as obstructive symptoms and include changes in urine stream such as slowing or spraying of stream. The stream can be intermittent, and there may be hesitance, straining to void, and dribbling at the end of the void. Complications are more common in untreated men and can include urinary retention, overflow incontinence, recurrent UTIs, and kidney failure.

Some men have BPH and remain asymptomatic. BPH does not increase prostate cancer risk, but the clinical presentation is similar to that of prostate cancer. When manifestations of prostate cancer appear, the disease is usually advanced. Physical examination findings consistent with BPH include a large (> 17 grams or bigger than a walnut; normal is 7-16 grams), palpable prostate that is smooth, symmetrical, and rubbery. Asymmetry or nodules are consistent with prostate cancer while an exquisitely tender prostate is associated with prostatitis. See chapter 8 for discussion of reproductive function.

Diagnosis and Treatment Diagnosis of BPH is accomplished with a history, physical examination, and measurement of the prostate-specific antigen (PSA). Other diagnostic tests are conducted to evaluate for other possible causes of LUTS. Urinalysis and renal function exams (e.g., BUN, creatinine) are usually normal with BPH. While hematuria may occur with BPH, evaluation for other causes should be conducted as hematuria is also associated with urinary tract cancers. Other diagnostic procedures for BPH diagnosis are usually not necessary unless there is concern or risk for other urinary disorders such as cancer, urinary retention, or kidney disease. In men with moderate to severe LUTS and diagnosed BPH, other diagnostic procedures can include uroflowmetry, postvoid residual measurements, cystoscopy, and rectal ultrasound.

Treatment centers on relieving the urinary obstruction. Pharmacologic strategies to improve urine flow include alpha-1 blockers and 5α-reductase inhibitors. Alpha-1– adrenergic blocking agents cause relaxation of bladder neck and urethra, leading to decreased resistance while 5α-reductase inhibitors shrink or limit growth of the prostate. Anticholinergics can be used for men with irritative symptoms. Phosphodiesterase type 5 inhibitors can be used for men with BPH (relaxes smooth muscle in bladder neck, urethra, and prostate) and erectile dysfunction (relaxes smooth muscle in penis, improving blood flow). Herbal remedies (e.g., saw palmetto) have also been used, although only limited evidence supports their effectiveness. Behavioral modifications include limitation of fluids around bedtime, reducing diuretic

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type drinks (e.g., caffeine, alcohol), and making sure the bladder empties completely (i.e., double voiding). Men with BPH who sit to urinate have a reduction in LUTS as the pelvic and hip muscles are more relaxed, allowing for faster and stronger force of urination and better bladder emptying. Other strategies to improve BPH symptoms include minimally invasive procedures such as laser therapy, transurethral needle ablation, transurethral electrovaporization of the prostate, hyperthermia, high-density forced ultrasound, intraurethral stents, and transurethral balloon dilation. Partial or complete surgical removal of the prostate gland may be necessary. Additionally, use of alcohol should be avoided because it can make symptoms worse.

Diagnostic Link

Prostate-Specific Antigen SA is a glycoprotein found in all prostatic epithelial cells. An increase may be indicative of prostatic enlargement; thus, this test is used to screen for prostatic cancer as well as an indicator of the extent of

prostate cancer and treatment success or failure. Since prostate size can normally increase with aging, reference ranges vary by age. Prostatitis will cause an increased PSA. Digital rectal examination can cause a minor clinically insignificant elevation. 5α-reductase inhibitors shrink the prostate size and may cause a 50% or greater decrease in serum PSA, so the PSA needs to be evaluated within this context.

Conditions Resulting in Impaired Renal Function Kidney disorders and injury, specifically the nephron (i.e., glomerulus, tubules, and arteriole), will lead to alteration in the formation of urine. While other structures are considered as part of the kidneys (e.g., renal calyx and pelvis), usually disorders that stem from this area (e.g., nephrolithiasis and pyelonephritis) result in problems of elimination. Problems of elimination, whether or not from the lower tract (i.e., bladder or prostate), can result from kidney insult and subsequent impairment in urine formation. Glomerular disorders are a common cause of kidney failure.

Polycystic Kidney Disease Polycystic kidney disease (PKD) is an inherited disorder characterized by numerous, grapelike clusters of fluid-filled cysts in both kidneys (FIGURE 7-17). These cysts enlarge the kidneys while compressing and eventually replacing the functional kidney tissue. The exact trigger for the formation of the cysts is unknown, but genetic defects result in abnormal tubular epithelium.

FIGURE 7-17 Polycystic kidney disease.

Courtesy of Dr. Edwin P. Ewing, Jr./CDC.

BOX 7-3 Application to Practice Hematuria is common and can be due to benign conditions (e.g., strenuous exercise) or serious disorders (e.g., renal cell carcinoma).

Review the following cases and determine the most likely cause of the hematuria. Discuss data that support your decision as well as diagnostic and treatment strategies.

Case 1: A 50-year-old White man is complaining of left-sided flank pain that started about 3 hours ago. He describes the pain as sharp and intermittent. He notes that his urine is a bit darker, but he denies seeing blood. The pain started after he finished mowing a client’s lawn (he is a gardener). He denies dysuria, urgency, or fever.

Past medical history: gout. Medications: allopurinol 100 mg orally every day. Allergies: no known drug allergies (NKDA). Social history: denies smoking, alcohol use, or drug misuse. Physical examination: temperature 98.5° F, pulse 96 beats/minute, respiration rate 20 per min, blood

pressure 138/88 mmHg. General: anxious, holding left side, and moving around; otherwise exam is unremarkable. Urinalysis: positive for blood with 15 RBCs per HPF; remainder unremarkable.

Case 2: An 8-year-old Black girl is complaining of burning when urinating for the past day. She reports wetting herself at school because she was unable to hold it until she was able to get to the bathroom. When she toileted, she voided only small amounts. She denies fever, back, or suprapubic pain. The child is accompanied by her mother.

No past medical history or medications. Allergies: penicillin (hives). Vaccines: up to date. Physical examination: vital signs and exam are within normal limits. Urine dipstick: positive for leukocytes, nitrites, and blood

Case 3: A 68-year-old White man is concerned because he thinks he is peeing blood. He noticed it about 1 month ago, and he thought it was related to sex as he noticed it right after intercourse. However, he has had two other episodes within the past two weeks not related to sexual intercourse. He denies fever, dysuria, frequency, abdominal, back, or pelvic pain. He states he used to have a weak stream and have to urinate at night, but these symptoms have improved since starting finasteride (5α-reductase inhibitor).

Past medical history: BPH. Medications: finasteride. Allergies: no known drug allergy (NKDA). Social history: has smoked 1 pack of cigarettes per day for the past 40 years; drinks two to three beers on

the weekends. Physical examination: body mass index 32; vital signs and exam are within normal limits. Urinalysis with microscopic evaluation: positive for blood with 40 RBCs/HPF; no casts or dysmorphic cells

noted.

Prognosis and progression of the disease vary widely, depending on the type of PKD. Autosomal dominant PKD is the most common type; it has been mapped to mutations on the short arm of chromosomes 4 (for PKD2) and 16 (for PKD1). Both

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these genes encode for polycystin-1 and polycystin-2, and these proteins are involved in cellular growth, differentiation, and calcium signaling in the kidneys. This form of PKD occurs in both children and adults, but it is much more common in adults, with symptoms often emerging in middle age. Autosomal recessive PKD, like most recessive conditions, is far less common. This type can be detected prenatally or soon after birth, but it can appear in infancy or childhood. The recessive PKD occurs due to mutations on PKHD1 gene which causes decreased or absent fibrocystin. This protein’s role is not clear; however, fibrocystin seems to be involved in kidney development. Recessive PKD tends to be extremely serious and progresses rapidly, resulting in renal failure and generally causing death in infancy or childhood. PKD affects males and females equally regardless of age.

Learning Points

The Urinary System he urinary system is a basic human septic system. The kidneys remove waste and unneeded substances from the blood to have them excreted. The kidneys collect these products in the form of urine much like a

toilet, and flushing the toilet is much like what the kidneys do in sending the urine to the bladder. The bladder acts like a septic tank, holding the waste until the tank is full. When full, the bladder (and the septic tank) must be emptied.

When obstructions occur at any point in the urinary system, urine backs up, much like the septic system would do if it were obstructed. This backflow can cause severe damage in both cases: in the urinary system, the kidneys become damaged by the irritation and pressure of the excess urine; in the septic system, the house becomes damaged from the corrosive septic contents.

Clinical Manifestations Clinical manifestations depend on the individual’s age and the type of PKD. These manifestations reflect the structural changes associated with the disease and the resulting renal impairment. In neonates, manifestations include the following signs and symptoms:

Potter facies, which are pronounced epicanthic folds (skin folds at the corner of the eyes on either side of the nose), pointed nose, small chin, and floppy, low-set ears Large, bilateral, symmetrical masses on the flanks Respiratory distress (caused by fluid accumulation from renal impairment) Hyponatremia (due to dilution from fluid accumulation)

In adults, manifestations include the following signs and symptoms:

Lumbar or flank pain Increased abdominal girth Swollen, tender abdomen

Grossly enlarged, palpable kidneys

Some other symptoms may affect both groups:

Hypertension (due to activation of the renin–angiotensin–aldosterone system) Hematuria (due to impaired glomerular filtration) Nocturia (related to an inability to concentrate urine) Uremia (waste accumulation due to renal impairment) with symptoms such as drowsiness

Other conditions that may occur in conjunction with PKD include brain aneurysms, cysts in other organs (especially the liver), and colon diverticula. Because of the renal impairment associated with this condition, PKD can lead to critical complications such as renal insufficiency, pyelonephritis, cyst rupture, retroperitoneal bleeding, and chronic kidney disease. Other, less serious complications include anemia, hypertension, and renal calculi (kidney stones).

Diagnosis and Treatment Diagnosis of PKD consists of a history, physical examination, and imaging of the kidneys, usually with a renal ultrasound. Other imaging modalities can include a CT or MRI. Genetic testing confirms the diagnosis. Screening of patients with a family history usually involves renal ultrasound and genetic testing. Genetic testing for screening purposes in asymptomatic individuals with a positive family history should be completed by clinicians experienced in providing counseling. Information pertaining to the benefits and consequences of testing should be discussed, such as family planning and awareness of symptoms.

PKD often progresses slowly, leading to end-stage renal disease. The following treatment strategies focus on controlling symptoms and preventing complications:

Pharmacology, including the following agents: Antibiotics (when infections are present) Analgesics (for pain) Antihypertensive agents for stringent blood pressure control Diuretics Statins for cardiovascular risk reduction

Adequate hydration Low-salt and low-protein diet Surgically draining cystic abscesses or retroperitoneal bleeding Dialysis Kidney transplant

Glomerular Disorders Within the kidney are millions of filtering units composed of tufts of capillaries in between the afferent and efferent arterioles. The glomerulus sits inside the Bowman capsule (Figure 7-2). An in-depth look at the glomerulus is necessary as disorders are categorized or described based on the glomerular structure (e.g., membranous glomerulonephritis) (FIGURE 7-18). There are three layers of the glomerulus. The inner layer is the endothelial lining that is fenestrated. The middle layer is the glomerular basement membrane. The basement membrane acts as a barrier to large molecules. Surrounding these two layers are the outer layer of parietal epithelial cells that transition to the tubular structures or podocytes. The podocytes are footlike structures that connect the outer layer to the basement membrane and cover the capillaries. The podocytes are another important barrier in the filtration of large molecules. The inside of the glomerulus is surrounded and supported by an interglomerular matrix, mesangium, which consists of mesangial cells.

FIGURE 7-18 A schematic representation of fine structure of glomerular filter as visualized by electron

microscopy. A Segment of glomerular capillaries. B Cross-section through the center of the glomerulus, including part of the Bowman capsule.

Several possible injuries can occur to the various microcomponents of the glomerulus and cause various types of disease. These disorders are grouped into clinical syndromes. Additionally, glomerular disorders are termed based on the cellular (i.e., histologic) changes, the affected glomerular layer in the capillary membrane or supporting structure, the location and extent of the glomerular lesions, and underlying dysfunction. The following terminology is used to describe glomerular injury:

Diffuse and focal: Lesions that involve all or most (> 50%) of the glomeruli (plural)are termed diffuse, and lesions that involve some (< 50%) of the glomeruli are termed focal (e.g., focal segmental glomerulonephritis).

Global and segmental: When a whole glomerulus (singular) is affected, the lesion is termed global, and the lesion is considered segmental if only a portion (< 50%) of the glomerulus is affected.

Proliferative, sclerosing, and necrotizing: These terms are structural (histologic) descriptors. Proliferative refers to an increase in glomerular cells (e.g., mesangial, endothelial, basement membrane). Proliferation in the extracapillary space forms specific lesions that are termed crescents, which are made of macrophages, fibroblasts, and other cells. These crescent cells accumulate in the Bowman space and represent a rupture of the capsule. Sclerosing refers to glomerular scar formation, and when the scarring is between the glomerulus and tubules, it is referred to as interstitial fibrosis. Necrotizing refers to cellular death.

Multiple causes and mechanisms of glomerular disorders can lead to dysfunction. The pathogenesis of glomerular injury can include immunologic and nonimmunologic mechanisms (e.g., hypertension, diabetes) and most often a combination of both. Hereditary diseases are due to many different types of genetic mutations. The inciting cause of glomerular disorders can include infections (e.g., streptococcus), toxin exposure (e.g., drugs, chemicals), autoimmune diseases (e.g., systemic lupus erythematosus), and vascular disorders (e.g., hypertension). The cause of glomerular disorders can also be idiopathic. Glomerular disorders manifest as a variety of clinical syndromes and includes asymptomatic hematuria and/or proteinuria, nephritic, and nephrotic syndromes. The two broad categories of glomerular disease are glomerulonephritis and glomerulosclerosis.

Glomerulonephritis Glomerulonephritis is an inflammatory disorder of the glomeruli, and most forms occur as a result of activation of immune mechanisms (FIGURE 7-19). The triggering antigens can be endogenous, such as in systemic lupus erythematosus, or

exogenous, such as in infections from streptococci or hepatitis C. The trigger, however, is often unknown. Glomerulonephritis may occur when there is a genetic predisposition to develop an immune response to triggering antigens.

FIGURE 7-19 Immune mechanisms of glomerular injury.

Glomerulonephritis involves a humoral and cellular mediated immune response. The humoral response is a key mechanism of injury as many glomerular disorders (up to 90%) involve the development of immune complexes that are composed of immunoglobulins and complement components. The antigens can be nonrenal, such as in the DNA nucleosome complexes in lupus, or abnormal IgA, as in IgA nephropathy. These antigens can be passively trapped, can bind to receptors on mesangial cells, or can be planted in the glomerulus and then bound to antibodies. In any situation, the depositions of these complexes activate the complement system and stimulate an immunologic response with release of multiple substances (e.g., cytokines and nitrous oxide). The result is capillary wall injury with increased permeability. The basement membrane, which acts as a charge-selective contact, loses its negative charge. Large proteins, such as albumin and red blood cells, are able to pass through into the filtrate and manifest as hematuria and proteinuria. Platelets and T cells play a role in the development of glomerular disease even in the absence of antibodies being deposited (e.g., as in focal segmental glomerulosclerosis). Platelets aggregate and lead to thrombosis and release of vasoactive substances that cause vasodilation and contribute to worsening capillary permeability. The cellular mediated T cell response results in macrophages and lymphocyte release, which each contribute to proliferation into the extracapillary space and crescent formation. The damaged glomerular cells and macrophage proliferation lead to obstruction to blood flow, which reduces glomerular blood flow and, in turn, GFR. Sclerosis and fibrosis continue, and ultimately, renal failure develops.

Antigens are usually nonrenal in origin; however, some antigens can be a normal (or intrinsic) part of the glomerular basement membrane. In anti–glomerular basement membrane (anti-GBM) glomerulonephritis, usually immunoglobulin G (IgG) and, at times, IgA or IgD target type IV collagen in the membrane. This type of immune response (type II hypersensitivity) often results in rapid and progressive renal failure. The anti-GBM antibodies also react with pulmonary alveolar basement membrane and cause pulmonary hemorrhage. Anti-GBM is often referred to as Goodpasture disease or Goodpasture syndrome, and the terms are sometimes used synonymously. Anti-GBM is rare but aggressive. Causes are generally unknown but may be due to infection (e.g., influenza), toxin, or drug exposure. Treatment centers on removal of antibodies through plasmapheresis and inhibiting antibody production (e.g., with corticosteroids).

Glomerulonephritis is associated with two clinical syndromes—nephritic syndrome and nephrotic syndrome. Nephritic syndrome is associated with an immune response that is inflammatory. Nephrotic syndrome is associated with an immune response that is noninflammatory. The location of the injury in the

glomerulus can be a determinant of whether the patient will have a nephritic or nephrotic clinical presentation. These two clinical syndromes can both be present in some disorders and some disorders progress from one to another.

Nephritic Syndrome A key feature of nephritic syndrome is the passage of leukocytes, red blood cells, and plasma proteins which occur as a result of inflammation. Glomerular disorders that affect endothelial and mesangial cells (Figure 7-18) are exposed to all the factors activated during the immune response such as neutrophils, macrophages, and complement proteins. The result is glomerular inflammation, cellular proliferation, and capillary damage with red blood cells and white blood cells escaping into the urine (i.e., hematuria and leukocyturia). Proteins, usually albumin, will also be present in the urine but in much smaller amounts than in nephrotic syndrome. Glomerulonephritis with nephritic syndrome can occur after an infection (i.e., acute postinfectious glomerulonephritis) and with other disorders such as lupus nephritis. Nephritic syndrome can also present clinically as rapidly progressive glomerulonephritis.

Acute postinfectious glomerulonephritis usually occurs after an infection with group A beta-hemolytic streptococci. The disorder is the most common cause of acute glomerulonephritis in children, particularly in developing countries. The incidence has decreased in countries such as the United States due to treatment of streptococcal infections of the throat (e.g., pharyngitis) or skin (e.g., impetigo). The risk is highest in children between the ages of 5 and 12. The incidence in adults is greater after age 60, and adults are more likely to be infected with staphylococcus. Adults with diabetes, alcoholism, cancer, or intravenous drug addiction are at higher risk for developing acute postinfectious glomerulonephritis. Other organisms causing acute glomerulonephritis can include viruses such as hepatitis or parasites. The mechanism of acute postinfectious glomerulonephritis includes the formation of immune complexes, which are composed of the antigenic organism streptococcus with IgG and C3 complement. Infection with staphylococcus reacts more with IgA in addition to IgG. The immune complexes are either circulating in the blood or formed within the glomerulus. The complexes activate the immune system, resulting in proliferation of cells in the endothelial and mesangial cells. The capillary membrane becomes permeable.

Up to 50% of patients with acute poststreptococcal glomerulonephritis can be asymptomatic or have mild hematuria. Symptoms usually occur 1–2 weeks after a throat infection and up to 6 weeks after impetigo. In patients infected with staphylococcus, the infection can be from the skin, heart, bone, and other areas but not usually the throat as in streptococcus. Some patients with acute poststreptococcal glomerulonephritis can present with a more severe complete acute

nephritic syndrome, which is characterized by sudden hematuria. Patients may describe their urine color as a tea or cola. The urine usually has dysmorphic cells with or without red blood cell casts. Pyuria is also present. Proteinuria levels can vary and are usually not in the nephrotic range (i.e., ≥ 3.5 grams per day). The thickened membrane decreases blood flow and GFR, leading to sodium and water retention as well as oliguria. The retention causes generalized edema and hypertension, which can range from mild to severe. Manifestations may also include malaise, irritability, and fever. Acute hypertension can cause central nervous system manifestations (e.g., headache, vomiting, and seizures). Other complications can include fluid overload with pulmonary edema, acute renal failure, and rarely hypertensive encephalopathy. Adults who are more likely to have staphylococcal infection may have cutaneous vasculitis, which imitates other vasculitis causing glomerulonephritis such as IgA vasculitis (Henoch-Schönlein purpura) and antineutrophil cytoplasmic antibody (ANCA) vasculitis.

Diagnosis is usually made based on clinical findings with a history of recent streptococcal or staphylococcal infection (e.g., positive culture or serologic antistreptolysin titers). In addition to the abnormal urine findings, complement levels (C3 and CH50 total complement) levels are low. Renal biopsy to diagnose streptococcal infection is usually not indicated as resolution of the disorder usually begins within 1 month. With staphylococcal infections, a kidney biopsy is usually necessary to confirm diagnosis due to the multiple differential diagnoses. Treatment includes antibiotics and supportive care that includes managing fluid overload with salt and water restriction and diuretics. Dialysis may be necessary with fluid overload, hyperkalemia, and uremia (elevated BUN) that are not responding to other therapies. Adults with staphylococcal infection can have resolution but often have persistent proteinuria and can progress to end-stage renal disease.

IgA vasculitis (i.e., Henoch-Schönlein purpura) is a systemic immune vasculitis that affects mainly small vessels throughout the body. The vessels affected are usually in the skin and cause palpable purpura. Affected vessels in the gastrointestinal tract will cause abdominal pain, and affected vessels in the musculoskeletal system will cause arthralgia and arthritis. The disease is mostly seen in children between the ages of 3 and 15 with a higher prevalence in boys than girls. The disorder, in about 20% of children, can affect the glomerulus. Renal involvement is more likely in older children and adults and is more likely to be associated with more severe renal disease. Glomerular blood vessel damage and inflammation occur due to the deposition of immune complexes (usually IgA), resulting in nephritic syndrome (e.g., hematuria with minimal to no proteinuria). Nephrotic syndrome is not as common. With limited renal involvement (e.g., mild hematuria and proteinuria), therapy may not be required, and close monitoring may be all that is necessary. Those individuals with more renal involvement may need corticosteroids and other therapies such as those discussed with other

nephropathies. The disorder is usually self-limiting, and complete remission occurs usually within 1 month but may take longer in those individuals who have more significant renal involvement.

Rapidly progressive glomerulonephritis (i.e., rapidly progressive crescentic glomerulonephritis) is a rare clinical syndrome with serious consequences if not diagnosed early. The disorder is a manifestation of severe glomerular injury. The disorder can manifest quickly over a period of days to months and is more common in adults over the age of 50. The disorder is characterized by extensive crescent formation (which is the shape of the Bowman capsule). There are three types or mechanisms of injury:

Type 1: This type is an anti-glomerular basement membrane antibody disease (Goodpasture syndrome) with IgG antibodies forming against pulmonary and alveolar capillary membrane. Type 2: Immune complexes are deposited in the glomeruli due to multiple disorders that cause immune complex development such as lupus nephritis, IgA nephropathy, and postinfectious glomerulonephritis. Type 3: This type is a form of necrotizing glomerulonephritis called Pauci- immune glomerulonephritis, where there are few, if any, immune complexes. Rather, serum ANCA attack small blood vessels. This type of glomerulonephritis will develop with systemic diseases such as granulomatous disease (e.g., Wegener granulomatosis) or microscopic polyangiitis.

Fibrin, macrophages, and T cells cause inflammation with proliferation of these substances into the Bowman space regardless the mechanism of injury. Collagen and fibrous deposits develop into crescents, which decreases glomerular blood flow and, in turn, glomerular filtration rate.

Onset may be rapid with signs similar to other nephritic syndromes (e.g., oliguria, hematuria, edema, and hypertension) or insidious with fatigue and edema. Renal insufficiency as manifested by a serum creatinine of > 3 mg/dL is often present at diagnosis. Other manifestations may be present if there are other systemic diseases such as in pauci-immune glomerulonephritis. Those individuals with anti-GBM may have hemoptysis since the alveolar membranes are also a target of the immune complexes.

Diagnostic tests are similar to other disorders and geared toward looking for the underlying causes. Tests may include serum ANCA, antinuclear antibodies, and anti- GBM antibodies. Renal biopsy may be necessary. The number of crescents that form play a part in the severity of the disease, and those patients with fewer crescents have a better prognosis and a slower disease progression. Treatment consists of immunosuppressive therapy with corticosteroids or cyclophosphamide. Plasmapheresis may be considered to remove circulating antibodies.

W

Diagnostic Link

Proteinuria vs. Albuminuria hile the GFR is a measure of renal function, the presence of protein/albumin in urine is a sign of kidney damage. The two major groups of serum proteins are albumin and globulins, and these can be measured

in the urine. The total amount of protein (albumin and nonalbumin) excreted by adults is usually 150 mg/day. Glomerular disorders are usually associated with the passage of large molecules such as albumin into the urine (i.e., albuminuria). Tubular disorders are usually associated with the passage of lower molecular weight proteins such as immunoglobulins into the urine . The urine dipstick primarily detects albumin and only when the levels are above 300 mg/day (formerly known as macroalbuminuria). However, diluted urine may reveal a false negative. Low levels of albumin in the urine are associated with kidney disease, an albumin-to-creatinine (ACR) ratio on a random (spot) urine sample or a 24-hour collection should be done. The ACR will detect albumin levels in the range of 30–300 mg/day (formerly called microalbuminuria). Detection of other proteins (including albumin) such as immunoglobulin light chains that are present in multiple myeloma can be accomplished with a screening tool known as the sulfosalicylic acid test.

Nephrotic Syndrome Glomerular disorders resulting in nephrotic syndrome are a result of the immune injury affecting mainly podocytes (i.e., visceral epithelial cells) (Figure 7-18). Podocytes are an important barrier to proteins passing to the filtrate. Proteins also pass due to the loss of the negative charge on the endothelial and basement membrane that repelled proteins. Injury, therefore, causes massive quantities of proteins to pass into the urine. The proteinuria for nephrotic syndrome is defined as 3.5 g/day or greater in adults and 50 mg/kg of body weight in children. The protein lost is mainly albumin, but other plasma proteins may be present in the urine (e.g., transferrin, clotting inhibitors). Glomerular inflammation is usually minimal, so hematuria is absent or minor. No red blood cell casts are present in the urine. Due to the massive protein loss, hypoalbuminemia occurs (serum < 3 g/dL). The colloid oncotic pressure decreases, causing water to go into the interstitial spaces, and generalized edema develops. Sodium and water are retained, worsening the edema. The decreased oncotic pressure causes the liver to produce more albumin, but it is insufficient to maintain levels in comparison to the decline. Additionally, the decreased oncotic pressure stimulates the liver to increase the production of lipids, so nephrotic syndrome causes hypercholesteremia (cholesterol > 300 mg/dL) and hypertriglyceridemia. The lipids can be present in the urine (lipiduria) and can be seen as fatty casts or oval fat bodies. Additionally, immunoglobulins are excreted in the urine; this loss of immune cells, in turn, increases the individual’s risk for infection.

Nephrotic syndrome can be due to primary kidney disease such as minimal change disease, which is a common cause in children. Adults develop nephrotic syndrome usually due to systemic disorders such as diabetes, systemic lupus erythematosus, or amyloidosis. Membranous nephropathy is a common cause of primary kidney disease in adults that causes nephrotic syndrome.

Most cases of primary nephrotic syndrome in children are idiopathic. Among the idiopathic cases, many children histologically have podocyte loss and minimal changes on renal biopsy. Immunoglobulin deposition is absent. These minimal changes are termed minimal change disease, which is also known as lipoid nephrosis. Affected children are usually between the ages of 2 and 6 years old. Children with minimal change disease do not usually have hypertension and hematuria. Renal function may be normal or impaired due to intravascular volume depletion, and complement levels are normal. Due to the volume loss, there may be hemoconcentration and increased platelets with risk for hypercoagulation and thrombosis. Minimal change disease is usually treated with steroids.

A common cause of primary nephrotic syndrome in adults is membranous nephropathy (i.e., membranous glomerulonephritis). The disease, however, can also be associated with systemic disorders such as hepatitis B, autoimmune disorders and certain drugs (e.g., nonsteroidal anti-inflammatory drugs). The disorder is more common in White men but can occur in women and other ethnicities (e.g., there is higher incidence in China). The diagnosis reflects that the histologic changes occur in the basement membrane, which becomes thickened, but there is no cell proliferation as seen with other glomerular disorders. The membrane becomes thickened due to immune complex deposits formed from antibodies (e.g., IgG) and various antigens such as M-type phospholipase A2 receptors expressed on podocytes. Clinical manifestations are those of nephrotic syndrome (e.g., marked proteinuria and hypoalbuminemia), and diagnosis is made based on its presentation. Diagnostic tests can include a renal biopsy; however, serologic testing can detect antigens and antibodies associated with membranous nephropathy. Treatment includes immunosuppressive therapy (e.g., steroids), alkylating agents (e.g., cyclophosphamide), and calcineurin inhibitors (e.g., cyclosporine). Hypertension and kidney protection are accomplished with the use of angiotensin-converting enzyme inhibitors and/or angiotensin-2 receptor blockers. Some patients have complete remission while others progress to renal failure.

Focal segmental glomerulosclerosis is a histologic description for sclerotic lesions that occur in parts of the glomeruli (segmental) and some of the glomeruli (focal). The sclerosis is often present in adults and children with nephrotic syndrome. These lesions are more common in Blacks as compared to Whites. The disorder is often idiopathic. Patients can also have mild proteinuria with renal insufficiency that occurs due to glomerular injury from drugs (e.g., heroin and interferon) or viral infections such as human immunodeficiency virus. Genetic mutations can cause podocyte structural lesions and alter filtration barriers in the glomerulus (e.g., basement membrane). The genetic mutations will usually manifest as nephrotic syndrome in infancy and childhood.

IgA nephropathy (i.e., Berger disease) is a common cause of primary glomerulonephritis in adolescents and young adults (i.e., ages 15–30 years). The

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highest incidence is in Asians and Whites. IgA immune complexes are deposited in the mesangium. The inciting factors leading to the development of IgA nephropathy are unclear; however, there may be dysregulation in the synthesis and metabolism of IgA with mesangial cell affinity and reaction to the antibodies. The deposits cause cell proliferation, an inflammatory response with subsequent crescent formation, interstitial fibrosis, and segmental sclerosis.

BOX 7-4 Application to Practice A 20-year-old Black woman is complaining of increasing fatigue, swelling in her legs, and darker urine. She denies any fever or other symptoms. She was diagnosed with systemic lupus erythematosus 1 year ago. She has been taking chloroquine, and she takes ibuprofen for joint pain about one or two times a month.

Physical examination: pulse 98 per minute; blood pressure 150/100 mmHg; remainder of exam is unremarkable except for 2+ pitting edema in her lower extremities.

Laboratory results: urinalysis with hematuria (10 RBCs per HPF) with no casts; proteinuria of 8 g/24 hr; low complement level; serum creatinine of 1.31 mg/dL.

A diagnosis of lupus nephritis is made pending renal biopsy results. Answer the following questions:

What is the incidence and epidemiology of lupus nephritis? Which clinical manifestations and laboratory findings are consistent with lupus nephritis? Explain why the clinical manifestations develop. Describe how lupus nephritis develops.

BOX 7-5 Application to Practice A 13-year-old boy presented to the clinic complaining of a sore throat that persisted for 2 days. After those 2 days, he developed fever, nausea, and malaise. A throat culture revealed the presence of group A beta- hemolytic streptococci, and the child was started on antibiotic therapy. The child’s symptoms gradually improved, but approximately 2 weeks later, he returned to the clinic because the fever, nausea, and malaise returned. He became tachypneic and short of breath. The mother noted that his eyes were puffy, his ankles were swollen, and his urine was dark and cloudy.

On examination, the child’s blood pressure was 148/100 mmHg, his pulse was 122 beats/minute, and his respirations were 35/minute. Orbital and ankle edema were present. Crackles were auscultated bilaterally. No heart murmurs were found. Slight tenderness to percussion over the flank areas was noted.

A chest X-ray showed evidence of congestion and edema in the lungs. The patient’s hematocrit was 37%,

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and his WBC count was 11,200/mm3. Blood urea nitrogen was 48 mg/dL (normal is less than 20 mg/dL). Urinalysis results showed that the patient’s protein was 2+ (24-hour excretion was 0.8 g), specific gravity was 1.012, and there were moderate amounts of RBCs and WBCs in the urine. Serum albumin was 4.1 g/dL (normal is 3.5–4.5).

Which evidence supports the conclusion that this patient has a kidney disease? Which clinical pattern of kidney disease does this patient have? Explain the symptoms. Which morphologic changes would you expect in the kidney? What is the prognosis? What are the possible short- and long-term complications of this disease? Is it necessary to hospitalize the patient?

Clinical presentation may be asymptomatic and the disorder is found with incidental screening. The urine may reveal mild proteinuria or microscopic hematuria. Other patients may have episodes of gross hematuria with an upper respiratory infection. Patients can also complain of flank pain as the renal capsules stretch. Episodes of hematuria and proteinuria can recur for several years, and progression is gradual. Diagnosis is usually accomplished with a renal biopsy. Treatment is aimed at preventing chronic kidney disease through managing hypertension and kidney protection with the use of angiotensin-converting enzyme inhibitors and/or angiotensin-2 receptor blockers. Lipid levels should be low to reduce the cardiovascular risks associated with chronic kidney disease. Anti- inflammatory and immunosuppressive therapy benefits are not clear in IgA nephropathy and such therapy is usually reserved for renal disease that is progressing (e.g., increased serum creatinine or persistent proteinuria).

Chronic glomerulonephritis is a result of progressive types of glomerulonephritis that usually lead to chronic kidney disease. The underlying disorder may be difficult to determine as multiple glomerular changes may be present. Hyperlipidemia, hypertension, systemic lupus erythematosus, and diabetes mellitus are all associated with the development of chronic glomerulonephritis.

Kidney Injury and Disease The pivotal role that the kidneys play in maintaining homeostasis becomes clear when these organs stop performing that role. Renal failure refers to the kidneys’ inability to function adequately; it is classified as either acute or chronic. See chapter 6 for a discussion of fluid, electrolyte, and acid–base homeostasis.

Acute Kidney Injury Acute kidney injury (AKI), formerly known as acute renal failure, refers to a sudden loss of renal function. The loss of renal function, which is generally reversible, most commonly occurs in critically ill, hospitalized patients. Causes include disorders such as sepsis, volume deficits (e.g., heart failure, cirrhosis), and nephrotoxic drugs (e.g., vancomycin). Prerenal disorders along with acute tubular necrosis are the most

common cause of AKI in hospitalized patients. AKI has a mortality rate of 10–60% depending on the underlying etiology. Its causes are divided into three categories:

1. Prerenal conditions, which disrupt blood flow on its way to the kidneys: Extremely low blood pressure or blood volume (e.g., hemorrhage, sepsis, dehydration, shock, and traumatic injury) Heart dysfunction (e.g., myocardial infarction and heart failure) Liver disease with portal hypertension

2. Intrarenal conditions, which directly damage the structures of the kidneys and can be further divided into vascular disease, glomerular disease, or tubular and interstitial disease: Reduced blood supply within the kidneys (e.g., atherosclerosis; renal vein thrombosis, renal aneurysm, and aortic dissection) Hemolytic uremic syndrome (associated with infection with certain strains of E. coli, in which bacterium toxins damage small blood vessels; it is the leading cause of acute kidney failure in children) Glomerular disorders (e.g., glomerulonephritis and acute interstitial nephritis [usually associated with an allergic reaction to certain nephrotoxic medications]) Tubular disorders (e.g., obstructions from myoglobinuria, multiple myeloma light chains, uric acid casts) Toxic injury (usually from alcohol, cocaine, heavy metals, solvents, fuels, chemotherapy drugs, bowel preparations containing phosphate, and contrast dyes)

3. Postrenal conditions, which interfere with the urine excretion: Bilateral ureter obstruction (e.g., nephrolithiasis and tumors) Bladder obstruction and dysfunction (e.g., BPH, tumors, and nerve innervation disruption)

Acute tubular necrosis (ATN) or acute tubular injury is a common cause of intrarenal AKI. The most common cause of ATN is ischemia due to decreased renal perfusion. The exposure to nephrotoxic drugs and substances is another common cause. Many nephrons drain into a single collecting duct (Figure 7-2). A reduction in blood flow to the kidneys sets the stage for the development of ATN. The endothelial cells in the microcirculation of the kidneys become injured. The blood vessels become more permeable, and the inflammatory response is triggered. Leukocytes, macrophages, and complement are activated with release of chemical mediators (e.g., chemokines or tumor necrosis factor). These microcirculatory changes further contribute to the reduction in renal blood flow, further worsening tubular injury. Sodium, water, and transport of other substances is impaired, and the tubular border sheds. This shedding can result in tubular casts in the urine. The tubules can become obstructed from the cellular debris. The intraluminal obstruction causes the

pressure to rise in the lumen, and fluid backs up. The fluid moves from the lumen to the interstitium. Necrosis develops along multiple areas of the tubule. ATN is generally reversible.

Clinical Manifestations AKI has an abrupt onset (usually over a period of 48 hours) and progresses through four phases. The progression through these phases is particularly characteristic of acute tubular necrosis. The individual is usually asymptomatic in the initial phase. Although renal damage is occurring, the nephrons that are still functioning compensate for those that are not. During the second (oliguric) phase, impaired glomerular filtration leads to solute and water reabsorption. This reabsorption decreases daily urine output to approximately 400 mL or less, such that waste products begin to accumulate (uremia). The second phase can last a few days to a few weeks. In the third (diuretic) phase, renal function gradually returns as healing and cellular regeneration occur. Diuresis occurs due to tubular damage that impairs the kidneys’ ability to concentrate the urine. Daily urine output in this phase can be as much as 5 L. The excessive urine output can lead to dehydration and electrolyte imbalances. The third phase can last days to weeks. In the recovery stage, glomerular function gradually returns to normal. This final stage can persist for 3–12 months. Depending on the age and overall health of the individual, full renal function may be regained.

As previously mentioned, the initial phase of AKI is asymptomatic. As renal function is lost, symptoms appear. Clinical manifestations vary depending on the AKI phase. In the oliguric phase, manifestations include:

Decreased urine output Electrolyte disturbances (usually increased levels) Fluid volume excess Azotemia Metabolic acidosis

In the diuretic phase, manifestations include:

Increased urine output Electrolyte disturbances (usually decreased levels) Dehydration Hypotension

In the recovery phase, symptoms begin resolving.

Diagnosis and Treatment The diagnostic criteria for AKI in adults and children are those defined by the Kidney Disease: Improving Global Outcomes guidelines and are as follows: 1) increase in serum creatinine by ≥ 0.3 mg/dL within a 48-hour period; or 2) increase in serum creatinine to > 1.5 times baseline, which has occurred in the prior 7 days; or 3) urine volume < 0.5 mL/kg/hour for 6 hours. Diagnostic procedures for AKI include those to identify both the renal injury and its underlying cause. These procedures consist of a history and physical examination. Often in the hospital, a cause can be identified (e.g., hypotension, sepsis, or drug administration). Evaluation of serum creatinine trends may reveal when an injury occurred particularly if the serum creatinine was normal and then suddenly increased. Diagnostic tests will include a BUN, blood chemistry, arterial blood gases, and complete blood count. Urine evaluation includes a urinalysis, urine osmolality, urine sodium, and fractional excretion of sodium. Distinguishing ATN from prerenal AKI can be determined by evaluating the concentration of the urine. With ATN, concentration is impaired, while in prerenal AKI the resorptive function is maintained. Urinalysis may reveal myoglobin or various casts (e.g., brown granular, tubular epithelial cells). Treatment strategies for AKI vary depending on the phase and the cause. As an example, volume replacement is indicated in hypovolemia. Different fluid and electrolyte disturbances occur in the second and third phases, requiring different strategies for these phases. Some patients (e.g., those with fluid overload, hyperkalemia, acidosis, and uremia) with AKI may require temporary dialysis (e.g., hemodialysis or peritoneal dialysis) until renal recovery occurs. Continuous renal replacement therapy (CRRT) is an alternative to hemodialysis. CRRT is preferred for patients who are hemodynamically unstable. Patients may have less hypotension than with hemodialysis as CRRT is continuous and slower. Solute removal with CRRT is also higher than with hemodialysis. Other supportive strategies include the following measures:

A diet that is high in calories and carbohydrates but restricted in protein, sodium, potassium, and phosphates Hypertension management Anemia treatment with synthetic erythropoietin Infection prevention strategies (e.g., hand washing, limiting visitors, and aseptic technique)

Chronic Kidney Disease Chronic kidney disease (CKD) consists of the gradual, irreversible loss of renal function. An estimated 23 million adults are living with CKD in the United States (NIH, 2013). Several conditions can initiate the slow, progressive destruction of the nephrons with diabetes mellitus and hypertension as the two most common causes.

Renal diseases such as polycystic kidney disease, pyelonephritis, and glomerulonephritis damage nephrons in a variety of ways. Systemic illnesses such as lupus erythematosus and sickle cell anemia can cause CKD. Aging confers a risk for CKD as the kidneys generally become less efficient and are exposed to more conditions that can cause damage.

Regardless of which disorder has caused CKD, nephrons are progressively damaged. This damage results in the inability of the kidneys to perform critical filtration, resorptive, and endocrine functions. Inability of the kidney to perform results in water (e.g., increased volume) and electrolyte imbalances (e.g., hyperkalemia), accumulation of nitrogenous wastes (e.g., azotemia), acid–base imbalances (e.g., metabolic acidosis) as well as altered vitamin D, calcium, and phosphate balance (e.g., osteodystrophy). These alterations are usually slow to develop and often do not manifest until there is advanced renal disease as the kidneys have a remarkable capacity to compensate for failing nephrons. The compensatory mechanisms ultimately lead to further damage to surviving nephrons.

Two key factors are postulated to contribute to the progression of CKD— intraglomerular hypertension and glomerular hypertrophy. When nephrons are damaged and lost, surviving nephrons take over filtration function in an attempt to maintain GFR, a process known as hyperfiltration. There is adaptive renal vasodilation, reduction in glomerular permeability, and an adaptive rise in intraglomerular pressure in response to a reduced GFR. As a result, the glomeruli hypertrophy, which causes glomeruli injury. Further cellular mechanisms that are not completely understood include endothelial cell damage. Glomerular epithelial cells detach from the capillary wall, allowing water and solutes to pass more freely, but large molecules (e.g., IgM, fibrinogen) get trapped, producing hyaline casts and lumen narrowing. The mesangial cells produce cytokines and begin to expand, further crowding the capillary area. The structural and functional changes all lead to glomerulosclerosis (i.e., scarring). Tubulointerstitial injury in CKD in the form of dilation and fibrosis is present even if the primary area of injury is the glomerulus. The tubulointerstitial injury is thought to occur due to vessel changes and accumulation of inflammatory substance in the tubules.

In 2002, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines defined and classified CKD based on five stages (TABLE 7-5). In 2012, the guidelines were updated to include albuminuria as increased levels have been associated with increased mortality, cardiovascular events, and end-stage renal diseases. The definition and diagnosis of CKD is based on the following criteria:

TABLE 7-5 CKD Stages Based on GFR and Albuminuria Levels

GFR stages GFR (mL/min/1.73 m2)/term

G1 ≥ 90 normal or high

G2 60–89 mildly decreased

G3a 45–59 mildly to moderately decreased

G3b 30–44 moderately to severely decreased

G4 15–29 severely decreased

G5 < 15 kidney failure or dialysis

Albuminuria stages AER mg/day

A1 < 30 normal to mildly increased

A2 30–300 moderately increased

A3 > 300 severely increased

GFR = glomerular filtration rate; AER = albumin excretion ratio.

1. Kidney damage for ≥ 3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR

2. GFR < 60 mL/min/1.73 m2 for ≥ 3 months, with or without kidney damage

Kidney damage is defined as albuminuria (albumin excretion rate > 30 mg/24 hours; ACR > 30 mg/g), urine sediment abnormalities, electrolytes disorders due to tubular disorders, kidney disorders based on histology or structural abnormalities, and history of kidney transplant.

Clinical Manifestations Clinical manifestations are complex and dependent on the degree of renal function lost. These manifestations also reflect the complications associated with CKD (TABLE 7-6). Initially, CKD is often asymptomatic because the remaining nephrons compensate for those lost to the disease. Clinical manifestations develop insidiously as 50% of the nephrons are destroyed. Multiple systems are affected as CKD progresses. These complications worsen as the renal function declines.

TABLE 7-6 Complications of Chronic Kidney Disease

System Manifestations and etiology Treatment

General appearance Tired, weak, sallow (yellow or pale) skin color due to anemia and toxins

Dialysis and epoetin alfa

Integumentary Itching due to phosphate crystals and urea crystals (uremic frost) Dry, decreased sweating due to decreased oil and sweat gland activity

Dialysis and palliative care

Sensory Metallic taste in mouth and fishy breath odor (uremic fetor) due to toxins

Dialysis

Cardiopulmonary Hypertension

Related to salt and water retention, erythropoietin (20% of patients on this therapy develop CKD), or increased renin production Accelerated renal damage if not controlled development of heart failure

Limiting salt and fluids Angiotensin-converting enzyme (ACE) inhibitors, angiotensin-2 receptor blockers and other agents

Pericarditis

Result of metabolic toxins Hemodialysis

Chest pain, fever, friction rub, and decreased cardiac output

Heart disease Heart failure (in 75% of patients needing dialysis), ischemic heart disease, cardiomyopathy

Result of increased workload of the heart (left ventricular hypertrophy) secondary to anemia, dialysis (shunting of blood), fluid overload, hypertension, hyperlipidemia, and atherosclerosis

Salt and fluid restriction Diuretics (loop) ACE inhibitors and angiotensin- 2 receptor blockers

Hematologic Coagulopathy

Platelet dysfunction due to abnormal aggregation and adhesion Increased bleeding time Platelet count slightly decreased May have petechiae or purpura Increased risk of thrombosis

Desmopressin (causes release of factor VIII from endothelial cells)—used before surgery

Anemia

Related to decreased erythropoietin production (occurs when glomerular filtration rate falls below 20–25 mL/min), iron deficiency (e.g., anorexia, dietary restrictions, hemodialysis blood loss), uremia causes bone marrow suppression Red blood cell destruction due to hemodialysis

Epoetin alfa if hematocrit is below 33% (hemoglobin levels should increase no more than 1 g/dL every 3–4 weeks so hypertension does not develop) Intravenous iron for patients on dialysis (oral absorption of iron is poor)

Gastrointestinal Anorexia, nausea, vomiting, hiccups, ulceration—related to metabolic toxins (e.g., ammonia) PTH

Dietary protein restriction Dialysis

Endocrine Sexual dysfunction

Decreased libido, impotence, and infertility Decreased estrogen levels in women—no ovulation; menorrhagia; amenorrhea Decreased testosterone levels in men

Dialysis and a healthy diet to restore fertility

Glucose impairment

Glucose intolerance Peripheral insulin resistance Serum insulin high Kidneys cannot clear insulin from the bloodstream

Lower doses of hypoglycemic agents for some patients with diabetes

Mineral metabolism Renal osteodystrophy (disorder of calcium, phosphorus, and bone) leading to bone pain, fractures, muscle weakness, and calcium deposits in the blood vessels, soft tissue, heart, and lungs

Low glomerular filtration rate, slower phosphorus excretion, increased calcium excretion Increase in parathyroid hormone secretion, leading to a high bone turnover rate In stage V, buffering of excess hydrogen ions by leaching of large stores of calcium phosphate and calcium carbonate from the bones (bone demineralization)

Restriction of dietary phosphorus Phosphorus-binding drugs such as calcium carbonate Vitamin D (suppresses parathyroid hormone)

Neurologic Uremic encephalopathy

Appears when glomerular filtration rate falls below 10–15 mL/min or because of hyperparathyroidism Symptoms: poor concentration (first sign) that progresses to confusion, asterixis, weakness, nystagmus, and hyperreflexia

Dialysis

Peripheral nervous system Peripheral neuropathy (restless leg syndrome, distal pain and burning, and loss of deep tendon reflexes), usually symmetrical, lower limbs more commonly affected Impotence and autonomic dysfunction

Metabolic Hyperkalemia

Glomerular filtration rate below 10–20 mL/min Hemolysis, trauma, and acidosis Diet high in citrus fruits/juices Medications such as ACE inhibitors and nonsteroidal anti-inflammatory drugs

Monitoring of cardiac status Calcium chlorides, insulin, glucose (insulin moves potassium into cells), bicarbonate, or an exchange resin Dietary potassium restriction

Acid–base disorders Damaged kidneys

Cannot produce enough ammonia or buffer hydrogen ions Arterial pH generally between 7.33 and 7.37 Buffering of excess hydrogen ions by large stores of calcium phosphate and calcium carbonate from the bones

Maintenance of serum bicarbonate above 21 mEq/L by giving alkali supplements such as sodium bicarbonate, calcium bicarbonate, or sodium citrate

Modified from Story, L. (2017). Pathophysiology: A Practical Approach (3rd ed.). Burlington, MA: Jones & Bartlett Learning.

These manifestations include the following signs and symptoms:

Hypertension (see chapter 4) Polyuria with pale urine (early) Oliguria or anuria (absent urine output) with dark-colored urine (late) Anemia Bruising and bleeding tendencies Electrolyte imbalances, specifically hyperkalemia, hypocalcemia, hypomagnesemia, and hyperphosphatemia Muscle twitches and cramps (related to hypocalcemia and hyperphosphatemia; see chapter 6) Pericarditis, pericardial effusion, pleuritis, and pleural effusion (secondary to uremia) Heart failure (see chapter 4) Respiratory distress and abnormal breath sounds (due to pulmonary edema associated with congestive heart failure; see chapter 4) Sudden weight change (usually increased because of fluid retention) Edema of the feet and ankles (due to fluid retention) Azotemia Peripheral neuropathy, restless legs syndrome, and seizures Nausea and vomiting Anorexia Malaise Fatigue and weakness Headaches that seem unrelated to any other cause Sleep disturbances Decreased mental alertness Flank pain Jaundice Persistent pruritus Recurrent infections (due to an impaired immune response because of uremia)

Diagnosis and Treatment Diagnosis of CKD is based on the criteria previously discussed (e.g., GFR and ACR). Diagnostic procedures then focus on identifying the underlying cause and any complications that have developed as a result of the development of CKD.

The main goal of CKD treatment is to stop or slow disease progression, usually by controlling the underlying cause. Additionally, strategies to treat and prevent complications will be necessary (Table 7-6). Doses of any medications will likely need adjustments; with limited excretion capability, medication toxicity is probable when the usual doses are given. Without treatment, CKD has a mortality rate of 100%. Conservative management strategies are employed early but evolve into more aggressive measures as renal function declines and include renal replacement

therapy with dialysis or kidney transplant. In children with CKD, transplant is the best option to allow for optimal growth and development and better outcomes.

C H A P T E R S U M M A R Y

The urinary system maintains homeostasis through a complex filter (kidney) that can regulate pH, fluid, electrolytes, and endocrine functions (e.g., blood glucose). Additionally, the urinary system is the main site for excreting waste products and other harmful substances obtained from the food and water ingested orally. A functioning urinary system is crucial to maintaining health, and disease in this system can have detrimental effects on other systems and the body as a whole. Prevention and early treatment of these diseases are paramount to avoiding these consequences. Maintaining a healthy lifestyle (e.g., drinking plenty of fluids, avoiding harmful chemicals, preventing sexually transmitted infection, exercising, and smoking cessation) can help preserve urinary health. Many chronic diseases, such as hypertension and diabetes mellitus, can lead to kidney disease, so controlling blood pressure and blood glucose is crucial.

R E F E R E N C E S A N D R E S O U R C E S

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de Jong, Y., Pinckaers, J., Brinck, R., Nijeholt, A., & Dekkers, O. (2014). Urinating standing versus sitting: Position is of influence in men with prostate enlargement. A systematic review and meta-analysis. PLOS ONE, 9(7), e101329.

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T

C H A P T E R 8

Reproductive Function

L E A R N I N G O B J E C T I V E S

Discuss normal reproductive anatomy and physiology. Differentiate congenital reproductive disorders. Summarize issues with fertility. Differentiate penile, testicular, and scrotal disorders. Differentiate disorders that affect menstruation. Summarize disorders of pelvic support. Differentiate uterine and ovarian disorders. Differentiate breast disorders. Differentiate infectious disorders of the reproductive system. Summarize cancers of the reproductive system. Apply understanding of reproductive system alterations in describing various common disorders such as leiomyomas, erectile dysfunction, and sexually transmitted infections. Develop diagnostic and treatment considerations for various reproductive disorders.

he reproductive system is composed of the structures responsible for procreation; therefore, a healthy reproduction system is necessary for the survival of the species. This system is responsible for transmitting genetic

material to offspring. The male reproductive system generates sperm and transports it to the female reproductive system. The female reproductive system produces ova. When a sperm fertilizes an ovum, the female reproductive system nurtures and safeguards the embryo as it develops into a fetus, with this process lasting until birth. The primary difference between the two systems is the varying hormone levels, which cause the reproductive system to develop differently.

Anatomy and Physiology Normal Male Reproductive System The male reproductive system includes organs involved in the generation (spermatogenesis) and transportation of sperm. These organs include the penis, scrotum, testes, duct system, and accessory glands (FIGURE 8-1; TABLE 8-1). In addition to producing sperm, the male reproduction system produces sex hormones (mostly testosterone) that give males their distinct characteristics (e.g., facial hair, increased muscle mass, and low voice pitch). Parts of the male reproductive system work with the urinary system to aid in urinary elimination (e.g., penis and urethra). Because the male reproductive and urinary systems are integrated, disorders in one system generally affect the other system (see chapter 7 for more discussion of urinary function).

FIGURE 8-1 The male reproductive system. A Organs of the male reproductive system. B Interior view of the testis.

TABLE 8-1 The Male Reproductive System

Component Function

Testes Produce sperm and male sex steroids

Epididymis Store sperm; provide nourishment for sperm maturation

Vas deferens Conduct sperm to urethra

Sex accessory glands Produce seminal fluid that nourishes sperm

Urethra Conduct sperm to the outside of the male body

Penis Organ of copulation

Scrotum Provide proper temperature for testes and protection due to several sensory receptors

Penis The penis is part of the male external genitalia; it contains erectile tissue that fills with blood during sexual arousal. The penis deposits sperm in the female reproductive system during sexual intercourse. The penis consists of three cylinders —the corpus spongiosum (which contains the urethra) and two corpora cavernosa (FIGURE 8-2). The penis structure includes the root, shaft, and glans (enlarged tip). Penis length can vary considerably, but the average length is 2–5 inches when flaccid and 4–7 inches when erect. Penis appearance can also vary from person to person.

FIGURE 8-2 Anatomy of the penis.

A sheath of loose skin, called the foreskin, covers the glans penis at birth. The foreskin is often surgically removed (circumcision) shortly after birth for hygienic, cultural, or religious reasons. If the foreskin is not removed, it usually becomes fully retractable usually by the age of 3 due to frequent erections breaking up adhesions (i.e., foreskin to glans). The glans produces an oily secretion that can combine with dead skin to form a cheesy substance called smegma. If the smegma is not regularly removed from under the foreskin, the penis can become irritated and infected. The glans also has an opening, or meatus, that allows for ejaculation (propulsion of sperm-containing fluid) and urination.

Scrotum

The scrotum is a fibromuscular sac of skin just below the penis that contains the testes, epididymis, and lower spermatic cords. The scrotum maintains the proper testicular temperature for spermatogenesis by contracting to draw the testes closer to the body to warm them and relaxing to drop the testes farther from the body to cool them. Various sensory receptors to pain, pressure, touch, and temperature are on the scrotum to serve as a protective mechanism for the underlying testes.

Testes The testes, or gonads, produce sperm (i.e., gametes) and the sex hormones testosterone and androgens. Spermatogenesis develops in most males by 16 years of age. Spermatogenesis, in contrast to ova production, occurs throughout life. The testes form in the abdominal cavity in utero and descend through the inguinal canal into the scrotum in approximately the seventh month of gestation when stimulated by rising testosterone levels. Occasionally, they will descend shortly after birth (usually by 3 months of age). Seminiferous tubules produce sperm, and the tubules are the bulk of testicular volume. The seminiferous tubules have specialized cells known as Sertoli cells that are necessary to provide nourishment to developing sperm (i.e., spermatids). Development takes about 70–80 days. The sperm then travel to a fingerlike projection on the posterior portion (in most men) of the testes known as the epididymis. The sperm mature during storage in the epididymis, making them capable of movement. The testes can produce approximately 50,000 sperm per minute.

The testes produce hormones (especially testosterone) in their Leydig cells. Other sources of testosterone and androgen are the adrenal glands (See chapter 10 on endocrine function).

The male sex and reproductive hormones are controlled by the hypothalamus, pituitary, and other feedback mechanisms (FIGURE 8-3). Neurotransmitters such as norepinephrine stimulate gonadotropin-releasing hormone (GnRH) from the hypothalamus, and the neurotransmitters, serotonin and dopamine, inhibit GnRH from the hypothalamus. GnRH stimulation occurs in a pulsatile fashion, which causes the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the anterior pituitary. Prolactin release affects hormone production. These hormones cause stimulation of the testes. Subsequently, the various effects of these hormones are as follows:

FIGURE 8-3 Hormonal control of testicular function: testosterone, FSH, and LH participate in a negative feedback loop.

LH: Stimulates Leydig cells to produce and secrete testosterone (about 5–7 mg a day) FSH: Stimulates Sertoli cells (seminiferous tubules) promoting spermatogenesis Inhibin: Secreted by Sertoli cells; causes inhibition of FSH, which leads to reduction in spermatogonia (germ cells that eventually become sperm)

Testosterone is one of the main male sex hormones. Other hormones include 5- alpha-dihydrotestosterone (DHT) and estradiol. Testosterone, DHT, and estradiol hormones regulate LH secretion. Testosterone and DHT directly inhibit LH secretion from the pituitary gland while estradiol inhibits LH but does so by inhibiting GnRH from the hypothalamus. Inhibin is an important inhibitor of FSH with some effects from estradiol and minor regulation from testosterone.

The process of testosterone synthesis in the Leydig cells occurs in multiple steps (FIGURE 8-4). Testosterone, under LH stimulation, is produced initially by the conversion of cholesterol to pregnenolone then to dehydroepiandrosterone (DHEA) to androstenediol, and then to testosterone. In the testes, a small amount of testosterone is aromatized to estradiol or DHT. The enzyme, 5-alpha-reductase mediates the reduction of testosterone to DHT. Inhibition of this enzyme with 5- alpha-reductase inhibitors (e.g., finasteride [Proscar]) are used to treat benign prostatic hyperplasia. While some estradiol is synthesized in the testes, most of the estradiol (estrone also) is produced in adipose tissue and other tissue such as the brain, skin, and bone. Estradiol effects include sexual function, bone growth, and body fat. While some DHT is produced in the testes, the majority is produced in the skin and liver. DHT is a potent androgen and is important in prostatic growth and male balding. Propecia, is another 5-alpha-reductase, that can be used for balding in men. See chapter 7 for a discussion of benign prostatic hyperplasia.

FIGURE 8-4 Testosterone synthesis and metabolism.

Testosterone in plasma is mostly bound to sex hormone–binding globulin (SHBG) and albumin. About 0.5–3% of testosterone is free (i.e., unbound). SHBG has a stronger bind to testosterone in comparison to albumin, so this testosterone is

considered inactive. Serum SHBG increases with age; therefore; less testosterone is available as a man ages.

Testosterone and the metabolites (DHT and estradiol) give males their classic secondary sex characteristics (e.g., facial hair and deep voice) and sexual function (e.g., libido, erection, and satisfaction). Testosterone also regulates metabolism and protein anabolism (encourages skeletal growth and muscle development and lowers fat mass), and promotes potassium excretion and renal sodium reabsorption. Additionally, testosterone contributes to male pattern baldness and acne in some men. Testosterone increases erythropoiesis.

Duct System The male reproductive system contains a complex tube structure to deliver sperm from the testes to the female reproductive system. This duct system includes the epididymis, vas deferens, spermatic cord, ejaculatory duct, and urethra. Once they are mature, sperm leave the epididymis and travel to the vas deferens. The testicular artery and venous plexus, lymph vessels, nerves, connective tissue, and cremaster muscle (which contracts or relaxes the scrotum) surround the vas deferens; together, these structures make up the spermatic cord. The spermatic cord essentially suspends the testes and is the testicular supply line. The vas deferens widens at the prostate, forming a pouch called the ampulla. The ampulla joins the seminal vesicles (a pair of pouches that secrete an alkaline ejaculatory fluid containing sugar, protein, and prostaglandins to nurture and protect the sperm) to form the ejaculatory duct. The sperm and the ejaculatory fluid join in the vesicles to form semen (i.e., ejaculate). The semen flows from the ejaculatory duct to the urethra, where it is propelled from the penis during sexual intercourse.

Accessory Glands The primary function of the accessory reproductive glands is to facilitate ejaculation. Sexual stimulation initiates the ejaculatory process. When a male is sexually stimulated, his sperm travel from the epididymis to the vas deferens to the seminal vesicles and ejaculatory duct. Fluid from the prostate gland (a chestnut-shaped gland located at the base of the urethra) mixes with the sperm and secretions of the seminal vesicles. This prostate fluid further decreases the ejaculatory fluid’s acidity, increases sperm motility, and prolongs sperm life. The alkaline medium counteracts the acidity of vaginal secretions that would otherwise kill the sperm. The Cowper glands (two pea-sized glands found adjacent to the urethra) secrete another alkaline fluid into the urethra to neutralize acidity caused by urine transportation. The Cowper gland secretions can sometimes be seen at the meatus before ejaculation. This secretion aids in lubrication of the penis during sexual intercourse and may contain some sperm left over from a previous ejaculation; therefore, these secretions can

cause pregnancy even if the penis is withdrawn prior to ejaculation.

Erection and Ejaculation Erections start occurring in utero and continue throughout the life of a man. Penetration of the penis during sexual intercourse is accomplished due to the ability of the penis to become erect. An erection can occur with stimulation, which results in parasympathetic nerve impulses in the spinal cord (sacral area) to release nitric oxide; simultaneously sympathetic nerve fibers, which cause constriction, are inhibited. The release of nitric oxide leads to arteriolar dilation, and blood fills in the corpora cavernosa and, to a lesser degree, the spongiosum of the penile shaft. The spongiosum does not fully expand so that semen can travel through the urethra. The filling of this tissue with blood causes expansion of the erectile tissue, and the penis enlarges and elongates (i.e., erection or tumescence). The erection is maintained due to the compression and constriction of the veins which prevents outward blood flow. Collagen fibers that surround the penis prevent curvature when the penis is erect.

The actual expulsion of semen from the penis (i.e., ejaculation) is the result of motor neurons stimulating muscular contractions of the glands and ducts of the reproductive system—particularly the ampulla, seminal vesicles, and bulbocavernosus muscle (the muscle surrounding the corpus spongiosum). During ejaculation, a valve at the bladder closes to prevent urine from entering the urethra and killing the sperm. An orgasm, the climax of pleasurable sensations, usually accompanies the ejaculation. Ejaculated semen contains sperm (about the volume of a pinhead) and secretions (about 2–6 mL [a tablespoon]) from the seminal vesicles, prostate, and Cowper glands. One ejaculation contains approximately 300 million sperm. While erections occur throughout life, ejaculation occurs with the commencement of spermatogenesis. After ejaculation or if there is cessation of stimulation of the penis, the reverse occurs in the vasculature; the veins dilate and blood flows outward from the arterioles causing detumescence (flaccidity).

Normal Female Reproductive System The female reproductive tract is a complex system that includes organs to manage the generation of eggs (oogenesis), transportation of eggs (ovulation) for fertilization (impregnation), support of fetal development (gestation), birth of the fetus (parturition), and feeding of the offspring through lactation. To accomplish all these functions, the female reproductive system requires a delicate hormone balance and operational organs. These organs include the ovaries, fallopian tubes, uterus, vagina, external genitalia, and mammary glands (FIGURE 8-5, FIGURE 8-6, FIGURE 8-7, and FIGURE 8-8). In addition to facilitating the system’s function, the hormones (specifically estrogen and progesterone) produced by the female

reproductive system give females their distinct characteristics (e.g., enlarged breasts, wide hips, and high-pitched voice).

FIGURE 8-5 Side view of the female reproductive system.

FIGURE 8-6 Front view of the female reproductive system.

FIGURE 8-7 The female external genitalia.

FIGURE 8-8 The female mammary glands.

The female reproductive system is intimately intertwined with the physiologic functions of nearby structures in the female pelvis. The female pelvis contains organs of the urinary and gastrointestinal systems along with organs for the

reproductive system; thus, the female pelvis is the site for urination, defecation, menstruation, ovulation, copulation (sexual intercourse), impregnation, pregnancy, and parturition. Because of the close proximity of these three systems, problems in one system can lead to problems in the others.

Ovaries The ovaries are paired, almond-shaped organs located on each side of the uterus (Figure 8-6; FIGURE 8-9). The suspensory and ovarian ligaments and the mesovarium (fold in the peritoneum) hold the ovaries in place. The ovaries produce hormones (primarily estrogen, progesterone, and inhibin) that regulate reproductive function and secondary sex characteristics (e.g., enlarged breasts, wide hips, and high-pitched voice). Estrogen is also produced in smaller amounts by breast and adipose tissue and during pregnancy by the placenta. The ovaries also produce testosterone and other androgens, but the levels are lower in women (e.g., up to 70 ng/dL) in comparison to men (e.g., up to 1,000 ng/dL). Men, likewise, have lower levels of estrogen in comparison to women. The adrenal cortex production of androgens can be significant in women, while in men adrenal androgens are not as influential.

FIGURE 8-9 Structure of the ovary.

There are three types of estrogen—estradiol, estrone, and estriol. Estradiol is the most potent and prevalent, particularly up to menopause, at which time estrone becomes the predominant estrogen. Estradiol is produced in the ovarian follicles (theca cells and granulosa cells) under FSH stimulation, while the corpus luteum produces progesterone, estrogen, and inhibin under LH stimulation. In the ovaries, androgens are converted to estradiol and estrone. Estriol is a metabolite of estradiol and estrone. All estrogens are derived from androgens (FIGURE 8-10). Estrogen effects, like testosterone, are systemic. In the reproductive tract, estrogen is important in reproductive growth and maturation of the breast, uterus, fallopian tubes, and external genitalia. Nonreproductive effects include alteration of lipids, reduction of osteoclastic activity, inhibition of platelet adhesiveness, increases in collagen, maintenance of skin, and neuroprotection of memory and cognition. The lipid effects include increases in high-density lipoprotein and decreases in low- density lipoprotein; changes in osteoclastic activity includes reduction in bone breakdown; and skin maintenance refers to elasticity and healing.

FIGURE 8-10 Estrogen synthesis.

Progesterone is mainly secreted by the corpus luteum and in small amounts by the follicles. During pregnancy, the placenta secretes progesterone. Progesterone principally targets the uterus, breasts, and brain. Progesterone can have

antiestrogenic effects when progesterone levels are high (LH is inhibited) and estrogen is inhibited. Progesterone is used as a contraceptive because the estrogen inhibition prevents ovulation. Progesterone is a key hormone required in the maintenance of pregnancy because it allows the uterus to thicken (hypertrophy), prevents uterine contractions, prepares the breast for lactation, and protects the fetus from maternal antibodies.

The ovaries also contain the precursors to mature eggs (oocytes). During oogenesis, the oocytes mature into ova (mature eggs). By the 30th week of gestation, the female fetus has approximately 7 million follicles (biologic units, each containing a single oocyte). These 7 million follicles degenerate to approximately 2 million follicles by birth. By puberty approximately 400,000 follicles remain. Ova are not continually produced throughout a woman’s lifetime, which is a key difference from spermatogenesis. All the ova in the ovaries remain in a state of prophase for as long as 45 years. During the reproductive years, the follicles mature as they are exposed to pituitary hormones—specifically, FSH and LH. During the ovulation phase of the menstrual cycle, the mature follicle ruptures, releasing the mature ovum into the fallopian tubes (FIGURE 8-11). The ovum travels to the uterus for fertilization by the sperm. Meiosis completion in egg cells occurs during fertilization. Fewer than 500 of each woman’s ova mature and become fertile. Although approximately a dozen follicles begin developing during each cycle, usually only one makes it to ovulation. Multiple births (e.g., twins or triplets) may occur when more than one ovum is produced, released, and fertilized. Once the mature follicle releases the ovum, the empty follicle (called the corpus luteum) secretes progesterone to signal the endometrium to prepare for fertilization. The release of an older woman’s ova can result in abnormal meiosis and a higher risk for chromosomal abnormalities and congenital diseases. See chapter 1 for an explanation of prophase and meiosis.

FIGURE 8-11 The menstrual cycle.

Fallopian Tubes The fallopian tubes are two cylindrical structures that extend from the fundus of the uterus to near the ovaries. The ends of the tubes near the ovaries are fimbriated

(fringelike) to capture the ovum after ovulation. The tubes use a ciliary and muscular action to move the ovum toward the uterus as well as to assist sperm in moving from the uterus toward the ovum that is likely still in one of the tubes. If fertilization occurs, the same ciliary and muscular action moves the fertilized egg (zygote) from the tube to the uterus for implantation (FIGURE 8-12). Occasionally, the zygote does not reach the uterus but rather becomes implanted outside the uterus; this event is called an ectopic pregnancy. The most common site for ectopic pregnancies is the fallopian tubes. Ectopic pregnancies cannot develop normally and can be life threatening.

FIGURE 8-12 Fertilization and implantation of the embryo.

Uterus The uterus is a hollow, pear-shaped organ held in place by the broad, round, and uterosacral ligaments. Usually, the uterus is tilted forward (anteverted) over the bladder, but it is tilted backward (retroverted) in approximately 20% of women. A woman with a retroverted uterus is more likely to experience menstrual discomfort or pain with intercourse (i.e., dyspareunia), but she should not experience any unusual fertility issues.

During pregnancy, the fetus grows and develops inside the uterus. The thick uterine wall consists of three layers that serve to carry, nurture, and deliver the fetus.

Endometrium: The endometrium is the inner mucosal lining of the uterus, which undergoes hormonal changes to facilitate and maintain pregnancy. During pregnancy, the placenta (a vascular organ) develops to nourish the fetus through

the umbilical cord (which contains two arteries and one vein). The placenta attaches to the endometrium on one side and surrounds the fetus on the other (FIGURE 8-13). The uterus expels the placenta within a few minutes after birth. The endometrium is the lining that sheds during menses.

FIGURE 8-13 The developing placenta and embryo.

Myometrium: The myometrium is the middle layer of the uterus; it consists of smooth muscle and a vascular system. During pregnancy, the vascular system radically increases to support the fetus. During childbirth, the myometrium contracts to push the fetus out through the vaginal canal. After childbirth or abortion (spontaneous or induced pregnancy termination), this layer contracts to constrict blood vessels and control bleeding. Perimetrium: The perimetrium is the outer, serous layer that covers all of the fundus and part of the corpus, but none of the cervix (the narrow opening from the uterus to the vagina). The incomplete coverage of this layer allows for surgical access into the uterus without requiring an incision into the peritoneum (the membrane that lines the abdominal cavity). The cervical glands secrete a mucus that covers the cervical os (opening) to provide protection against organisms traveling to the upper reproductive structures (e.g., the uterus). The mucus changes with the menstrual cycle and around ovulation becomes clear, slippery, and can be stretched between the fingers. The mucus protects the sperm from the acidic vaginal environment and helps sperm to move through the cervix.

The menstrual cycle (Figure 8-11) is a series of monthly changes that begin at puberty and continue through the reproductive years. The average age of onset of menstruation (menarche) is approximately 13 years. Hypothalamus maturation and subsequent hormone increases trigger the menstrual cycle. Initiation of this cycle is marked by the onset of menstruation (shedding of the endometrium). The menstrual cycle is usually a 28-day cycle (ranges from 25 to 28 days) that consists of two phases—the proliferative/follicular (estrogen-dominated) and secretory/luteal (progesterone-dominated) phases. The follicular phase lasts approximately 14–21 days and starts with menses and ends before the surge of LH. The luteal phase lasts approximately 14 days and begins with the LH surge and ends with onset of the next menstrual cycle.

At the beginning of the follicular phase, estrogen and progesterone levels are low, causing GnRH stimulation and FSH and LH secretion from the anterior pituitary gland. FSH release leads to estrogen production, and the follicles develop with both hormones. The LH also starts to rise. The small, select group of follicles then secretes inhibin, which starts suppression of FSH. Increasing estrogen also suppresses FSH and LH. While the follicle is developing, estrogen starts prepping the uterus by causing proliferation and leading to an increase in stringy cervical mucus (i.e., spinnbarkeit).

Estradiol levels peak around one day before ovulation. Normally, high estradiol and progesterone levels would cause FSH and LH suppression due to negative

feedback mechanisms, but for poorly understood reasons, the reverse happens. The high hormone levels cause a positive feedback mechanism with increases in FSH and an LH surge. This surge marks the beginning of the luteal phase. About 36 hours after the LH surge, the oocyte is released from the follicle (i.e., ovulation occurs); it travels to the fallopian tubes, and the follicle becomes the corpus luteum. The remaining follicles are reabsorbed by the body. The corpus luteum secretes predominantly progesterone (referred to as the secretory phase) which causes several endometrial effects (e.g., maintaining thickened endometrium and glandular secretions).

At the end of the luteal (secretory) phase, the uterus is ready to receive and nourish a zygote. If fertilization does not occur, the LH and FSH start to decline, resulting in the corpus luteum producing less estrogen and progesterone. The corpus luteum atrophies (becomes corpus albicans). The thickened uterine lining sloughs off, signaling the beginning of menstruation. Menstruation expels the unfertilized ovum and maintains a healthy uterine lining that is prepared for fertilization.

If fertilization and pregnancy occur, the endometrium thickens, and vascularization develops. After implantation of the zygote (5–6 days after fertilization), the placenta secretes human chorionic gonadotropin to stimulate the corpus luteum to continue estrogen and progesterone production. The continued estrogen and progesterone production will suppress FSH and LH production, preventing further ovulation and menstruation. Human chorionic gonadotropin secretion continues until the placenta fully develops and begins making its own estrogen and progesterone, a phase that usually begins by the end of the first trimester.

The menstrual cycle continues to be repeated throughout a woman’s reproductive years until estrogen levels begin to decline with age. As a result of the decreased estrogen levels, ovulation and menstruation become less frequent and more erratic. This change in the menstrual cycle usually begins between 45 and 55 years of age. Menopause refers to the complete cessation of the menstrual cycle. In addition to changes in the menstrual cycle, the declining estrogen levels associated with menopause can cause the following manifestations:

Atrophy of the breasts and internal reproductive organs Decreased vaginal secretions (which can make sexual intercourse painful) Behavioral changes (e.g., irritability, anxiety, and depression) Headaches Insomnia (may be due to hot flashes, anxiety, or depression) Hot flashes (one of the hallmarks and most common symptom of perimenopause and menopause; usually worsens at night and causes sweating) Collagen decreases (results in increased wrinkling of skin)

Decreased bone density Increased cardiovascular risks

These manifestations can vary in severity, but in most cases, they are mild and improve with time. Hormone replacement therapy can decrease severity of the symptoms (particularly hot flashes), but careful consideration should be given prior to initiating such therapy because it is associated with an increased risk of breast cancer, thrombus (blood clot), and stroke.

Vagina The vagina is a hollow, tunnellike structure located between the bladder and the rectum and extends from the cervix to the external genitalia. This muscular canal is usually 2–4 inches in length, and it can expand in width (e.g., during parturition). The vagina serves as a passageway for sperm to travel to the fallopian tubes, for the body to discharge menstrual fluid, and to birth the fetus. Sperm enter the vagina when the male partner inserts his penis during sexual intercourse. Ejaculation propels the semen into this canal, where the sperm begin their journey to the fallopian tubes. In the mucosal lining of the vagina, Skene glands secrete a protective, lubricating fluid during sexual intercourse. Stimulation of the vagina can produce orgasm, but often clitoral stimulation is necessary, whether directly or indirectly, through vaginal intercourse. The vaginal wall is lubricated by the cervical mucous glands and transudate from the walls (the vagina has no mucous glands). The vagina is acidic due to normal bacterial flora production of lactic acid. This acidic environment serves a protective function against infections but is harmful to sperm. Adolescents have a more alkaline vaginal environment, placing them at greater risk for infections.

The vagina may contain a thin connective tissue that covers the external vaginal opening to some degree, called the hymen (FIGURE 8-14). All hymens have openings large enough to permit menstrual flow passage or tampon insertion, but the openings are generally too small to permit an erect penis to enter without tearing. Tearing of the hymen does not usually cause significant discomfort, but it may cause a few drops of blood to be noticed. In addition to sexual intercourse, physical activity can partially or completely tear the hymen; therefore, the absence or presence of the hymen is not a reliable indicator of virginity.

FIGURE 8-14 The various types of hymens.

External Genitalia The external female genitalia contain several structures that are collectively referred to as the vulva. These structures include the mons pubis, labia majora, labia minora, clitoris, and vestibule. The size, color, and shape of these structures as well as hair distribution and skin texture can vary significantly from person to person. The mons pubis is the pad of fat over the pubic bone (symphysis pubis) that becomes covered with hair after puberty. The labia majora are the two large, fatty skin folds that protect the perineum and aid in lubrication; they become prominent and darkened after puberty. The labia minora are two small, firm skin folds just inside the labia majora; they have a rich blood and nerve supply. The two labia minora connect at their upper portion to form the clitoris. The clitoris is very sensitive to stimulation and becomes filled with blood during sexual arousal, and stimulation of the clitoris is often required for orgasm. It contains two corpora cavernosa, similar to the penis. Bartholin glands lie just within the labia minora and provide lubrication during sexual intercourse. The vestibule refers to the area that contains the urethral and vaginal opening.

Mammary Glands The mammary glands are in the breasts. Although both males and females have mammary glands, they are functioning structures only in females. The mammary glands are not a reproductive organ per se, but they can have a role in sexual arousal and provide nourishment to the newborn. Each breast contains 15–20 clusters of milk-secreting mammary glands that open into the nipple. The mammary glands do not make milk unless stimulated to do so. Prolactin, a hormone released by the anterior pituitary gland, prompts milk production. During pregnancy, increased estrogen levels trigger prolactin secretion, which matures the mammary glands and

prepares them for milk production. After childbirth, prolactin secretion initially decreases as the estrogen levels return to nonpregnancy levels, but the newborn’s suckling then stimulates increased prolactin production.

Each breast in both sexes contains a nipple surrounded by an areola (area of pigmentation). The areolar glands (i.e., Montgomery glands) are sebaceous glands that produce secretions that protect and lubricate the nipple and areola during breastfeeding.

Congenital Disorders Abnormalities of the urinary and reproductive systems are the most common congenital defects. Because of these systems’ close relationship, an abnormality in one system will often lead to an abnormality in the other. Additionally, fetal development of both systems is intertwined. The reproductive system continues its development until birth; however, even though the system is formed at birth, it is incapable of reproduction until it matures during puberty. Numerous congenital disorders of the reproductive system are possible, most of which are structural problems. Sexual organs arise from the same fetal tissue, meaning the tissue that produces a penis in males will produce a clitoris in females. Therefore, the controlling factor are hormones, specifically androgens. The presence of male hormones leads to development of male reproductive organs while the absence leads to development of female reproductive organs. But if a fetus is genetically programmed to be male (XY) or female (XX) and the androgens are deficient (usually causes male development issues) or excessive (usually causes female development issues) disorders can result. Some disorders cause mild symptoms (e.g., epispadias and hypospadias), whereas others may cause infertility and gender ambiguity (e.g., testicular or ovarian agenesis).

Epispadias Epispadias refers to the condition in which the urethral meatus inner lining is exposed and occurs on the dorsal surface of the penis instead of the end (FIGURE 8-15). The urethral opening may extend the entire length of the penis. Additionally, the penis may be shorter, be wider, or have an abnormal curve. Epispadias is rare (1 in 117,000 newborn boys) and usually develops during the first month of gestation (Jayachandran, Bythell, Platt, & Rankin, 2011). This malformation can also affect females (1 in 484,000 newborn girls), with the meatus often being placed in the clitoris. Epispadias is more likely to cause urination problems in men and sexual dissatisfaction in women. Men with epispadias are not necessarily infertile, but they may have trouble propelling the semen adequately during ejaculation. Both males and females with epispadias are at increased risk for urinary tract infections.

FIGURE 8-15 Epispadias. (A) Male. (B) Female. Courtesy of Dr. Gavin Hart/CDC; Reproduced from Ebert, A., Reutter, H., Ludwig, M., & Rösch, W.H. (2009). The

exstrophy-epispadias complex. Orphanet Journal of Rare Diseases, 4, 23. doi:10.1186/1750-1172-4-23. Creative Commons license available at http://creativecommons.org/licenses/by/2.0.

Urinary defects, such as bladder exstrophy (in which part or all of the bladder is present outside the body) (FIGURE 8-16), often occur with this type of congenital condition. Classic bladder exstrophy occurs in 3.3 per 100,000 births. Along with exstrophy, other organ systems such as the reproductive tract, digestive system, pelvic bone, and muscles are often exposed. Exstrophy–epispadias complex (EEC) refers to a spectrum of congenital abnormalities that includes epispadias, classic bladder exstrophy, cloaca exstrophy (the bladder and intestines are exposed at birth), and several variations. EEC occurs due to a rupture of fetal tissue (the cloacal membrane), leading to an embryologic defect in abdominal wall development (the lower abdominal contents herniate). This defect occurs during the first trimester. The prevalence of this condition ranges from 1 per 10,000 births (EEC involving classic exstrophy) to 1 per 200,000 births (EEC involving cloaca exstrophy).

FIGURE 8-16 Bladder exstrophy. Photo from Ebert, A. K., Reutter, H., Ludwig, M., & Rösch, W. H. (2009). The exstrophy-epispadias complex.

Orphanet Journal of Rare Diseases, 4(1), 23.

The exact cause of epispadias and EEC is unknown, but these defects are thought to result from an event occurring early in pregnancy. Risk factors include parental history of epispadias or exstrophy (which carries a 500 times greater risk than the general population) and maternal factors including young age, high parity, and smoking.

Diagnosis of epispadias is typically made through a physical examination. Other procedures may be used to identify associated conditions and determine the severity of this congenital defect, including intravenous pyelogram (X-ray of the kidneys, bladder, and ureters using radioactive isotopes), pelvic X-ray, computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound of the urinary system and genital structures. The diagnosis can be made prenatally with an ultrasound. In males, surgical procedures may use the foreskin to repair the defect, but urinary incontinence is common in postoperative patients. In patients with EEC, the goal is to protect the external structures (e.g., prevent injury, cover with plastic wrap, and use mist tents) until repair can be done. Surgical repair of EEC may also include closure of the abdominal wall and urinary or intestinal diversions. Multiple procedures may be required to achieve the desired cosmetic outcome, urine flow control, and sexual function.

Hypospadias Hypospadias refers to the condition in which the urethral meatus is on the ventral surface of the penis instead of the end (FIGURE 8-17). According to the Centers for Disease Control and Prevention (CDC, 2016a), hypospadias is a commonly occurring congenital defect, affecting 5 out of 1,000 newborn boys. Like epispadias, hypospadias can vary in severity, and the opening can extend along the length of the penis or be located on the scrotum or perineum. Males with this condition may also have a downward curvature of the penis, called chordee, that becomes apparent with an erection. Hypospadias does not usually affect females. Hypospadias can occur with other congenital reproductive anomalies such as a bifid scrotum (lack of separation of labioscrotal fold) or cryptorchidism which can be the cause of gender ambiguity. This ambiguity may lead to inappropriate surgical gender assignment. Genetic studies prior to any gender assignment procedures can minimize this risk.

FIGURE 8-17 Hypospadias. Courtesy of K. Mae Lennon, Tulane Medical School; Clement Benjamin/CDC.

The exact cause of hypospadias is unknown, but it is thought to result from a disruption in androgen stimulation during development of the male external genitalia. The androgenic disruption is due to a combination of environmental exposure (e.g., medication exposure in utero) and genetic vulnerability. Risk increases with maternal factors such as age greater than 35 years, obesity, use of fertility treatments, and hormone therapy just before or during pregnancy.

Diagnosis of hypospadias is made through a physical examination. Imaging tests (e.g., MRI, CT, X-rays, and ultrasound) may be performed to identify other congenital defects. Surgical repair (often in stages) can improve the penis’s appearance as well as the patient’s urinary and sexual function. Surgery can be done as early as 4 months of age but should be undertaken before 18 months of age.

Cryptorchidism Cryptorchidism is a common congenital genitourinary tract condition in which one or both testes do not descend from the abdomen to the scrotum prior to birth (FIGURE 8-18). Cryptorchidism means hidden testis and can also include an absent testis or testes. The absence occurs because the testes never developed or they atrophied. A case of bilateral absent testes is termed anorchia. Usually the undescended testes remain along the path of descent, but they can also deviate from that path, which is

called ectopic testes. Approximately 2–5% of full-term males are born with one or two undescended testicles. Rarely, both testes are undescended. Risk factors for cryptorchidism include:

FIGURE 8-18 Potential sites for cryptorchidism.

Prematurity (birth before 37 weeks’ gestation) Low birth weight Small size for gestational age Multiple fetuses (e.g., twins) Family history of cryptorchidism or other problems of genital development Maternal estrogen exposure during the first trimester Maternal alcohol use during pregnancy Maternal cigarette smoking or secondhand smoke exposure during pregnancy Maternal diabetes (type 1 diabetes, type 2 diabetes, or gestational diabetes) Parental exposure to some pesticides

Occasionally, a testicle that descended normally by birth may disappear later in childhood, often due to muscular reflexes that develop in puberty. A retractile testicle moves back and forth between the scrotum and the lower abdomen due to the cremasteric reflex. In this case, the testicle is easily returned to the scrotum through gentle manipulation. An ascending testicle, or acquired undescended testicle, refers to a testicle that has returned to the lower abdomen and cannot easily be guided back into the scrotum.

Diagnostic procedures for cryptorchidism include a history, physical examination, self-testicular examinations (the condition places the individual at increased risk for testicular cancer later in life), abdominal ultrasound, MRI, laparoscopy (visualization using a small camera through a small abdominal incision), and open abdominal exploratory surgery. Additionally, hormone levels and genetic studies can distinguish potential causes and complications.

In most cases, the testes descend by 9 months of age without treatment; however, cryptorchidism treatment should be done by 6 months of age because the testes are unlikely to descend after this time. Early treatment prevents permanent damage to the testicles and improves fertility during later life. Testes that do not naturally descend into the scrotum before birth are considered abnormal, and the individual is at increased risk for cancer and infertility even with repair. Treatment strategies include the following measures:

Manual manipulation Hormonal therapy (specifically human chorionic gonadotropin and GnRH to induce descent) Surgical repair (either laparoscopic or open) such as orchidopexy (wherein a testicle is brought down in a pouch and stitched into place) Orchiectomy (testicle removal) Testicle implants Hormone replacement (specifically testosterone if the testicle is removed or damaged)

Infertility Issues Infertility describes a biologic inability to contribute to reproduction. The ability to conceive and support a fetus requires functioning male and female reproductive systems. If a couple has been unsuccessful in conceiving after 1 year of actively trying (unprotected sexual intercourse at least once monthly), they should consult a fertility expert.

Male problems that can lead to infertility include decreased sperm or sperm abnormalities (e.g., defects in spermatogenesis and abnormal sperm transport), hormone deviations (e.g., usually hypogonadotropic hypogonadism), and physical impediments. Hypogonadotropic hypogonadism is due to hypothalamus or pituitary disorders that cause GnRH or gonadotropin deficiencies. Spermatogenesis problems are usually idiopathic. Multiple disorders that are congenital (e.g., Klinefelter syndrome, cryptorchidism), genetic (e.g., Y chromosome defects), or acquired (e.g., varicocele, antisperm antibodies) can affect testicular spermatogenesis. Sperm transport issues can be caused by any disorder affecting structures that are involved and deliver sperm, such as the epididymis, vas deferens, and ejaculatory ducts.

Diagnostic procedures for infertility in males include a history, physical examination, sperm analysis, cultures of penal drainage if infection is suspected, hormone analysis (e.g., FSH, LH, thyroid-stimulating hormone, testosterone, and prolactin), and imaging studies (e.g., ultrasound and vasography). Genetic testing may also be indicated (e.g., Y and X chromosome defects and CFTR gene mutations).

The most common female infertility problem is ovulation dysfunction. Other female infertility problems include hormone deviations (e.g., hyperprolactinemia), transport disorders (e.g., stenosis or tumors of the fallopian tubes or cervix), uterine defects (e.g., endometriosis, positioning, and placenta development), and pelvic adhesions (fibrotic tissue that binds organs together). Normally, women who ovulate have monthly menses and molimina (i.e., bloating, breast tenderness, and dysmenorrhea). An ovulatory cause of infertility is indicated if menses and molimina are absent or irregular. Many conditions can cause ovulation dysfunction (e.g., extreme exercise, eating disorders, and hyperprolactinemia), and they can be categorized as hypothalamic-pituitary in origin or as being due to other systemic origins (e.g., polycystic ovarian syndrome, thyroid disorders, and Cushing disease). Disorders that affect transport of the oocyte and sperm can be caused by tubal disease and pelvic adhesions. Tubal disease is usually due to pelvic inflammatory disease caused by sexually transmitted infections. Uterine fibroids (leiomyomata) and endometriosis, which also cause ovarian tissue damage and impair ovulation, are some uterine disorders that cause infertility.

Diagnostic procedures for infertility in females include a history, physical

examination, ovulation testing, hysterosalpingography, ovarian reserve testing to determines the quality and quantity of eggs available, hormone analysis, imaging studies, and genetic testing. Hysterosalpingography is an X-ray of the uterus with radioactive isotopes; hormones analyzed can include FSH, LH, thyroid-stimulating hormone, prolactin, estrogen, and progesterone; and imaging studies can include ultrasound and hysterosonography.

Treatment for infertility includes the following measures:

Lifestyle modifications (e.g., weight loss, stress reduction, and smoking cessation) Endocrinopathies Human chorionic gonadotropin, GnRH, testosterone, and estrogen supplements, estrogen modulator Estrogen receptor blockers (increase GnRH secretion) Dopamine agonists (inhibit prolactin release) Gonadotropins (stimulate gonadal steroid hormones)

Immunotherapy for males with antisperm antibodies Alpha-sympathomimetic agents for males with retrograde ejaculation (closes the bladder neck) Collagen injections to the bladder neck Sperm treatment to wash and concentrate sperm Antimicrobial therapy if infection is present Coenzyme Q (may increase sperm quantity and quality) Metformin (decreases insulin resistance, making ovulation more likely to occur) Intrauterine insemination Tubal and uterine tumors/adhesions (removal of the tumor, breaking up adhesions) In vitro fertilization

Disorders of the Penis Disorders of the penis can result in erectile issues as a result of vascular, neurogenic, or psychological issues. Penile disorders can impair urinary functioning such as those due to foreskin issues and sexual functioning. These disorders can be a manifestation of an underlying systemic disorder or due to local trauma or infection. Most can be managed with medications and surgery. Some penile disorders can potentially lead to penile necrosis and emergent care is necessary.

Erectile Dysfunction Erectile dysfunction (ED), or impotence, refers to the recurring or consistent inability to attain or maintain a penile erection sufficient to complete sexual intercourse. Other sexual dysfunction disorders include diminished libido and abnormal ejaculation (e.g., premature). A decreased libido usually coexists with other sexual dysfunction, and most causes are the same as ED. The most common sexual disorder is ED. Although ED can occur at any age, it commonly starts around the age of 40 and becomes more of a problem in older men. Risk factors associated with ED development include obesity, smoking, sedentary lifestyle, and obstructive sleep apnea. Infrequent sexual intercourse (e.g., less than once per week) may be associated with or a consequence of higher ED risks. ED can be transient or permanent, depending on the etiology.

An erection results from psychological, neurologic, and vascular processes, as well as hormonal influences. ED can result from dysfunctions in any of these areas. Psychological causes include anxiety, depression, guilt, stress, and relationship issues. Normally, the brain receives perceived sensual input (e.g., visual erotic images and auditory stimuli) and signals are sent to an erection center in the spinal cord (T11–L2); there is also a sacral erection center (S2 to S4). The spinal cord then sends signals to divert blood to the corpora cavernosa. Neurologic disorders stroke, multiple sclerosis, or dementia can result in ED. Disruption in testosterone will cause decreased libido and ED. Testosterone maintains nitric oxide levels, which are a requisite for acquiring and maintaining an erection. Nitric oxide causes cavernosal relaxation so that blood flow is maximized, and the penis can engorge. Nitric oxide promotes the nucleotide cyclic guanosine monophosphate. This nucleotide causes smooth muscle relaxation with vasodilation and increased blood flow. The phosphodiesterase 5 enzyme inhibitors (e.g., sildenafil [Viagra]) prevent the breakdown of cyclic guanosine monophosphate. Cigarette smokers and patients with diabetes mellitus have low nitric oxide levels. Thyroid disorders such as hypothyroidism can alter testosterone production and prolactin disorders such as hyperprolactinemia can suppress gonadotropin secretion and thereby suppress testicular function both resulting in ED.

In addition to nitric oxide, a requisite for acquiring and maintaining an erection is

adequate arterial blood flow. Cardiovascular disorders (e.g., arteriosclerosis and hypertension) are often associated and a common cause of ED. Cardiovascular disorders and ED have similar risk factors, and ED may even be an early warning sign of cardiovascular disease. Hyperlipidemia, diabetes mellitus, and smoking cause vascular dysfunction and, therefore, can lead to ED. In these disorders, endothelial dysfunction is the mechanism causing ED.

Pelvic trauma and prostate surgery can cause vascular and neurologic interruption and lead to ED. Pharmacotherapeutic agents can cause ED. Some common categories include antihypertensives, antidepressants, antipsychotics, and antiandrogens. Use of alcohol and other recreational substances such as cocaine can cause ED. Penile anatomic issues can cause ED such as those caused by Peyronie disease. In Peyronie disease a fibrotic plaque forms on the tunica albuginea (i.e., connective, fibrous tissue that surrounds the corpora cavernosa). The cause is unknown, but genetic predisposition, trauma, and local ischemia can lead to plaque formation. The plaque that develops leads to a curved or bent penis, a mass, pain, and ED. Peyronie disease can resolve without treatment or remain stable. Treatment can include oral pentoxifylline (nonspecific phosphodiesterase inhibitor) or intralesional injections with collagenase (breaks up collagen deposits). Penile traction therapy can be used in conjunction with medications.

Diagnostic procedures for ED consist of a history and physical examination. If the ED began suddenly and abruptly, the cause is usually psychogenic unless there is trauma or surgery associated with potential ED. If a man has ED but has nocturnal erections, a vascular and neurologic cause are more likely in comparison to a psychogenic cause. Detumescence after penetration is also usually psychological (e.g., anxiety). Laboratory evaluation usually begins with identifying common causes (e.g., cardiovascular disorders, diabetes mellitus) with glucose testing, a lipid profile, and testing thyroid hormone and testosterone levels. Comprehensive metabolic testing should also include an evaluation of the liver and kidney. Additional hormone analysis (e.g., sex hormone binding globulin, prolactin, and LH) may be necessary depending on clinical findings (e.g., gynecomastia and visual field defects). Nocturnal penile tumescence testing can be done to evaluate for psychogenic versus physiologic ED. This test can even be done with a monitoring device in a patient’s own home during sleep. Ultrasound (e.g., of the penis and testicles, as well as transrectal ultrasound) and dynamic infusion cavernosometry and cavernosography may be necessary and can determine areas of vascular disorder, such as arterial obstruction or venous leakage. Cavernosography involves an X-ray of the penis after injecting contrast dye into penile blood vessels. A variety of treatment options are available, some of which are costly and are not covered by most insurance plans. When ED has a physiologic origin, identifying and resolving the cause is the priority. Treatment strategies include the following measures:

H

Psychological counseling Testosterone replacement Phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil [Cialis], and vardenafil [Levitra]) Other medications (e.g., adrenergic antagonists) Herbal remedies (e.g., ginkgo, ginseng, and saw palmetto) Prostaglandin E injections directly into the corpus cavernosum or intraurethral insertion (similar to a suppository) Penis pumps or vacuum devices Surgical penile implants Vascular surgery

Just as with estrogen replacement in women, testosterone replacement must be carefully considered prior to initiating therapy because it is associated with an increased risk of myocardial infarction, stroke, and prostate cancer.

Phimosis and Paraphimosis Phimosis occurs when the foreskin cannot be retracted from the glans penis. Physiologic phimosis—not being able to retract the foreskin—is common during the first 3 years of age, but the foreskin should become retractable as the child grows. Pathologic phimosis can result from poor hygiene, infections, and inflammation. Elderly men are at risk of this condition due to loss of skin elasticity and infrequent erections. Phimosis can lead to urinary obstruction and pain.

Diagnostic Link

Laboratory Evaluation of Hypogonadism ypogonadism results in low testosterone levels and sperm production. Several laboratory tests can be done to determine whether the issue is due to primary disorder indicating disease of the testes or

secondary disorder indicating disease of the pituitary or hypothalamus or a combination of both. Testosterone levels are normally highest in the early morning and slowly decline throughout the day. To be accurate, serum measurements should be done in the morning. Total testosterone is a measure of bound and free testosterone and is often the initial test to evaluate for testicular hypofunction. Free testosterone is a reflection of unbound active (i.e., bioavailable) testosterone. Low total and/or free testosterone is consistent with hypogonadism. Determination of whether the hypogonadism is primary or secondary often requires additional laboratory evaluation. Sex hormone binding globulin (SHBG) levels reflect the bound testosterone (some is also bound to albumin). Low levels of SBHG occur with common disorders such as obesity, insulin resistance, and type 2 diabetes mellitus. High levels of SHBG occur with aging and common disorders such as high estrogen levels and liver disease. High levels can result in less available free testosterone (i.e., more testosterone is bound to SHBG). Low levels mean there is more available unbound testosterone; however, testosterone levels can still be low, indicating possible hypogonadotropism. Gonadotropic hormone levels influencing testosterone levels include FSH, LH, and prolactin and are a reflection of pituitary response to changing testosterone levels. FSH and LH measurements can distinguish between primary and secondary hypogonadism. Low total and/or free testosterone with high FSH and LH is consistent with primary hypogonadism. Low testosterone and/or free testosterone with low FSH and LH (which may be inappropriately normal) is consistent with secondary hypogonadotropic hypogonadism. Elevated prolactin levels inhibit gonadotropin release and reflect secondary

hypogonadotropic hypogonadism.

Paraphimosis refers to a condition in which the foreskin is retracted and cannot be returned over the glans penis. Paraphimosis may occur when the foreskin is forcibly retracted or when the patient or caregiver does not replace the foreskin during hygiene. In paraphimosis, the penis becomes constricted and the glans becomes edematous. If paraphimosis is not resolved, the lack of blood flow can lead to local skin necrosis and, rarely, infarction and gangrene, making it a medical emergency.

Treatment strategies for paraphimosis includes manual reduction, which requires pain control and swelling reduction or surgeries such as emergency circumcision and dorsal slit reduction, which involves cutting a constricting band of foreskin. Elective circumcision can be considered after the resolution of paraphimosis. Phimosis can be treated with circumcision, topical steroid cream, and foreskin stretching.

Priapism Priapism is a prolonged (usually 4 hours or more), painful erection. The unwanted, unrelenting erection is not a result of sexual stimulation. Priapism usually results from too much blood shunting within the corpus cavernosum (referred to as nonischemic or high-flow priapism). Nonischemic priapism is usually caused by penile or perineal trauma. The more common type of priapism is due blood becoming trapped in the penis (referred to as ischemic or low-flow priapism). In ischemic priapism, the smooth muscles’ relaxation is impaired, causing a compartment syndrome (i.e., increased pressure in a confined space). Nitric oxide dysfunction may be a mechanism for some priapism disorders. Priapism is most common in boys between 5 and 10 years old and in men 20 to 50 years of age. Priapism occurs in conjunction with a variety of blood, circulatory, and nervous dysfunctions, including:

Sickle cell anemia (the most common cause in pediatric cases) Leukemia and other hematologic disorders (e.g., multiple myeloma) Trauma (e.g., bicycling, urologic procedures) Tumors (e.g., prostate, bladder, and renal carcinomas; melanoma) Diabetes mellitus and other metabolic disorders (e.g., gout) Spinal cord injuries Neurologic diseases (e.g., multiple sclerosis and stroke) Medications (e.g., phosphodiesterase inhibitors, anticoagulants, and antianxiety agents) Alcohol and illicit drugs (e.g., cocaine, ecstasy, and marijuana) Poisonous venom (e.g., from a scorpion or black widow)

Diagnostic procedures can identify the type of priapism. They include a history, physical examination, penile arterial blood gases, complete blood count (CBC), and toxicology tests. With ischemic priapism, a Doppler ultrasound will show minimal or absent blood flow, so this test is useful in differentiating the two types of priapism. Other tests may be necessary to look for underlying disorders such as a CT or MRI for tumors. An erection lasting more than 4 hours is considered a urologic emergency warranting immediate medical attention. Without medical attention (urgent urologic consultation), priapism can lead to ischemia, necrosis, ED, and infertility, and the likelihood of complications is associated with the duration of the priapism. Nonischemic priapism does not usually lead to long-term issues.

Treatment focuses on managing the underlying cause and varies depending on the type of priapism. Strategies for ischemic (low-flow) priapism include the following:

Needle aspiration of blood Injection of medications directly into the penis (e.g., alpha-adrenergic sympathomimetic agents) Surgical placement of a shunt

Strategies for nonischemic (high-flow) priapism include the following:

Cold application Lower abdominal pressure Surgical repair of trauma

Additional interventions regardless of type include the following:

Analgesics Sedation Hydration Urinary catheterization

Disorders of the Testes and Scrotum Disorders of the testes and scrotum are usually structural in origin, and some can cause infertility (e.g., cryptorchidism). These disorders can be acquired or congenital, and most can be resolved with minimal residual effects. Infectious causes are discussed with sexually transmitted infections.

Hydrocele A hydrocele is an accumulation of fluid between the layers of the tunica vaginalis (the membrane covering the testes) or along the spermatic cord (FIGURE 8-19). This condition can affect one or both testes. A hydrocele often occurs as a congenital defect, affecting approximately 10% of newborn males. In this case, the vas deferens does not close properly as the testes descend into the scrotum and peritoneal fluid drains from the abdomen. A congenital hydrocele usually disappears without treatment by 1 year of age. An inguinal hernia—a condition in which a section of the intestine passes through the abdominal wall—commonly occurs in infants with hydroceles. In adults, hydroceles are commonly idiopathic. An acquired hydrocele occurs because of inflammation, infection, trauma, and tumors.

FIGURE 8-19 Hydrocele.

Hydroceles are usually painless, but the scrotum feels heavy. The fluid

accumulation can be small or large, sometimes liters. The swelling generally worsens over the course of the day. This scrotum enlargement can be differentiated from other testicular disorders by transillumination (transmission of light through tissue). Hydroceles will transilluminate, whereas solid tumors will not (FIGURE 8-20).

FIGURE 8-20 Transillumination of hydrocele. © SPL/Science Source.

Diagnostic procedures for hydroceles consist of a history, physical examination (including transillumination), and ultrasound. In most cases, the hydrocele resolves without any action other than treating the underlying cause. Strategies to encourage reabsorption of the fluid include scrotal elevation on a rolled towel, sitz baths (warm- water treatments for the perineum), and heat/cold application. Large amounts of fluid can compromise testicular blood flow, requiring aspiration, but surgical removal (hydrocelectomy) of the hydrocele sac is preferred due to recurrence with aspiration.

Spermatocele A spermatocele is a benign, sperm-containing cyst that develops between the testis and the epididymis (FIGURE 8-21). If it is < 2 cm, it is called an epididymal cyst. Usually the cyst is painless, soft, and small, but it can grow quite large, leading to

increased discomfort. Additionally, the cyst is moveable and may transilluminate light. The exact cause of this common condition is unknown, but it is thought to be caused by a blockage of the duct system, infection, inflammation, or trauma. Diagnostic procedures are similar to those for hydroceles. The cyst usually does not cause problems but may require surgical removal (spermatocelectomy) if it is large.

FIGURE 8-21 Spermatocele.

Varicocele A varicocele is a dilated vein in the spermatic cord (FIGURE 8-22). Much like varicose veins in the leg, this condition results from valve issues that allow blood to pool in the veins. These valve issues can be caused by congenital defects (e.g., incompetent or absent valves) or obstructions (e.g., tumors and thrombi). Varicoceles are more common in men ages 15–25 (typically appear around puberty) and are often seen on the left side of the scrotum. For unknown reasons, they occur more frequently in infertile men (approximately 40% greater risk). Additionally, varicoceles are the most common cause of low sperm counts and decreased sperm quality because of testicular ischemia. Varicoceles that appear suddenly in an older man may be caused by a renal tumor that has blocked blood flow.

FIGURE 8-22 Varicocele.

Varicoceles are much more common (approximately 80–90%) in the left testicle than in the right testicle because of several anatomic factors. These factors include the angle at which the left testicular vein enters the left renal vein, a lack of effective antireflux valves at the left testicular and renal vein juncture, and increased renal vein pressure. Unilateral right varicoceles are rare and are more likely to be due to obstruction (e.g., renal vein thrombosis and inferior vena cava obstruction) as the right gonadal vein empties into the inferior vena cava. Some varicoceles may be asymptomatic while some may cause mild pain that is described as dull and aching. Extensive varicoceles can be tender and painful. The dilated veins give the scrotum a bag-of-worms feeling upon palpation, and the blood pooling may give a sense of

heaviness in the scrotum. The testicular heaviness and pain are usually present when standing, and lying down relieves the symptoms. To palpate or visualize smaller varicoceles, a Valsalva maneuver (i.e., bearing down) may be necessary, and varicoceles can disappear in a lying position. The testicle can atrophy due to an increased scrotal temperature. Additionally, men with varicoceles may experience fertility issues.

Diagnostic procedures for varicoceles are similar to those for hydroceles. In suspected underlying pathology (e.g., thrombosis), a CT of the abdomen with contrast is usually done. Treatment is often unnecessary unless the varicocele causes discomfort, impairs semen, or if testicular atrophy occurs, particularly in men who want to continue to have children. Treatment strategies include scrotal support (e.g., wearing briefs or a jock strap), surgical repair (open or laparoscopic), embolectomy, and sclerotherapy (injection of an irritant into the vein that causes the vessel to harden and fade).

Testicular Torsion Testicular torsion refers to an abnormal rotation of the testes on the spermatic cord (FIGURE 8-23). Sudden scrotal edema and pain develop as the twisting compresses the blood vessels (reduces arterial flow and obstructs venous outflow), leading to ischemia and necrosis. Immediate treatment is required to restore blood flow and minimize testicular damage. After approximately 12 hours, irreversible ischemic damage can occur. Scrotal pain can also be due to torsion of the appendix testis or appendix epididymis (each a small tissue appendage left from embryonic development). These appendages are pedunculated and can also twist resulting in torsion. Torsion of the appendix testis or appendix epididymis is more likely in boys between 7 and 12 years of age.

FIGURE 8-23 Testicular torsion.

Testicular torsion is more common during the first year of life with another peak

incidence at puberty and up until the age of 18. It is most frequently caused by trauma, but it can also occur after strenuous exercise or spontaneously, especially in males whose testicles are not secured in the scrotum due to congenital differences. The primary manifestation is sudden, severe testicular pain (usually unilateral) with or without a predisposing event. Other manifestations may include scrotal swelling, nausea, vomiting, dizziness, and hematospermia (bloody semen). In children, nighttime testicular pain can be a sign of testicular torsion, possibly due to nocturnal sexual stimulation and cremasteric contractions. Physical exam findings may reveal a negative cremasteric reflex (normally when the inner thigh is stroked the testicle contracts up) and a testicular mass. The testicle can be high up (due to spermatic cord shortening), and instead of being longitudinal, the testicle may be in a transverse position (i.e., bell clapper deformity).

Diagnostic procedures include a history, physical examination, testicular Doppler ultrasound to determine blood flow, and scrotal ultrasound, which will reveal absent blood flow to the affected testicle. With appendage torsion, blood flow will be normal or even increased due to the inflammation. Surgery will be required to treat testicular torsion and should be performed within 6 hours to prevent testicular necrosis. Manual manipulation by rotating the testicle gently away from the midline may be used to untwist the testes, but surgery will be required to secure the testicle (orchiopexy) and prevent recurrence. Appendage torsion usually resolves within 10 days without surgery.

Disorders of Pelvic Support Muscles, ligaments, and fascia normally support the bladder, uterus, and rectum in the female pelvis (Figure 8-5; Figure 8-6). These supportive structures weaken with age, excessive stretching (e.g., due to childbirth and chronic constipation), obesity, and trauma (e.g., large baby, forceps delivery, and hysterectomy). Decreasing hormone levels at the onset of menopause can further atrophy these structures. With weakened support, the organs can shift out of normal position, causing pelvic organ prolapse (i.e., herniation) into the vaginal walls.

Traditionally, pelvic organ prolapse has been categorized based on physical examination findings and presumptive organ prolapse (e.g., cystocele refers to bladder prolapse). Physical examination findings can be misleading, and a posterior collapse, which is usually associated with a rectal prolapse, may be due to another organ. Therefore, pelvic organ prolapse is preferably described based on the site that the prolapse is visualized rather than the suspected organ prolapse. These categories include:

Anterior compartment prolapse: Usually associated with cystocele (i.e., bladder prolapse) Posterior compartment prolapse: Usually associated with rectocele (i.e., rectal prolapse) Apical compartment prolapse: Usually associated with uterine and cervical prolapse or the vaginal vault after hysterectomy

Other organs than can prolapse include the intestines (i.e., enterocele, sigmoidocele) and the urethra (i.e., urethrocele). In many women, more than one organ is affected.

Clinical Manifestations Women can be asymptomatic or have symptoms related to the prolapsed organs. Pelvic organ prolapse often causes vaginal, urinary, defecatory, and sexual dysfunction. Most women will complain of vaginal or pelvic pressure (e.g., rectal pressure) and report a sensation of something coming out of their vagina. If the prolapse is beyond the vaginal opening (i.e., introitus), a woman may even see the organ (e.g., cervix). The urinary symptoms are the result of the organ (usually anterior or apical prolapse) kinking the urethra. This partial blockage results in variable symptoms of obstructions such as incomplete emptying, urine coming out slowly, or weak stream. Due to the variable obstruction symptoms, changing position or splinting may improve urine flow. Stress incontinence and overactive bladder symptoms (e.g., urgency and frequency) also occur. These urinary symptoms predispose women to cystitis (i.e., bladder infections). During sexual intercourse,

urine can leak, and enuresis can also occur. Problems with defecation can occur with any type of prolapse because any of the organs cause pressure as they prolapse. Chronic constipation can even cause prolapse. However, bowel dysfunction is more common with posterior and apical prolapse (e.g., rectocele and uterine prolapse). The bowel symptoms include incomplete emptying and constipation. Due to difficulties with fecal emptying, applying pressure with a finger in the vagina or perineum can facilitate evacuation. Fecal incontinence, while not common, can occur with or without sexual intercourse. Pelvic organ prolapse may cause pain with sexual intercourse (i.e., dyspareunia) and women may avoid sexual activity due to concerns about incontinence or embarrassment regarding their body image.

When conducting a physical examination for pelvic organ prolapse, a woman is usually in a dorsal lithotomy position. The prolapse may be evident immediately upon visualization of the introitus or may be seen while the woman performs a Valsalva maneuver. The prolapse may be evident in a supine position. A bulge seen in the anterior wall (superior) of the vagina is classified as anterior compartment prolapse (FIGURE 8-24); a bulge of the posterior wall (inferior) of the vagina is classified as a posterior compartment prolapse; and visualization of the cervix descending into the vaginal vault (canal) is classified as an apical compartment prolapse. The simplified Pelvic Organ Prolapse Quantification can be used by general clinicians to grade the severity of the organ prolapse. This system involves measurements along anatomic points in the vagina.

FIGURE 8-24 Cystocele. © Dr. P. Marazzi/Science Source.

Diagnosis and Treatment Diagnosis is usually made on findings of the history and physical examination. Diagnostic procedures are generally used to evaluate for bladder or bowel dysfunction. In asymptomatic women, treatment is not necessary. Treatment strategies include Kegel exercises (isometric exercises to strengthen the pelvic muscles) and avoidance of straining. A vaginal pessary device (a vaginally inserted ring that supports the bladder) is a nonsurgical option. A pessary must be removed and cleaned routinely. The effectiveness of estrogen therapy (if the woman is postmenopausal) is controversial. Incontinence interventions can include bladder training and protective garments. Various surgical options, such as vaginal mesh, are available.

Menstrual Disorders The menstrual cycle can vary from woman to woman. The duration and the amount of menstrual bleeding fluctuate to some degree, but a standard pattern can be expected. The usual duration of menstruation is 4–8 days, and the usual amount of bleeding for the entire menstruation is usually ≤ 80 mL. The frequency ranges from 24 to 38 days. The normal menstrual cycle can be associated with pain and cramping (i.e., dysmenorrhea). The normal menstrual cycle can also be associated with various physical and emotional symptoms (i.e., premenstrual syndrome). A comparison can be made to a patient’s baseline menstrual cycle if there is a complaint of a menstrual abnormality.

Menstrual disorders can encompass abnormalities in menstrual bleeding, dysmenorrhea, or premenstrual syndrome. Some menstrual disorders may be a manifestation of a minor, easily treatable problem, while other menstrual disorders are an indication of a serious problem.

Abnormal Uterine Bleeding Abnormal uterine bleeding (AUB) is defined as a menstrual bleeding abnormality in the frequency of a cycle, volume of blood loss, or duration of flow. AUB also includes precocious puberty—menstrual bleeding prior to the usual start of menses. AUB is generally a manifestation of an underlying disorder. AUB generally presents as vaginal bleeding and refers to the uterus as the source of the bleeding. However, other genital tract sources can cause vaginal bleeding, including the cervix, the vaginal vault, the vulva. Urinary (e.g., hematuria) and gastrointestinal (e.g., rectal bleeding) disorders can be mistaken for uterine bleeding.

In 2011, the Menstrual Disorders working group of the International Federation of Gynecology and Obstetrics revised AUB terminology (Munro, Critchley, Broder, & Fraser 2011). The new terms replaced commonly used terms such as menorrhagia, metrorrhagia, polymenorrhea, and hypermenorrhea, which lacked a clear definition and led to confusion pertaining to diagnosis and treatments. As an example, menorrhagia was used in several ways to describe heavy menstrual bleeding regardless of timing (e.g., regular, irregular, or random). Dysfunctional uterine bleeding, often used to describe AUB, is also considered an outdated term. The new terminology has been an attempt to create a common language and definitions for describing AUB internationally. The new terminology has been adopted in the United States. Amenorrhea is a term that continues to be used. Menstrual bleeding key classifications are as follows:

Chronic AUB: Uterine bleeding that has been abnormal in frequency, regularity, duration, and/or volume for at least the majority of the past 6 months. Acute AUB: A single episode of uterine bleeding (in a woman of reproductive

age and nonpregnant) that is of sufficient quantity to require immediate intervention to prevent further blood loss. Heavy menstrual bleeding (HMB): Increased menstrual volume (daily or total monthly) as perceived by the woman and that interferes with various aspects of her life (e.g., physical or social). Intermenstrual bleeding (IMB): Menstrual bleeding that occurs between regular, well-defined cyclical menses. IMB can be random or predictable. Amenorrhea: Absence of menses.

Abnormal uterine bleeding causes can often be differentiated by age or reproductive transitions. The ages are divided as premenarche, early menarche, reproductive age, menopausal transition (i.e., perimenopause), and menopause. These categories exclude pregnancy-related AUB. The mechanism and causes of AUB are extensive and can include hormonal disorders, anatomic alterations, iatrogenic effect, systemic disorders, or a combination of several mechanisms.

Amenorrhea Amenorrhea refers to the absence of menstruation. With this condition, menstruation may have never occurred or may have ceased. Amenorrhea is considered primary if menstruation has not occurred by 16 years of age. However, an evaluation for disorders should be carried out earlier than 16 if growth and sexual development (e.g., breast development and pubic and axillary hair) are absent. Genetic or anatomic abnormalities are the usual causes of primary amenorrhea, and the mechanism involves the hypothalamus, pituitary gland, ovaries, or other parts of the genital tract. Hypothalamic and pituitary tumors result in abnormal GnRH levels. Stress, sudden weight loss, and extreme reduction in body fat (such as caused by eating disorders or incurred by athletes) is termed functional hypothalamic amenorrhea as there is no underlying pathologic disease. Ovarian disorders can cause primary amenorrhea as a result of abnormal ovarian development (i.e., dysgenesis) due to disorders such as Turner syndrome. Congenital abnormalities can cause vaginal disorders such as transverse vaginal septum and vaginal agenesis, or they can cause uterine developmental disorders such as uterine agenesis. A simple defect that can occur without other disorders and causes amenorrhea is an imperforate hymen. A minor surgical procedure to perforate the hymen can be performed to allow normal menstrual flow.

Secondary amenorrhea is defined as absence of menses for more than 3 months in a female who had regular menstrual cycles or absence of menses for 6 months in a female who had irregular menses. Oligomenorrhea (i.e., infrequent menstrual bleeding) is defined as fewer than nine menstrual cycles per year or a cycle length that is longer than 35 days. The causes of oligomenorrhea are the same as for secondary amenorrhea. Oligomenorrhea is usually an anovulatory bleeding

pattern. The most common cause of secondary amenorrhea is pregnancy during reproductive age and menopause (average onset age 51)—both normal physiologic conditions. Lactation will also cause amenorrhea. Pathologic causes of secondary amenorrhea, as with primary amenorrhea, include hypothalamus, pituitary, ovarian, or other genital tract disorders. Hypothalamic and pituitary disorders could be due to tumors (e.g., prolactinoma) and infiltrative diseases (e.g., sarcoidosis). Systemic diseases (e.g., histiocytosis and hemochromatosis) can lead to altered GnRH levels and subsequent secondary amenorrhea. Functional hypothalamic amenorrhea due to the same causes as in primary amenorrhea (e.g., stress and weight loss) can cause secondary amenorrhea. Ovarian disorders include ovarian tumors or, more often, primary ovarian failure or insufficiency at an early age (< 40 years). The causes of primary ovarian failure can include ovarian autoimmune destruction, dysgenesis, medication effects (e.g., from chemotherapy), or environmental toxins. Often the cause of primary ovarian insufficiency is unknown. Polycystic ovarian syndrome is a complex disorder with multiple hormonal alterations and can be a cause of secondary amenorrhea. A uterine cause of secondary amenorrhea is known as Asherman syndrome (i.e., intrauterine adhesions). The adhesions and scarring in the endometrial lining are usually the result of instrumentation (e.g., during dilatation and curettage or ablation).

Heavy and Intermenstrual Bleeding HMB is one the most common types of AUB, and the terms are often used interchangeably even though amenorrhea is included in the AUB definition. The most common causes of HMB and IMB vary depending on whether the woman is pregnant, of reproductive age, or experiencing perimenopause or menopause. The causes of HMB and IMB in nonpregnant females can be categorized by the PALM- COEIN system. PALM refers to structural disorders, and COEIN refers to nonstructural disorders. The acronym refers to the following disorders:

P polyps (endometrial or cervical tumors that are usually benign) A adenomyosis (endometrial type glands within the endometrium) L leiomyoma (benign tumors of the uterine smooth muscle) M malignancy (e.g., leiomyosarcoma [cancerous uterine tumor]) and

hyperplasia (abnormal thickening of the endometrial lining, which may lead to uterine cancer)

C coagulopathy (bleeding disorders such as von Willebrand disease) O ovulatory dysfunction (lack of ovulation due to several disorders or unknown

reasons [e.g., stress, weight change, and thyroid disorders]) E endometrial disorder (primary disorder of the endometrium that usually

causes regular, cyclic menses that are most likely ovulatory) I iatrogenic disorder (result of medications [e.g., estrogen, progestin, and

A

androgens] or intrauterine devices) N not yet classified

During perimenopause, the menstrual cycle changes due to a normal physiologic reduction in ovarian hormone secretion that occurs with aging. However, AUB can also occur due to underlying pathology, and the most likely causes include structural disorders such as polyps, fibroids, and adenomyosis. Malignant disorders such as uterine cancer or leiomyosarcoma are more prevalent with aging.

Any bleeding after menopause (i.e., 1 year without a menstrual cycle) is considered abnormal. The causes often include endometrial polyps and malignant disorders. Hormone replacement therapy can also cause postmenopausal bleeding.

Learning Points

Menstruation in Early Menarche UB can be seen the initial 1–2 years after menarche. During this time, missed menses and infrequent menses, and even episodes of heavy menstrual bleeding can occur and are not necessarily a reflection of

an abnormality. Commonly this abnormal pattern is due to an immature hypothalamic-pituitary-ovarian axis. These patterns are generally anovulatory; however, the transition to ovulatory, regular menses is not known and pregnancy can occur.

Dysmenorrhea Dysmenorrhea is painful menstruation. Most women experience some mild lower abdominal cramping during menstruation, but with dysmenorrhea, the cramping pain impairs usual daily activities. The pain begins at the conclusion of ovulation and continues through menstruation. Primary dysmenorrhea may appear in early menarche and often has no known etiology. Dysmenorrhea may also appear later in life secondary to a number of conditions (e.g., endometriosis or reproductive cancers). In many cases of dysmenorrhea (especially the primary type), the condition resolves following childbirth and decreases with aging. The pathogenesis of dysmenorrhea, particularly primary, is excessive prostaglandin secretion which produces strong uterine muscle contractions and blood vessel constriction, intensifying the normal uterine ischemia associated with menstruation. These contractions and ischemia generate strong, intermittent abdominal pain that can radiate to the back, legs, and perineum. Excessive prostaglandins can also cause nausea, vomiting, diarrhea, headaches, and dizziness. Diagnostic procedures may be performed to identify the dysmenorrhea and underlying cause—specifically, a history, physical examination, pelvic ultrasound, laparoscopy, and hysteroscopy. Treatment strategies focus on relieving the discomfort and resolving the underlying etiology. These strategies include analgesics (especially nonsteroidal anti- inflammatory drugs [NSAIDs] because they inhibit prostaglandin secretion), oral contraceptives (which prohibit ovulation), and heat application or warm baths.

Premenstrual Syndrome Premenstrual syndrome (PMS) refers to a group of physical and emotional symptoms that affect women during the menstrual cycle. Most women experience symptoms similar to PMS. The criteria for diagnosis of PMS, however, is the presence of at least one symptom that causes dysfunction (economic or social) 5 days before menstruation and is present for three consecutive menstrual cycles. PMS occurs more often in women between their late 20s and late 40s who have at least one child, a personal or family history of major depression, and a history of postpartum depression or affective mood disorder. The pathogenesis of PMS is poorly understood. During the luteal phase of the menstrual cycle (Figure 8-11), estrogen and progesterone are thought to normally cause neurotransmitter changes, particularly serotonin. PMS occurs during the luteal phase, so estrogen and progesterone levels are normal; however, there is possibly an abnormal response to the neurotransmitters.

Clinical manifestations of PMS include irritability, depression, mood swings, fatigue, headache, abdominal bloating, changes in bowel pattern, joint pain, breast tenderness, weight gain, and sleep disturbances. Premenstrual dysphoric syndrome is a severe form of PMS that is characterized by severe depression, tension, and irritability. Diagnostic procedures for PMS center on a thorough history (focusing on gynecologic complaints) and physical examination. Treatment strategies are individualized and often include hormone therapy such as oral contraceptives, diuretics, antidepressants (especially selective serotonin reuptake inhibitors), analgesics (specifically NSAIDs), and lifestyle measures (e.g., stress reduction regular exercise). Additional measures such as dietary changes (e.g., small frequent meals, decreasing sodium and sugar, or reduction in soda and caffeine) have yielded inconsistent results. Likewise, supplementation with vitamin B6, calcium, magnesium, or primrose oil lack data regarding efficacy.

Disorders of the Uterus The uterus is a crucial organ for reproduction in females. Conditions that affect the uterus include benign or malignant tumors, congenital disorders, infections, and hormonal imbalances that may affect menstruation and fertility. Benign and malignant tumors can include leiomyomas and leiomyosarcomas; congenital disorders can include abnormal uterine positioning and uterine agenesis; and infections can include endometritis and pelvic inflammatory disease.

Endometriosis With endometriosis, the endometrium tissue begins growing and forming lesions in areas outside the uterus. Although such ectopic endometrial tissue most commonly occurs in the fallopian tubes, ovaries, and peritoneum, it can be found anywhere in the body. The endometrial lesions can be superficial or deep and are made of stromal and endometrial glands (like normal endometrial tissue). The abnormal endometrial tissue continues to act like normal endometrial tissue would during menstruation—thickening, breaking down, and bleeding—even though it is outside the uterus. The endometrial lesions, however, are estrogen dependent and resist the effects of progesterone. Without an outlet, the blood becomes trapped and irritates the surrounding tissue. Pain, cysts, scarring, and adhesions develop because of the inflammation, with the scarring and adhesions resulting in altered ovarian function, impaired fertilization, and implantation.

The exact cause of endometriosis is unclear, but numerous theories have been proposed. One theory holds that menstrual blood containing endometrial cells flows back through the fallopian tubes (called retrograde menstruation), takes root, and grows. Another theory proposes that the bloodstream carries endometrial cells to other sites in the body. Other theories speculate that a predisposition toward endometriosis may be carried in the genes of certain families or an inappropriate immune response may contribute to endometriosis development. Still other theories suggest that certain cells that are responsible for embryonic reproductive development are present within the abdomens of some women and these cells retain their ability to become endometrial cells under genetic or environmental influences later in life.

Risk factors for endometriosis include early onset of menstruation, late onset of menopause, nulliparity, short menses cycles (≤ 27 days), heavy menstrual bleeding, low body mass index, being tall (> 68 inches), severe physical or sexual abuse during childhood or adolescence, and disorders that obstruct menstrual flow.

Clinical Manifestations Clinical manifestations depend on the severity of the endometriosis but often worsen

as the endometriosis progresses (FIGURE 8-25). Most cases are diagnosed in patients between 25 and 35 years of age. Clinical manifestations are due to the inflammatory response and anatomic abnormalities. The types of manifestations are dependent on the lesion locations. The manifestations of endometriosis include the following:

FIGURE 8-25 Stages of endometriosis.

Dysmenorrhea—dull or crampy pelvic pain or pressure that begins before menses, lasts throughout menses, and can persist for a few days after the end of menses Low back pain Bowel dysfunction (e.g., dyschezia [pain with bowel movements], diarrhea, and constipation) Urinary dysfunction (e.g., frequency, urgency, and dysuria) Pain during or after sexual intercourse Infertility Adnexal (ovarian, fallopian tubes, or supporting ligaments) mass Pain during vaginal examination Uterus or cervix immobility or displacement upon pelvic examination

Diagnosis and Treatment Diagnosis is usually made with a history, physical examination, and pelvic ultrasound. A laparoscopy confirms the diagnosis. Treatment strategies focus on minimizing discomfort and maximizing childbearing potential (if desired) and includes:

Analgesics (particularly NSAIDs) Hormone therapy (e.g., estrogen and progestin together, progestin monotherapy, GnRH agonists and antagonists, and danazol) Surgical repair (laparoscopy or hysterectomy)

Leiomyomas A leiomyoma, or uterine fibroid, is a firm, rubbery growth of the smooth muscle of the myometrium (FIGURE 8-26). Leiomyomas are the most common benign pelvic tumors in women, and they are classified according to their location (FIGURE 8-27). At least 25% of women have symptomatic leiomyomas, but as many as 70% of all women have fibroids by the age of 50 (Zimmerman, Bernuit, Gerlinger, Schaefers, & Geppert, 2012). Leiomyomas are more frequent in Blacks, and the reason for this higher incidence is unknown. Other risk factors include obesity, advancing age, hypertension, and nulliparity. Other factors such as high consumption of red meat, low vitamin D levels, and alcohol are possibly associated. The cause of leiomyomas is unknown, but tumor growth is monoclonal—involving the expansion of a single cell. Most tumors seem to grow during the menstruation years in the presence of estrogen and shrink after menopause. Tumor growth was thought to increase during pregnancy, but recent research suggests that growth actually levels off during

pregnancy. Leiomyomas usually occur as multiple, well-defined, unencapsulated masses.

FIGURE 8-26 Leiomyomas. © ChaiwatUD/Shutterstock.

FIGURE 8-27 Leiomyoma classification.

Clinical Manifestations Most leiomyomas are asymptomatic and go undetected. Clinical manifestations depend on the leiomyoma size, which can range from microscopic to weighing

several pounds, and location. The growing fibroid can cause pressure on adjacent structures. Pressure from the fibroid can result in symptoms such as pelvic pain, bladder dysfunction, dyspareunia, and constipation.

Heavy menstrual bleeding (volume and/or duration) and the passage of clots can cause dysmenorrhea. Risk for heavy menstrual bleeding usually occurs with submucosal and intramural fibroids, but the risk is low with subserosal fibroids. Degenerating fibroids can cause pelvic pain. Although they do not usually interfere with fertility, leiomyomas do increase the risk of spontaneous abortion and preterm labor slightly. The risk for fertility and pregnancy problems increases as the tumor size increases. Physical examination findings consistent with a leiomyoma include an enlarged, mobile, and irregularly shaped uterus. Leiomyomas that have prolapsed or are on the cervix can be infrequently seen during a vaginal speculum exam. A large, fixed, immobile uterus or one that is rapidly enlarging may be due to a malignant tumor such as leiomyosarcoma instead of a benign leiomyoma

Diagnosis and Treatment Diagnosis is made with a history, physical examination, and pelvic and transvaginal ultrasound. A CBC is done to evaluate for anemia. Other diagnostic procedures can include hysteroscopy (uterine endoscopy), biopsy (to rule out malignancy), laparoscopy, and MRI. Most leiomyomas are harmless and do not require treatment. Symptom severity and childbearing intentions should be considered when choosing treatment options. Treatment strategies include simple monitoring. Hormone therapy (e.g., GnRH agonists/antagonists and progestin) can be used to shrink the fibroid and reduce symptoms. Oral contraceptives with estrogen-progestin (i.e., combined) can be used to reduce risk of fibroid development and menstrual bleeding, but the combined hormones may cause fibroid growth. Other treatment strategies include analgesics such as NSAIDs; surgery such as myomectomy or hysterectomy; myolysis (laparoscopic laser treatment); endometrial ablation, which uses heat to destroy the uterine lining; and uterine artery embolization, which obstructs uterine blood supply. Additionally, anemia treatment may be necessary.

Disorders of the Ovaries A variety of benign and malignant conditions can affect the ovaries. Ovarian disorders can be congenital, such as hypogonadism and Turner syndrome, or acquired, such as ovarian cancer, but many have a genetic basis. While some disorders, such as functional cysts, are simple, others, such as polycystic ovarian syndrome, are complex and cause systemic issues. Ovarian disorders can affect the woman’s hormonal balance and fertility status.

Ovarian Cysts Ovarian cysts are benign, fluid-filled sacs on the ovary. Often the cyst forms during the ovulation process when a follicle or follicles are stimulated. Instead of the dominant follicle releasing the egg, the fluid stays in the follicle or the nondominant follicles do not get reabsorbed or regress, creating a follicular cyst. Inadequate development of the corpus luteum can cause a corpus luteum cyst. Because these cysts form during normal physiologic events, they are termed functional cysts. Follicular cysts are more common, but corpus luteum cysts can cause more symptoms. Other ovarian cysts include dermoid cysts (i.e., ovarian teratoma), which develop from ovarian germ cells. While the functional and dermoid cysts are benign, a small number (< 3%) of dermoid cysts can become malignant. In most cases, they disappear without treatment. On occasion, however, they rupture, causing discomfort. This common condition most frequently occurs during the childbearing years. Complications are rare, but ovarian cysts can lead to hemorrhage, peritonitis, infertility, and amenorrhea.

When present, abdominal pain or discomfort is the most prevalent clinical manifestation. Pain occurs when the cyst bleeds, ruptures, twists, or exerts pressure on nearby structures. Pain may also be associated with bowel movements and sexual intercourse. Other clinical manifestations include abnormal menstrual bleeding and abdominal distention. A mass on the ovaries may be felt if the cyst has not completely collapsed. Although rare, ovarian cysts can cause an ovarian torsion (similar to testicular torsion), cutting off blood flow and leading to potential for ovarian necrosis. Prompt recognition of ovarian torsion (the patient has acute, severe unilateral pelvic pain) and emergency surgery are necessary.

Diagnosis is accomplished with a history and physical examination. Human chorionic gonadotropin should be performed to assess for pregnancy, particularly ectopic pregnancy. A pelvic and transvaginal ultrasound or an MRI may be necessary. If the imaging studies reveal masses with malignant characteristics, then a biopsy is necessary. A CBC can evaluate for anemia due to bleeding. A CA-125 serum biomarker can evaluate for ovarian cancer. Evaluation for different tumors in the ovary, such as germ cell tumor, may be accomplished by measuring various serum markers (e.g., alpha fetoprotein or inhibin).

Treatment strategies for benign cysts can include simply following up to evaluate for cyst changes such as enlargement. Most cysts resolve without treatment. Oral contraceptives can reduce the incidence of cyst development. An ovarian cystectomy (removal of a cyst from an ovary) or oophorectomy (removal of ovary) may be necessary.

Polycystic Ovary Syndrome Polycystic ovary syndrome (PCOS) is considered one of the most common endocrine disorders, affecting approximately 5 million women of reproductive age (CDC, 2019). The syndrome is characterized by functional ovarian hyperandrogenism (present in 90% of women with PCOS) and insulin-resistant hyperinsulinemia (present in 50% of women with PCOS) leading to menstrual and ovulatory dysfunction (FIGURE 8-28). The pathogenesis is complex, and the etiology is mostly unknown and theoretical. The syndrome is thought, however, to begin in utero with a resulting congenital dysfunction that causes a predisposition to subsequent development of PCOS. The congenital factors can be hereditary or acquired. The congenital dysfunction predominantly affects the ovaries. In congenitally predisposed individuals, epigenetic and environmental factors (e.g., obesity and insulin resistance) result in PCOS.

FIGURE 8-28 Unified minimal model of PCOS pathophysiology. (A) Ovarian hyperandrogenism is nearly universal in PCOS and can account for all the cardinal clinical features of the syndrome: hyperandrogenemia,

oligo-anovulation, and polycystic ovaries (1). Pituitary LH secretion is necessary to sustain the ovarian androgen excess but is not sufficient to cause it. (B) About half of patients with functional ovarian hyperandrogenism have

insulin-resistant hyperinsulinism (2). Insulin-resistant hyperinsulinism acts on theca cells to aggravate hyperandrogenism, synergizes with androgen to prematurely luteinize granulosa cells, and stimulates

adipogenesis. The increased hyperandrogenemia provokes LH excess (3), which then acts on both theca and luteinized granulosa cells to worsen hyperandrogenism. LH also stimulates luteinized granulosa cells to secrete estradiol (4), which suppresses FSH secretion. These hyperinsulinism-initiated changes in granulosa cell function further exacerbate PCOM and further hinder ovulation. Obesity increases insulin resistance, and the resultant increased hyperinsulinism further aggravates hyperandrogenism. Heaviness of lines and fonts represents

severity. Both functional ovarian hyperandrogenism and insulin resistance typically have an intrinsic basis. This model does not exclude the possibility that the unknown intrinsic ovarian defects that underpin the ovarian steroidogenic dysfunction also involve granulosa cell folliculogenesis as well. The figure also does not depict

other associated defects, such as the functional adrenal hyperandrogenism that often accompanies the ovarian hyperandrogenism and the contribution of excess adiposity to peripheral androgen production and gonadotropin

suppression.

The syndrome manifestations become evident during puberty and adolescence. During puberty, GnRH release normally occurs, triggering LH release and FSH release. The LH release stimulates the ovarian theca cells to produce androgens (e.g., androstenedione). The FSH release stimulates ovarian granulosa cells to produce estrogen. Ovarian theca androgens are important as they are precursors for estrogen production and fertility (follicle growth and development). The balance between the theca cell androgen production and granulosa cell estrogen production, despite triggering by LH and FSH, is regulated within the ovaries. Theca cell and granulosa cell factors respond to androgen and estrogen levels and basically ignore or respond to LH and other mediators (e.g., inhibin). Small contributions of androgens also come from the adrenal glands.

In PCOS, the dysfunctional ovarian theca cells are overly sensitive to LH and oversecrete androgens. The excessive androgens also affect the granulosa cells as they normally rely on the theca cell coordination to start progesterone and continue preovulatory follicle development. The excess androgens cause the growth of a lot of small follicles. Increased LH causes premature luteinization of the follicle (the one that would have been dominant) and the follicle does not mature. This results in oligo-anovulation. While ovarian dysfunction is primary in PCOS, the excess androgen production also causes an impairment in the GnRH negative feedback mechanism, causing more GnRH secretion. As a result, LH secretion increases, and the ovaries respond by producing more androgens. It is theorized that most likely androgen excess leads to LH excess rather than LH excesses causing androgen excesses. LH causes increased abnormal secretion of estradiol, which in turn suppresses FSH. Therefore, FSH levels are usually low. In a small number of women with PCOS (8%) androgen excesses are due to isolated primary functional adrenal hyperandrogenism. Some women have a combination of both ovarian and adrenal dysfunction causing hyperandrogenism.

Insulin-resistant hyperinsulinemia is the second most common characteristic of PCOS and is present in approximately 50% of patients. The insulin resistance causes a compensatory excess insulin secretion (hyperinsulinemia). In PCOS, the muscle is resistant to the metabolic effects of insulin but the ovaries, fat tissue, and adrenal glands remain responsive to insulin; in other words, they are not resistant. The insulin perpetuates theca and granulosa cells to produce more androgens and more small follicles. Hyperinsulinemia contributes to obesity. The reason for obesity in PCOS is not well understood.

Inherited traits and disorders that increase risk for PCOS development include abnormal ovarian morphology (form), elevated testosterone, sex-binding hormone globulin, and metabolic syndrome (e.g., defects in insulin resistance and obesity). Various genetic markers are being evaluated (e.g., DENND1A [DENN domain- containing protein 1A], which encodes a protein that is overexpressed and leads to increased steroid hormone production). A maternal history of PCOS is also a risk for PCOS development.

There have been multiple definitions and criteria for describing PCOS since the syndrome was first recognized in 1935. In 2012, an NIH evidence-based methodology workshop was conducted on PCOS (Johnson, Kaplan, Ouyang, & Rizza, 2012). At the workshop criteria were developed for four different phenotypes (observable characteristics from the genotype) for PCOS in adults:

Phenotype (classic PCOS): Hyperandrogenism, oligo-anovulation, and polycystic ovary Phenotype 2 (hyperandrogenic anovulation): Hyperandrogenism with oligo- anovulation Phenotype 3 (ovulatory PCOS): Hyperandrogenism with a polycystic ovary but without ovulatory dysfunction Phenotype 4 (nonhyperandrogenic PCOS): Oligo-anovulation and a polycystic ovary

The severity of hyperandrogenism, menstrual disorders, and symptoms decreases from phenotype 1 to phenotype 4. Criteria for adolescents with PCOS varies somewhat from adult criteria as menstrual disorders and other hyperandrogenic symptoms (e.g., acne) are common and can be normal during adolescence. The criteria for PCOS in adolescence is as follows:

Abnormal uterine bleeding pattern that is not explained by other disorders and is abnormal for gynecologic developmental age. Symptoms persistent (e.g., > 1 year). Evidence of hyperandrogenism—persistent testosterone elevation, moderate to severe hirsutism, and moderate to severe inflammatory acne.

Clinical Manifestations There are multiple potential causes, and the various phenotypes result in different clinical manifestations. Functional ovarian hyperandrogenism is the cause of most clinical features in PCOS. The clinical manifestations as a result of excess androgens include:

Skin manifestations—hirsutism (abnormal facial and body hair), acne, and male pattern baldness Menstrual disorders—infrequent menses (oligomenorrhea) and anovulation; episodes of heavy menstrual bleeding can occur Obesity Ovarian cysts—usually multiple and small

Polycystic ovary syndrome increases the risk for developing obesity, insulin resistance, diabetes mellitus, dyslipidemia, and cancer (especially endometrial and breast cancers). Women may also have a higher incidence of sleep apnea, depression, or nonalcoholic fatty liver disease.

Diagnosis and Treatment Diagnosis of PCOS is accomplished with a history, physical examination, and hormone levels (e.g., testosterone, LH, FSH, and estradiol). A transvaginal ultrasound may reveal cysts. The absence of cysts does not rule out PCOS, and the presence of cysts does not confirm diagnosis. Additional tests can evaluate for glucose and lipid abnormalities (e.g., hemoglobin A1c, lipid panel, etc.).

Weight loss with diet and exercise may improve symptoms and ovulation. Hormonal therapy (e.g., combined oral contraceptives and progestin-only treatment) will improve symptoms of hyperandrogenism, regulate menses, and protect the endometrium from hyperplasia. Spironolactone can be added to the oral contraceptives to further lower androgen levels. Metformin can be used to improve insulin sensitivity and can restore ovulation. Fertility issues need to be addressed, and ovulation can be induced (e.g., with clomiphene). Any other complications (e.g., depression) or manifestations of the disorder should also be treated.

Disorders of the Breasts Breast disorders can be benign (e.g., fibrocystic breast disease) or malignant (e.g., breast cancer). Most breast disorders are not life threatening; however, malignancies should always be ruled out when breast symptoms are noted. These conditions can affect lactation, breastfeeding, and self-image.

Benign Breast Masses Benign breast masses are often detected by palpation and/or on imaging studies such as a mammogram. Breast masses can occur anywhere in breast tissue such as the ducts, lobules, and connective tissue. While many masses are benign, some are associated with an increased risk of breast cancer. Breast masses are categorized based on their tissue type, which includes nonproliferative lesions, proliferative lesions without atypia, and lesions with atypical hyperplasia. The types of common masses included in these categorization and risk of breast cancer are as follows:

BOX 8-1 Application to Practice Abnormal uterine bleeding is a common gynecologic complaint. Review the following scenarios and determine a likely cause and describe the mechanism that leads to the abnormal bleeding pattern.

Scenario 1: A 13-year-old girl is having episodes of amenorrhea and infrequent menses. Her menarche was at the age of 12, she denies being sexually active, and a urine pregnancy test is negative.

Scenario 2: A 60-year-old woman who has been in menopause for 5 years is having episodes of menstrual bleeding for the past 2 months. She said sometimes it is just spotting but at times she has worn a small sanitary pad. She is overweight and says despite her efforts she struggles to lose weight.

Scenario 3: A 21-year-old woman is having episodes of amenorrhea and infrequent menses. Her menarche was at the age of 14 and her menses have sometimes been regular. She is overweight and says despite her efforts to lose weight, she does not do so. She is generally very healthy otherwise and the only medication she is taking is doxycycline for acne, which she feels is getting worse. She said her mother’s menstrual pattern was the same and that her mother told her she had trouble getting pregnant (the patient is an only child). She is sexually active, her partner uses condoms consistently, and her urine pregnancy is negative.

Nonproliferative: The most common type of masses are breast cysts, which are usually fluid-filled masses that can be solitary, multiple, or in clusters. Cysts are classified as simple, complex, and complicated. The cancer risk for each type of cyst is as follows: simple cyst not associated with cancer; complex rarely

associated with cancer (< 1%); and complicated with slightly higher association with cancer than others (1–23%). Fibrocystic changes or fibrocystic disease are terms that are commonly used by clinicians in reference to nonproliferative disease, but this description encompasses many types of breast masses and therefore is nonspecific. Proliferative without atypia: The most common type of breast mass overall is a fibroadenoma, which is a solid mass containing glandular and fibrous tissue that can be solitary or multiple. Simple fibroadenoma are not associated with an increased cancer risk, while complex fibroadenomas confer a slightly increased risk. Atypical hyperplasia: These masses can be ductal or lobular and are associated with ductal carcinoma in situ or lobular carcinoma in situ, respectively.

There are many other breast masses that are considered benign, such as lipomas, fat necrosis (mass that occurs after trauma), galactoceles (masses caused by obstructed milk ducts), and adenomas. There are also many benign breast masses usually associated with low or varying risks for breast cancer, such as ductal papillomas (solitary or multiple) and sclerosing adenosis (lobular mass), Masses can become more prominent and painful during menstruation because of hormone fluctuations. During perimenopause and menopause, hormonal changes and lobular decreases can result in increased breast masses. Although the exact cause is unknown, the condition is thought to be a result of hormones. Breast cysts are more frequent during the childbearing years than in the postmenopausal years.

Clinical Manifestations Clinical manifestations of breast masses can include changes such as increases in size or pain before or during menstruation. The breast mass can be solitary (most common) or multiple or occur in clusters. Some masses are large while others are small. The mass can feel smooth or firm and is often discrete (distinct or separate). The consistency can be rubbery, squishy, grapelike, and even hard. Physical examination findings alone are insufficient to determine whether a mass is benign or malignant. Nipple discharge is not common with benign breast masses, and any discharge that is spontaneous, persistent, or bloody is consistent with breast cancer.

Diagnosis and Treatment Diagnostic procedures for breast masses consist of a history with a focus on breast cancer risk and a physical examination. Masses are evaluated with an ultrasound, which by itself is often sufficient for women < 30 years of age. Further testing, however, regardless of age, is dependent on the ultrasound findings. A biopsy to rule out breast cancer can be done with fine needle aspiration, core biopsy (a piece of

mass removed), or excisional biopsy (whole mass is removed). Mammograms are often done, particularly for older women with masses. Usually no treatment is required for masses that have no risks for cancer. When necessary, treatment strategies are largely symptomatic and include needle aspiration of fluid, surgical removal of cysts, analgesics (e.g., NSAIDs or acetaminophen), a supportive bra, heat/cold application, limitation of dietary fat, and avoidance of caffeine and chocolate (although research is inconclusive about this strategy). Vitamin E, vitamin B6, magnesium, and evening primrose oil may improve symptoms, but the use of these supplements remains controversial. Additionally, oral contraceptives can minimize symptoms. Danazol is an androgen that can reduce breast nodules and pain but is associated with significant side effects (e.g., weight gain, irregular menses). Due to these androgenic side effects, danazol is usually reserved for women who have severe pain not responsive to other treatments. Benign breast masses that are associated with a risk of breast cancer need to be monitored more often. Chemoprevention with use of drugs such as selective estrogen modulators (e.g., tamoxifen) can be considered; however, risks and benefits should be thoroughly evaluated.

Mastitis Mastitis refers to an inflammation of the breast tissue that can be associated with infection and lactation. This condition usually develops within 6 weeks of childbirth. In most cases, a staphylococcal or streptococcal bacterium is introduced to the nipple through the breastfeeding process, but mastitis can also occur in the absence of lactation or breastfeeding. Impaired nipple or skin integrity increases the likelihood of mastitis developing. The infection usually invades the breast’s fatty tissue, triggering an inflammatory response (e.g., edema, redness, warmth). The edema puts pressure on the milk ducts, causing pain and palpable lumps. Despite popular belief to the contrary, breastfeeding can occur in the presence of mastitis, but it may be uncomfortable. In some cases, however, flow of milk may become blocked and abscesses can develop.

Clinical manifestations usually appear suddenly and include the following signs and symptoms:

Breast tenderness, swelling, redness, and warmth (FIGURE 8-29)

FIGURE 8-29 Mastitis. Courtesy of Sarah Coulter-Danner.

Breast lumps Pain or a burning sensation continuously or while breastfeeding Flulike symptoms (e.g., fever, malaise, chills, nausea, and vomiting) Nipple discharge (usually purulent) Enlarged nearby axillary lymph nodes

Diagnostic procedures for mastitis include a history, physical examination, and cultures of drainage and/or breastmilk. Treatment strategies consist of antibiotic therapy, adequate hydration, rest, analgesics (e.g., acetaminophen and NSAIDs), supportive bra, heat/cold application, adequate milk expression, and needle aspiration. During treatment, breastfeeding is safe and should be encouraged (except if the mother is human immunodeficiency virus [HIV] positive).

Reproductive Tract Infections Infections can occur anywhere along the reproductive tract or organs. There are various modes of transmission. Infections can arise from the urinary system or be sexually transmitted. Some infections are due to alterations in the host such as an alteration in vaginal flora seen in candidiasis. Many of the infections are easily resolved with treatment, however some infections are lifelong and periodic exacerbations can occur. Infections that are untreated can have detrimental effects such as infertility.

Prostatitis Prostatitis refers to inflammation of the prostate, which can be either acute or chronic. Prostatitis may be caused by a variety of conditions (e.g., bacteria, sperm, trauma, stress, and urinary catheter) that trigger the inflammatory process. Normally, the prostate has protective mechanisms to prevent ascending infection such as the flushing action of urination and ejaculation. Additionally, it contains secretions that have an antimicrobial action (possibly attributable to their zinc content). However, owing to its close proximity to the urinary system, urethra, or bladder, bacteria can migrate through the prostate ducts, and there is intraprostatic reflux of urine. The most common pathogen causing prostatitis is gram-negative Escherichia coli. Prostatitis is more common in young and middle-aged men and those in immunocompromised states. Prostatitis with epididymitis and urethritis leads to sexually transmitted infections (especially chlamydia and gonorrhea).

Prostatitis is classified into four categories.

Category 1: Acute bacterial prostatitis Usually seen in younger men Usually results from a urinary tract infection (often E. coli) or sexually transmitted (often N.gonorrhoeae and C. trachomatis) Least common Easiest to diagnose and treat, but can be life threatening

Category 2: Chronic bacterial prostatitis Usually results from recurrent urinary tract infection Relatively uncommon Persists longer than 3 months Indolent (causes little to no pain)

Category 3: Chronic prostatitis/chronic pelvic pain No clear etiology and may be inflammatory or noninflammatory No bacteria are present, but immune cells can be found Most common and least understood Manifestations last longer than 3 months; can disappear and reappear without

warning Category 4: Asymptomatic inflammatory prostatitis No clear etiology No bacteria are present, but immune cells can be found May be associated with infertility

Clinical Manifestations Clinical manifestations of prostatitis vary depending on the type. These manifestations include the following signs and symptoms:

Dysuria Difficulty urinating, such as dribbling or hesitancy Urinary frequency and urgency Nocturia Pain in the abdomen, groin, lower back, perineum, or genitals Painful ejaculation Indications of infection such as fever, chills, and myalgia (with acute bacterial prostatitis) Recurrent urinary tract infections (with chronic bacterial prostatitis)

Diagnosis and Treatment Diagnostic procedures for prostatitis consist of a history, physical examination (including a digital rectal examination), and urine gram stain and culture. Men with acute bacterial prostatitis are acutely ill (e.g., fever and malaise), and symptoms are not subtle as in chronic forms of prostatitis. The digital exam with acute prostatitis should be performed gently as a vigorous exam can result in bacteremia. The exam is also very painful. The prostate will also be edematous. With acute prostatitis, the urine will be positive for pyuria (white blood cells) and bacteriuria. Treatment strategies include long-term antibiotics. Hospitalization may be necessary for those with presumptive bacteremia or urinary retention. A urinary catheter should not be inserted with acute prostatitis due to the risk of septicemia and rupture of a prostatic abscess, if present. Abscesses should be suspected when treatment has been delayed or when symptoms do not improve with antibiotic therapy. Diagnosis of an abscess can be confirmed with a transrectal ultrasound of the prostate or a CT scan.

Diagnostic tests for chronic prostatitis include urine and prostatic fluid samples. The prostate fluid sample culture will be positive for pathogens in chronic bacterial prostatitis. The urine sample may be negative or positive for pathogens. Other diagnostic procedures may include cystoscopy, urodynamic studies, CT scan, or transrectal ultrasound, which may reveal prostatic calculi.

Treatment strategies for chronic bacterial prostatitis, as with acute, include long-

term organism-specific antibiotic therapy, analgesics (e.g., NSAIDs and acetaminophen), antipyretics, adequate hydration, and sitz bath. Other strategies can include treatment for urinary symptoms (e.g., alpha blockers and anticholinergics), and acupuncture and extracorporeal therapy may be beneficial for chronic pelvic pain.

Epididymitis Epididymitis describes an inflammation of the epididymis, the duct connecting the testes to the vas deferens. It is a common cause of scrotal pain in adults. Ascending bacterial infections or sexually transmitted infections usually initiate this inflammatory process. Bacteria, most commonly E. coli and Pseudomonas aeruginosa, frequently spread to the epididymis from the urinary system. Urinary tract infections, particularly from obstructions due to benign prostatic hypertrophy or other urethral strictures, are the most frequent etiology in men > 35 years of age. Gonorrhea and chlamydia are the typical sexually transmitted culprits (TABLE 8-2). Sexually transmitted infections are more frequent in men < 35 years of age. In boys (prior to puberty) or adolescents who are not sexually active, the causative organisms are usually viruses (e.g., adenoviruses) or atypical bacteria such as Mycoplasma pneumoniae. Men who engage in insertive anal sex, regardless of age, are at risk of epididymitis due to enteric bacteria (e.g., E. coli). The urethral or bladder bacteria ascend from the vas deferens to the epididymis. Some other causes of epididymitis include Mycobacterium tuberculosis and the antidysrhythmic medication amiodarone (Cordarone). Mycobacterium results in chronic epididymitis with symptoms of pain in the scrotum, testicle, or epididymis lasting longer than 6 weeks and should be suspected in those with a history of tuberculosis or recent exposure. Risk factors for developing epididymitis include the following conditions:

TABLE 8-2 Sexually Transmitted Infections

Disease characterization Common STI pathogens

Urethritis, cervicitis Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium

Epididymitis N. gonorrhoeae, C. trachomatis Men engaging in insertive anal intercourse: Escherichia coli

Pelvic inflammatory disease* N. gonorrhoeae, C. trachomatis, M. genitalium

Prostatitis N. gonorrhoeae, C. trachomatis

Vaginal discharge Trichomonas vaginalis

Ulcers Treponema pallidum (syphilis) Herpes simplex virus 1 and 2 (genital herpes)

Condyloma (warts) Human papillomavirus type 6 and type 11 (Condyloma acuminata) T. pallidum (condyloma lata)

*Often polymicrobial

Being uncircumcised Recent surgery or a history of structural problems in the urinary tract Urinary catheterization Sexual intercourse with more than one partner and failure to use condoms

The inflammatory and infectious process can lead to abscesses, fistulas (the cutaneous scrotal type), infertility, testicular necrosis, and chronic epididymitis.

Clinical Manifestations Clinical manifestations of epididymitis reflect the inflammatory and infectious processes:

Indicators of infection (e.g., fever, chills, and myalgia) Testicular tenderness (acute onset) and edema; can develop scrotal wall erythema (epididymo-orchitis) and fluid accumulation (like a hydrocele) Prehn sign (elevating the scrotum relieves pain) Penile discharge Bloody semen (i.e., hematospermia) Painful ejaculation Dysuria Groin pain

Diagnosis and Treatment Diagnostic procedures for epididymitis focus on identifying the causative agent and consist of a history, physical examination, urinalysis, cultures (urine and penile discharge), and sexually transmitted infection testing particularly for gonorrhea and chlamydia. Treatment strategies center on eliminating the infection and decreasing discomfort. These interventions include the following measures:

BOX 8-2 Application to Practice Epididymitis and testicular torsion are both causes of scrotal pain. Testicular torsion requires prompt recognition and surgical intervention to avoid testicular damage. Epididymitis is easily managed with antibiotics. Differentiation between the two disorders is important. Review the case and answer the questions.

Case: A 15-year-old presents to the emergency department complaining of sudden onset of right-sided

1. a. b.

2. a. b.

3.

a. 1. b. 2. c. d.

4. a. b. c. d.

5.

scrotal and groin pain. He states the pain is constant and extreme. He said it started about 2 hours ago during basketball practice at school, but he denies any trauma to the scrotum. He is worried that he has a sexually transmitted infection as he just started having sexual intercourse with his girlfriend and he did not use condoms. He says he feels nauseated and thinks he is going to vomit. He said he noticed this same pain once before, but it went away within a few seconds and he did not tell anyone.

Vital signs: Temperature 98.9° F; pulse 100 beats per minute; respirations 20 breaths per minute; blood pressure 120/70 mmHg.

Physical examination reveals a healthy-appearing adolescent who is anxious and grimacing. The patient has edema and erythema of his right scrotum. His scrotum is tender, and the patient only tolerated superficial palpation.

The most likely diagnosis based on his history is: Epididymitis Testicular torsion

Erythema and edema of the scrotum are only present with epididymitis. True False

Which of the following clinical manifestations are consistent with epididymitis, and which are consistent with testicular torsion?

Positive Prehn sign Testicular torsion Negative cremasteric reflex Epididymitis Testis elevated on affected side Fever

Which diagnostic test is most appropriate to confirm the suspected diagnosis? A complete blood count with differential An MRI of the scrotum A Doppler ultrasound of the scrotum A urine culture and sensitivity

Discuss the treatment plans for testicular torsion and epididymitis.

Antibiotic therapy Analgesics (especially NSAIDs) Bed rest Scrotal support (wearing briefs instead of boxers) and elevation (on a rolled towel) Cold application Screening and treatment of sexual partners

Within 3 days of starting antibiotics, the symptoms should improve. Lack of symptom improvement may indicate other causes of testicular pain or complications of epididymitis (e.g., abscess). Further diagnostic testing may include a scrotal ultrasound.

Candidiasis Candidiasis is a yeast infection caused by the common fungus Candida albicans. This condition usually occurs as an opportunistic infection that can arise anywhere in

the body (especially the skin and the gastrointestinal tract), but the focus of the discussion here is the infection’s effects on the reproductive system.

In the reproductive system, candidiasis most frequently occurs in the vulva and vagina (i.e., vulvovaginal candidiasis) and is a common cause of vaginitis (inflammation of the vagina). Candida and many other microorganisms are part of the normal flora present in the vagina, which usually exist in a balanced state. Imbalance may occur in the presence of vaginal pH changes; normally, the vagina is slightly acidic. This acidic state is mainly maintained by lactobacillus that break glycogen down into lactic acid. Antibiotic therapy can increase vaginal pH (making it more alkaline), leading to yeast overgrowth. Other factors contributing to such imbalance include decreased immune response (e.g., due to corticosteroid medications or HIV). Candidiasis is more common in those with increased estrogen level and increased glucose in the vaginal secretions which can occur with pregnancy, oral contraceptive use, diabetes mellitus, and obesity. Bubble baths and feminine products can also alter the delicate pH balance. Synthetic and tight-fitting clothes will also increase the risk of Candida infection. Candidiasis is not sexually transmitted, but men may develop balanitis (inflammation of the glans penis) after having sexual intercourse with an infected partner (especially if a partner has recurrent vaginal candidiasis). If the foreskin is also affected, then the condition is termed balanoposthitis. Balanitis is more common in men with diabetes mellitus and those who are uncircumcised.

Clinical Manifestations Clinical manifestations of candidiasis include the following signs and symptoms:

A thick, white vaginal discharge that is curdlike (resembles cottage cheese) and nonodorous Vulvar erythema and edema Vaginal and labial pruritus (can be intense) and burning White patches on the vaginal wall Dysuria (burning occurs when urine touches the vulva rather than while it is exiting) Painful sexual intercourse

At times, the vaginal discharge can be thin, loose, and watery as opposed to the typical thick, white discharge. Men have similar symptoms such as white curdlike exudate, pruritis, and erythematous small papules or white patches on the penis and foreskin.

Diagnosis and Treatment

Vulvovaginal candidiasis diagnosis is often made clinically but is best evaluated with in-office vaginal microscopy. The vaginal discharge is placed on a slide and 10% potassium hydroxide (KOH) is added onto the slide. The KOH destroys cellular elements so that yeast buds, hyphae, and pseudohyphae can be visualized in the presence of a Candida infection (FIGURE 8-30). The vaginal pH with candidiasis is usually normal (4.0–4.5). A culture of the discharge can be performed, particularly if manifestations are consistent with candidiasis yet microscopy was negative. Candida glabrata is responsible for approximately 10% of vulvovaginal candidiasis, and the organism is usually not seen with microscopy. Balanitis or balanoposthitis diagnosis can also be made with a history, physical examination, and an in-office microscopic evaluation of the exudate.

FIGURE 8-30 Polymorphonuclear granulocyte leukocytes PMNs and yeast pseudohyphae.

Courtesy of University of Washington STD Prevention Training Center.

Treatment focuses on reestablishing normal flora balance, minimizing tissue irritation, and increasing comfort. Treatment strategies can also be used for prevention of candidiasis:

Antifungal agents (available in oral or topical forms; some are available without a prescription) Perineum care (including cleaning from front to back, keeping the perineum area clean and dry, avoiding soap and rinsing with water only, and taking warm—not hot—baths) Avoidance of douching Resisting the urge to scratch Practicing safe sex (tissue irritation increases the risk for contracting a sexually transmitted infection) Avoidance of feminine hygiene sprays, fragrances, or powders in the genital area Avoidance of extremely tight-fitting clothing (which may cause irritation) Wearing cotton underwear or cotton-crotch panty hose and avoiding underwear made of silk or nylon (these materials are not very absorbent and restrict airflow, increasing sweating in the genital area and irritation) Controlling blood glucose (if diabetic) Eating yogurt with live cultures or taking Lactobacillus acidophilus or probiotic tablets (a practice for which effectiveness, however, is questionable and controversial)

Most cases of uncomplicated candidiasis (e.g., ≤ 3 episodes a year, mild to moderate symptoms, or in healthy, nonpregnant females) can be treated at home and without medical supervision. Self-management is not recommended in situations that may be due to a more complicated infection such as:

Symptoms are severe Fever or pelvic pain is present The patient has a negative history for candidiasis Pregnancy Immunosuppression or uncontrolled diabetes mellitus Other vaginal infections are present or possibly present The patient has recurrent infections (≥ 4 episodes a year)

If self-management strategies are not successful, a healthcare provider should be consulted.

Sexually Transmitted Infections Sexually transmitted infections (STIs), sometimes referred to as sexually transmitted diseases, encompass a broad range of infections that can be contracted through sexual contact (including oral–genital contact, anal contact, and vaginal intercourse). More than 30 different sexually transmissible bacteria, viruses, and parasites have been identified; some of these pathogens can also be transmitted from mother to child during pregnancy and childbirth as well as through blood contact (e.g., HIV and syphilis). Some STIs result from ectoparasites such as pediculosis pubis caused by Phthirus pubis (i.e., crab louse) and scabies caused by Sarcoptes scabiei. Some STIs (e.g., chlamydia and gonorrhea) are easily eradicated with appropriate treatment, whereas others (e.g., genital herpes and condylomata acuminata) persist for a lifetime. See chapter 2 for a discussion of HIV. See chapter 13 for a discussion of Sarcoptes scabiei.

The CDC reported that 2,295,739 cases of STIs were reported in 2017 alone (CDC, 2017). Many STIs go undiagnosed and not all STIs are reportable therefore making the incidence much higher. Laws mandate that three STIs be reported to the CDC: chlamydia, gonorrhea, and syphilis. In 2017, increases were seen in the prevalence of all three of these nationally reported STIs. Other STIs are not required to be reported (e.g., genital herpes and condylomata acuminata); therefore, their actual prevalence may be much higher than the CDC’s estimates.

STI prevalence rates vary depending on the geographic region within and outside the United States. STI rates have been increasing in the United States despite education efforts directed toward their prevention. Since 2013, chlamydia rates have increased 22%, gonorrhea rates have increased 67%, and syphilis rates have increased 76% (CDC, 2018). Some of this increase may be attributed to changes in societal attitudes toward sex and pregnancy (e.g., less fear, less sexual education, and more media inundation) as well as changes in screening practices (e.g., less funding for local and state screening programs).

Bacterial STIs Bacterial STIs are common and are usually treated with minimal residual effects. Screening generally focuses on identifying the causative organism through cultures of exudate, rapid assay tests, and fluorescent antibody tests. Bacterial STIs, particularly gonorrhea and chlamydia, can cause a spectrum of disorders but are often characterized by urethritis, cervicitis, epididymitis, and pelvic inflammatory disease (Table 8-2). The bacteria causing syphilis is categorized as one of several STIs that can cause a genital ulcer. Treatment of bacterial STIs usually requires a simple course of antibiotics. If taken properly, the antibiotics will resolve the infection. Reinfection is common, but it can be minimized by refraining from sexual activity until bacteria are eradicated, by practicing safe sex (e.g., using condoms and dental

dams), and by sexual partners receiving treatment.

Chlamydia Chlamydia is caused by Chlamydia trachomatis, an intracellular parasitic bacterium that requires a host cell to reproduce. Chlamydia is the most commonly reported STI in the United States; more than 1.7 million cases were reported to the CDC in 2017. According to the CDC (2018), chlamydia rates have increased by 22% since 2013. Chlamydia rates are high across all groups and regions in the United States, but the burden of chlamydia is the highest in women, American Indians/Alaska Natives, Blacks, and persons living in the District of Columbia (CDC, 2017).

Chlamydia can be transmitted through sexual contact and infects the mucosal epithelium along the urogenital tract. There are 11 serotypes labeled from A through K. Genotypes D–K cause urogenital, rectal, pharyngeal, and conjunctival infections. Mother-to-child transmission during childbirth, many times, occurs in the form of neonatal conjunctivitis (an eye infection that can lead to blindness). Chlamydia can cause pharyngitis. Another chlamydia species, Chlamydia pneumoniae, causes pneumonia, and this organism is not sexually transmitted. Chlamydia genotypes A– C can cause trachoma, a non–sexually transmitted conjunctivitis and are the leading causes of infectious blindness worldwide. The incubation period for sexually transmitted chlamydia is 7–14 days after infection; however, the period of infectivity is not clear in asymptomatic cases. See chapter 14 for a discussion of trachoma. See chapter 5 for a discussion of pharyngitis.

Clinical Manifestations Often called the silent STI, chlamydia is usually asymptomatic in both males and females. Chlamydia most commonly infects the cervix, causing cervicitis. In men, the urethra is the most commonly infected site, and infection results in urethritis. In men, chlamydia is a common cause of sexually transmitted causes of epididymitis and prostatitis, and it is associated with pelvic inflammatory disease in women. Chlamydia can cause proctitis (inflammation of the distal rectal mucosa) particularly in men who engage in receptive anal intercourse. Chlamydia can be isolated in the throat but it is generally asymptomatic. When present, clinical manifestations include the following signs and symptoms:

Mucopurulent endocervical discharge from the cervix and cervical friability (bleeds easily when endocervix touched) Vaginal discharge that is purulent or mucopurulent (usually comes from the cervix, not the vagina) Mucoid, mucopurulent, or watery penile discharge Menstrual disorders such as intermenstrual or postcoital bleeding

L

Dysuria Painful sexual intercourse (dyspareunia) Rectal pain and mucopurulent discharge

Complications of untreated chlamydia include pelvic inflammatory disease, which can then lead to infertility and chronic pelvic pain. Chlamydia during pregnancy can cause complications such as premature membrane rupture and preterm delivery. Reactive arthritis (i.e., Reiter syndrome) is an uncommon chlamydia-associated disorder in men. Reactive arthritis manifestations include a triad of symptoms— urethritis, arthritis (e.g., acute onset, knee pain), and uveitis (iris redness and swelling).

Diagnosis and Treatment Because of this STI’s high prevalence and potential to cause neonatal complications, it is recommended that all pregnant women be screened for chlamydia and receive treatment if they are found to be infected. The U.S. Preventive Services Task Force (2014) also recommends annually screening all sexually active women who are < 25 years old (LeFevre, 2014). Guidelines have not been established for screening in men or older women; however, screening should be offered to those engaging in riskier behaviors such as having multiple partners or unprotected sexual intercourse.

Diagnosis is made with a history and physical examination. Diagnostic testing can be accomplished in several manners. The source of the specimen can be a urine sample or swabs of the genitourinary tract—vaginal, endocervical, or urethral (men). The diagnostic technique that is most accurate and considered the gold standard is nucleic acid amplification testing (NAAT). With this method, detection is made by amplification of the DNA or RNA of a pathogen (e.g., C. trachomatis). NAAT can be done on urine or vaginal or endocervical specimens. Some NAAT (e.g., Xpert CT/NG) can provide results within 90 minutes. Chlamydia antibodies may take several weeks to appear in the serum, so antibody testing is not often used. Due to the availability of better tests, culture tests are rarely used. Antigen testing and DNA genetic probe methods can be used but require a swab from the urethra or cervix.

Learning Points

Chlamydia and Genital Ulcers ymphogranuloma venereum (LGV) is caused by C. trachomatis serovars L 1-3. LGV causes a lymphoproliferative reaction as the infection spreads from the primary site to draining lymph nodes. This

reaction is in contrast to mucosal chlamydial infection which is usually confined to the site of infection. The incidence is highest in tropical and subtropical areas of the world, however, LGV has been increasingly reported in men who have sex with men particularly in temperate climates (e.g. Western Europe, parts of North America [large outbreak in New York]). HIV is a risk factor. The initial infection is a genital ulcer with an incubation period of 3-12 days. The ulcer heals and is often missed as it is usually small and there are no other symptoms. Subsequently 2-6 weeks after the initial infection severe inflammation and invasive infection appear in the inguinal and/or femoral lymph nodes. Buboes (large, painful, lymph nodes) that are unilateral can

develop. In those who are exposed rectally proctocolitis may occur with or without a urogenital ulcer and manifest as rectal bleeding, mucoid discharge, anal pain, constipation, fever, and tensemus. Clinical presentation can vary and diagnostic testing is not standardized making diagnosis difficult. Antibiotics are the treatment of choice and the buboes may need to be drained.

Treatment usually consists of antibiotics such as azithromycin (Zithromax) (usually one dose) or doxycycline (usually one week of therapy). Erythromycin or quinolones (e.g., levofloxacin) are alternative choices. Gonorrhea often occurs as a coinfection, and treatment may be necessary. Sexual partners, usually those within 60 days prior to infection, should also be screened and treated. If the last sexual exposure was > 60 days ago, then the most recent sexual partner should be screened and treated. Subsequent testing for cure is not necessary, and a repeat NAAT within 3 weeks may be positive due to the presence of nonviable organisms. Medication resistance is uncommon. There is, however, a high rate of reinfection, and appropriate follow-up (usually within 3 months) and testing for new infection may be necessary. Pregnant women are usually retested. Additionally, avoiding vaginal childbirth by electing to have a cesarean section delivery may decrease the chances of mother-to-child transmission. Patients should avoid sexual intercourse until 7 days after completion of therapy.

Gonorrhea Gonorrhea (referred to colloquially as the clap) is caused by N. gonorrhoeae, an aerobic bacterium that has developed many drug-resistant strains. The incidence of gonorrhea was declining, but the CDC (2018) reported a 67% increase since 2013; gonorrhea remains a very commonly reported disease to the CDC. According to the CDC (2017), gonorrhea rates are highest in men, Blacks and American Indians/Alaska Natives, and for persons living in the District of Columbia.

The N. gonorrhoeae bacterium attaches to the epithelial mucosa of the urethra, cervix, mouth or anus, causing irritation and inflammation. The N. gonorrhoeae bacterium can adapt to the genital tracts, change its surface structure (like a chameleon changes color), multiply in various forms, and avoid the immune system. Gonorrhea is transmissible through sexual contact and from mother to infant during childbirth. Mother-to-child transmission usually results in neonatal conjunctivitis. Gonorrhea can also cause pharyngitis and transmission is more common with fellatio in comparison to cunnilingus. Outside the body, the bacterium dies within a few seconds.

Clinical Manifestations Gonorrhea is often asymptomatic. Clinical manifestations, if they occur, usually do not appear until 2–10 days after infection exposure, but the incubation period is usually 2–5 days for men. Gonorrhea most commonly infects the cervix, causing

cervicitis, but the urethra is also often coinfected in women as opposed to chlamydia. In men, the urethra is the most common infected site and results in urethritis. In men, gonorrhea can be a cause of sexually transmitted epididymitis, although more often it is chlamydia alone or as a coinfection. In women, gonorrhea is associated with pelvic inflammatory disease. Gonorrhea can cause proctitis (inflammation of the distal rectal mucosa), particularly in men who engage in receptive anal intercourse. Men are more likely than women to experience symptoms. When present, clinical manifestations are similar to those of chlamydia and include the following signs and symptoms:

Mucopurulent endocervical discharge (can be more copious than with chlamydia) and cervical friability (bleeds easily when endocervix touched) Vaginal discharge that is purulent or mucopurulent (usually from the cervix, not the vagina) (FIGURE 8-31)

FIGURE 8-31 Gonococcal infection. Courtesy of CDC.

Mucoid, mucopurulent or watery penile discharge (spontaneous, more copious than with chlamydia) Menstrual disorders, including intermenstrual or postcoital bleeding or heavy menstrual bleeding

Dysuria Painful sexual intercourse (dyspareunia)

Complications of untreated gonorrhea include pelvic inflammatory disease, which can then lead to infertility and chronic pain. Gonorrhea during pregnancy can cause complications such as premature membrane rupture, preterm delivery, and spontaneous abortion. Additionally, gonorrhea can spread to other locations in the body (disseminated gonococcal infection); in such a case, complications may include purulent arthritis (usually of the hands, wrists, ankles, knees, and elbows), tenosynovitis (tendon inflammation usually in the wrists/hands and ankles/feet), dermatitis (usually of the hands and lower extremities), and endocarditis.

Diagnosis and Treatment Because of this STI’s high prevalence and potential to cause neonatal complications, it is recommended that all pregnant women be screened for gonorrhea and receive treatment if they are infected. The U.S. Preventive Services Task Force (2014) also recommends annually screening all sexually active women who are < 25 years old (LeFevre, 2014). Guidelines have not been established for screening in men or older women; however, screening should be offered in those engaging in riskier behaviors such as having multiple partners or unprotected sexual intercourse.

Diagnosis is made with a history, physical examination, and several testing options. The source of the specimen can be a urine sample or swabs of the genitourinary tract—vaginal, endocervical, or urethral (men). As with chlamydia, the diagnostic technique that is most accurate and considered the gold standard is NAAT. With this method, detection is made by amplification of the DNA or RNA of a pathogen (e.g., N. gonorrhoeae). NAAT can be done on urine or vaginal or endocervical specimens. Some NAAT (e.g., Xpert CT/NG) can provide results within 90 minutes. Gonorrhea antibodies may take several weeks to appear in the serum, so this test is not often used. Antibiotic resistance with gonorrhea can occur, so culture of the discharge can be sent to evaluate for antibiotic susceptibilities. Antigen testing and DNA genetic probe methods can be used but require a swab from the urethra or cervix.

Treatment usually consists of antibiotics with ceftriaxone (cephalosporin) in one dose and azithromycin in one dose. Gonorrhea resistance to multiple classifications of antibiotics is becoming a worldwide problem, and there is an increased prevalence in men having sex with men. Other antibiotics such as doxycycline, while not preferred, can be used. Chlamydia often occurs as a coinfection, but it is already covered with the usual treatment of azithromycin for gonorrhea. Sexual partners, usually those within 60 days prior to infection, should also be screened and treated. If the last sexual exposure was > 60 days ago, then the most recent sexual partner should be screened and treated. Subsequent testing for cure is usually not

necessary, but treatment failure due to antibiotic resistance can occur. A repeat NAAT should not be done within 2 weeks after infection as there may be a false positive due to the presence of nonviable organisms. A culture to test for cure can be done 7 days after therapy is completed. If symptoms recur soon after completion of therapy (e.g., within 5 days), treatment failure or reinfection are possibilities. Appropriate follow-up (usually within 3 months) is recommended. Pregnant women, however, are usually retested. Additionally, avoiding vaginal childbirth by electing to have a cesarean section delivery may decrease the chance of mother-to-child transmission. Patients should avoid sexual intercourse until 7 days after completion of therapy.

Bacterial Vaginosis Bacterial vaginosis (BV) is a common cause of vaginal discharge. BV occurs as result of a reduction in vaginal flora, Lactobacillus, with an increase in a variety of bacterial species and anaerobes (e.g., Gardnerella vaginalis). The prevalence is highest in women of reproductive age. BV is not classified as an STI. However, BV only occurs in sexually active women, and BV risk is associated with increased number of sexual partners, whether they are male or female.

Lactobacillus produces hydrogen peroxide, which maintains a low pH and is a natural microbicide that prevents the overgrowth of normal anaerobic bacteria in the vagina. A decrease in Lactobacillus results in a pH rise, and bacterial anaerobes multiply. The bacterial overgrowth produces enzymes causing the breakdown of proteins in the vagina, resulting in volatile amine production. These amines cause the symptoms that occur in BV, such as a foul-smelling vaginal discharge. G. vaginalis has long been recognized as one of the key pathogens in BV. It is theorized that this organism forms a film on the wall of the vaginal epithelium, and other bacteria adhere to this film and accumulate.

Clinical Manifestations Most women with BV are asymptomatic. Manifestations, if present, include increased vaginal discharge that is off-white/gray, thin with an unpleasant fishy odor that worsens after sexual intercourse or menses. Other symptoms, such as dysuria and dyspareunia, occur with coinfection rather than BV alone. BV is often described when discussing vaginitis; however, BV does not cause vaginal inflammation like vulvovaginal candidiasis and trichomoniasis (two other common causes of vaginal discharge). BV is a risk factor for development of several STIs (e.g., herpes simplex 2 virus, gonorrhea, and chlamydia).

Diagnosis and Treatment Diagnosis is made based on a history, physical examination, and the presence of at

least three of the Amsel criteria: 1) characteristic vaginal discharge, 2) elevated pH, 3) clue cells (FIGURE 8-32), and 4) fishy odor. Vaginal microscopy is recommended to evaluate for the presence of clue cells on a saline wet mount slide (discharge is placed on a slide and normal saline is placed on top). Clue cells are vaginal epithelial cells that are full of adherent coccobacilli giving the cell a roughened, stippled appearance. Additionally, a strong, fishy odor is produced when a drop of KOH is placed on a swab with vaginal discharge if BV is present—termed a positive whiff test or positive amine test. A culture is not useful in BV due to the complex vaginal flora changes and because many organisms that would cause a positive culture are in women without BV.

FIGURE 8-32 Clue cells. Courtesy of University of Washington STD Prevention Training Center.

BV can resolve spontaneously without treatment; however, treatment is usually initiated to relieve symptoms and prevent the risk of getting other STIs. Treatment consists of antibiotics such as metronidazole or clindamycin. These medications can be administered intravaginally or taken orally. If oral doses are given, they should be administered over time as opposed to the one-dose regimen used for trichomoniasis

(discussed later in this chapter). Treatment of asymptomatic sexual partners is not necessary as transmission is not from the male partner. Incidence of BV in women who have sex with women is higher, and these sexual partners should be evaluated and treated if symptomatic. Recurrence of BV within 1 year is high and may be due to reinfection or treatment failure.

Pelvic Inflammatory Disease Pelvic inflammatory disease (PID) is a general term that refers to an acute infection of the female reproductive system (e.g., endometritis [uterus], oophoritis [ovaries], and salpingitis [fallopian tubes]). PID is usually a result of a sexually transmitted infection that ascends to the upper genital tract and is not usually used in reference to pelvic infections due to other causes (e.g., cervical surgery). Pelvic infections from another source of infection, however, can cause similar manifestations as PID due to STIs. The focus of this section will be on PID due to STIs. According to the CDC (2016b), PID diagnoses have declined in recent years, but an average of 5% of all U.S. women will have PID in their lifetime.

In this infection, bacteria (often gonorrhea or chlamydia) usually ascend through the reproductive tract. Mycoplasma genitalium is another common organism. PID, however, is often polymicrobial, and often the exact microbe is unknown. Risk factors for PID are the same as for acquiring other STIs (e.g., multiple sexual partners, sexual intercourse with an infected partner, or history of prior STIs or PID). PID most commonly occurs in women 15 to 25 years of age.

In PID, organisms enter the upper genital tract through the endocervical canal as a result of cervical disruption (e.g., cervicitis). The normally protective endocervical canal is breached, and the normal vaginal flora is altered, allowing ascension of pathogens into the upper genital tract. The infection triggers the inflammatory response, resulting in mucosal irritation, edema, and purulent exudate. The edema and exudate can obstruct the reproductive structures, and the exudate can migrate to the peritoneal cavity through the uterus and fallopian tube openings, increasing the risk of peritonitis. Abscesses (tubo-ovarian) and septicemia (bacterial blood infection) can develop and become life threatening. The liver and peritoneal surfaces can become inflamed and result in a syndrome known as Fitz-Hugh–Curtis or perihepatitis. This complication occurs in up to 14% of women with PID (NORD, 2009). Perihepatitis is thought to occur as a result of bacteria traveling through the blood or lymphatics to the right upper quadrant or possibly due to an autoimmune reaction to C. trachomatis or N. gonorrhoeae. Manifestation includes severe right upper quadrant pain. Adhesions and strictures frequently result from PID, leading to chronic pelvic pain, ectopic pregnancies, infertility, and problems with surrounding structures.

Clinical Manifestations

Clinical manifestations of PID vary slightly depending on the severity of the infection. Manifestations can be subtle or severe and include the following:

Indications of infection such as fever, chills, myalgia, and leukocytosis (with acute forms and more likely to indicate peritonitis or pelvic abscess) Pain or tenderness in the pelvis, lower abdomen, or lower back (sudden and severe with acute forms and more likely to indicate peritonitis or pelvic abscess) Dysmenorrhea—a bacterial invasion is more likely during or shortly after menses Abnormal vaginal and cervical discharge (usually purulent) Postcoital bleeding; intermenstrual bleeding, or heavy menses Dyspareunia Urinary frequency and dysuria

Bimanual pelvic examination findings include cervical motion tenderness (pain when the examiner moves the cervix ) and uterine and adnexal tenderness, as well as purulent endocervical and/or vaginal discharge.

Diagnosis and Treatment Diagnosing PID consists of a history and physical examination. A presumptive clinical diagnosis is made in young, sexually active women (especially if they are engaging in risky sexual behaviors) with lower abdominal or pelvic pain and pelvic exam findings of cervical motion or uterine and adnexal tenderness. Because PID can result in serious reproductive disorders, treatment should be given with just the presence of clinical findings. Additional manifestations can further support the diagnosis (e.g., mucopurulent discharge). Diagnostic tests include evaluation for chlamydia and gonorrhea (e.g., NAAT testing of discharge) and other pathogens. Ultrasound, CT, or MRI of the pelvis may reveal various findings such as thickened, fluid-filled fallopian tubes). A CBC may reveal and infection with increased leukocytes. Laparoscopy can also be done.

Treatment strategies include broad-spectrum antibiotic coverage due to the polymicrobial pathogens that are commonly present with PID. A majority of women with uncomplicated PID can be treated on an outpatient basis. Hospitalization may be necessary for patients with severe systemic manifestations (e.g., fever and severe abdominal pain), complicated PID (e.g., tubo-ovarian abscess), inability to tolerate oral medications, pregnancy, or possible nonadherence to therapy. Follow- up to evaluate for improvement should be done within 3 days. Screening and treatment of sexual partners (usually those within the last 60 days prior to the onset of symptoms) is important to prevent spreading and reinfection. If the last sexual exposure was > 60 days prior, then the most recent sexual partner should be screened and treated. Sexual activity should be delayed until after completion of therapy, resolution of symptoms, and treatment of partner(s). Practicing safe sex

should be emphasized. Abscesses may need treatment with needle aspiration or surgical removal. As with gonorrhea and chlamydia, follow-up should be conducted at 3 months due to higher reinfection rates.

Syphilis Syphilis is an ulcerative infection caused by Treponema pallidum, a spiral-shaped (spirochete) bacterium that requires a warm, moist environment to survive (FIGURE 8-33). According to the CDC (2018), syphilis rates have increased by 76% since 2013, including a significant increase in congenital syphilis. Syphilis is transmitted through skin or mucous membrane contact with infected, ulcerative lesions (chancres). Additionally, the bacterium can cross from the mother through the placental barrier to the fetus after the fourth month of gestation (congenital syphilis). T. pallidum causes infection wherever the pathogen is introduced such as in the mouth or on the genitals or breasts. Syphilitic lesions also provide an opportunity for the transmission and acquiring other STIs.

FIGURE 8-33 T. pallidum, the spirochete that causes syphilis.

Courtesy of Bill Schwartz/CDC.

When a person becomes infected with syphilis, T. pallidum begins to replicate and forms the characteristic ulcerative lesion (i.e., chancre). Some organisms go to the lymph nodes and then start spreading throughout the body. Syphilitic infection causes activation of the innate and adaptive cellular immune response. The humoral immune response begins (antibodies start developing). The chancre may heal due to

this immune response. The body’s immune response alone, however, is insufficient to keep the spirochetes from spreading, so antibiotic treatment is necessary to avoid disease progression.

Syphilis occurs in stages, each with its own clinical manifestations:

Primary syphilis: Primary syphilis (also known as early syphilis) is the first stage. Painless chancres (usually one) form at the site of infection about 2–3 weeks after the initial infection is acquired (FIGURE 8-34), along with local lymphadenopathy (enlarged lymph nodes). The chancres can appear up to 90 days after initial infection. The chancres often go unnoticed and disappear about 4–6 weeks later, even without treatment. The chancres begin as a papule then ulcerate, and the lesions are hard, have raised edges, and are usually about 2 cm in size. The ulcers can have different appearances, so syphilis should be considered in any painless genital ulcer. The bacteria become dormant, and no other symptoms are present. Because the individual may not test positive during this stage, the test should be repeated later. Even if he or she tests negative, the infected individual is contagious during this stage.

FIGURE 8-34 Chancre characteristic of primary syphilis. Courtesy of Dr. Gavin Hart and Dr. N.J. Fiumara/CDC.

Secondary syphilis: Secondary syphilis (also part of early syphilis) occurs about

2–8 weeks after the first chancres form. Approximately 33% of those individuals with infection who do not receive treatment for primary syphilis will develop this second stage, which is characterized by a generalized, nonpruritic, brown-red rash (FIGURE 8-35). Most commonly the rash is on the trunk, extremities, and palms and soles (FIGURE 8-36). The rash tends to be symmetric and is macular (flat) or papular (raised) and scaly. The rash, however, can take on different appearances (e.g., smooth or nodular). Condyloma lata are wartlike skin lesions that usually occur on the mouth, perineum, anus, vulva, and inner thighs. Mucous patches can develop in the mouth. Other symptoms include malaise, fever, patchy hair loss, malaise, headache, myalgia (muscle ache), arthralgia, sore throat, poor appetite, and weight loss. Lymph nodes in the neck, axilla, groin, and epitrochlea are usually enlarged. Other findings can include hepatitis, gastric lining inflammation and ulceration, and renal abnormalities (e.g., acute nephritis). These symptoms will often go away without treatment, and again, the bacteria become dormant. The individual will test positive (if untreated) and is contagious during this stage, especially with direct contact with the rash. Condyloma lata lesions are highly contagious.

FIGURE 8-35 Skin rash characteristic of secondary syphilis. Courtesy of J. Pledger, BSS/VD/CDC.

FIGURE 8-36 Syphilis affecting the hands. Courtesy of CDC.

Latent or tertiary syphilis: Latent or tertiary syphilis is the final stage of syphilis. The early latency stage begins when the secondary symptoms disappear and usually occurs within the first year of infection. The late latency stage starts after 1 year and can last for years. During latency periods, there are no symptoms. Tertiary syphilis is a symptomatic stage, and manifestations occur in the cardiovascular system (e.g., aortic dilation and aortic valve regurgitation) or granulomatous, nodular lesions (i.e., gummas) can develop in different organs throughout the body, usually the skin and bones. Multiple central nervous system manifestations can occur with late syphilis, such as progressive dementia and ataxia. Tertiary syphilis manifestations can occur as late as 30 years after infection. The individual will test positive (if untreated).

In utero, the fetus is protected from syphilis by a membrane known as Langhans layer for the first 4 months of the pregnancy. Consequently, screening and treating the mother prior to the fourth month of gestation can significantly decrease the likelihood that the fetus will contract the infection. Untreated early maternal syphilis infections lead to fetal demise in approximately 40% of cases. Congenital syphilis can lead to multiple defects affecting the bones, teeth, liver, lungs, and nervous system.

Diagnosis and Treatment Diagnostic procedures include a history and physical examination. Diagnostic tests include nontreponemal and treponemal serologic tests. Nontreponemal tests (e.g., venereal disease research laboratory test or rapid plasma reagin) are measures of biomarkers released from the spirochete and IgG and IgM antibodies are reported as a titer. As an example, a nontreponemal test titer may be reported as 1:32, which reflects the dilution ratio. The nontreponemal tests are nonspecific and there can be false positive rates, and require evaluation with a treponemal test. Nontreponemal test titers are used to evaluate treatment success (e.g., the titers should decrease by fourfold, that is, 1:32 to 1:8). Nontreponemal tests will eventually become negative after treatment. Treponemal tests (e.g., fluorescent treponemal antibody absorption) measure antibodies directed against specific treponemal antigens, so it is more specific than nontreponemal tests. The tests are reported as reactive or nonreactive. The test results will remain positive for life in a patient with syphilis, even if treated, so only a nontreponemal test can be used to evaluate for reinfection. Nontreponemal tests have usually been used initially because they were easier and cheaper; however, newer versions of treponemal tests are easier and are being used for initial testing. Treatment usually consists of antibiotics such as penicillin (preferred), a penicillin derivative, doxycycline, or tetracycline.

Viral STIs Many STIs are caused by viruses. In terms of their severity, these infections can range from minor (e.g., condylomata acuminata) to life threatening (e.g., HIV). Viral STIs can also lead to several reproductive cancers (e.g., human papillomavirus). Molluscum contagiosum, caused by a poxvirus, is sexually transmitted in adults. Viral infections are the most difficult STIs to treat because viruses are highly adaptive and elusive. Treatment options for the various infections depend on the causative virus.

Genital Herpes Genital herpes is an infection that causes blisters (vesicles) on the genitals and in the reproductive tract. Genital herpes is caused by the herpes simplex virus (HSV),

which belongs to a family containing more than 70 herpes viruses. Some other common viruses in this family include cytomegalovirus (which can cause mental retardation and fetal demise with maternal infections), varicella-zoster virus (which causes chickenpox and shingles), and Epstein-Barr virus (which can cause infectious mononucleosis and lymphoma).

HSV occurs in two forms—HSV type 1 and HSV type 2. Generally, HSV type 1 infections occur above the waist, whereas HSV type 2 infections occur below the waist. HSV type 1 infection most frequently manifests as a cold sore (a small blister on the mouth or nose). Most cases of genital herpes (70%) are caused by HSV type 2. HSV type 2 infections can also spread above the waist, and HSV type 1 infections can spread below the waist through oral–genital sexual contact. HSV type 2 is also transmissible through direct skin-to-skin contact. Although the risk of transmission is greatest when lesions are present, HSV can be spread when lesions are not apparent or when lesions are not present (i.e., they are asymptomatic or subclinical viral shedding has occurred). HSV type 2 is also transmissible from mother to child.

Contracting genital herpes during pregnancy creates the greatest risk to the fetus —spontaneous abortion. HSV can also be transmitted to the infant during childbirth if an active genital herpes infection is present at the time of delivery. Transmission of this infection during childbirth can result in encephalitis and brain damage. If lesions are present at the time of birth, a cesarean section should be performed to minimize these risks. Rarely, HSV can be transmitted to the fetus through the placenta, causing an infection prior to birth. Pregnant women should be monitored for genital herpes throughout their pregnancy.

Genital herpes is not a reportable disease to the CDC; however, data from healthcare clinics indicate that the prevalence of genital herpes has been increasing for the last 50 years, albeit with declining numbers of cases (incidence) occurring in the most recent years. According to the CDC (2017), rates of genital herpes are highest in Blacks.

Both types of HSV infections are characterized by recurrent episodes of the lesions. Most people with HSV type 2 will experience recurrence of the lesions; however, recurrence is much less frequent with HSV type 1. The virus causes an initial infection at the entry site, but then it travels along the dermatome to the nerve root, where it remains protected and dormant until the next outbreak (recurrence), which will occur at the same site. In either case, the lesions appear and progress similarly. Recurrent episodes begin with a tingling or burning sensation at the site just before the lesion appears (prodrome). The lesions first appear as vesicles (< 0.5 cm clear fluid filled lesions [blister]) surrounded by erythema. These vesicles rupture, leaving behind a painful ulcerative lesion with watery exudate (FIGURE 8-37). Ultimately, a crust forms over the ulcer, and it heals spontaneously in 3–4 weeks. Because genital herpes creates an opening in the skin, the individual is at risk for contracting other STIs.

FIGURE 8-37 Genital herpes blisters on the external genitalia. © Mediscan/Visuals Unlimited, Inc; © Dr P. Marazzi/Science Source.

Clinical Manifestations Genital herpes manifestations are dependent on whether the lesions occur shortly after being infected for the first time (i.e., primary infection), whether the lesions occur for the first time after antibodies have developed, or whether the lesions are due to recurrent infection.

Primary herpes genitalis begins at the actual time of infection and antibody development. The time from exposure to this primary infection can range from 2 to 12 days. This first occurrence of the infection can be either very painful, mildly painful, or completely asymptomatic (75% of cases). When present, clinical manifestations associated with this stage include multiple painful 1–2 mm vesicular lesions that can be pruritic and accompanied by malaise, low-grade fever, and groin lymph node enlargement. The lesions can be in the vulvar area or on the cervix, penis, buttocks, or thighs. The lesions usually heal in about 10–20 days. Viral shedding is high during this first stage, making transmission more likely.

There is a period when herpes genitalis antibodies are formed. Antibodies do not protect an individual against reinfection, but they do tend to make the recurrent episodes less severe. The virus travels up the nerve root and becomes dormant (FIGURE 8-38). The individual is asymptomatic while the virus is dormant. The lesions can appear for the first time after antibodies are already formed. This first episode is considered nonprimary as the actual time of infection occurred in the past. A first presentation with antibodies already formed will cause a presentation with fewer lesions and fewer systemic symptoms in comparison to primary infection.

FIGURE 8-38 Herpes simplex virus movement in the nervous system.

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Recurrent herpes genitalis is characterized by the reactivation of the virus and clinical manifestations. During this stage, the virus travels back down the nerve root to the skin and causes a vesicle at the same site as with the first stage. The duration of lesions is usually shorter (< 10 days), and viral shedding usually occurs for up to 5 days. The number of recurrences varies from none to many in a lifetime. Factors that can trigger a recurrence include stress, menstruation, and illness.

Diagnosis and Treatment Diagnosis for genital herpes is based on a history, physical examination, and confirmation with laboratory testing. Diagnostic testing is dependent on whether lesions are present or not. If lesions are present, vesicular fluid should be sent for viral culture. The blister might need to be unroofed to acquire the fluid. Viral cultures are best performed early in the disease course. Polymerase chain reaction viral DNA or RNA of the lesion or serum can also be done. Both tests can differentiate between HSV 1 and HSV 2. Serologic testing can detect antibodies to HSV 1 or HSV 2. Genital herpes is a significant public concern because the lesions and symptoms are not always apparent, transmission can occur with or without symptoms, and no cure exists. Genital herpes can cause a great deal of psychological stress for patients because of the ongoing fear of outbreaks and the need to disclose the information about their infection status to partners.

Treatment options include antiviral medications that can suppress the number of outbreaks as well as minimize the severity and duration of the first infection and recurrences. Avoiding recurrence triggers, especially stress, can also prevent outbreaks. Implementing stress reduction strategies (e.g., yoga, meditation, journaling, and distraction) is advised. Secondary bacterial infections can develop from the lesions, so proper hygiene (e.g., washing the area with soap and water several times a day, keeping the area dry, and wearing loose-fitting clothing and cotton underwear) is advised during outbreaks. Because the risk of transmission is highest when lesions are present, sexual activity should be avoided during outbreaks. Due to the lifelong implications of genital herpes, prevention is the best treatment strategy. Prevention strategies center on safe sex practices such as using condoms and limiting sexual partners.

Learning Points

Uncommon Causes of Genital Ulcers yphilis and herpes are the most common causes of genital ulcers. LGV is another STI that presents as an ulcer along with two other uncommon organisms: chancroid (organism: Haemophilus ducreyi) and

granuloma inguinale (organism: Klebsiella granulomatis). Chancroid is rare in the United States; however, because few laboratories are able to test for the organism, the actual incidence is unknown. Chancroid starts with a genital papule that erupts into multiple ulcers with pus draining from lymph nodes. The ulcers are painful and are 1-2 cm in diameter. Buboes may develop. Granuloma inguinale (i.e., donovanosis) is rare in the United States. Manifestations include slowly progressive painless ulcers that have raised rolled edges and usually

without lymphadenopathy.

Condylomata Acuminata Condylomata acuminata, or anogenital warts, are benign growths caused by human papillomavirus (HPV). More than 200 different types of HPV exist, several of which can cause condylomata acuminata. HPV can only infect humans and can cause mucosal or cutaneous disorders. Condylomata acuminata can occur on the external genitals, vaginal wall, cervix, anus, thighs, lips, mouth, and throat. The genotypes causing most genital warts (90%) are types 6 and 11. In addition to condylomata acuminata, HPV infection can lead to the development of reproductive tract cancer in women (cervical, vulvar, and vaginal) and penile cancer in men. HPV can also cause oropharyngeal and anal cancers. There are various genotypes that cause cancer such as 16 and 18. HPV can have an incubation period that lasts up to 6 months. The immune system clears most HPV within 2 years (about 90%), though some infections persist. Most sexually active men and women will contract HPV at some point in their lives as HPV can be contracted with just skin-to-skin contact. Transmission can occur from mother to fetus.

Clinical Manifestations Condylomata acuminata may be asymptomatic, depending on their location. Transmission, as with other viruses, can occur without the presence of a lesion. The time from infection to the development of lesions can be 3 weeks to 8 months. The lesions vary in appearance, texture, and size (FIGURE 8-39; FIGURE 8-40). Growths can be raised, flat, rough, smooth, flesh-colored, white, gray, pink, cauliflower-like, large, or barely visible. Additional symptoms may include abnormal bleeding, discharge, or itching.

FIGURE 8-39 Genital warts on the penis. Courtesy of Dr. M.F. Rein/CDC.

FIGURE 8-40 Genital warts on the vagina. Courtesy of Joe Millar/CDC.

Diagnosis and Treatment Diagnosis of condylomata acuminata is based on a history and clinical findings. While there are no treatments for HPV itself, treatments exist for the serious conditions that HPV can cause (e.g., cervical cancer). A vaccine is available to prevent HPV infections. Various HPV vaccines can provide protection anywhere from two to nine of the most common types of HPV that cause cancer and genital

A

warts. Vaccination is recommended for both males and females (ideally to be administered around 11 or 12 years of age, before sexual activity is initiated). Using condoms and dental dams can also reduce the risk of HPV transmission.

Most condylomata acuminata are harmless, but they can be removed for aesthetic purposes. Removal of the growths will not cure the underlying condition, so the growths may reappear. Condylomata acuminata can be removed using chemicals (e.g., podophyllin), cryosurgery (freezing the tissue with liquid nitrogen), electrocauterization (heating the tissue with electricity), laser therapy (burning the tissue with a light), or surgical excision.

As with other STIs, sexual partners of individuals with HPV infection should also be screened and treated. Condylomata acuminata can be fatal if transmitted to infants at birth, so cesarean section deliveries are advised for pregnant women with this STI.

Learning Points

Adult Male Circumcision and STIs dult male circumcision can reduce the rate of transmission of sexually transmitted infections, particularly HIV and genital ulcers, warts, and herpes simplex virus and possibly other STIs such as gonorrhea and

chlamydia. Removal of the foreskin allows the skin on the glans penis to keratinize (create a protective thickening), which provides a protection against organisms. Additionally, the prepuce has Langerhans cells that HIV targets. In addition to circumcision reducing risk in men, women who have sexual partners who are circumcised also have a reduced risk of an STI.

Protozoan STIs Like candidiasis infections, protozoan infections often arise when the body’s natural defenses are altered; unlike candidiasis, however, some of these infections can be transmitted through sexual contact. Protozoan STIs are usually easily treated and resolve with minimal issues.

Trichomoniasis Trichomoniasis (colloquially referred to as the trich) is caused by Trichomonas vaginalis, a one-celled anaerobic organism. This extracellular parasite can burrow under the mucosal lining. In men, the organism primarily resides in the urethra and, in most cases, causes no symptoms. In women, the organism resides in the vagina, and the infection becomes symptomatic when vaginal microbial imbalance occurs. The T. vaginalis organism cannot survive in the mouth or the rectum. The incidence, in contrast to other STIs, is higher in men and women > 40 years of age, but another peak is seen in women around the age of 20. Coinfection with bacterial vaginosis and STIs is common. Trichomonas can cause complications in women (e.g., PID in HIV-infected women, and infertility), and trichomonas can be associated with disorders such as prostatitis and epididymitis in men.

Myth Busters

A common misconception is that condoms protect users against all STIs. While condoms are highly effective against most STIs, some of these infections have been known to spread despite condom use. Some STIs can be transferred through sexual contact that does not involve insertion intercourse (e.g., skin to skin contact of genitalia and oral sex).

Another common misconception is that condoms can break off or slip off easily. Some are concerned that a condom may not fit; however, there are many different shapes and sizes. When used properly this is unlikely. Proper use includes: 1) using throughout the whole sexual act; 2) using only latex condoms with no oil- based lubricants; 3) checking expiration dates on condoms; 4) keeping condoms away from extreme heat; 5) removing the condom while the penis is erect and holding the rim of the condom prior to withdrawal; 6) not reusing condoms; and 7) checking for tears or breakage after withdrawal. Some may think two condoms are better than one but simultaneous use increases friction leading to a higher likelihood of tears or breaks. STIs that can spread through skin-to-skin contact even with a condom in place include HPV, HSV, and syphilis. Additional strategies, such as receiving the HPV vaccination, receiving genital herpes suppression therapy, and treating syphilis early, can decrease the likelihood of contracting and

1. a. b. c.

2. a. b. c.

3. a. b. c.

4. a. b. c.

5.

spreading these infections.

BOX 8-3 Application to Practice Most women at some point in their life will get a vaginal infection. Vaginal infection can be characterized by complaints of vaginal discharge. Three common causes of vaginal discharge are bacterial vaginosis, trichomoniasis, and vulvovaginal candidiasis. Review the following case and answer the questions.

Case: A 40-year-old woman comes in complaining of an increased thin whitish vaginal discharge that started about 5 days ago. She said it is so much that she needs to wear a small sanitary pad. She also noted that she had a funny odor after having sexual intercourse, and she says the odor continues despite her attempts to control it with douching. Physical examination reveals a thin white discharge around the vaginal wall with no erythema. Examination of the discharge includes a positive KOH whiff test and a vaginal pH > 4.5. Vaginal microscopy reveals clue cells.

What is a likely cause of the vaginal discharge? Trichomoniasis Bacterial vaginosis Vulvovaginal candidiasis

Which of the clinical manifestations confirms the diagnosis? The thin white discharge Malodorous discharge Presence of clue cells on a saline wet mount slide

The cause of this vaginal discharge disorder is due to: An alteration in the vaginal flora Overgrowth of yeast due to antibiotic use A sexually transmitted organism, T. pallidum

Which is the primary treatment of this vaginal discharge disorder? Fluconazole Metronidazole Clindamycin

Describe the mode of transmission, common organism, clinical manifestations, and treatment of the other two diagnoses not chosen in question 1.

Clinical Manifestations Up to 75% of men and women with trichomoniasis are asymptomatic. In men, the infection is often transient and resolves in a few weeks without treatment. If symptoms are present, they are similar to infections causing urethritis (e.g., clear or mucopurulent penile discharge and dysuria). In women, the primary clinical manifestation is copious amounts of odorous, frothy, thin, white or yellow-green vaginal discharge. This discharge can irritate the vagina and vulva. The cervix can

develop petechiae, which can appear like the surface of a strawberry (termed a strawberry cervix), but this appearance occurs in < 2% of cases. Additional symptoms may include itching, painful intercourse, and dysuria. Trichomonas can infect the paraurethral glands. Women can remain asymptomatic carriers for several months. Trichomoniasis during pregnancy can cause complications such as premature rupture of membranes or preterm delivery. Newborns who contract the infection during delivery can have a fever, respiratory problems, urinary tract infections, and vaginal discharge.

Diagnosis and Treatment Diagnostic procedures for trichomoniasis include a history and physical examination. As with vulvovaginal candidiasis and bacterial vaginosis (two other common causes of vaginal discharge), vaginal microscopy is important in evaluating the vaginal discharge. On a wet mount slide, mobile trichomonads can be seen (FIGURE 8-41). The vaginal pH is usually > 4.5. Other diagnostic tests can include NAAT for Trichomonas RNA. Rapid tests (e.g., results can be provided in 45 minutes) can evaluate for antigen or DNA. Cultures can be used, but it can take a week to obtain results. Trichomonads can sometimes be seen in a liquid Pap smear, but a liquid Pap smear should not be used for diagnosis because of many false positives. In men, microscopy is not accurate and a NAAT or culture is the preferred test. Trichomoniasis is easily treated with metronidazole (Flagyl), an antibiotic that treats bacteria and parasite infections usually as a one-time dose (e.g., 2 grams). Intravaginal metronidazole therapy is not as effective for trichomoniasis treatment. Sexual partners should also be treated to prevent reinfection. Follow-up testing is often done due to the high risk of reinfection. Repeat testing can be done as soon as 2 weeks and up to 3 months after treatment completion. Untreated or prolonged infections can increase the risk of cervical cancer and HIV. Patients should avoid sexual intercourse until 7 days after completion of therapy.

FIGURE 8-41 Wet prep: Trichomoniasis. University of Washington STD Prevention Training Center.

Cancers Malignancies of the reproductive system may either originate in the reproductive tract or spread there from other sites. Some of these cancers have high rates of successful treatment (e.g., testicular cancer), whereas others have high mortality rates (e.g., ovarian cancer). Typical cancer diagnosis, staging, and treatments are generally utilized with these tumors (see chapter 1 for more on cellular function).

Penile Cancer Penile cancer is a rare malignancy. The most common type is squamous cell carcinoma. Its exact cause is unknown, but risk is thought to be increased by various penile disorders or conditions such as the presence of smegma, being uncircumcised, poor hygiene, phimosis, and HPV infections. Penile cancer usually occurs in older men. Penile cancer appears as a thick, gray-white lesion (Bowen lesion) or a red, shiny lesion (erythroplasia of Queyrat) (FIGURE 8-42) or a painless lump. Inguinal lymphadenopathy may also be present. Prognosis is good with early diagnosis and treatment, but a penectomy (removal of the penis) may be required if the cancer is extensive or does not respond to the usual cancer treatments (e.g., chemotherapy, radiation, and surgical excision).

FIGURE 8-42 Penile cancer. Courtesy of William R. Smart/Susan Lindsley/CDC.

Prostate Cancer Prostate cancer is the most common cancer among men, particularly Blacks (American Cancer Society, 2019). The most common type is adenocarcinoma. The tumors are slow growing, and 80% of cases are diagnosed while the cancer is still confined to the prostate, improving the prognosis. Prostate cancer is the second leading cause of cancer deaths in the United States, but the 5- and 10-year survival rates for this disease are improving. Prognosis improves with early diagnosis and treatment and worsens with advancing age. Increased screening with prostate- specific antigen (PSA) and prostate biopsy for those with elevated PSA have contributed to these newly improved survival rates. The exact cause of prostate cancer remains unknown, but men’s risk is thought to increase with age (the peak is between 65 and 75 years of age). However, prostate cancer in Black men usually occurs at a younger age. A family history (first-degree relatives) or a family history of other cancers such as breast, ovarian, or pancreatic cancer increases prostate cancer risk. Breast cancer variants may contribute to the development of prostate cancer, particularly aggressive forms, and other common genetic factors are being explored. Consumption of high-fat diet, and androgen hormone replacement (some tumors are androgen dependent) and other risk factors (e.g., STIs) may contribute to prostate cancer development.

As the tumor grows, the prostate enlarges and impedes the urethra; therefore, prostate cancer presents with similar clinical manifestations as benign prostatic hyperplasia (e.g., urinary difficulties and erectile dysfunction). Additional manifestations may include bloody semen and hematuria. Digital rectal exam may reveal prostate nodules, induration, or asymmetry, however a rectal exam can only detect tumors on the posterior and lateral aspects of the gland (areas palpable via the rectum). Men, however, are often asymptomatic when diagnosed. If prostate cancer metastasizes, the bones are usually affected, and bone pain is a likely complaint. See chapter 7 for a discussion of benign prostatic hypertrophy.

Diagnostic procedures to evaluate the prostate include measurements of PSA level, which is elevated in any prostate enlargement. Free PSA, which measures unbound PSA, can differentiate between benign prostatic hypertrophy and prostate cancer. The free PSA measurement is used to calculate the ratio of free to total PSA and a low ratio (< 15%) is suspicious for prostate cancer. Prostatic acid phosphatase (which is high in prostate cancer) testing may be used. Biopsy, however, is necessary to make the diagnosis. Prostate cancer treatment follows the path of the usual cancer treatments and can vary depending on the cancer stage. If the cancer is diagnosed in an early stage, careful observation (called active surveillance)

instead of immediate treatment is appropriate for many patients. Treatment includes a combination of a radical prostatectomy (complete prostate removal), radiation, and orchiectomy (removal of the testes) or antitestosterone drug therapy. These treatments often impact the patient’s quality of life due to their side effects or complications (e.g., urinary and erectile dysfunction), which may be short or long term. Researchers are exploring new biologic markers in an effort to improve the differential diagnosis between indolent and aggressive prostate cancer so as to minimize unnecessary treatment of the indolent variant (American Cancer Society, 2019).

Testicular Cancer Testicular cancer is an uncommon cancer. Men ages 15–35 years old and White men are at higher risk of developing this type of cancer than other groups. Most cases of testicular cancer occur due to germ cell tumors, which can be a slow- growing (seminoma) tumor or, less commonly, a fast-growing (nonseminoma) tumor. Risk for developing testicular cancer is thought to be increased by family history, infection, trauma, tobacco use, testicular abnormalities (e.g., atrophy or dysgenesis), and cryptorchidism. Testicular cancer usually affects one testicle, but it can affect both. Metastasis, when it happens, usually occurs to the nearby lymph nodes, lungs, liver, bone, and brain.

Testicular cancer is often asymptomatic. When present, clinical manifestations usually include a hard, painless, palpable mass that does not transilluminate; testicular discomfort or pain; testicle enlargement; and gynecomastia (femalelike breasts).

Testicular cancer is highly curable even when it has metastasized to other sites. Early diagnosis and treatment enhance prognosis. Monthly testicular self- examinations are the cornerstone of early detection. The evaluation of a testicular mass begins with a bilateral scrotal ultrasound. A CT scan of the abdomen and pelvis and a chest X-ray or CT of the chest are done to evaluate for metastasis. Other diagnostic procedures include measurement of tumor markers such as alpha fetoprotein, beta human chorionic gonadotropin, and lactate dehydrogenase. In most cases, an orchiectomy is advised to evaluate the tissue histology and control the tumor but chemotherapy and radiation may also be used to treat this disease. Prior to orchiectomy, semen can be preserved in case of a desire to preserve fertility. Testicular cancer can reoccur in the remaining testicle, so testicular self- examinations and follow-up are crucial.

Breast Cancer Breast cancer is the most common malignancy in women and the second leading cause of cancer death in women (American Cancer Society, 2019). While breast

cancer can occur in men, its rates are highest in White women, although Black women are more likely to die from it. The risk of breast cancer increases with advancing age (most occur in women > 50 years of age). Hormonal alterations throughout life increase chances of cell mutations and breast cancer risk. Risk factors for breast cancer include early menarche, late menopause, nulliparity or pregnancy after 30, and no history of breastfeeding. Other risk factors include a history of benign atypical hyperplasia and chest-wall radiation.

A family history (up to 10% of breast cancers) and inherited genetic predisposition—usually due to defects on the BRCA1 and BRCA2 genes—increase breast cancer risk. Obesity and excessive alcohol consumption (more than one to two drinks per day) can also increase breast cancer risk. Exogenous estrogen exposure (e.g., oral contraceptives, hormone replacement therapy) may increase the risk for breast cancer, although current formulations have minimized this risk. In many circumstances of breast cancer, there are no identifiable risks. See chapter 1 for discussion of BRCA1 and BRCA2 mutations.

As with many cancers, breast cancer is a clonal disease. Cells reproduce due to a combination of an inherited germline cell variant that causes susceptibility to breast cancer development and somatic cell mutations (noninherited) (e.g., p53 mutation), along with environmental factors, which can then also cause cancer cells to reproduce. Breast cancer is a hormonally dependent disorder. Inherited defective genes, particularly BRCA1 mutations can cause breast cancer in up to 80% of women and ovarian cancer in 33% of women. Breast cancers due to BRCA1 are almost always negative for receptors to estrogen (ER), progesterone, and human epidermal receptor 2 (HER2)—these are termed triple negative cancers. These cancers tend to be very aggressive. BRCA1 tumors can also be associated with ER- positive breast cancer.

There are many types of breast cancer, and each type can have different pathology, genetic basis, and clinical manifestations. Breast cancers are mainly adenocarcinomas (i.e., glandular tissue cancer). Most breast cancers originate in the epithelial lining of the duct system (structures that carry milk from the lobules), but such a malignancy may also arise in the lobules (structures that produce milk). Breast cancers are categorized by histologic type, and the most common type of invasive breast cancer is infiltrating ductal carcinoma (i.e., invasive ductal carcinoma) that is nonspecific, which accounts for approximately 75–80% of all breast cancers. There are several other rare subtypes of invasive ductal carcinoma such as tubular carcinoma, medullary carcinoma, and mucinous carcinoma. The second most common histologic type is infiltrating lobular carcinoma (i.e., invasive lobular carcinoma). Other uncommon types of breast cancers include Paget disease (starts in ducts and spreads to nipple and areola), sarcomas, and lymphomas. Noninvasive breast cancer includes ductal carcinoma in situ (DCIS) which consists of malignant epithelial cells that have not invaded the stroma (i.e., cells have

remained in situ) but rather are confined in the breast ducts. Lobular carcinoma in situ (LCIS) malignant cells are confined in the lobules. Both DCIS and LCIS are considered cancer precursors, although cancer may never develop. The risk for progression depends on several factors such as the grade of the lesion (e.g., low or high risk), the hormone receptor status (e.g., positive for the human epidermal receptor 2), and the age and race of the woman (young, Black women have a higher risk for invasiveness). DCIS is more common than LCIS, and the risk for future invasive cancer is somewhat higher than with LCIS.

Breast cancers can be described by molecular subtypes that are based on the genes a cancer expresses, creating a genomic profile. The various subtypes have different rates of progression, prognosis, and response to therapy. There are several molecular subtypes such as luminal A, luminal B, triple negative, basal-like, HER2 enriched, and normal-like. These subtypes are described based on whether the cancer is hormone receptor positive or negative for estrogen and/or progesterone, or HER2 negative or positive. The Ki-67 protein level can be used to determine the degree of tumor proliferation along with several other prognostic profiling tools (e.g., Oncotype Dx). As an example the normal-like molecular subtype is described as a hormone-receptor positive (estrogen-receptor and/or progesterone-receptor), HER2- negative breast cancer with low levels of the protein Ki-67. While advances have been made, intensive research efforts are ongoing to determine and refine the use of genomic profiling.

Clinical Manifestations Breast cancer manifestations can vary. The tumor can infiltrate the surrounding tissue and adhere to the skin, causing dimpling. In its early stages, the tumor moves freely, but it becomes fixed as the cancer progresses. Most classic breast masses will be one dominant, hard, immovable mass with irregular borders (uneven edges). The upper quadrant of the breast is where a majority of breast cancers occur. Small masses (< 1 cm) are often not palpable. As the disease advances, nearby axillary lymph nodes may become enlarged and palpable. Skin changes can include erythema, dimpling, or puckering that looks like the peel of an orange (FIGURE 8- 43). The nipple can be laterally displaced or retracted, with spontaneous discharge (e.g., bloody). Metastasis can occur early depending on the type of breast cancer, and in most cases, several nodes are affected at the time of diagnosis. Widespread metastasis quickly follows and usually involves the lungs, bone, and liver, which manifests as cough, bone pain, and nausea and jaundice, respectively. Further indications that the cancer has metastasized include skin ulcers, edema in the arm next to the affected breast, and weight loss.

FIGURE 8-43 Changes in the breast caused by advanced breast cancer. Courtesy of Leonard V. Crowley, MD, Century College.

Early diagnosis and treatment are crucial to positive outcomes. Regular breast self-examinations allow women to become familiar with their breasts and is particularly important for women at increased risk. Another diagnostic procedure specific to breast cancer is the mammogram (which can detect masses as small as 1 mm), but like other screening tools, it is not perfect. Most (95%) of the 10% of women who have abnormal mammograms do not have cancer (American Cancer Society, 2019).

Currently, screening guidelines vary depending on the recommending organization. Screening should generally begin around the age of 40–45 in women with an average risk. The screening can be annual or biennial. As women get older (between 50 and 55) screening frequency recommendations vary from annual to biennial (American Cancer Society, 2018; U.S. Preventive Services Task Force, 2018). After age 75 mammogram benefits are inconclusive but can be continued if life expectancy is longer than 10 years. (American Cancer Society, 2018). Women in high-risk groups should start annual mammograms sooner (typically age 30) in addition to receiving an annual MRI. Men at high risk for breast cancer should have a clinical exam yearly and learn how to do breast self-examination starting at age 35.

Diagnosis and Treatment Recent advances in breast cancer treatments (especially in chemotherapies) have significantly increased survival rates for this disease. Treatment strategies vary depending on the stage, but usually breast cancer requires an aggressive, multimethod treatment (e.g., chemotherapy, radiation, surgery, and hormone therapy) to improve outcomes. The life-threatening nature of breast cancer, along with the changes in body image that result from treatment, can increase the need for coping and support interventions (e.g., support groups and counseling). Those

patients with evidence of breast cancer (e.g., BRCA1 or high DCIS) may be offered prophylactic therapies such as hormone therapy or surgery.

Cervical Cancer Cervical cancer rates have been declining in recent years with advancements in screening. Cervical cytology screening (i.e., Pap smear)—the long-standing cervical screening method—can now detect precancerous changes (dysplasia). Procedures can be performed to remove these precancerous cells, limiting the likelihood of these changes progressing to permanent malignant changes (FIGURE 8-44). The precancerous cells are 100% treatable; however, malignant changes can return if carcinogen exposure continues. Almost all cervical cancers (99.7%) are caused by HPV infection with subtypes 16 and 18 accounting for 70% of cancers. The latency period from exposure to HPV to development of cervical cancer is 10–15 years, making it a slow-developing cancer. Most risk factors for cervical cancer are the same as those that increase the risk of contracting HPV (e.g., having multiple sex partners and not practicing safe sex). According to the National Cancer Institute (2016), Hispanic women have the highest incidence of cervical cancer, while Black women have the highest mortality rates from this disease.

FIGURE 8-44 Development of cervical cancer.

Early-stage cervical cancer is usually asymptomatic. When present, clinical manifestations include the following signs and symptoms:

Continuous vaginal discharge, which may be pale, watery, pink, brown, bloody, or foul smelling Abnormal uterine bleeding (intermenstrual or postcoital bleeding)

Indications of advanced cervical cancer include the following conditions:

Anorexia Weight loss Fatigue Pelvic, back, or leg pain Unilateral lower extremity edema Heavy menstrual bleeding Leaking of urine or feces from the vagina Bone fractures

The Pap smear remains the cornerstone of early cervical cancer detection. An abnormal cervical cytology indicates the need for a cervical biopsy and removal of a portion of the cervix (i.e., cervical conization). Administration of the HPV vaccine, however, may prevent the cancer. Precancerous and early malignant changes can be treated using a loop electrosurgical excision procedure, cryotherapy, and laser therapy. Advanced cancer will require chemotherapy, radiation, and surgery (usually a hysterectomy). The survival rate is usually 100% when cervical cancer is treated early, but the rate decreases as the disease advances.

Endometrial Cancer and Uterine Sarcoma Endometrial cancer, or cancer of the uterus, is a common malignancy in women. According to the American Cancer Society (2019), endometrial cancer is the fourth most frequent cancer in women and the sixth leading cause of cancer death in women, with a 5-year survival rate of approximately 82%. White women have the highest prevalence rates, but Black women have the highest mortality rates. Most endometrial cancers (80%) are endometrioid (a type of adenocarcinoma). The exact cause of this disease is unknown, but unopposed estrogen (i.e., estrogen without opposing progesterone) may be a major factor in its development. Unopposed estrogen is more likely in women with prolonged episodes of amenorrhea and anovulation (e.g., PCOS) or obesity. Additional risk factors for developing endometrial cancer include diabetes mellitus and hypertension.

The most significant finding indicating the possible presence of endometrial cancer is abnormal painless vaginal bleeding (the cancer erodes the endometrium), especially after menopause. After the age 45, any menstrual disorders such as intermenstrual or heavy menstrual bleeding may be due to endometrial cancer. Additional clinical manifestations that are usually late signs include nonbloody vaginal discharge, pelvic pain, weight loss, palpable pelvic mass, and pain during sexual intercourse.

The Pap smear does not detect cancers above the cervix, but some Pap smear findings can be due to malignant cells including adenocarcinoma, atypical glandular cells, and the presence of endometrial cells in women ≥ 40 years of age. Endometrial biopsy is the diagnostic procedure of choice when this malignancy is suspected. Transvaginal ultrasound with the finding of a thickened endometrium in a postmenopausal woman is suspicious for endometrial cancer. If diagnosed early, endometrial cancer can be successfully treated with chemotherapy, radiation, hysterectomy, and hormone therapy.

Uterine sarcoma is a malignant uterine tumor and is not as common as endometrial carcinoma. These tumors are rare, accounting for only 3% of uterine cancers, and the incidence increases with aging. These tumors arise from the myometrium or connective tissue. The types of sarcoma include endometrial stromal sarcomas, leiomyosarcoma, and adenosarcoma. These tumors can be aggressive but can be found at an early stage. The most common manifestations are postmenopausal bleeding, AUB in premenopausal women, abdominal or pelvic pain, and pressure and abdominal distention. Physical examination findings reveal an enlarged uterus. Diagnosis is often made during a myomectomy or hysterectomy, as imaging studies such as an ultrasound do not differentiate benign from malignant tumors. Endometrial biopsy is not reliable. Treatment can include hormone therapy, chemotherapy, radiation, and surgery.

Ovarian Cancer Ovarian cancer is a relatively common cancer in women. According to the American Cancer Society (2019), ovarian cancer incidence rates have declined, but this disease remains the fifth leading cause of cancer death in women. Prevalence and mortality rates are the highest in White women. Ovarian cancer causes concern because there is no reliable screening test for this disease, it is difficult to treat, and it has often metastasized at the time of diagnosis. However, advances in treatment are improving the survival rates (5-year survival rates are approximately 46%).

Most ovarian cancers (95%) form in epithelial cells, and the remainder are from other cells (e.g., germ cell tumors). Risk factors for developing ovarian cancer include genetic predisposition (defects on the BRCA1 and BRCA2 genes), advancing age, infertility or nulligravida (never pregnant), excessive estrogen exposure, obesity, and androgen hormone therapy.

Myth Busters

Several misconceptions around breast cancer warrant discussion.

Myth 1: Breast implants, use of antiperspirant, and wearing underwire bras increase breast cancer risk. Facts: There is no evidence that links these factors to breast cancer. Breast implants can make it more difficult to detect tumors with a breast self-examination depending on the surgical technique used to insert the implants. Placing the implants behind the muscle wall can improve the ability to detect any tumors. Nevertheless, breast implants, antiperspirant, and underwire bras do not increase breast cancer risk.

Myth 2: Only older women need to worry about breast cancer. Facts: Breast cancer risk does increase with age, but women of all ages can develop breast cancer.

Myth 3: Breast cancer always runs in families. Facts: Family history does increase the likelihood of developing breast cancer, but most women who develop breast cancer do not have a family history of breast cancer.

Myth 4: There is no need to worry about breast cancer if no BRCA1 and BRCA2 mutation is present. Facts: BRCA1 and BRCA2 mutations do increase breast cancer risk, but 90–95% of women who are diagnosed with breast cancer do not have either a family history or this genetic mutation.

Data from American Cancer Society (2019). What are the risk factors for breast cancer? Retrieved from http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-risk-factors

Early clinical manifestations of ovarian cancer can be vague, and the more common symptoms include abdominal distention (bloating), pelvic or abdominal pain, eating disturbances (e.g., feeling full quickly), and urinary frequency or urgency. Additional symptoms are not as specific and can include bowel pattern changes, gastrointestinal discomfort (e.g., gas, indigestion, and nausea), pain during sexual intercourse, malaise, and menstruation changes.

CA-125, a protein that is produced in response to several conditions, including ovarian cancer, is often examined as a part of the diagnostic and treatment process. Because it is not specific to ovarian cancer, imaging studies (e.g., pelvic and

transvaginal ultrasound) and a biopsy are still required for definitive diagnosis. During treatment, a declining CA-125 level is considered a favorable response to interventions. Surgery and chemotherapy are the preferred treatment strategies. Surgery may include a bilateral salpingo-oophorectomy (removal of both ovaries and fallopian tubes) and a hysterectomy.

C H A P T E R S U M M A R Y

The reproductive systems in males and females are responsible for procreation and hormone balance. Disorders of the reproductive system range from harmless to life threatening. These disorders are most often infections or tumors (benign and malignant). Reproductive function is closely connected with the endocrine, cardiovascular, and nervous systems and, therefore, can affect those systems. Maintaining reproductive health can decrease the likelihood of issues within this system. Strategies to promote reproductive health include practicing safe sex; abstaining from alcohol, smoking, and illicit drug use; maintaining a healthy weight; and limiting exposure to radiation and chemicals.

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T

C H A P T E R 9

Gastrointestinal Function

L E A R N I N G O B J E C T I V E S

Discuss normal gastrointestinal anatomy and physiology. Differentiate congenital defects of the gastrointestinal system. Summarize causes of common clinical manifestations (dysphagia, vomiting, diarrhea, constipation). Differentiate disorders of the upper gastrointestinal system. Differentiate disorders of the gallbladder, liver, and pancreas. Differentiate infectious disorders of the gastrointestinal system. Summarize conditions of the gastrointestinal tract that are life threatening. Differentiate chronic inflammatory and noninflammatory disorders of the lower gastrointestinal system. Apply understanding of gastrointestinal system alterations in describing various common disorders such as gastroesophageal reflux disease, peptic ulcer disease, cholecystitis, appendicitis, hepatitis, cirrhosis, diverticulitis, inflammatory bowel disease, and irritable bowel syndrome. Develop diagnostic and treatment considerations for various gastrointestinal system disorders.

he gastrointestinal (GI) system, or digestive system, consists of structures responsible for consumption, digestion, and elimination of food (FIGURE 9-1). These processes provide the essential nutrients, water, and electrolytes

required for the body’s physiologic activities. Structures of the GI system include an alimentary canal through which food is passed and accessory organs that aid digestion (FIGURE 9-2). The alimentary canal includes the oral cavity, pharynx, esophagus, stomach, small intestine, large intestine, and anus. The accessory organs include the salivary glands, liver, gallbladder, bile ducts, and pancreas.

FIGURE 9-1 Functions of the gastrointestinal system.

FIGURE 9-2 The structures of the gastrointestinal system.

Disorders of the GI system can result in nutritional deficits and metabolic imbalances. These conditions vary from mild (e.g., constipation) to life threatening

(e.g., pancreatitis) in severity and often present as vague, nonspecific manifestations that reflect a disruption in the system’s normal functioning.

Anatomy and Physiology The GI tract is divided into upper and lower divisions, which will be further discussed in upcoming sections. Additionally, the liver, gallbladder, and pancreas are collectively referred to as the hepatobiliary system because of their close location to each other and their complementary functions. The walls of the GI tract have four layers (FIGURE 9-3). The mucosa is the innermost layer that produces mucus. Mucus facilitates movement of the GI contents and protects the GI tissue from the extreme pH conditions of the GI tract (the stomach’s pH is in the range of 1–2) necessary for digestion. The epithelial mucosa cells have a high turnover rate because of erosion associated with food passage and the highly acidic environment. The submucosa layer consists of connective tissue that includes blood vessels, nerves, lymphatics, and secretory glands. The muscle layer includes circular and longitudinal smooth muscle layers. This layer contracts in a wavelike motion to propel food through the GI tract, an action called peristalsis. The serosa is the outer layer of the wall; however, the outer layer of the esophagus is adventitia. Within the layers of the GI tract are three neuronal plexuses that make up the enteric nervous system. These plexuses include the submucosal plexus (Meissner plexus), myenteric plexus (Auerbach plexus), and the subserosal plexus.

FIGURE 9-3 The layers of the gastrointestinal tract. B: © Donna Beer Stolz, PhD, Center for Biologic Imaging, University of Pittsburgh Medical School.

The peritoneum is the large serous membrane that lines the abdominal cavity. The outer parietal peritoneum layer covers the abdominal wall as well as the top of the bladder and uterus. The inner visceral peritoneum layer encases the abdominal organs. This double-walled membrane is similar to the pericardial sac and the pleural membrane. The peritoneal cavity is the space between these two layers; it contains serous fluid to decrease friction and facilitate movement. The mesentery is a double-layer peritoneum that is a serous membrane. The mesentery is continuous with the serosa that contains blood vessels and nerves that supply the intestinal wall.

It supports and connects the organs and intestines while allowing flexibility to accommodate peristalsis and varying content volumes.

Upper Gastrointestinal Tract The upper GI tract includes the oral cavity, pharynx, esophagus, and stomach (Figure 9-2). Food usually enters the GI tract through the mouth (consumption), where chemical and mechanical digestion begins. Issues with the mouth or swallowing can create a need to bypass the mouth and esophagus and introduce the food or a food supplement directly into the stomach or small intestine. Chewing, or mastication, pulverizes the food into small pieces, and saliva from the salivary glands moistens and further breaks down the food (TABLE 9-1). Saliva contains enzymes (e.g., salivary α-amylase), which start the process of carbohydrate digestion and antibodies (e.g., IgA) that can kill or neutralize bacteria. Saliva also consists of water, mucus, and electrolytes (e.g., potassium and sodium). The smell, taste, feel, and thought of food triggers the olfactory nerve (cranial nerve II) to initiate saliva and gastric acid secretion. Various receptors located throughout the mouth can distinguish tastes (e.g., salty and bitter), and their stimulation adds to the satisfaction of eating. Saliva secretion is controlled by the autonomic nervous system. Parasympathetic cholinergic fiber stimulation inhibits salivation, and sympathetic adrenergic stimulation leads to salivation. Healthy teeth and gums play a key role in maintaining adequate nutrition.

TABLE 9-1 Digestive Juices and Hormones and Actions*

Source Type Action

Salivary glands Bicarbonate Salivary lipase

Moistens food Digests fat

Stomach Hydrochloric acid Pepsin Gastric lipase Intrinsic factor Mucus Gastrin Histamine Ghrelin Somatostatin

Digests protein Kills bacteria Digests protein Digests fat Aids in absorption of vitamin B12 in the small intestine Protects stomach lining Stimulates gastric acid secretion, histamine, and pepsinogen Stimulates gastric acid secretion Stimulates hunger (hypothalamus) Inhibits gastrin, gastric acid secretion, histamine, and pepsinogen

Liver Bile acids Cholesterol Phospholipids Immunoglobulins

Dissolve fats Excreted in bile Aid in absorption of fats Act as antibodies

Small intestine Motilin Secretin

Increases motility in GI tract Inhibits gastric acid secretion; stimulates production of

Cholecystokinin Serotonin

bicarbonate Stimulates gallbladder to release bile and pancreas to release pancreatic juice; decreases rate of gastric emptying Activates GI immune response; stimulates intestines (e.g., secretion, motility)

Pancreas Bicarbonate Water Amylase Lipases Proteases

Protects digestive enzymes Neutralizes acid Carries enzymes Digests starch and glycogen Digest fats Digest protein

*Partial list of types and actions

The tongue pushes the semisolid food mass (bolus) to the back of the throat, where it is swallowed (FIGURE 9-4). All activities up to the creation of a bolus are under voluntary control.Food passing the trigeminal (cranial nerve V) glossopharyngeal nerve (cranial nerve IX), and vagus (cranial nerve X) initiates the swallowing reflex, which is an involuntary action. These nerves relay information to the swallowing center in the medulla and pons; the swallowing center then coordinates the movement of the food from the mouth through the pharynx and into the esophagus with use of the trigeminal, glossopharyngeal, vagus, and hypoglossal (cranial nerve XII). This orchestrated movement prevents food from entering the nearby trachea and lungs (a phenomenon called aspiration). The esophagus has muscular rings to move the food toward the stomach (FIGURE 9-5). As the food nears the stomach, the normally closed lower esophageal sphincter (LES) relaxes to allow the food to enter the stomach. The LES also prevents the stomach contents from refluxing into the esophagus. Relaxation of the LES occurs as a result of vagal impulses and the hormones progesterone, secretin, and glucagon. However, vagal stimulation through cholinergic fibers will increase LES sphincter tone along with the hormone gastrin.

FIGURE 9-4 Swallowing.

FIGURE 9-5 Peristalsis. (A) Peristaltic contractions in the esophagus propel food into the stomach. (B) When food reaches the stomach, the gastroesophageal sphincter opens, allowing food to enter.

The stomach is an expandable food and liquid reservoir. When it is empty, the stomach wall shrinks, forming wrinkles called rugae (FIGURE 9-6). Prior to the arrival of food into the stomach, gastric acid secretion begins in preparation for the arrival of food. As the stomach fills, the rugae unfold and the wall stretches to accommodate a volume up to 4 liters. Rugae inside the gastric glands have different cells that secrete various substances. These cells include parietal cells that secrete hydrochloric acid, intrinsic factor, and gastroferrin; mucous cells that secrete an alkaline mucus; chief cells that secrete pepsinogen (a precursor to pepsin); G cells that release gastrin; D cells that secrete somatostatin; and enterochromaffin cells that secrete histamine. Parietal cells (i.e., oxyntic cells) are found mainly in the fundus while G cells are in the pyloric glands of the antrum. Some gastric secretions are released directly into the stomach, while others are secreted into the blood and then travel to the stomach or intended tissue. Inside the stomach, hydrochloric acid and enzymes (Table 9-1) further chemically digest the food, and peristaltic churning further mechanically digests the food. This new food mixture is referred to as chyme. The highly acidic nature of chyme aids in digestion and destroys bacteria. The epithelial cells of the stomach’s inner lining are densely packed together to prevent damage to the tissues through contact with the acidic stomach contents. For additional protection, bicarbonate is secreted to neutralize the acid, and numerous glands are in the stomach. These glands coat the inner lining of the stomach with a thick layer of mucus. Nutrients are not absorbed in the stomach; instead, the food is simply prepared for absorption. However, alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), and aspirin are absorbed in the stomach. Chyme leaves the stomach through the pyloric sphincter in small (1–3 mL), intermittent amounts. As it passes through the pyloric sphincter into the duodenum, liver and pancreatic secretions (Table 9-1) are added to continue the digestion process. Much like the LES, the pyloric sphincter prevents reflux of bile from the small intestines into the stomach. In addition to extrinsic sympathetic and parasympathetic innervation, the stomach is controlled by the intrinsic plexuses of the enteric nervous system.

FIGURE 9-6 Rugae of the stomach. © Captain Hook/Shutterstock.

Lower Gastrointestinal Tract The lower GI tract comprises the small intestine (duodenum, jejunum, and ileum), large intestine (cecum, colon, and rectum), and anus (Figure 9-2). The small intestine is the longest section of the GI tract (approximately 20 feet long in adults). This length allows for adequate nutrient absorption as the small intestine continues the digestion process. The duodenum, which is located retroperitoneally, in conjunction with digestive juices from the liver and pancreas, are important sites for mixing of food. Carbohydrate, protein, fat, bile, vitamins, and minerals are digested and absorbed in different locations of the small intestines. In the small intestine, the enzymes that have been secreted into the GI tract break the large food molecules into smaller molecules, which are then absorbed. These smaller molecules are transported to the circulatory and lymphatic system. Muscular rings slowly move the food mixture through the small intestine using a peristaltic wave motion. The wall of the small intestine contains numerous circular folds (plicae circulars) covered with

villi and microvilli, particularly in the jejunum and ileum (FIGURE 9-7). These projections increase the surface area available for absorption of nutrients. Each villus contains capillaries, nerves, and lymphatic vessels that play key roles in this absorption. In between the villi are the intestinal glands (i.e., crypts of Lieberkühn) that are the sites where stem cells differentiate into multiple types of cells (e.g., goblet cells and enterocytes). The small intestine also contains cells that secrete fluid to neutralize pH and enzymes to facilitate digestion. Much like the stomach, the small intestine produces a large amount of protective mucus. Immune cells such as lymphocytes, plasma cells, and macrophages are located beneath the villus in lymph nodules in areas known as Peyer patches. These cells act as a defense against microorganisms. Antimicrobial peptides, immunoglobulins, and enzymes are produced as part the defensive role of the GI tract. As with other parts of the GI tract, intestinal motility is under the control of the vagus nerve, the enteric nervous system, and various hormones.

FIGURE 9-7 Villi of the small intestines. B: © Donna Beer Stolz, PhD, Center for Biologic Imaging, University of Pittsburgh Medical School.

After making its long journey through the small intestine, the chyme ultimately reaches the large intestine (in approximately 3–5 hours). The large intestine is approximately 5 feet long and about twice the diameter of the small intestine. The large intestine does not contain villi. The large intestine has few enzyme-secreting cells but has a large number of goblet cells and enterocytes (absorptive cells). The cecum and colon muscle layers are structured into a succession of pouches called

haustra with a band of muscle (teniae coli) that runs through the haustra (Figure 9- 2). This structure gives the intestine a gathered look. The small intestine ends in a pouch called the cecum. The appendix is also attached to the cecum. This small, wormlike structure seemingly has no function, but it does have plenty of potential to cause harm. The ileocecal valve is a sphincter that controls flow of digested material from the ileum to the cecum and prevents substances from refluxing into the small intestine. The ileocecal valve is normally closed, and peristalsis from the ileum will stimulate intrinsic fibers and cause the valve to open. The colon makes up most of the large intestine. Unlike the coiled small intestine, the colon has three relatively straight sections—termed the ascending, transverse, and descending colons. The descending colon becomes the sigmoid colon.

The mixture entering the colon from the small intestine includes water, unabsorbed food molecules, indigestible food remnants (e.g., cellulose), and electrolytes (sodium and potassium). The colon absorbs 90% of the water and electrolytes, and Escherichia coli feed off the undigested or unabsorbed food remnants. E. coli organisms constitute a large population of bacteria normally found in the GI tract. These bacteria synthesize several key vitamins (e.g., vitamins B12, B1, B2, and K) that are later absorbed by the large intestine. As the chyme moves through the colon, it changes into a fecal mass. The fecal mass is moved through the colon by way of segmental movements passing the mass from the haustra. Peristaltic movements further promote colonic emptying. Feces contain the remaining undigested or unabsorbed remnants along with bacteria (one-third of the feces). Feces also introduce mucus (approximately 300 mL daily) to aid in bowel movements, even in times of decreased dietary intake. Because the feces are denser than the contents in the small intestines, the colon’s muscular rings must be thicker to propel the feces until they reach the rectum (this usually takes approximately 18 hours). The movement of feces from the sigmoid colon to the rectum is controlled by the rectosigmoid sphincter. The rectum serves as a reservoir to store the feces.

Much like the bladder, the rectum expands when feces enter this area, stimulating the stretch receptors in the sigmoid colon and rectal wall. These receptors send an impulse through the enteric nervous system and spinal cord (which controls the external sphincter) to elicit the defecation reflex. During defecation, the internal and external anal sphincters relax, and the rectum contracts to expel the feces. Stool passage is best accomplished in a squatting or sitting type position as the puborectal muscles relax and the anorectal angle straightens. Gravitational forces also assist with stool passage. Defecation is consciously controlled (except in infants and young children) and may require assistance from abdominal muscles. The Valsalva maneuver, which involves taking a breath and then pushing, causes an increase in intrathoracic and intra-abdominal pressure and facilitates the passage of stool. Defecation control requires both appropriate

muscular and nervous function. The urge to defecate can be delayed up to a point through voluntary contraction of the external sphincter, but the longer the feces remain in the large intestine, the more water from them will be absorbed, making the feces more difficult to expel.

In addition to the nerves that control defecation, the enteric nervous system and the sympathetic and parasympathetic nervous systems innervate the GI tract. Activation of the sympathetic nervous system slows digestive activity, whereas activation of the parasympathetic nervous system increases digestive activity.

Liver The liver is an organ that is a hub of activity. This large organ performs as many as 500 different functions. Some of the liver’s primary roles are vital for homeostasis and include the following:

Metabolize carbohydrates, protein, and fats. Synthesize glucose, protein (albumin, globulins—alpha and beta), amino acids, enzymes, cholesterol, triglycerides, and clotting factors. Store glucose (glycogen), fats (lipids), and micronutrients (e.g., iron, copper, and vitamin B12) and release them when needed. Detoxify the blood of potentially harmful chemicals (e.g., alcohol, nicotine, and medications). Maintain intravascular fluid volume through the production of circulating proteins (see chapter 6). Metabolize medications to prepare them for excretion. Produce bile (necessary for emulsification of fat and fat-soluble vitamins). Inactivate and prepare hormones for excretion. Remove damaged or old erythrocytes from blood to recycle iron and protein (see chapter 3). Serve as a blood reservoir (stores approximately 450 mL of blood that can be used when needed). Convert fatty acids to ketones.

A tough membrane (Glisson capsule) protects this crucial organ. The liver has a dual blood supply. The liver is a small part of the body weight (approximately 2.5%) but receives 25% of cardiac output. The hepatic artery carries oxygenated blood from the general circulation to the liver at a rate of approximately 300 mL per minute to nourish the liver. The portal vein carries partially deoxygenated blood from the stomach, pancreas, spleen, and gallbladder as well as from the small and large intestines, to the liver at a rate of approximately 1,000 mL per minute so that the liver can process nutrients and digestion by-products.

The liver is one of the few body organs that can regenerate. As much as 75% of

the liver tissue can be lost or removed, yet the remaining liver tissue can slowly regenerate into a whole liver again. This regeneration occurs primarily due to certain liver cells (hepatocytes) that act as stem cells. A single hepatocyte can divide into two daughter cells. During regeneration, steps should be taken to protect the liver from damage (e.g., avoiding hepatotoxic medications and substances).

In addition to providing regeneration capabilities, the hepatocytes produce bile and perform most of the liver’s other activities. The hepatocytes constantly produce bile at a rate of approximately 600–1,200 mL per day. Bile is a green or yellowish liquid that contains water, bile salts (formed from cholesterol), conjugated bilirubin, cholesterol, and electrolytes (including bicarbonate). Bile salts are necessary to emulsify fats and fat-soluble vitamins (A, D, E, and K) so that they can be absorbed in the small intestine. The distal ileum reabsorbs most of the bile and returns it to the liver through the portal vein for recycling. The bicarbonate ions in the bile neutralize the acidic gastric contents so that the intestinal and pancreatic enzymes can perform their functions. The bile flows from the liver through a duct system to either the gallbladder for storage or on to the duodenum (see FIGURE 9-8). The gallbladder is a small (usually no larger than a golf ball), saclike organ located on the undersurface of the liver that serves as a reservoir for bile. In addition to storing the bile, the gallbladder concentrates it by removing water and electrolytes, leaving bile salts, bile pigments, and cholesterol. The presence of chyme in the small intestine triggers the gallbladder to contract, releasing bile into yet another duct system, where it travels to the small intestine. The hormone cholecystokinin, which is produced by the small intestine when there is fat, also controls gallbladder contraction. If the gallbladder requires surgical removal, the bile constantly flows directly from the liver to the small intestine.

FIGURE 9-8 Gross anatomy of the human liver and gallbladder. The liver, gallbladder, stomach, pancreas, and duodenum, with a detail of the related ducts. Hepatopancreatic sphincter of Oddi, hepatopancreatic ampulla of Vater, duodenum, duodenal papilla, pancreatic duct of Wirsung, cystic duct, common bile duct, common hepatic

duct, pancreas, stomach, liver, gallbladder.

Pancreas The pancreas is an organ that is nestled underneath the stomach and liver (with the head tucked under the duodenum and the tail touching the spleen). It has exocrine and endocrine functions. The exocrine functions include producing enzymes, electrolytes (e.g., bicarbonate ions), and water necessary for digestion (Table 9-1). A duct system (see Figure 9-8) carries these substances to the duodenum to join the chyme. The endocrine functions include producing hormones (insulin, glycogen, somatostatin, and pancreatic polypeptide) to help regulate blood glucose, thereby maintaining homeostasis. See chapter 10 for more on endocrine function.

Gastrointestinal Changes Associated With Aging The GI system undergoes a few changes with aging. The stomach lining may shrink and become inflamed, leading to atrophic gastritis. Stomach acid production occasionally can decrease (a condition called achlorhydria) because of atrophic gastritis. Achlorhydria can cause decreased intrinsic factor production, resulting in vitamin B12 deficiency and slow digestion. Changes in the liver associated with age include reduced blood flow, delayed drug clearance, and a diminished capacity to regenerate damaged liver cells. Additionally, changes in the metabolism and

absorption of lactose, calcium, and iron can occur. In particular, the small intestine absorbs less calcium with advancing age, so increased calcium intake is needed to prevent bone mineral loss and osteoporosis. The production of some enzymes, such as lactase (which aids in the digestion of lactose, a sugar found in dairy products), declines with age. Peristalsis also decreases with age, increasing the risk of constipation. Intestinal microflora changes can result in increased susceptibility to disease.

Understanding Conditions That Affect the Gastrointestinal System When considering alterations in the GI system, organizing them based on their basic underlying pathophysiology can increase understanding. These concepts are based on the two major underlying pathologic issues—altered nutrition and impaired bowel elimination that result in alterations in movement of intestinal content and disruption in secretory and absorptive functions. Conditions that alter nutritional status include issues with consuming, digesting, and absorbing food. Examples of these conditions include cleft lip, pancreatitis, and celiac disease, respectively. Regardless of the cause of the altered nutrition, the result is similar—inadequate nutritional states in which individuals may be underweight, malnourished, and vitamin deficient. Conditions impairing bowel elimination generally manifest as constipation and diarrhea. These issues may be either the primary condition or a symptom of another condition. Additionally, conditions that cause altered nutrition may cause issues with elimination.

Disorders of the Upper Gastrointestinal Tract and Accessory Organs Disorders of the upper GI tract generally cause issues with nutrition and range in severity from mild to life threatening. These disorders can be congenital or acquired (e.g., peptic ulcers). Upper gastrointestinal tract disorders can result in manifestations such as dysphagia or vomiting. Depending on their severity, most of these disorders can be resolved or managed with minimal residual effects.

Congenital Defects Congenital defects of the digestive system can affect the upper and the lower GI tract (to be discussed later in chapter) (FIGURE 9-9). These congenital disorders, including cleft lip, cleft palate, and pyloric stenosis, are common and not usually life threatening, but they may cause nutritional and self-image issues.

FIGURE 9-9 Diagram of gastrointestinal malformations. A. Meckel’s diverticulum, B. Esophageal atresia with distal tracheoesophageal fistula (type C), C. Congenital diaphragmatic hernia, D. Imperforate anus

Cleft Lip and Cleft Palate Cleft lip and cleft palate are the most common types of congenital craniofacial malformations that are apparent at birth. The Centers for Disease Control and Prevention (CDC, 2017a) estimates that cleft palate without cleft lip occurs in 1 of

every 2,650 births in the United States, and cleft lip with or without cleft palate occurs in 1 of every 4,440 births. Some infants with cleft lip or palate have other anomalies, and there are over 100 syndromes associated with clefts. These conditions usually develop between the fourth and ninth weeks of gestation and are multifactorial in origin. Such defects have been associated with genetic mutations, maternal diabetes, drugs (e.g., anticonvulsants), toxins, viruses, vitamin deficiencies, alcohol consumption, and cigarette smoking. Clefts are most frequent in children of Native American, Hispanic, and Asian descent, whereas Black children are the least likely to have a cleft. Males are twice as likely as females to have a cleft lip. Females, however, are twice as likely as males to have a cleft palate. A cleft lip and palate can affect the appearance of an individual’s face and may lead to feeding issues, speech problems, ear infections (e.g., otitis media), and hearing problems. The conditions may vary in severity from a small notch in the lip to a complete groove that runs into the roof of the mouth and nose (FIGURE 9-10). These defects may occur either separately or together.

FIGURE 9-10 Cleft lip and palate.

Courtesy of Leonard V. Crowley, MD, Century College.

Clinical Manifestations Cleft lip may appear unilaterally or bilaterally (on either side of the midline of the upper lip). This defect results from failure of the maxillary processes and nasal elevations or upper lip to fuse during development. Cleft palate results from failure of the hard and soft palates to fuse in development, creating an opening between the oral and nasal cavities. At times, a cleft palate may just involve the muscles, and the cleft palate may be covered by the mouth lining (i.e., submucous cleft palate) often making these types of defects difficult to see. In addition to lip and palate deformities, teeth and nose malformations may be present. Feeding problems result from these deficits due to an insufficient ability to suck. An infant with a cleft lip and/or palate is also at high risk for aspiration when the nasal cavity is open. The inability to make sounds using the lips and tongue impairs speech development.

Diagnosis and Treatment Diagnostic procedures for cleft lip/palate consist of a history, physical examination, and prenatal ultrasound. Orofacial clefts can often be detected after 12 weeks’ gestation. Treatment strategies for cleft lip/palate include temporary measures (e.g., special nipples or dental appliances) until surgical procedures are recommended. Surgical repair of the defect is necessary to close the gap. Cleft lip repair is recommended before age 3 months, and cleft palate repair is recommended by 18 months of age. Follow-up procedures are often necessary from 2 years through the adolescent years and depending on the type of cleft. Treatment can span over 20 years. Cosmetic plastic surgery can improve the appearance of the defect. Surgical repair in utero is currently being explored. The major advantage of surgical repair before birth is little or no scarring. Speech therapy, including language and eating interventions, as well as orthodontist consultation can promote normal growth and development. Additionally, a multidisciplinary team (including an audiologist, speech and language therapist, and a pediatrician) is frequently required to manage severe cases.

Esophageal Atresia Esophageal atresia is a result of congenital malformation of the esophagus. The malformation leads to two separate esophageal sections—an upper and a lower section that are not connected (Figure 9-9). There are four types (type A, B, C, and D) with two separate sections, and most cases (88%) are associated with a tracheoesophageal fistula (TEF) (type C). The CDC (2017b) estimates that esophageal atresia occurs in 1 of every 4,300 pregnancies. Most of the cases of

esophageal atresia with TEF involve the lower half of the esophagus connecting with the trachea. A tracheoesophageal fistula can also occur without esophageal atresia and this is termed type E Many cases of esophageal atresia are associated with other congenital anomalies such as anal atresia, cardiac defects, and renal defects. The risk of esophageal atresia is higher in infants as their father’s age increases and if their mothers used assistive reproductive technology to become pregnant.

Clinical Manifestations Prenatally, esophageal atresia should be suspected when there is polyhydramnios (excess amniotic fluid), however many cases are not detected prenatally. Clinical manifestations of esophageal atresia are dependent on whether a TEF is present or absent. Manifestations in the infant occur immediately after birth. Saliva and secretions are unable to descend the esophagus because the upper esophagus is closed off. The infant will start drooling, choking, and have difficulty breathing. The infant may choke with feeding, as he or she is unable to swallow during feedings. If there is no TEF, the infant may have a scaphoid-shaped abdomen with no gas because food and liquids are not going through from the esophagus to the stomach. If there is a TEF with the distal esophagus section, the abdomen can become distended, causing breathing difficulties. The gastric contents can also reflux through the fistula, leading to an aspiration pneumonia, which is associated with a higher incidence of death. Complications of esophageal atresia with or without TEF include recurrent aspiration, pneumonia, and atelectasis.

Diagnosis and Treatment Diagnosis is usually made at birth. The atresia is evaluated by attempting to pass a catheter into the stomach and an inability to do so is suspicious for atresia. The catheter location is assessed with an X-ray, and the catheter will be curled up in the upper esophageal pouch with an atresia. The TEF may be evident on chest X-ray, and the GI tract will be filled with gas. Diagnostic tests for the evaluation of other associated abnormalities may include an echocardiogram, renal sonogram, and X- ray of the spine and limbs. Once a diagnosis is made, initial treatment will include continuous suction of the esophagus to prevent complications (e.g., choking and pneumonia). Surgical repair of the esophageal defects and TEF is the mainstay of treatment. Surgery may need to be performed in stages, such as when the gap between the upper and lower pouch of the esophagus is too large. With a large gap, surgery may have to be postponed until the esophagus grows longer, usually in a few months.

Diagnostic Link

M Liver Injury

easurement of liver enzymes is a common serologic test. These enzymes are markers of liver injury and include ALT, AST, ALP, and bilirubin. ALT is mainly in the liver, and elevated serum levels are a marker of

liver injury while AST is present in the liver and other organs (e.g., cardiac and skeletal muscle, kidney, and brain) and therefore elevated levels can be indicative of an injury to the liver and/or other organs. ALT, therefore, is a better marker of liver injury in comparison to AST. The magnitude of the aminotransferase elevations can vary depending on the type of liver injury. As an example, acute viral hepatitis and ischemic hepatitis can cause levels to go up 25 and 50 times the upper limits of normal, respectively. Fatty liver disease not due to alcohol, on the other hand, can cause milder elevations (e.g., < 4 times the upper limit of normal). Alkaline phosphatase is derived from the bone and liver, and elevated serum levels can indicate injury in either organ. The γ-glutamyl transpeptidase (GGT) can confirm that the elevated ALP is due to liver injury as the γ- glutamyl transpeptidase rises with liver injury but not with bone disorders. Lactic dehydrogenase is found in the liver and in tissue throughout the body. While it is elevated with liver injury, elevations can also occur with many other disorders, so it is not as specific as other markers for liver injury.

Pyloric Stenosis Pyloric stenosis, also known as infantile hypertrophic pyloric stenosis, is a narrowing and obstruction of the pyloric sphincter. The pyloric sphincter muscle fibers become thick and stiff, making it difficult for the stomach to empty food into the small intestine. This condition can be present at birth, or it may develop later in life (rarely in children older than 6 months). Most cases present at approximately 3 weeks of life. The exact cause of pyloric stenosis is unknown, but it is thought to be multifactorial—that is, a combination of environmental and hereditary factors. Use of macrolides such as azithromycin and erythromycin in early infancy has demonstrated a strong association with increased pyloric stenosis risk. Evidence also suggests that exposure in utero with breastfeeding due to maternal use or increases this risk. Although it is the most common cause of intestinal obstructions in infancy, pyloric stenosis is relatively uncommon (occurring in 2–4 infants per 1,000 births) (Singh & Sinert, 2015). Pyloric stenosis is most common in Whites and in males.

Clinical Manifestations Clinical manifestations of pyloric stenosis usually appear within several weeks (3–6) after birth. In the congenital form, the hypertrophied pyloric muscle can be palpated as a hard, olive-shaped mass in the abdomen (right upper quadrant), and vomiting (usually after every feeding, often projectile, and sometimes with hematemesis being noted) is usually the first symptom. Additional manifestations include the following signs and symptoms: persistent hunger (the infant often wants to eat soon after vomiting), regurgitation, belching, abdominal pain, failure to gain weight, and wavelike stomach contractions that result from the increased peristaltic effort to pass food through the narrowed areas. Dehydration, electrolyte imbalances, and pH disturbances (usually metabolic alkalosis) may occur; however, advances in

B

diagnostic imaging have led to earlier diagnosis and a decreased incidence of dehydration. Hyperbilirubinemia can be associated with pyloric stenosis, known as the icteropyloric syndrome. The hyperbilirubinemia can be conjugated or unconjugated (more common).

Diagnosis and Treatment Diagnostic procedures for pyloric stenosis include a history, physical examination, abdominal ultrasound, blood chemistry (to identify and monitor fluid and electrolyte imbalances), and a complete blood count (to rule out other causes such as infection). A test of bilirubin and liver enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) is performed when an infant has jaundice. Surgical repair called pyloromyotomy is recommended to open the sphincter, but balloon dilation may be used in high-surgical-risk infants. Additionally, fluid, electrolyte, and pH imbalances may need correction. Signs and symptoms usually resolve within 24 hours of surgical repair. In most cases, feedings are restarted within 8 hours of surgery.

Diagnostic Link

Bilirubin Measurement ilirubin is another marker of liver injury or function, but it is not as good of a marker as other measures such as ALT. Bilirubin is a by-product of heme metabolism (mainly hemoglobin breakdown), and the breakdown

results in unconjugated bilirubin (not water soluble). The unconjugated bilirubin is sent to the liver for conjugation (it is water soluble) where most is readily cleared from the body through bile and out into the small intestines and in feces. Measurements can be direct, reflecting conjugated bilirubin, or indirect, reflecting unconjugated bilirubin. Bilirubin levels reflect the balance between production and clearance, so high levels can occur with increased production, decreased use, and too little excretion. High unconjugated levels reflect too much bilirubin that has not been conjugated by the liver so there is either too much heme being metabolized (as in sickle cell anemia) at a rate that is higher than the liver can handle or there is a problem with the liver’s conjugating capacity (e.g., Gilbert syndrome). High conjugated bilirubin, which has already been processed by the liver, can indicate there is a problem with the secretion of the bilirubin into the bile, preventing it from exiting (e.g., biliary obstruction, hepatitis) and causing it to back up into the blood.

Dysphagia Dysphagia, or difficulty swallowing, usually develops secondary to a condition that causes mechanical obstruction of the esophagus or impaired esophageal motility (FIGURE 9-11). Dysphagia may be due to a disorder in the pharynx (i.e., oropharyngeal dysphagia), which is characterized by difficulty initiating swallowing, or or esophagus (i.e., esophageal dysphagia), which is characterized by difficulty swallowing after initiating a swallow. Dysphagia can occur as a result of intrinsic (originating with the esophagus lumen) or extrinsic (originating outside the esophagus lumen) mechanical obstruction. Numerous conditions can lead to dysphagia:

FIGURE 9-11 Causes of dysphagia.

Mechanical obstructions, including those caused by the following:

Congenital atresia (congenital separation of the upper and lower esophagus) Esophageal stenosis or stricture (may be developmental or acquired) Esophageal diverticula (outpouching of the esophageal wall) Esophagitis (e.g., infectious, eosinophilic) Tumors (esophageal or of nearby structures)

Neurologic disorders, including those caused by the following: Stroke Cerebral damage (e.g., traumatic brain injury) Achalasia (failure of the LES to relax because of loss of innervations) Parkinson disease Alzheimer disease Huntington disease Cerebral palsy Multiple sclerosis Amyotrophic lateral sclerosis Guillain-Barré syndrome

Muscular disorders, including those caused by muscular dystrophy

Functional dysphagia is a sense of solid and/or liquid food lodging, sticking, or passing abnormally through the esophagus. With functional dysphagia, there is no evidence of esophageal, mucosal, or structural abnormality, and the dysphagia is not attributable to other disorders such as achalasia or gastroesophageal reflux disease. Dysphagia can also have iatrogenic causes, resulting from many head and neck surgeries and procedures such as laryngectomy, tracheostomy, endotracheal intubation, esophageal dilatation, or radiation. Dysphagia can also occur as a result of medication side effects. Medications that relax the muscles, suppress the nervous system, or damage the mucosa, such as sedatives, narcotics, antipsychotics, NSAIDs, or potassium chloride tablets, may cause dysphagia. Dysphagia has likewise been associated with several psychiatric conditions, including anxiety, depression, somatoform disorders, hypochondriasis, conversion disorders, and eating disorders. Dysphagia can have an acute and sudden onset, and generally, this onset is due to food that is impacted in the esophagus (usually beef or chicken) that completely blocks off the esophagus. In these circumstances, the food is extracted or pushed into the stomach with a grasping device during an upper endoscopy.

Clinical manifestations include a sensation of food being stuck in the throat, choking, coughing, pocketing food in the cheeks, difficulty forming a food bolus, delayed swallowing, and painful swallowing (odynophagia). Dysphagia may occur with solids, liquids, or with both, and the distinction is important to determine the probable underlying disorder. As an example, difficulty only with swallowing solid foods may indicate that the esophageal lumen has a stricture. Dysphagia can be

intermittent (e.g., esophageal spasms) or progressive (e.g., due to peptic stricture or achalasia). Dysphagia not only causes alterations in nutrition, but also poses an aspiration risk.

Diagnostic procedures focus on identifying the underlying cause and consist of a history, physical examination, barium swallow, chest and neck X-rays, esophageal pH measurement, esophageal manometry, upper endoscopy, flexible endoscopic evaluation of swallowing with sensory testing, videofluoroscopic swallow study, and esophagogastroduodenoscopy (EGD). Manometry measures the movement and pressure in the esophagus and stomach through a small nasogastric tube. Flexible endoscopic evaluation of swallowing with sensory testing uses a small, lighted camera to view the mouth and throat while examining how the swallowing mechanism responds to such stimuli as a puff of air, food, or liquids. A videofluoroscopic swallow study is a videotaped X-ray of the entire swallowing process in which foods or liquids along with the mineral barium are consumed. EGD is a visualization of the esophagus, stomach, and duodenum using a small, lighted camera. Treatment strategies are specific for the causative condition and can include surgery (e.g., myotomy [cutting of the muscle] and endoscopic balloon dilation) or botulinum toxin injection to allow the muscle to relax to facilitate swallowing. Additionally, interventions are employed to maintain the patient’s nutritional status and prevent aspiration (e.g., soft or pureed foods, thickened liquids, small bites, and no use of straws).

Vomiting Vomiting, or emesis, is the involuntary or voluntary forceful ejection of chyme from the stomach up through the esophagus and out the mouth. Vomiting is a common event that results from a wide range of conditions. It may be protective (e.g., with drug overdose or infections) or result from reverse peristalsis (e.g., with intestinal obstructions). Increased intracranial pressure can cause sudden projectile vomiting. Additionally, vomiting may be associated with other symptoms such as severe pain (e.g., migraines or renal calculi). The medulla coordinates vomiting, and drugs, toxins, and chemicals can stimulate this vomiting center. See chapter 11 for details on neural function.

Regardless of the cause, vomiting requires the collaboration of several structures (FIGURE 9-12). Involuntary vomiting occurs through the following sequence:

FIGURE 9-12 Vomiting reflex.

1. A deep breath is taken. 2. The glottis closes and the soft palate rises. 3. Respirations cease to minimize the risk of aspiration. 4. The gastroesophageal sphincter relaxes. 5. The abdominal muscles contract, squeezing the stomach against the diaphragm

and forcing the chyme upward into the esophagus. 6. Reverse peristaltic waves eject chyme out of the mouth.

Vomiting may be preceded by nausea (a subjective urge to vomit) or retching (a strong unproductive effort to vomit). Recurrent vomiting can be exhausting because of the strong muscular contractions. Additionally, recurrent vomiting can lead to fluid, electrolyte, and pH imbalances. Aspiration of chyme into the lungs can cause serious damage and inflammation. This event can occur if the individual is supine or unconscious when vomiting occurs. Aspiration can also occur when the vomiting or cough reflex is suppressed from drugs (e.g., anesthesia or narcotics) or disease (e.g., stroke).

The characteristics of the contents vomited (called vomitus) are significant and can illuminate the underlying cause of the vomiting event. Hematemesis describes the condition in which blood is present in the vomitus. Blood in vomitus has a characteristic brown, granular appearance similar to coffee grounds. This appearance results from protein in the blood being partially digested in the stomach. Blood in the stomach is irritating to the gastric mucosa, so the stomach attempts to expel it. Hematemesis can occur from several conditions that can cause upper GI bleeding (e.g., gastric ulcers and esophageal varices). Yellow- or green-colored vomitus usually indicates the presence of bile. This type of vomitus can occur as a result of a GI tract obstruction. A deep brown color of vomitus may indicate content from the lower intestine, possibly fecal. This type of vomitus frequently results from intestinal obstruction. Conditions that impair gastric emptying (e.g., pyloric stenosis) can cause recurrent vomiting of undigested food.

The force with which the vomiting occurs is important. Projectile vomiting occurs when the vomitus exits the mouth with such force that it is propelled over a short but significant distance. It is often sudden, with excessive vomitus with each attack, and not preceded with nausea. Projectile vomiting is associated with intestinal obstructions, delayed gastric emptying, increased intracranial pressure, poisoning, and overeating.

Diagnostic procedures for vomiting focus on identifying causative agents as well as fluid, electrolyte, and pH imbalances (usually metabolic alkalosis). These procedures vary and may include a history, physical examination, and blood chemistry, among others. Treatment strategies center on the cessation of vomiting, maintaining hydration, restoring acid–base balance, and correcting electrolyte alterations. These strategies may vary depending on the severity of the vomiting:

Antiemetic medications (e.g., dimenhydrinate [Dramamine], ondansetron [Zofran], and promethazine [Phenergan]) Oral or intravenous fluid replacement Correcting any electrolyte imbalances (see chapter 6) Restoring acid–base balance (see chapter 6)

Hiatal Hernia

A hiatal hernia occurs when a section of the stomach protrudes upward through an opening (hiatus) in the diaphragm into the thoracic cavity. There are two categories of hiatal hernia—sliding hernia (type I) and paraesophageal hernia (types II, III, and IV). A sliding hiatal hernia is the most common type, accounting for approximately 95% of cases. With a sliding hernia, the gastroesophageal (GE) junction is displaced above the diaphragm. The stomach remains aligned, and the stomach fundus remains below the GE junction (FIGURE 9-13). With paraesophageal hernias, the GE junction remains below the diaphragm, and the stomach fundus herniates through the hiatus (type II). Paraesophageal hernias, however, can result in both the GE junction and the fundus herniating (type III—a combination of type I and type II). The combination type is the most common of the paraesophageal hiatal herniations. When there is a large opening, the stomach and other organs (e.g., colon, pancreas) can also herniate (type IV). Sliding hiatal hernias develop from GE junction disruption that is progressive, while paraesophageal hernias usually occur as a result of laxity of the ligaments that hold the stomach in place. The cause of the hernias is not clear; however, they are more likely to occur with congenital malformation (e.g., short esophagus, large hiatal opening), iatrogenic factors (e.g., the patient is postgastrectomy or has had lower esophageal surgeries), or trauma. Factors exacerbating sliding hiatal hernias include activities that increase intrathoracic pressure (e.g., coughing, vomiting, or straining to defecate) or increased intra-abdominal pressure (e.g., pregnancy and obesity). Risk factors associated with hiatal hernias include advancing age and smoking. Small hiatal hernias may go undetected and rarely cause problems. Large hiatal hernias can cause chyme to reflux into the esophagus, irritating the mucosa. When the stomach protrudes through the diaphragm (paraesophageal), it creates a pouch (hernia sac). This sac can alter blood flow. There is also an increased risk for ulcer development and strangulation of the sac that can lead to ischemia, perforation, bleeding, and obstruction.

FIGURE 9-13 Sliding hiatal hernia.

B: © Scott Camazine/Science Source.

Clinical Manifestations A hiatal hernia by itself rarely causes symptoms. Clinical manifestations in a sliding hiatal hernia reflect the inflammation of the esophagus and stomach due to reflux of gastric acid, air, or bile. These manifestations include indigestion, heartburn (pyrosis), frequent belching, nausea, chest pain, strictures, and dysphagia. Manifestations worsen with recumbent positioning, eating (especially after large meals), bending over, and coughing. Conversely, these symptoms often improve when standing as the organ returns to its usual position. Additionally, a soft upper abdominal mass (protruding stomach pouch) may be visualized especially when intra-abdominal pressure is increased such as by coughing, laughing, or straining. With paraesophageal hernias, reflux symptoms are not as common, but the patient may experience fullness after eating, epigastric or substernal pain, nausea, and retching due to the herniation.

Diagnosis and Treatment Diagnostic procedures for hiatal hernia consist of a history, physical examination, barium swallow, upper GI tract X-rays, manometry, and EGD. Treatment strategies focus on relieving inflammation by decreasing regurgitation of chyme and healing the mucosa. Such strategies include eating small, frequent meals (six small meals per day), avoiding alcohol, assuming a high Fowler position after meals, sleeping with the head of the bed elevated 6 inches, smoking cessation, losing weight (if overweight), as well as taking antacids, acid-reducing agents (e.g., histamine2 blockers and proton pump inhibitors), and mucosal barrier agents. Surgical repair (e.g., fundoplication) may be necessary for hiatal hernias, particularly for paraesophageal hernias, not relieved by these strategies.

Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) is a condition where chyme (acid, pepsin) periodically backs up from the stomach into the esophagus. Occasionally, bile can back up into the esophagus. The presence of these gastric secretions irritates the esophageal mucosa (FIGURE 9-14). Mechanisms for development of GERD are a result of abnormalities in the LES (e.g., relaxation, decreased pressure, or GE disruption). Reflux can also occur due to issues with acid clearance. Normally, the esophagus clears the acid via peristalsis, and bicarbonate in saliva neutralizes acid. Impairment of these protective mechanisms as a result of impaired esophageal peristalsis and problems with saliva bicarbonate neutralizing the acid (e.g., decreased saliva production) can result in GERD. Gastric motility issues such as

pyloric stricture or gastroparesis can result in a higher likelihood of reflux because chyme sitting in the stomach for prolonged periods can become more acidic, increasing the risk for chyme to reflux. Various factors can cause or contribute to LES abnormalities and development of GERD. Pressure changes may originate from many sources such as obesity, pregnancy, or other circumstances (e.g. coughing or bending) that increase intra-abdominal pressure. Smoking, drinking alcohol, certain foods, and certain medications can alter LES pressure. Foods that alter LES pressure include chocolate, caffeine, carbonated beverages, citrus fruit, tomatoes, spicy or fatty foods, and peppermint. Medications with LES-altering effects include nitrates, sedatives, beta blockers, calcium channel blockers, and anticholinergic agents. GERD can cause esophagitis (esophageal inflammation), usually through activation of the immune system (e.g., cytokine release). Esophagitis is typically diagnosed based on endoscopy findings (termed erosive or reflux esophagitis) because not all patients affected by GERD have esophageal injury (termed nonerosive reflux disease). Conversely, those patients with esophagitis may have minimal GERD symptoms. Reflux esophagitis is not so much a consequence of increased acid secretion but rather occurs due to the amount of time the reflux is in contact with the esophageal mucosa. Another key determinant to the amount of injury caused by reflux is the acidity of that reflux (the more acidic the higher chance of injury). Physiologic reflux is a normal reflux that occurs after eating, and this type of reflux does not cause symptoms and is short lived.

FIGURE 9-14 Gastroesophageal reflux disease. © Gastrolab/Science Source.

Clinical Manifestations GERD varies in severity depending on the degree of LES weakness. Clinical manifestations include heartburn (early), which is described as epigastric or retrosternal pain (usually after a meal or when recumbent), and regurgitation of food, which is described as a gastric content coming back up into the throat or mouth. This reflux can lead to a “sour taste.” Other symptoms can include nausea (usually after eating), dry cough, laryngitis, pharyngitis, and sensation of a lump in the throat. Some patients with GERD may hypersalivate (i.e., they have water brash). Symptoms such as dysphagia and odynophagia may occur with GERD. These symptoms are usually indicative of long-standing heartburn and mucosal injury or ulceration and not a simple, uncomplicated GERD. The pain associated with GERD is often confused with angina and may warrant steps to rule out cardiac disease. See chapter 4 for further discussion of cardiovascular function.

GERD can result in esophageal and nonesophageal complications such

esophagitis, Barrett esophagus (normal esophageal squamous epithelium becomes metaplastic columnar epithelium), strictures, ulcerations, esophageal cancer, asthma exacerbation, and chronic laryngitis. GERD is one of the top three reasons for a chronic cough (the other two are asthma and postnasal drip) in the absence of smoking and use of angiotensin-converting enzymes. Risk for Barrett esophagus, considered a precursor to adenocarcinoma of the esophagus, is higher in those with long-standing GERD (at least 5 years) and the presence of other criteria (e.g., obesity, smoking).

GERD complications or other possible diagnosis, such as gastrointestinal malignancy, should be suspected in individuals with symptoms other than heartburn and regurgitation (e.g., dysphagia and odynophagia). Other concerning features include GI bleeding (e.g., melena and hematochezia), persistent vomiting, new onset dyspepsia after age 60, anorexia, unexplained weight loss, anemia, or a first-degree relative with GI cancer.

Diagnosis and Treatment Diagnosis of GERD is generally made clinically based on a history and physical examination in those with heartburn and/or regurgitation. Diagnostic testing is usually not necessary; however, testing is indicated in the presence of symptoms other than heartburn and regurgitation or if there is concern for the presence of GERD complications, such as Barrett esophagus, or other disorders like GI malignancy. Diagnostic testing with concerning presentations will include an EGD. Esophageal pH monitoring and esophagus manometry may also be done. Treatment strategies focus on balancing pressures and reducing acid, including the following:

Eating small, frequent meals and avoiding eating 2–3 hours before bedtime Assuming a high Fowler position for 2–3 hours after meals Elevating the head of the bed approximately 6 inches Losing weight Avoiding triggers (e.g., trigger foods, alcohol, medications, and nicotine) Avoiding medications that cause gastric irritation (e.g., aspirin and other NSAIDs) Avoiding clothing that is restrictive around the waist Taking certain drugs and herbal remedies, including: Acid-reducing agents (e.g., proton pump inhibitors and histamine2 blockers) Mucosal barrier agents (e.g., sucralfate, sodium alginate) Antacids (e.g., Maalox and Tums) for symptom relief, not preventive Herbal therapies (e.g., licorice, slippery elm, and chamomile)

Having surgery (e.g., Nissen fundoplication or implantation of a reflux management device)

Gastritis Gastritis refers to an inflammation of the stomach’s mucosal lining. The inflammation can involve the entire stomach or a region. Acute mucosal injury can also occur with minimal or no inflammation (i.e., gastropathy). Gastritis can be either acute or chronic; each type has its own presentation, although this can vary.

Acute gastritis is commonly caused by infections or autoimmune conditions. Infections are often due to Helicobacter pylori, which is a gram-negative spiral bacterium transmitted through the fecal–oral route. Most H. pylori exposure occurs during childhood, and most infections are asymptomatic. Acute infection with H. pylori, however, can cause acute gastritis. Other organisms (e.g., E. coli, streptococci, staphylococci) can also cause acute gastritis. Neutrophilic infiltration characterizes acute gastritis. Gastritis can be caused by internal and external irritants. These irritants can include bile reflux, alcohol, cocaine, and medications (e.g., NSAIDs, chemotherapy agents, and alendronate). Severe stress due to major surgery, traumatic injury, burns, or severe infections can cause acute gastritis because of tissue ischemia and decreased gastric motility resulting from the stress response. Acute gastritis can be a mild, transient irritation, or it can be a severe ulceration with hemorrhage. It usually develops suddenly and is likely to be accompanied by nausea and epigastric pain.

Chronic gastritis is associated with the presence of lymphocytes, plasma cells, and macrophages, as opposed to acute gastritis where there is neutrophil infiltration. Chronic gastritis generally proceeds through phases. Initially, the gastritis is superficial, then the inflammation extends deeper in the mucosa and the gastric glands are affected. The final phase is gastric atrophy, during which glandular structures are lost. Chronic gastritis can be characterized as type A or type B based on the location of the injury, or both types can coexist (type AB). Type A is less common than type B and generally affects the fundus and the body of the stomach while sparing the antrum. Type A is associated with autoimmune processes (e.g., pernicious anemia and Hashimoto disease) that results in autoantibody development against parietal cells or intrinsic factor. The H+-K+ATPase is the specific antigen targeted by the autoantibodies. Because the parietal cells are the target with type A (i.e., autoimmune gastritis), achlorhydria (reduced or absent hydrochloric acid) occurs and results in increased gastrin production by G cells found in the antrum. Hypergastrinemia occurs as a result of the increased gastrin and causes hyperplasia of the cells. The cellular changes can increase the risk for gastric tumors and gastric cancer development. The resulting lack of intrinsic factor can cause vitamin B12 deficiency (see chapter 3 for more on hematopoietic function.).

Type B is usually the result of a H. pylori infection. In contrast to type A, the stomach antrum is affected, but the fundus and body can also become infected. H. pylori embeds itself in the mucous layer, activating toxins and enzymes that cause inflammation. H. pylori is equipped with flagella that help it move, molecules that

help it adhere, and enzymes that neutralize the gastric acid in its immediate vicinity (see FIGURE 9-15).

FIGURE 9-15 The (A) location and (B) progression of peptic ulcers associated with Helicobacter pylori infection. H. pylori produce toxic virulence factors such as urease and cytotoxins that act at different levels of infection. Urease neutralizes stomach acidity by degrading urea present on epithelial cells, whereas cytotoxins are

involved in the development of ulcers.

Why some people experience complications from H. pylori infections and others do not is not clear; however, genetic vulnerability, lifestyle behaviors such as smoking, and different strains of H. pylori may increase susceptibility to the bacterium’s effects. Long-term use of NSAIDs (e.g., ibuprofen or naproxen) can contribute to chronic gastritis by reducing cyclooxygenase, a key substance that

helps preserve the mucosal lining. Alcohol and smoking can also contribute to chronic gastritis development.

Clinical Manifestations The clinical manifestations of gastritis reflect injury of the mucosal lining. These symptoms include indigestion, heartburn, epigastric pain, nausea, vomiting, anorexia, and malaise. The presence of hematemesis and dark, tarry stools can indicate ulceration and bleeding. Chronic gastritis develops gradually and can last for months to years. It is likely to be accompanied by a dull epigastric pain and a sensation of fullness after minimal intake. Nausea and vomiting may occur. In some cases, chronic gastritis can be asymptomatic. As with acute gastritis, GI bleeding may occur.

Chronic gastritis increases the risk for peptic ulcers, gastric cancer, anemia, and hemorrhage.

Diagnosis and Treatment Diagnosis of gastritis consists of a history and a physical examination along with diagnostic tests to evaluate for the cause. Imaging tests can include an EGD to evaluate the mucosal lining and H. pylori testing. Active H. pylori infection is evaluated with the urea (produced by H. pylori) breath test or H. pylori stool antigen. Serum H. pylori antibodies will not distinguish between acute or prior infection. Additional tests often include a complete blood count (CBC; to identify anemia) and stool analysis for occult blood). Acute gastritis is often self-limiting and resolves within a few days. Irritants should be identified and discontinued or avoided. Treatment strategies vary depending on the underlying etiology. For instance, bacterial infections, such as those caused by H. pylori, require antibiotic therapy. Chronic disease management is important to limit any complications associated with this inflammation. In addition to etiology-specific interventions, pharmacologic management may include antacids, acid-reducing agents (e.g., histamine2-receptor antagonists or proton pump inhibitors), and mucosal barrier agents.

Peptic Ulcers Peptic ulcer disease (PUD) refers to stomach or duodenal lesions that extend through the muscularis mucosae (FIGURE 9-16). The incidence of PUD has been declining in recent years, but it remains a common condition that affects approximately 4.5 million people in the United States each year (Anand, 2015). The two common risk factors for developing PUD are NSAID use and H. pylori infections —both are more likely with advancing age. Other associated factors include chronic disease (especially pulmonary and renal) and certain gastric tumors (e.g., those

associated with Zollinger-Ellison syndrome). Contributing factors also include those associated with development of GERD (e.g., stress, smoking, and alcohol use). Family history of ulcer disease, particularly duodenal ulcer, confers a risk.

FIGURE 9-16 Peptic ulcer. © Jose Luis Calvo/Shutterstock.

Ulcers vary in severity from superficial erosions to complete penetration through muscle, damaging blood vessels and even eroding through the GI tract wall. Regardless of its etiology, PUD develops because of an imbalance between destructive forces (e.g., excess acid production) and protective mechanisms (e.g., decreased mucus production). The imbalance generally occurs as a result of a superimposed process (e.g., H. pylori infection or NSAID use) as opposed to a primary defect in normal secretory, protective, and repair mechanisms.

Duodenal ulcers account for 80% of cases as opposed to gastric ulcers. Duodenal ulcer onset is typically between the age of 20 and 50 years. Duodenal ulcers are most commonly associated with excessive gastric acid with or without H. pylori infections. H. pylori, however, is associated in a majority (95%) of cases. The proposed mechanism by which H. pylori results in duodenal ulcer formation is not well understood (Figure 9-15). Some theories include increased gastric acid secretion as a result of more gastrin release and low somatostatin. The bacterium, however also produces gastric urease which cleaves urea into ammonia and carbon

dioxide. This reaction ultimately leads to acid neutralization and allows the organism to colonize and survive the harsh acidic environment. Infection with duodenal ulcers causes a reduction in duodenal bicarbonate secretion, further lowering the pH and causing gastric metaplasia (i.e., gastric epithelial cells in the duodenum). The metaplasia causes an increased susceptibility to ulcer formation. The bacterium also stimulates an immune response with the release of inflammatory cytokines, which may contribute to ulcer formation. Increased NSAID use or other ulcerogenic medications can also promote duodenal ulcer formation. Patients with duodenal ulcers typically present with epigastric pain that is relieved in the presence of food. The pain may be more common at night.

Gastric ulcers, by comparison, are less frequent but more deadly. The age of onset is between the ages of 50 and 70. Gastric ulcers are associated with NSAID use, which increases with aging (e.g., to treat arthritis). H. pylori infection is also associated with gastric ulcer formation, but the incidence is somewhat lower (e.g., 60–80%) in comparison to the incidence in duodenal ulcer. Depending on the ulcer’s location in the stomach (e.g., antrum versus the body), acid level secretion may be normal, low, or high. As an example, ulceration in the distal antrum may have decreased antral somatostatin from D cells (inhibit gastrin G cells) and resulting increase in gastric acid secretion. An ulcer closer to the body (midportion of the stomach) is a reflection of atrophy of glands that contain parietal cells (oxyntic glands0 resulting in lower acid secretion. Gastric cancer risk is higher in those patients with gastric ulcers but not for those with duodenal ulcers. In contrast to duodenal ulcers, the pain experienced with gastric ulcers typically worsens with eating.

Stress ulcers describe PUD that develops because of a major physiologic stressor on the body (e.g., large burns, trauma, sepsis, surgery, or head injury). Stress ulcers associated with burns are generally called Curling ulcers, whereas stress ulcers associated with head injuries are generally called Cushing ulcers. Stress ulcers develop due to local tissue ischemia, tissue acidosis, entry of bile salts into the stomach, and decreased GI motility. Such ulcers most frequently develop in the stomach, and multiple ulcers can form within hours of the precipitating event. Often hemorrhage is the first indicator of a stress ulcer because the ulcer develops rapidly and tends to be masked by the primary problem.

Zollinger-Ellison syndrome is caused by duodenal or pancreatic neuroendocrine tumors, referred to as gastrinomas, that secrete gastrin. The tumors are sometimes cancerous. The incidence is rare (approximately 0.5 to 2 per million). The average age of diagnosis is between 20 and 50 years of age, and men have a higher incidence in comparison to women. The excessive gastrin causes parietal cells and enterochromaffin-like cells (histamine secreting) to produce an excessive quantity of gastric acid. The clinical manifestations are the same as those with other ulcers, but chronic diarrhea is present in many cases. The diarrhea is a result of the

high acid content affecting reabsorption, the inactivation of digestive enzymes, and the inhibition of sodium and water absorption by gastrin. Treatment will be similar to that for other ulcers, and tumor resection can reduce metastasis.

Clinical Manifestations Complications of PUD may involve GI hemorrhage, obstruction, perforation, bowel penetration, and peritonitis. Clinical manifestations of PUD resemble those associated with other conditions of GI inflammation (e.g., gastritis and GERD) and include:

Epigastric or abdominal pain Abdominal cramping Heartburn Indigestion Chest pain Nausea and vomiting (may include hematemesis—bright red blood or coffee ground appearance) Melena (dark, tarry stools) Fatigue Weight loss

Diagnosis and Treatment Diagnosis of PUD consists of a history and physical examination, but the diagnosis is confirmed with an EGD. A CT of the abdomen can also identify ulcers (nonperforated ulcers). Evaluation for the cause will include testing for H. pylori, a CBC to identify anemia, and a stool analysis (occult blood). Serum gastrin levels may be measured to evaluate for a gastrinoma. Treatment strategies include those discussed for gastritis. Additionally, surgical repair may be necessary for perforated or bleeding ulcers.

Prevention is crucial with stress ulcers to improve patient outcomes. Prophylactic medications (e.g., acid-reducing agents) are administered to persons at risk for developing stress ulcers.

Cholelithiasis Cholelithiasis, or gallstones, is a common condition (affecting 10–20% of all people in the United States) in which stones (calculi) of varying sizes and shapes form inside the gallbladder (Heuman, Allan, & Mihas, 2016) (FIGURE 9-17). Cholelithiasis is more common in fair-skinned women. Other risk factors include advancing age, obesity, diet (high fat, high cholesterol, and low fiber), rapid weight loss (like that

associated with bariatric surgery), pregnancy, hormone replacement, certain chronic diseases (e.g., diabetes mellitus, hyperlipidemia, and liver disease), and long-term parenteral nutrition. Three types of calculi can develop in the gallbladder or nearby ducts (TABLE 9-2; FIGURE 9-18), and the presence of calculi can cause inflammation or infection in the biliary system (cholecystitis).

FIGURE 9-17 Cholelithiasis. Courtesy of Leonard V. Crowley, MD, Century College; © Casa nayafana/Shutterstock.

FIGURE 9-18 Location of cholelithiasis.

TABLE 9-2 Types of Cholelithiasis

Type Characteristics

Cholesterol Most common Can be small or large, single or multiple Can cause obstruction, pain (biliary colic), and jaundice Strong association with female hormones Increased incidence with obesity, extreme dieting, and hypercholesterolemia

Bilirubin (pigmented) Usually multiple, small, black stones More common in Asians and in persons with chronic diseases that cause hemolysis (e.g., sickle cell anemia)

Mixed Usually found in large numbers Bilirubin center surrounded by cholesterol and calcium

Small calculi are often asymptomatic and excreted with the bile. Larger calculi are likely to obstruct bile flow and cause clinical manifestations. Biliary colic is caused by the contraction of the gallbladder while it is trying to move a stone (or biliary sludge) through the gallbladder outlet or cystic duct. Pressure in the gallbladder builds, leading to visceral pain.

Clinical Manifestations Most individuals with gallstones are asymptomatic, and the stones are found incidentally during abdominal imaging for other reasons. Of those who are asymptomatic, up to 25% can develop symptomatic disease (it can occur as late as 10 years after), and complication risk is low. In those patients with symptomatic gallstones, biliary colic is the typical manifestation. Biliary colic is a pain located in the right upper quadrant or epigastric area that can radiate to the back or right shoulder. The pain lasts from 30 minutes to 6 hours and usually peaks within 1 hour. The pain is described as intense and dull. Nausea, vomiting, and diaphoresis can accompany the pain. The pain usually occurs after eating a fatty meal, but the pain may be nocturnal for some patients. Physical examination may reveal no findings, particularly if no pain is present. The pain can recur, and the frequency can be variable (from hours to years). Those patients with biliary colic are at increased risk for complications.

Prior to complications, affected individuals will usually have had episodes of biliary colic, and symptoms of complications as an initial presentation are unusual. The most common complication of gallstones is acute cholecystitis, which is gallbladder inflammation as a result of cystic duct obstruction. The manifestations are the same as those of biliary colic. However, the pain is steady, severe, and typically prolonged (> 4 hours) and is accompanied by fever and leukocytosis. The Murphy sign is positive (pain is elicited when the patient takes a deep breath and upon palpation of the right upper quadrant). While most episodes of acute cholecystitis are due to gallstones, a few cases (< 10%) are acalculous. The cause of acalculous cholecystitis is gallbladder ischemia and stasis, and many risk factors are associated with development of this disorder (e.g., leukemia, AIDS, burns, diabetes mellitus, and renal disease). Gallstones can also be present in the common bile duct (i.e., choledocholithiasis) and results in acute cholangitis (stasis and infection in the biliary tract). The manifestations of choledocholithiasis include biliary colic symptoms and abnormal liver tests (i.e., elevated bilirubin and ALP). Acute cholangitis will cause fever, jaundice, and abdominal pain (Charcot triad). Gallstones can obstruct the pancreatic duct or the ampulla of Vater (leading to bile reflux into the duct); both obstructions can lead to acute pancreatitis. Other less common complications of gallstones include gallbladder gangrene, gallbladder cancer, and common hepatic duct obstruction. Additionally, inflammation can lead to gallbladder rupture. Gallstone disease is responsible for approximately 10,000 deaths annually in the United States—7,000 are attributed to acute complications and 3,000 are attributed to gallbladder cancer (Heuman, Allen, & Mihas, 2016).

Diagnosis and Treatment Diagnostic procedures for cholelithiasis consist of a history, physical examination,

and an abdominal ultrasound, which is very sensitive in detecting gallstones. An endoscopic ultrasound can be performed to detect even very small stones. Other tests that may detect gallstones include an abdominal X-ray, but only a small percentage of stones are radio-opaque, allowing them to be visible on X-ray. An abdominal computed tomography (CT) may identify gallstones. Other tests can include endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, and percutaneous transhepatic cholangiogram. Serum laboratory tests can include bilirubin levels, liver function tests, pancreatic enzymes (e.g., amylase and lipase), and a CBC. Treatment strategies for an acute attack will include pain management, usually with NSAIDs. Opioids can be used, but all (e.g., meperidine, morphine) have the potential to increase sphincter of Oddi pressure, which could worsen pain. Treatment strategies focus on removing the calculi, restoring bile flow, preventing reoccurrence, and include the following:

Low-fat diet Medications to dissolve the calculi (e.g., bile acids) Antibiotic therapy (if infection is present) Lithotripsy (e.g., extracorporeal shock wave) Surgically creating an opening for drainage (choledochostomy) Laparoscopic removal of calculi (through cholecystostomy tube) or gallbladder (cholecystectomy)

Disorders of the Liver Disorders of the liver are usually serious and often life threatening. The liver’s involvement in so many of the body’s activities results in a situation that can be complex to manage when this organ’s functions become disrupted. Liver disorders are often acquired through ingestion of hepatotoxic substances (e.g., medications or alcohol) or infections.

Hepatitis Hepatitis is an inflammation of the liver that can be caused by infections (usually viral), alcohol, medications such as acetaminophen (Tylenol), antiseizure agents, and antibiotics; or autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis, and scleroderma. Hepatitis can be acute, chronic, or fulminant, such as in liver failure. Additionally, this disease can be active or nonactive. People with nonviral hepatitis usually recover, but some people develop liver failure, liver cancer, or cirrhosis. Nonviral hepatitis is not contagious, whereas viral hepatitis is contagious. Like individuals with nonviral hepatitis, people with viral hepatitis usually recover in time with no residual damage. Advancing age and comorbidity increase the likelihood of liver failure, liver cancer, or cirrhosis in patients with hepatitis. Both viral and nonviral hepatitis can result in hepatic cell destruction, necrosis, autolysis, hyperplasia, and scarring.

Viral hepatitis accounts for approximately 50% of all cases of acute hepatitis in the United States (Buggs & Dronen, 2014). There are five types of viral hepatitis, each with its own general characteristics (TABLE 9-3). In the United States, viral hepatitis is most commonly caused by hepatitis A (HAV), hepatitis B (HBV), and hepatitis C (HCV). According to the CDC (2015b), rates of hepatitis A and B declined from 2000 to 2014, whereas hepatitis C cases have increased since 2000. Additionally, several genotypes for hepatitis B and C are possible. Hepatitis D can replicate independently, but HBV is necessary for the HDV virion (virus particle) to assemble and be secreted. Therefore, those patients with HDV are always dually infected with HBV.

TABLE 9-3 Types of Viral Hepatitis

Clinical Manifestations Acute hepatitis proceeds through four distinct phases—an asymptomatic incubation phase and three symptomatic phases. Clinical manifestations for each symptomatic

phase include the following signs and symptoms:

Prodromal phase: Starts 2 weeks after exposure to the virus; includes viral symptoms such as abdominal pain, nausea, vomiting, malaise, anorexia, low- grade fever, and headache Icteric phase: Begins 1–2 weeks after the prodromal phase and lasts up to 6 weeks; includes jaundice, pruritus, dark tea-colored urine (bilirubinuria) or clay- colored stools (lack bilirubin), hepatomegaly, and right upper quadrant pain Recovery phase: Resolution of jaundice approximately 6–8 weeks after exposure; enlarged liver for as long as 3 months

Chronic hepatitis, usually as a result of hepatitis B and C, is characterized by continued hepatic disease lasting longer than 6 months. Its symptom severity and disease progression vary depending on the degree of liver damage. An individual can live with chronic hepatitis for years (i.e., carrier state) but his or her health can quickly deteriorate with declining liver integrity. Chronic hepatitis can lead to cirrhosis and liver cancer. Fulminant hepatitis is an uncommon, rapidly progressing form that can quickly lead to liver failure, hepatic encephalopathy, or death within 3 weeks. Extrahepatic manifestations can occur with acute or chronic hepatitis and include rash and arthralgias.

Diagnosis and Treatment Diagnostic procedures for hepatitis include a history and physical examination, but diagnosis is confirmed with a serum hepatitis profile (TABLE 9-4). Additional tests may include liver function tests, clotting studies, liver biopsy, and abdominal ultrasound. Treatment strategies concentrate on prevention, and vaccinations are the cornerstone of hepatitis prevention. Vaccinations are available for HAV and HBV. HAV vaccination is recommended for all children starting at age 1 year, travelers to certain countries, men who have sex with men, intravenous drug users, persons with long-term liver disease, persons requiring repeated blood transfusions (e.g., those with hemophilia), and others at risk for exposure (e.g., living with someone who is hepatitis A positive). HBV vaccination is recommended for all infants beginning at birth, older children and adolescents who were not vaccinated previously, and adults at risk of developing this form of hepatitis (e.g., healthcare workers, men who have sex with men, and intravenous drug users). HBV vaccination is also recommended to prevent HDV infection as HDV requires HBV infection for development. Prevention also includes limiting exposure to the virus (e.g., by limiting exposure to blood, body fluids, and feces).

TABLE 9-4 Viral Hepatitis Profile

A

* HBeAg—if positive, indicates active replication virus; anti-HBe—if positive, indicates antibody has developed; virus nonreplicating. HBsAG—protein on surface of virus indicates acute or chronic infection. anti-HBs—indicates recovery and immunity. anti-HBc—indicates previous or ongoing infection; remains for life. anti-HBc—IgM; indicates acute infection (≤ 6 months).

Once viral hepatitis is contracted, there is no method of destroying the virus. Most cases of HAV and hepatitis E will resolve with no treatment, and care is supportive. The treatment of other types of viral hepatitis is dependent on the degree of liver damage or other circumstances such as pregnancy. Hepatitis can be treated with interferon injections to improve the immune response and antiviral (e.g., nucleotide or nucleoside analogs) medications to decrease viral replication (see chapter 2 for further discussion of immunity).

Learning Points

Acute Liver Failure cetaminophen in nontherapeutic ranges (> 4 grams/day) is the most common cause of acute liver failure (50%) in the United States. While most cases are due to intentional overingestion during a suicide attempt,

some individuals inadvertently take high doses when not taking medications as directed or when taking multiple medications that contain acetaminophen. Inadvertent, inappropriate dosing is a more common cause in young children. Liver toxicity is dose dependent, and toxicity is likely with doses of greater than 250 mg/kg or 12 grams over 24 hours. Toxicity threshold in children is usually 150 mg/kg. Clinical manifestations can be mild in the first 24 hours and are poor predictors of who will develop toxicity. Jaundice, hepatic encephalopathy, bleeding, lactic acidosis, hypoglycemia, and multiorgan failure may occur within 4 days if the person survives. Liver enzymes are exceedingly high (often > 10,000 IU/L) and prothrombin time are prolonged. Early identification and management increases chance of survival. Activated charcoal can be effective within 4 hours of acetaminophen ingestion. Acetylcysteine (Mucomyst) is an antidote and is best administered within 8 hours

of ingestion.

Additional strategies include rest, adequate nutrition (a diet high in carbohydrates, protein, and vitamins), increased hydration, and avoidance of alcohol. Affected individuals should be counseled on methods to avoid transmission, which can include not sharing toothbrushes or shaving equipment and covering wounds to prevent potential blood exposure. Hygienic practices are important and include hand washing as well as avoiding water and raw foods (foods should be cooked at a high temperature) in areas with poor sanitation. Liver transplant may be necessary in those patients with advanced liver diseases. The most common indication for liver transplantation in the United States is chronic HCV infection.

Cirrhosis Cirrhosis refers to chronic, progressive, irreversible, diffuse damage to the liver resulting in decreased liver function (FIGURE 9-19). The causes of cirrhosis are hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, and hemochromatosis. Other conditions that can lead to cirrhosis can include autoimmune conditions (e.g., primary biliary cirrhosis), hepatotoxic medications, hepatic venous obstruction (e.g., right-sided heart failure), and hereditary metabolic disorders (e.g., glycogen storage disease). Hepatitis C infection and chronic alcohol abuse are the most frequent causes of cirrhosis in the United States (Wolf, 2015). Nonalcoholic fatty liver disease, also known as nonalcoholic steatohepatitis, is becoming a more common cause of cirrhosis, reflecting the rising rates of obesity.

FIGURE 9-19 (A) Cirrhosis. (B) A normal liver. A: Courtesy of Dr. Edwin P. Ewing, Jr./CDC; B: © Clark Overton/Medical Images.

Liver fibrosis development in cirrhosis occurs at different rates depending on the underlying cause of the cirrhosis and the general health of the patient. The extracellular matrix of the liver includes various molecules (e.g., collagen, growth factors, glycosaminoglycans). With fibrosis, the extracellular matrix becomes degraded by proteases, which in turn affects the normal functioning of cells. The degradation occurs as a result of the activation of cells, particularly stellate cells, which release chemokines and other mediators. Production of collagens is increased along with other extracellular matrix components, and destructive liver enzyme production is increased. Regenerative nodules eventually develop, giving the liver a cobbly appearance; the liver blood flow is impaired; and bile flow is obstructed—all of which contribute to liver failure. Cirrhosis develops due to ongoing injury and progressive fibrosis. Cirrhosis may take as long as 40 years to develop. While cirrhosis is generally considered irreversible, early stages of fibrosis may be reversible. As an example, hepatitis C treatment can lead to reversal of fibrosis. The time frame from reversible to irreversible damage is unclear. Several advancements have been made in understanding the process of fibrogenesis and regression of fibrosis, leading to new antifibrotic therapies.

Clinical Manifestations Clinical manifestations of cirrhosis are similar regardless of the underlying cause. These manifestations can range from nonspecific symptoms such as anorexia, fatigue, and weight loss seen in compensated cirrhosis to manifestations that reflect decompensation and failure of the liver to accomplish its many functions (FIGURE 9- 20). As cirrhosis progresses, pressures rise in the hepatic artery and the portal vein (portal hypertension) as a result of the resistance created by abnormal liver changes (e.g., fibrosis, nodules) as well as due to the increased release of vasoconstrictors (e.g., norepinephrine) and reduction in release of vasodilators. Cirrhosis is an intrahepatic cause of portal hypertension and is one of the most common causes of portal hypertension in the United States. Portal hypertension is present in almost 60% of patients with cirrhosis. Prehepatic (e.g., portal vein thrombosis or stenosis) and posthepatic (e.g., right-sided heart failure) disorders can also lead to portal hypertension. Many consequences can result from portal hypertension because the portal vein receives blood from most of the GI tract. As the pressure rises in the portal system vessels, the veins become engorged, and varicosities (FIGURE 9-21) commonly develop in the esophagus, stomach, abdominal wall (caput medusa), spleen, and rectum (hemorrhoids). Bleeding, either slow or severe, can occur along these overstretched vessels—particularly in the esophagus. Varices will cause

hematemesis (reflects acute bleeding) and/or melena (reflects chronic bleeding). Esophageal bleeding has a high mortality and reoccurrence rate. Nearby organs utilizing the same circulation (e.g., the spleen, pancreas, and stomach) enlarge as pressures rise. Platelets become sequestered in the congested spleen (i.e., hypersplenism), causing thrombocytopenia that contributes to bleeding. Hypersplenism can cause neutropenia. See chapter 4 for more on cardiovascular function.

FIGURE 9-20 Effects of cirrhosis.

FIGURE 9-21 Development of esophageal varices.

Fluid accumulates in the peritoneal cavity (a condition referred to as ascites) as the portal hypertension pushes fluid back into the abdominal cavity and the damaged liver can no longer produce sufficient amounts of albumin (a protein responsible for maintaining colloidal pressure and fluid balance in the vessels; see chapter 6 for discussion of fluid homeostasis).

Ascites also develops as a result of vasodilation (due to substances such as increased nitric oxide) of splanchnic arteries in response to increased portal pressure, which causes increased portal venous inflow. The ascites then worsens the portal hypertension and contributes to systemic hypotension. Patients can accumulate up to 2 L of fluid in the peritoneal cavity. Ascites causes weight gain, dyspnea, and early satiety due to the increasing abdominal pressure. An abdomen with ascites appears distended and is dull to percussion (normal is tympanic). The vasodilation in the splanchnic arterial system causes poor circulation and activation of the renin–angiotensin–aldosterone system and sodium retention. Sodium retention leads to extracellular fluid volume and contributes to ascites as well as the

development of peripheral edema. Changes in protein metabolism result in decreased protein clotting factors, muscle wasting, and hyperlipidemia. Poor nutritional absorption in the intestines and poor dietary intake also contribute to malnutrition. Changes in glucose metabolism can lead to hyperglycemia or hypoglycemia. Malabsorption of vitamin D and calcium increases the risk for bone loss, resulting osteopenia and osteoporosis (see chapter 12 for more on musculoskeletal function).

Bile accumulation in the liver causes inflammation and necrosis. Because it cannot flow through the duct system to the intestine, bile enters the bloodstream and causes jaundice. Fats cannot be digested, and fat-soluble vitamins cannot be absorbed without the presence of bile. Additionally, the stools become clay colored without the presence of bile. The kidneys attempt to compensate for the excessive bile in the blood by increasing excretion, causing the urine to become dark. The kidneys can start to decline in function (i.e., they develop hepatorenal syndrome) as a result of the splanchnic artery vasodilation and other poorly understood changes in renal arterial circulation. The kidney decline will manifest as an increase in serum creatinine. The excessive bile is also excreted in the sweat, causing bile salts to accumulate on the skin. These bile salts cause intense itching. Estrogen builds up in both sexes, as the liver can no longer inactivate the hormone. Excessive estrogen produces female characteristics in men and irregular menstruation (anovulation) in women. Men develop hypogonadism with impotence, infertility, and testicular atrophy. Numerous toxins and waste products also accumulate as the liver fails to detoxify the blood. In particular, the buildup of ammonia produces neurologic impairment (i.e., hepatic encephalopathy) that presents as cognitive and mental status changes (e.g., confusion, disorientation, disordered sleep, and lethargy) as well as hand tremors (asterixis). Ulcers and GI bleeding occur as the excessive bile and inflammation impair the mucosa. GI bleeding, in combination with a high-protein diet, renal failure, and infection, can cause protein levels to increase. Excessive protein levels lead to the rapid onset of encephalopathy. Spontaneous bacterial peritonitis, usually as a result of E. coli, may also occur because of compromised host defenses and bacterial overgrowth common in persons with cirrhosis. The bacteria translocate from the intestines to the mesenteric lymph and then spread into the ascitic fluid, leading to potential bacteremia. Spontaneous bacterial peritonitis may cause fever, abdominal pain, altered mental status, and acute kidney injury. Liver damage can alter the pulmonary vasculature, resulting in hypoxemia (i.e., hepatopulmonary syndrome), and the increased portal pressures can also cause pulmonary artery vasoconstriction and pulmonary hypertension (i.e., portopulmonary hypertension).

Diagnosis and Treatment

Diagnostic procedures for cirrhosis include a history and physical examination. An abdominal ultrasound can be used to detect cirrhosis and manifestations such as ascites and splenomegaly. A liver biopsy is confirmatory but not always necessary particularly if the cause is known (e.g., alcoholism). Other tests can include an abdominal CT and abdominal magnetic resonance imaging (MRI). Laboratory tests will include a CBC, liver enzyme panel, clotting studies, platelet count, and stool examination for occult blood. Endoscopy can be performed to identify esophageal varices. Since there are more therapies aimed at reversing fibrosis, new noninvasive markers are being evaluated to measure and categorize the stages of fibrosis. Some of these markers include FibroSpect (evaluate markers associated with matrix breakdown such as hyaluronic acid and inhibitors of metalloproteinases) or calculation of the aspartate-to-AST to platelet ratio, and elastography (use of ultrasound and MRI to estimate liver stiffness).

Treatment strategies for cirrhosis are complex and vary depending on the underlying cause. The general treatment goals are aimed at slowing or reversing liver disease, preventing and treating complications, and managing clinical manifestations. Hepatitis-related cirrhosis is treated with antiviral agents and interferon. Alcohol and drugs should be completely avoided. Hepatotoxic medication doses may need to be adjusted if discontinuation is not possible. Vaccinations for hepatitis A and B should be administered to avoid further liver injury. Nutritional imbalances (usually treated with total parenteral nutrition [TPN]) and metabolic dysfunction are corrected to manage complications and promote optimal health. Bile acid–binding agents can aid bile excretion. Portal hypertension is treated with a surgically implanted shunt. Antacids and acid-reducing agents can minimize GI inflammation.

Specific complication management for the various aspects of cirrhosis includes:

Varices Nonselective beta blocker and endoscopic variceal ligation to prevent bleeding During acute bleeding, vasoconstrictive agents such as somatostatin, octreotide, or terlipressin and temporary balloon tamponade (e.g., use of Sengstaken-Blakemore tube) until variceal ligation, or esophageal sclerotherapy (injection of a sclerosing agent such as sodium morrhuate into varices) As a last resort, transjugular intrahepatic portosystemic shunt and other surgeries (e.g., portacaval shunts); highly effective but high mortality rate

Ascites—diuretics (e.g., spironolactone, furosemide), sodium restriction, therapeutic paracentesis (removal of fluid), or transjugular intrahepatic portosystemic shunt Spontaneous bacterial peritonitis—administration of antibiotics Hepatorenal syndrome—administration of albumin, alpha agonists (e.g.,

H

W

midodrine), and agents like those for varices (e.g., terlipressin, octreotide); liver transplantation Pulmonary complications—liver transplantation Hepatic encephalopathy—correct underlying cause (e.g., GI bleeding), hydration, correction of electrolyte imbalances, lactulose (type of laxative that can promote ammonia excretion in stools), nonabsorbable antibiotics (e.g., rifaximin) that can suppress intestinal flora and decrease endogenous ammonia production

A liver transplant usually offers the best outcome for individuals with cirrhosis, but not all patients are candidates for this therapy. Alcoholics must refrain from all alcohol consumption for a minimum of 6 months to be considered for transplant. Some hepatitis infections (hepatitis B more than C) can return after transplant, so patients with such infections may not be considered as good candidates for this treatment. Additionally, patients with any evidence of cancer are not considered transplant candidates.

Learning Points

Fatty Liver Disease epatic steatosis, also known as fatty liver disease, can occur as a result of chronic alcohol ingestion (alcoholic steatosis) or nonalcoholic causes (e.g., obesity, metabolic syndrome, type 2 diabetes mellitus).

Nonalcoholic steatosis is termed nonalcoholic fatty liver disease, or it is termed nonalcoholic steatohepatitis if hepatitis is present. The primary disorder in development of fatty liver disease is insulin resistance, which leads to lipolysis (lipid triglycerides broken down into glycerol and free fatty acids), increased synthesis of triglycerides, and uptake of free fatty acids. Fat, primarily triglycerides, infiltrate the hepatocytes. Fatty liver disease, regardless of type, can cause cirrhosis. Treatment strategies are aimed at managing the underlying causes such as weight loss, alcohol cessation, dyslipidemia control, and type 2 diabetes mellitus control.

Diagnostic Link

Liver Function hile various serum tests (e.g., ALT, AST, and ALP) are commonly termed liver function tests, these markers reflect injury more than they do function (e.g., they can be normal with advanced liver disease or

be abnormal due to other nonhepatic disorders). Some of the common serum markers that reflect function are albumin and prothrombin time, which reflect the liver’s synthesizing capacity. The liver is the site of albumin production, and low levels can indicate abnormal liver function. The liver is also the site of the synthesis of 11 blood coagulation proteins (e.g., fibrinogen, factor VII), and prothrombin is a commonly measured coagulation protein. High prothrombin levels can indicate abnormal liver function. Bilirubin is conjugated in the liver, and abnormalities can indicate abnormal liver function (see Diagnostic Link—Bilirubin Measurement box pertaining to bilirubin). Each of these tests has limitations regarding the accuracy of liver function, and several other markers indicate function (e.g., indocyanine green clearance); however, they are usually not used in clinical practice.

1. 2. 3. 4.

BOX 9-1 Application to Practice A 55-year-old woman is complaining of right upper quadrant pain for the past 5 hours. She said she has had two or three similar episodes in the past; however, they only lasted 1 hour, and the pain was not as severe as with this episode. She thought the prior episodes were due to heartburn, and she has taken over-the-counter antacids with some relief but this time she has not had relief. This episode is rated as an 8 of 10 scale (0 no pain, 10 severe pain). The pain is constant and does not radiate. She says the pain started a few hours after she had lunch (states she ate a fast-food burger). She feels nauseous but has not vomited. She has been getting chills but also feels sweaty. She feels warm but does not know if she has a fever as she has not checked her temperature. Past medical history: type 2 diabetes mellitus and dyslipidemia. Medications: metformin 1,000-mg 1 tablet twice a day; atorvastatin 10-mg 1 tablet a day; and estrogen/progestin hormone replacement therapy 0.3-mg/1.5-mg 1 tablet a day.

Social history: does not smoke or drink alcohol; works as a cashier in a grocery store, is married, and has no children.

Vital signs: temperature 101.0° F, heart rate 110 beats per minute, respiratory rate 20 breaths per minute, blood pressure 140/80 mmHg, body mass index 31 kg/m2.

Answer the following questions pertaining to this case.

What is the most likely diagnosis based on this history, vital signs, and body mass index? What are the data to support the diagnosis chosen in 1? What are expected physical examination findings? What are the expected findings on a complete blood count and abdominal ultrasound that would support the most likely diagnosis?

Disorders of the Pancreas Disorders of the pancreas are frequently grave. The pancreas has a significant role in maintaining homeostasis by regulating electrolytes, water, and glucose. Consequently, conditions affecting the pancreas can have a global impact on the individual’s health. Most often, the gallbladder is affected by pancreatic disorders because of the intricate relationship between these two organs.

Pancreatitis Pancreatitis is an inflammation of the pancreas that can be either acute or chronic. Causes of pancreatitis include cholelithiasis (the most common acute cause), alcohol abuse (the most common chronic cause), biliary dysfunction, hepatotoxic drugs, metabolic disorders (e.g., hypertriglyceridemia, hyperglycemia), trauma, renal failure, endocrine disorders (e.g., hyperthyroidism), pancreatic tumors, and penetrating peptic ulcer. When the pancreas is injured or its function is disrupted, the pancreatic acinar cells are activated and release pancreatic enzymes (phospholipase A, lipase, and elastase) that leak into the pancreatic tissue and initiate autodigestion. Trypsin and elastase are activated proteases that, along with lipase, break down tissue and cell membranes, resulting in edema, vascular damage, hemorrhage, and necrosis. Pancreatic tissue is replaced by fibrosis and dysfunction of the islets of Langerhans and acinar cells resulting in exocrine and endocrine changes

Acute pancreatitis is considered a medical emergency (FIGURE 9-22). The mortality rate from this condition is approximately 15%, but the rate increases with advancing age and comorbidity. Serious complications can develop with acute pancreatitis, including acute respiratory distress syndrome, renal failure, disseminated intravascular coagulation, systemic inflammatory response, and sepsis. Pseudocyst or abscess can form and cause pancreatic fluids and necrotic debris to collect in cystlike pockets. Large pseudocysts or abscesses that rupture can cause complications such as internal bleeding and infection (e.g., peritonitis). Recurrent acute pancreatitis episodes can lead to progressive and permanent damage and chronic pancreatitis.

FIGURE 9-22 Effects of acute pancreatitis.

Chronic pancreatitis can damage insulin-producing cells in the pancreas, leading

to the development of diabetes mellitus. Both acute and chronic pancreatitis can decrease pancreatic enzyme production, and these enzymes are necessary for digestion and absorption. Malnutrition and weight loss may occur, even when food intake remains stable. Long-standing inflammation caused by chronic pancreatitis can initiate cellular mutations and lead to pancreatic cancer. See chapter 10 for discussion of diabetes.

Clinical Manifestations Clinical manifestations vary depending on whether the pancreatitis is acute or chronic. Manifestations of acute pancreatitis are usually sudden and severe; in contrast, manifestations of chronic pancreatitis tend to be insidious. Monitoring for the development of complications is crucial to achieve positive patient outcomes. Clinical manifestations of acute pancreatitis are dependent on the severity (mild, moderate, or severe) and include the following symptoms:

Epigastric or midabdominal pain that radiates to the back, worsens after eating, and is somewhat relieved by leaning forward or pulling the knees toward the chest Nausea and vomiting Mild jaundice Fever Blood pressure and pulse changes (may be increased or decreased), tachypnea Retroperitoneal bleeding (severe cases) resulting in periumbilical ecchymosis (Cullen sign) or flank ecchymosis (Grey-Turner sign)

Clinical manifestations of chronic pancreatitis include these symptoms:

Epigastric or midabdominal pain that radiates to the back, worsens after eating, and is somewhat relieved by leaning forward or pulling the knees toward the chest Pancreatic insufficiency—fat malabsorption causing steatorrhea (loose, oily, fatty, odorous stools) Malnutrition—unintentional weight loss

Diagnosis and Treatment Diagnostic procedures for pancreatitis include those to verify the pancreatitis and those to identify complications. These procedures will consist of a history and physical examination. Serum amylase and lipase levels will be elevated during episodes of acute pancreatitis, usually up to three times their normal limits. Amylase levels rise within 12 hours after onset of acute pancreatitis and returns to normal

1.

a. b. c.

2. a. b. c. d.

3.

a. b. c. d.

4.

a. b. c. d.

within 5 days. Lipase levels rise within 8 hours and return to normal within 14 days. Since lipase levels remain elevated longer, they are a more reliable marker of acute pancreatitis. Immune markers, such as C-reactive protein, will be elevated and can be used as a marker of severity. A CBC may reveal leukocytosis and an increased hematocrit due to hemoconcentration. A chemistry profile may reveal an elevated blood urea nitrogen, hypocalcemia, and glucose abnormalities (high or low). Other laboratory testing that can be performed includes a liver enzymes panel, measurement of serum bilirubin level, arterial blood gases, and stool analysis (lipid and trypsin levels). Imaging studies will include either an abdominal CT with contrast, abdominal MRI, or abdominal ultrasound. Additional testing may include an endoscopic retrograde cholangiopancreatography or a magnetic resonance imaging cholangiopancreatography. These imaging studies are also used in the evaluation of chronic pancreatitis. Laboratory evaluations may be normal in chronic pancreatitis.

BOX 9-2 Application to Practice K.S. is a 35-year-old man who has been homeless for the past 5 years. He presents to the health department complaining of flulike symptoms and abdominal pain. K.S. has multiple tattoos and piercings. He admits to intravenous drug use and unprotected sexual behavior with multiple female partners. Blood tests reveal that K.S.’s liver enzymes are elevated. The healthcare provider suspects some type of hepatitis.

Considering K.S.’s lifestyle, which type or types of hepatitis has he most likely contracted? Explain your choice or choices.

Hepatitis A Hepatitis B Hepatitis C

How would you expect a differential diagnosis of hepatitis to be confirmed? Presence of viral particles in stool Elevated bilirubin and prothrombin time and low albumin Presence of the specific hepatitis antibodies in the blood Inflammation of the liver on ultrasound

Choose all of the following results that are consistent with an acute episode of hepatitis B infection. Discuss what each test measures.

Anti-HBs positive Anti-HBc (IgM) positive HBsAg positive HBsAG negative

K.S.’s girlfriend is also developing similar symptoms. Which of the following factors likely explains the onset of the girlfriend’s symptoms?

They probably ate the same food. They likely obtained the virus from contaminated water. They probably infected each other through sexual contact or drug activity. They likely became infected because of poor living conditions.

Management of pancreatitis requires early treatment and aggressive strategies to prevent complications. Patients with severe pancreatitis as well as altered vital signs (e.g., pulse < 40 or > 150 beats/minute) or other parameters (e.g., abnormal electrolytes) will likely need to be closely monitored in an intensive care unit. Treatment strategies will be dependent on the severity of the pancreatitis and will include the following measures:

Resting the pancreas by fasting, administering intravenous nutrition (e.g., TPN), and gradually advancing the diet from clear liquids as tolerated to a low-fat, low- residue diet; if oral nutrition not tolerated, feedings can be administered enterally (e.g., nasojejunal tube) Pancreatic enzyme supplements when the diet is resumed Maintaining hydration status with intravenous fluids Inserting a nasogastric tube with intermittent suction for persistent nausea and vomiting Antiemetic agents (if vomiting is present) Pain management (usually includes intravenous narcotic agents and analgesics) Antacids and acid-reducing agents Anticholinergic agents (which reduce vagal stimulation, decrease GI motility, and inhibit pancreatic enzyme secretion) Antibiotic therapy (if infection is present) Insulin (which treats hyperglycemia secondary to temporary or permanent pancreatic damage and TPN) Identifying and treating complications early (e.g., blood transfusions for hemorrhage, dialysis for renal failure, airway management for acute respiratory distress syndrome, surgical drain for abscesses, pancreatic debridement, and laparotomy for biliary obstruction)

Prevention of disease progression becomes the focus after an episode of acute pancreatitis and for chronic pancreatitis. Lifestyle modifications (e.g., cessation of alcohol and smoking) can prevent progression. Long-term pain management may be necessary (e.g., analgesics, nerve blocks).

Disorders of the Lower Gastrointestinal Tract Disorders of the lower GI tract can alter nutrition or impair elimination. These conditions range in severity from mild (e.g., diarrhea and constipation) to life threatening (e.g., appendicitis and peritonitis) and can be either congenital (e.g., celiac disease) or acquired (e.g., intestinal obstruction). Depending on their severity, most of these disorders can be resolved or managed with minimal residual effects.

Diarrhea Diarrhea refers to a change in bowel pattern characterized by an increased frequency, amount, and water content of the stool. This condition can result from an increase in fluid secretion (it is secretory), a decrease in fluid absorption (it is osmotic), or an alteration in GI peristalsis (motility is affected). Diarrhea can be acute (three or more loose stools per day and lasting < 14 days) or chronic (lasting longer than 4 weeks) and may be attributed to many conditions. Acute diarrhea is often caused by viral (more common) or bacterial infections (more common in severe cases).

Gastroenteritis is an intestinal disease manifested by acute onset of diarrhea, nausea, and vomiting due to an infection. Diarrhea can also be triggered by certain medications (e.g., antibiotics, antacids, and laxatives). Depending on the cause, acute diarrhea is usually self-limiting. Causes of chronic diarrhea are usually noninfectious and include inflammatory bowel diseases (e.g., Crohn disease and ulcerative colitis), malabsorption syndromes (e.g., celiac disease), endocrine disorders (e.g., thyroid disorders), chemotherapy, and radiation. In developing countries, chronic diarrhea is more commonly due to chronic infection of the GI tract (e.g., bacterial, parasitic).

Clinical manifestations of diarrhea vary depending on the underlying etiology. When this condition originates in the small intestine, stools are large, loose, and provoked by eating. Diarrhea originating in the small intestine is usually accompanied by pain in the right lower quadrant of the abdomen along with bloating and gas. Additionally, fever and occult blood in the stool are uncommon. Many organisms have been implicated in small bowel diarrhea, including E. coli, Salmonella, Vibrio cholerae, and Giardia lamblia. When diarrhea originates in the large intestine, stools are small and frequent. Diarrhea originating in the large intestine is frequently accompanied by pain and cramping in the left lower quadrant of the abdomen along with painful defecation. Fever and bloody or mucoid type stool is more common in large intestine diarrhea than with small intestine diarrhea. Many organisms have been implicated in large intestine diarrhea, including Clostridioides difficile, Shigella, and Campylobacter. Nausea and vomiting may also be present.

Blood in the stool may present as frank blood (bright red blood on the surface of the stool), occult blood (small amounts of blood hidden in the stool indicative of lower

GI tract disorders as the cause), or melena (dark, tarry stool from a significant amount of bleeding higher up in the GI tract). Additionally, bowel sounds may be hyperactive. Fluid, electrolyte, and pH (usually metabolic acidosis) imbalances can develop regardless of whether the diarrhea is acute or chronic (see chapter 6 for further details on fluid, electrolyte, and acid–base homeostasis).

Diagnostic procedures for diarrhea focus on identifying the underlying cause and any complications. These procedures may include a history (including usual bowel pattern and completion of the Bristol stool chart [FIGURE 9-23]) and physical examination. Additional testing is not generally indicated in acute diarrhea as most cases are self-limiting. Certain geographic regions in the world may have a higher prevalence of pathogenic intestinal organisms, so a travel history may provide clues to the source of the diarrhea. As an example, epidemics are often caused by S. dysenteriae and V. cholerae and are likely to occur in resource-limited countries such as parts of Central America, Africa, and South Asia. The CDC maintains information pertaining to outbreaks, recommended vaccines, and other travel-related health advice, and this information can be accessed at https://wwwnc.cdc.gov/travel. While diagnostic testing is usually not indicated, there are circumstances (e.g., severe presentations, immunocompromised patients, elderly patients, and public health concerns such as diarrhea in food handlers) that warrant stool analysis (e.g., ova and parasites, cultures, and occult blood). A CBC, blood chemistry, and other laboratory testing may also be indicated. Imaging studies may be necessary for those patients with complications such as peritonitis and bowel perforation, including an abdominal CT.

FIGURE 9-23 Bristol stool chart.

Data from: Lewis, S., & Heaton, K. (1997). Stool form scale as a useful guide to intestinal transit time. Scandinavian Journal of Gastroenterology, 32(9), 920–924.

Treatment strategies vary depending on the underlying etiology. Maintaining hydration status and correcting electrolyte and pH imbalances is crucial to managing acute or chronic diarrhea (see chapter 6 for further details on fluid, electrolyte, and acid–base homeostasis).

Acute diarrhea with infectious origins usually improves with short-term fasting. Generally, food consumption slows GI motility, allowing bacterial and viral toxins to increase. As toxin levels rise, diarrhea can become more severe. Antidiarrheal agents may be withheld for the same reason. Antibiotics may be necessary depending on the infectious agent. In noninfectious diarrhea, antidiarrheal agents slow GI motility and increase fluid absorption. Some additional medications that may be administered include anticholinergic and antispasmodic agents. Probiotics can maintain normal flora and reduce the duration of diarrhea. When oral intake is recommended, a clear liquid diet is usually ordered until the diarrhea subsides. At that time, the diet is advanced to a regular diet as tolerated. Dairy products and fatty foods are probably best avoided as both may aggravate diarrhea. Dietary fiber can be used to manage chronic diarrhea; the fiber acts like a sponge to absorb the excess water and increase bulk in the stool. Management of chronic diarrhea involves treating the underlying cause. Meticulous skin care can maintain skin integrity, especially in cases of bowel incontinence.

Constipation Constipation refers to a change in bowel pattern characterized by infrequent passage of stool. Bowel patterns vary from person to person, so the decrease in frequency is in reference to the individual’s typical bowel pattern. With constipation, the stool remains in the large intestine longer than usual. The longer the stool remains in the large intestine, the more water is removed from the stool. Consequently, the stool becomes hard and difficult to pass. Constipation is often caused by a low-fiber diet, inadequate physical activity, insufficient fluid intake, delaying the urge to defecate, or laxative abuse (which smooths intestinal rugae). Stress (sympathetic nervous system stimulation slows GI motility) and travel can also contribute to constipation or other changes in bowel habits. Diseases of the bowel such as irritable bowel syndrome, pregnancy, and medications such as narcotics, anticholinergic agents, and iron supplements can cause constipation. Other causes include mental health problems such as depression, neurologic diseases (e.g., stroke, Parkinson disease, and spinal cord injuries), and colon cancer. In addition, constipation is common in children who are toilet training, especially if they are not ready for training or are scared of toileting.

Constipation may involve pain during the passage of a bowel movement, inability to pass stool after straining or pushing for more than 10 minutes, or no bowel movements for more than 3 days. Additionally, bowel sounds may be hypoactive. The passage of large, wide stools may tear the mucosal membrane of the anus, especially in children. This tearing can cause bleeding and cause an anal fissure to develop. Chronic constipation can lead to pH disturbances (usually metabolic alkalosis), hemorrhoids (swollen, inflamed veins in the rectum or anus), diverticulitis, impaction, intestinal obstruction, and fistulas. See chapter 6 for discussion of metabolic alkalosis.

Diagnostic procedures for constipation focus on identifying the underlying cause. These procedures consist of a history (including usual bowel pattern and completion of the Bristol stool chart [Figure 9-23]), physical examination (may include a digital rectal examination), abdominal X-ray, upper GI series, barium swallow, colonoscopy (for visualization of the large intestine), and proctosigmoidoscopy (for visualization of the lower bowel).

Treatment strategies focus on reestablishing the individual’s usual bowel pattern and preventing future constipation episodes. These strategies may involve managing or removing any underlying causes. Strategies to treat and prevent constipation may include the following measures:

Increasing dietary fiber (e.g., vegetables, fruit, and whole grains) with concomitant increase in hydration (specifically water and juices) Avoid constipating foods (e.g., processed sugar, white flour, and red meat) Increasing physical activity Defecating when the initial urge is sensed Taking stool softeners (incorporates lipids and water into the stool) Limiting use of laxatives and enemas Digitally removing an impaction if present

Intestinal Obstruction An intestinal obstruction refers to blockage of intestinal contents in the small intestine (where it is most common) or the large intestine. Intestinal obstructions have two types of causes—mechanical and functional. Mechanical obstructions consist of physical barriers, whereas functional obstructions result from GI tract physiologic dysfunction. Mechanical obstructions can occur due to foreign bodies, tumors, adhesions, hernias, intussusception (telescoping of a portion of the intestine into another portion) (TABLE 9-5), volvulus (twisting of the intestine), strictures, Crohn disease, diverticulitis, Hirschsprung disease (also known as congenital megacolon), and fecal impaction (FIGURE 9-24). Postoperative adhesions and hernias account for approximately 90% of all mechanical small intestine obstructions. Tumors, diverticulitis, and volvulus are the most common causes of

mechanical large intestine obstructions. Functional obstructions, also called paralytic ileuses, usually result from neurologic impairment such as spinal cord injury; intra- abdominal surgery complications; chemical, electrolyte, and mineral disturbances; intra-abdominal infections such as peritonitis and pancreatitis; abdominal blood supply impairment; renal and lung disease; and use of certain medications such as narcotics.

FIGURE 9-24 Causes of intestinal obstruction.

TABLE 9-5 Causes of Intestinal Obstruction in Children

Depending on the cause and location, intestinal obstructions can develop either suddenly or gradually. Additionally, the obstruction can be either partial or complete. Tumors are also likely to be associated with gradual and partial obstruction. Chyme and gas initially accumulate at the site of the blockage. Over time, saliva, gastric juices, bile, and pancreatic secretions begin to collect as the blockage lingers. This GI fluid buildup increases serum electrolytes and protein and causes abdominal distention and pain. Intestinal blood flow can become impaired, leading to strangulation and necrosis. Intestinal contents will begin to seep into the peritoneal cavity as the pressure at the blockage increases. These complications are more likely to develop with a complete obstruction. If a complete obstruction goes untreated, death can occur within hours due to shock and cardiovascular collapse. Additional complications include perforation, pH imbalances, and fluid disturbances.

Clinical Manifestations

The following manifestations are a result of the GI tract blockage (FIGURE 9-25):

FIGURE 9-25 Effects of intestinal obstruction.

Abdominal distention Abdominal cramping and colicky pain Nausea and vomiting (usually gastric or bile contents) Constipation and inability to pass flatus Diarrhea (some of the intestinal liquid passes around the obstruction) Borborygmi (audible bowel sounds; associated with mechanical obstruction) Intestinal rushes (forcible intestinal contractions; associated with mechanical obstruction) Decreased or absent bowel sounds Anorexia

Restlessness, diaphoresis, tachycardia progressing to weakness, confusion, and shock

Diagnosis and Treatment Diagnostic procedures for intestinal obstruction are directed at identifying the obstruction, the underlying etiology, and complications. These manifestations consist of a history (including the usual bowel pattern), physical examination, blood chemistry, and CBC. Arterial blood gases, serum lactate, and blood cultures are performed for those patients who present with systemic signs such as fever, tachycardia, and hypotension. Imaging is necessary to confirm the diagnosis and usually includes an abdominal CT and abdominal X-ray. Other studies can include an abdominal ultrasound and contrast studies.

Treatment strategies depend on the underlying cause. Such strategies generally focus on correcting fluid, electrolyte, and pH imbalances; decompressing the bowel; and reestablishing bowel movements. A nasogastric tube with intermittent suctioning is inserted to decompress the bowel and relieve vomiting. Ambulation can help restore peristalsis. Laxatives should not be used in most cases until the obstruction is resolved. Surgery is frequently necessary to relieve mechanical obstruction.

Appendicitis Appendicitis refers to an inflammation of the vermiform appendix (FIGURE 9-26). The incidence of appendicitis is highest between the ages of 10 and 19 years old. Appendicitis occurs as a result of obstruction, possibly caused by hard stool (fecaliths), calculi, tumors, and infections. The inflammation process triggers local tissue edema, which obstructs the small structure. As fluid builds inside the appendix, microorganisms proliferate. The appendix fills with purulent exudate, and the stretched, edematous wall compresses area blood vessels. With blood flow compromised, ischemia and necrosis develop. The pressure inside the appendix escalates, forcing bacteria and toxins out to surrounding structures. Abscesses and peritonitis can develop as bacteria escape, and gangrene can result from the worsening necrosis. The pressure inside the appendix will continue to intensify until the appendix ruptures or perforates, releasing its contents. This release can accelerate peritonitis, which can be life threatening.

FIGURE 9-26 Appendicitis. Courtesy of Leonard V. Crowley, MD, Century College.

Clinical Manifestations Clinical manifestations reflect the pathogenesis characteristic of appendicitis. These manifestations vary significantly in severity, from asymptomatic to sudden and severe. The first symptom is often pain near the umbilicus. As swelling increases, the pain tends to move to the lower right quadrant of the abdomen (McBurney point). The pain gradually intensifies (over approximately 12–24 hours). It is often aggravated by movement, so patients tend to guard their abdomen. Due to normal anatomic variations, this pain may occur anywhere in the abdomen. The pain will temporarily subside if the appendix ruptures, but then will return and escalate as peritonitis develops. Anorexia, nausea, and vomiting are other classic manifestations of appendicitis in addition to pain. Abdominal distention and bowel pattern changes can also be associated with appendicitis. Other manifestations reflect the inflammation and infectious process (e.g., fever, chills, and leukocytosis). Various clinical maneuvers each with varying accuracy can be used to evaluate for physical signs of appendicitis, such as the psoas sign. This sign involves passively extending the right hip, which will elicit right lower quadrant pain if the appendix is inflamed. Additionally, the patient should be monitored for signs and symptoms of peritonitis

(e.g., abdominal rigidity, tachycardia, and hypotension).

Diagnosis and Treatment Urgent diagnosis and treatment are crucial for positive patient outcomes. Diagnostic procedures include a history and physical examination. A CBC with differential will reveal leukocytosis with increased bands (immature neutrophils) and mature neutrophils. An abdominal CT with or without contrast is preferred; however, an MRI or abdominal ultrasound can be performed and is the recommended imaging for pregnant women and children. Because of the life-threatening nature of appendicitis, surgery remains the cornerstone of treatment. In fact, appendicitis is one of the most common indications for emergency surgery in the United States. Performing the surgery prior to rupture of the appendix is paramount. Laparoscopic or open surgical procedure can be performed for nonperforated and perforated appendices, and the decision is based on surgeon preference, patient age, and condition. If the appendix ruptures, all of the appendix fragments and infectious materials are removed, and extensive irrigation of the abdominal cavity is performed to flush out any remaining bacteria. The wound may be left open to heal by secondary intention to decrease the risk of infection. Peritoneal drains may be inserted for abscesses. Long-term antibiotic therapy may be necessary to prevent and resolve any infections. Analgesics will be necessary to manage pain before and after surgery. Additionally, the patient should avoid activities that increase intra-abdominal pressure (e.g., straining and coughing).

Peritonitis Peritonitis is an inflammation of the peritoneum, the membrane that lines the abdominal wall and abdominal organs. Peritonitis usually presents as an acute condition and has an inpatient hospital mortality rate of up to 20%. Treatment centers on resolving the underlying cause. The inflammation may result from chemical irritation (e.g., ruptured gallbladder or spleen) or direct organism invasion (e.g., appendicitis and peritoneal dialysis) (FIGURE 9-27). Chemical irritation will lead to a bacterial invasion if not quickly treated. Peritonitis is also categorized as primary or secondary. Primary peritonitis occurs as a result of infection spreading from the blood or lymph. Secondary peritonitis occurs as a result of pathology of a visceral organ (e.g., perforation, trauma). Most cases of primary (spontaneous) peritonitis are due to advanced cirrhosis. The inflammatory response triggered by the chemical increases intestinal wall permeability. In turn, the increased permeability allows for passage of enteric bacteria. Necrosis or perforation of the intestinal wall also creates an opportunity for an enteric bacteria invasion. The most common organisms in spontaneous bacterial peritonitis are gram-negative E. coli and Klebsiella species. Secondary peritonitis due to perforation in comparison to

spontaneous peritonitis is usually polymicrobial, and the organisms involved are also often E. coli and other gram-negative rods.

FIGURE 9-27 Development of peritonitis.

Several protective mechanisms are activated along with the inflammatory response in an attempt to localize the problem. These mechanisms include producing a thick, sticky exudate that bonds nearby structures and temporarily seals

them off. Abscesses may form as the body attempts to wall off the infections. Peristalsis may slow down as a response to the inflammation, decreasing the spread of toxins and bacteria. These mechanisms merely slow the progression, however. If the underlying cause is not treated, the condition can become critical as septic shock and multisystem organ failure develop.

Clinical Manifestations Clinical manifestations reflect the inflammatory and infectious processes. These manifestations tend to be sudden and severe. The classic manifestation of peritonitis is abdominal rigidity. A rigid, boardlike abdomen develops because of a reflexive abdominal muscle spasm that occurs in response to the peritoneal inflammation. Inflamed tissue creates abdominal tenderness and pain. Rebound tenderness, pain that is worse upon removal of pressure, indicates parietal peritoneal inflammation. Large volumes of fluid can leak into the peritoneal cavity (a phenomenon called third spacing), leading to hypovolemic shock. This fluid contains protein and electrolytes, making it an optimal medium for bacterial growth. Nausea and vomiting are common responses to the intestinal irritation. Persistent inflammation impairs nerve conduction, which decreases peristalsis. This decreased peristalsis can, in turn, lead to intestinal obstruction. Sepsis develops as the bacteria and toxins migrate to the circulatory system through the inflamed membranes. Fever, malaise, and leukocytosis occur because of the infectious process. Additionally, the patient should be monitored for signs of septic shock and multisystem organ failure(e.g., tachycardia, hypotension, restlessness, and diaphoresis). See chapter 4 for details on cardiovascular function.

Diagnosis and Treatment Diagnostic procedures for peritonitis consist of a history, physical examination, CBC, abdominal X-ray (flat and upright), abdominal ultrasound, and abdominal CT. Paracentesis is performed to obtain peritoneal fluid for analysis (e.g., gram stain, culture, cell count with differential, and albumin). Other laboratory tests will include chemistry panel, liver enzymes, and other tests based on suspected underlying cause and patient status. Treatment strategies vary based on the underlying cause. The patient’s prognosis depends on the underlying cause along with the implementation of early and aggressive treatment. Management often includes surgical repair of the chemical leak and draining of the infected fluid. Long-term antibiotic therapy specific to the causative organism will be required. In addition, correction of any fluid and electrolyte imbalance may be required. Insertion of a nasogastric tube with intermittent suction can relieve abdominal distention and treat intestinal obstructions. TPN will be necessary to maintain nutritional status until the peritonitis is resolved.

Celiac Disease Celiac disease (also known as celiac sprue or gluten-sensitive enteropathy) is an inherited, autoimmune, malabsorption disorder of the small intestine. Although it is considered primarily a childhood disease, this condition can develop at any age. Celiac disease results from a combination of the immune response to environmental factors (dietary gluten and related proteins) and genetic predisposition. It affects approximately 1% of the general population worldwide. Celiac disease is most common in Whites and in females.

The most common gene locus with celiac is the HLA-DQ2 and HLA-DQ8. This genotype is essential to confer the disease, but their presence alone is insufficient to develop the disease. Other genes and environmental factors must also be present. Celiac disease results from a defect in the intestinal enzymes that prevent further digestion of gliadin—a product of gluten digestion. The triggering gluten proteins are ingredients in grains, wheat, barley, and rye. The combination of digestive dysfunction and immune activities creates a toxic environment for the intestinal villi. The villi atrophy and flatten. The fingerlike grooves between the villi (i.e., crypts) develop hyperplasia and elongate, resulting in decreased enzyme production and making less surface area available for nutrient absorption (FIGURE 9-28). Eventually, the malnutrition associated with celiac disease can cause vitamin deficiencies that deprive the brain, peripheral nervous system, bones, liver, and other organs of vital nourishment. These nutritional deficits, in turn, can lead to other illnesses. Celiac disease is associated with many conditions, including:

FIGURE 9-28 Effects of celiac disease on intestinal villi. © Biophoto Associates/Science Source.

Anemia (e.g., iron deficiency anemia) Arthralgia (bone and joint pain) Myalgia (muscle pain) Bone disease (e.g., osteoporosis, kyphoscoliosis, and fractures) Dental enamel defects and discoloration Growth and development delays in children Hair loss Hypoglycemia Mouth ulcers Increased bleeding tendencies (e.g., bruising and nose bleeds) Neurobehavioral or psychiatric disorders (e.g., depression, anxiety, and sleep problems) Neurologic disorders (e.g., seizures and peripheral neuropathy) Risk of malignancy (e.g., intestinal cancers and non-Hodgkin lymphoma) Skin disorders (e.g., dermatitis herpetiformis and eczema) Vitamin or mineral deficiency, either single or multiple nutrient (e.g., iron, folate, vitamin B12, and vitamin K)

Endocrine disorders (e.g., menstrual dysfunction, thyroid disease, type 1 diabetes, and adrenal insufficiency)

Tropical sprue is a small intestine disease characterized by malabsorption of nutrients, and a differential diagnosis is celiac disease. The disorder also causes endoscopic findings like those of celiac disease, such as villi atrophy and elongated crypts. The distinctions between the disorders are that tropical sprue is probably infectious in origin (bacterial, viral, parasitic, or amoebic) and occurs in tropical regions, especially India, Southeast Asia, Central America, South America, and the Caribbean. Tropical sprue should be suspected in anyone who has chronic diarrhea (> 1 month) and who has traveled to prevalent regions. Tropical sprue can be resolved with antibiotic therapy, unlike celiac disease, which becomes a lifelong condition.

Clinical Manifestations Clinical manifestations of celiac disease vary significantly from person to person—a factor that often delays diagnosis. In infants, clinical manifestations generally appear as gluten (e.g., in cereals) is added to their diet (usually around 4–6 months of age). Most of the clinical manifestations are GI in nature, but occasionally there are no GI symptoms. Other manifestations include arthritis and skin disorders. Some patients have silent/subclinical celiac disease—they have no symptoms but are seropositive for the disorder. The GI manifestations in infants and younger children are generally more intense than in older children and adults. The GI clinical manifestations may include the following symptoms:

Abdominal pain Abdominal distention, bloating, gas, and indigestion Anorexia Diarrhea (chronic or occasional)—bulky, foul smelling, and possibly floating Constipation (not as common) Changes in appetite (usually decreased) Lactose intolerance (common upon diagnosis; usually goes away following treatment) Nausea and vomiting Steatorrhea Unexplained weight loss (although people can be overweight or of normal weight upon diagnosis) Signs of vitamin deficiencies (e.g., bruising, fatigue, hair loss, paresthesia, and mouth ulcers)

Manifestations that are not GI in nature may include irritability, lethargy, malaise,

and behavioral changes. Additionally, the individual with celiac disease should be monitored for development of complications.

Diagnosis and Treatment Diagnostic procedures for celiac disease consist of a history, physical examination, celiac blood panel, and EGD with duodenal biopsy. The celiac blood panel includes serum antibody assays that can be divided into two groups:

1. Autoantibody testing: Immunoglobulin A antibody-endomysium antibodies (EMA-IgA) and immunoglobulin A antitissue transglutaminase (tTG-IgA)

2. Antibodies targeting gliadin: Immunoglobulin A antigliadin antibodies (AGA- IgA, AGA-IgG) and deamidated gliadin peptide antibody (DGP-IGA, DGP-IgG)

Other tests that can be considered include stool tests to evaluate for fat malabsorption, a lactose tolerance test, and a d-xylose test.

Dietary management is the cornerstone of treatment. Most people (approximately 90%) with celiac disease are effectively managed by eliminating gluten from their diet. Dietary changes may also be used as a part of the diagnosis. The individual is given a gluten-free diet to assess whether the symptoms improve. A gluten-free diet involves avoiding wheat and wheat products—rice and corn can be substituted. Once gluten is removed from the diet, the intestinal mucosa will return to normal after a few weeks. Even when symptoms are controlled with diet, the individual with celiac disease remains at risk for intestinal cancers; consequently, he or she should be periodically monitored for cancer development. Additionally, long-term support may be necessary for children and parents of children with celiac disease. If gluten is reintroduced into the diet, relapses can occur.

Inflammatory Bowel Disease Inflammatory bowel disease (IBD) describes chronic inflammation of the GI tract, usually the intestines. IBD is chiefly seen in women, Whites, persons of Jewish descent (Ashkenazi Jews), and smokers. It encompasses two disorders—Crohn disease and ulcerative colitis. Both conditions are characterized by periods of exacerbations and remissions that can vary in severity.

The exact cause of IBD is unknown, and the pathogenesis is poorly understood. This disease is thought to be caused by a genetically associated autoimmune state that occurs as a result of a dysregulated response by the mucosal immune system to the intestinal microbiota (TABLE 9-6). The GI immune system either reacts excessively or inadequately to intestinal microbiota, resulting in an imbalance in the immune response and development of IBD. The immune dysregulation causes alterations in the epithelial barrier, immune cells (e.g., T cells), and abnormal

secretion of immune-related mediators. Immune cells located in the intestinal mucosa are stimulated to release inflammatory mediators (e.g., histamine, prostaglandins, leukotrienes, and cytokines). These mediators alter the function and neural activity of the secretory and smooth muscle cells in the GI tract. The immune response may also be directed at other intraintestinal antigens (e.g., dietary products or tobacco smoke). Fluid, electrolyte, and pH imbalances develop. IBD can be painful, debilitating, and life threatening. Additionally, children have a more extensive intestinal involvement, and the disorder progresses rapidly in comparison to the progression in adults.

TABLE 9-6 Comparison of Inflammatory Bowel Disease and Irritable Bowel Syndrome

Crohn Disease Crohn disease is an insidious, slow-developing, progressive condition that often emerges in adolescence. Its exact cause is unknown, but T-cell activation leading to tissue damage has been implicated. This condition usually affects the intestines, particularly the distal ileum (most common), ileum and cecum, or the ileum and entire colon (it usually spares the rectum); however, it may occur anywhere along the GI tract from the mouth to the anus. When the disorder involves the colon only, it may be difficult to distinguish from ulcerative colitis. Crohn disease is characterized by patchy areas of inflammation involving the full thickness (transmural) of the

intestinal wall and ulcerations. These patchy areas and ulcerations, often called skip lesions, are separated by areas of normal tissue. The ulcers combine to form fissures divided by nodules (thickened elevations), giving the intestinal wall a cobblestone appearance (FIGURE 9-29). Eventually, the entire wall becomes thick and rigid, and the intestinal lumen becomes narrowed and potentially obstructed. Granulomas—that is, nodules consisting of epithelial and immune cells—develop on the intestinal wall and nearby lymph nodes because of the chronic inflammation. Over time, the damaged intestinal wall loses the ability to process and absorb food. The inflammation also stimulates intestinal motility, decreasing digestion and absorption.

FIGURE 9-29 Crohn disease. Courtesy of Leonard V. Crowley, MD, Century College.

Complications of Crohn disease can include malnutrition; anemia (e.g., iron deficiency); micronutrient deficiencies (e.g., vitamin D); and fluid, electrolyte, and pH imbalances. Intestinal complications can include the development of obstructions (e.g., small bowel), adhesions, abscesses, fistulas (e.g., bowel to bowel, bowel to bladder, bowel to vagina), and perforations.

Clinical Manifestations Clinical manifestations of Crohn disease reflect the inflammatory process and the digestive dysfunction (Table 9-6). These manifestations, which intensify during exacerbations, include the following symptoms:

Intestinal Manifestations Abdominal cramping and pain (typically in the right lower quadrant and may occur with defecation) Diarrhea (usually watery) Steatorrhea Constipation (as the intestinal lumen narrows) Palpable abdominal mass (thickened intestinal wall) Hematochezia (if ulcers begin bleeding) Anorexia Perianal fissures/fistulas Weight loss Delayed growth and development (e.g., poor weight gain) Delayed puberty

Extraintestinal Manifestations Mouth ulcers Arthralgia Skin disorders (e.g., erythema nodosum) Kidney stones Eye inflammation (e.g., uveitis and iritis)

Diagnosis and Treatment Diagnostic procedures for Crohn disease consist of a history, physical examination, stool analysis (including cultures and occult blood), CBC, blood chemistry with liver enzyme evaluation, C-reactive protein levels, and erythrocyte sedimentation rate. Colonoscopy will be done to evaluate the lower GI tract, while abdominal CT, abdominal MRI, barium studies (swallow and enema), or a capsule endoscopy (use of pill with a camera) may be used to evaluate the small bowel. Biopsies are also performed. Serologic markers (e.g., antineutrophil cytoplasmic antibodies) and stool markers (e.g., calprotectin) are usually done, however the accuracy of these tests is unclear. Treatment strategies focus on nutritional support, symptom relief, and complication minimization. Dietary management usually includes 1) a low-residue, high-calorie, high-protein diet; 2) oral nutritional supplements (e.g., Ensure and Sustacal); 3) multivitamin supplements; and 4) TPN as the disease progresses. Pharmacologic management usually includes 1) antidiarrheal agents; 2)

aminosalicylates (5-ASAs; to treat mild to moderate inflammation); 3) glucocorticoids (to treat moderate to severe inflammation); 4) immune modulators (e.g., thiopurines and tumor necrosis factor-α blocking agents) to suppress inflammatory response); 5) biologic agents (e.g., infliximab or adalimumab; to treat severe unresponsive Crohn disease); 6) analgesics; and 7) antibiotics if infection is present. Surgical intestine resection may be necessary as the disease progresses and complications develop. Additional strategies involve stress management (e.g., exercise, meditation, deep breathing, biofeedback, and acupuncture) and support (e.g., group involvement and counseling). There may be an increased risk for certain cancers (e.g., colon cancer), so appropriate screenings should be conducted.

Ulcerative Colitis Ulcerative colitis is a progressive condition of the rectum and colon mucosa that usually develops in the second or third decade of life. Inflammation triggered by T- cell accumulation in the colon mucosa causes epithelium loss, surface erosion, and ulceration. The ulceration begins in the rectum and extends in a continuous segment to involve the entire colon. Ulcerative colitis rarely affects the small intestine. The mucosa becomes inflamed, edematous, and frail. Necrosis of the epithelial tissue (specifically at the base of the crypts of Lieberkühn) can result in abscesses, known as crypt abscesses. As the body attempts to heal, granulation tissue forms, but the tissue remains fragile and bleeds easily. The ulcers merge together, creating large areas of stripped mucosa. Nutritional, fluid, electrolyte, and pH imbalances develop due to the lack of an adequate surface area for absorption. Complications of ulcerative colitis include the following conditions: malnutrition; anemia (e.g., iron deficiency); micronutrient deficiencies (e.g., vitamin D); and fluid, electrolyte, and pH imbalances. Intestinal complications can include the development of strictures and fistulas (e.g., bowel to bowel, bowel to bladder, bowel to vagina), pseudopolyps, perforations, and hemorrhage. Toxic megacolon is a life-threatening condition caused by rapid dilation of the large intestine and systemic toxicity (e.g., fever, tachycardia, leukocytosis). Liver disease can occur as a result of inflammation and scarring of the bile ducts.

Clinical Manifestations Clinical manifestations of ulcerative colitis reflect the inflammatory process and digestive dysfunction, and symptoms can range from mild to severe (Table 9-6). As is the case with Crohn disease, these manifestations intensify during exacerbations. Manifestations usually include the following symptoms:

Intestinal Manifestations Diarrhea (usually frequent [as many as 20 daily], watery stools containing blood

and mucus) Tenesmus (persistent rectal spasms associated with the need to defecate) and urgency Proctitis (inflammation of the rectum) Abdominal cramping Nausea and vomiting Weight loss

Extraintestinal Manifestations Arthralgia Skin disorders (e.g., erythema nodosum) Eye inflammation (e.g., uveitis, iritis)

Diagnosis and Treatment Diagnostic procedures for ulcerative colitis are the same as those for Crohn disease. Treatment strategies are also similar to those used for Crohn disease and focus on nutritional support, symptom relief, and complication minimization. Dietary management usually includes 1) a high-fiber, high-calorie, high-protein diet; 2) oral nutritional supplements (e.g., Ensure or Sustacal); 3) multivitamin supplements; and 4) TPN as the disease progresses. Pharmacologic management usually includes 1) antidiarrheal agents; 2) antispasmodics; 3) anticholinergics; 4) aminosalicylates to treat mild to moderate inflammation; 5) glucocorticoids to treat moderate to severe inflammation; 6) immune modulators to suppress inflammatory response; 7) biologic agents; 8) analgesics; and 9) antibiotics if infection is present. Surgical intervention (e.g., ileostomy or colostomy) may be necessary as the disease progresses and complications develop. Additional strategies involve stress management (e.g., exercise, meditation, deep breathing, biofeedback, and acupuncture) and support (e.g., group involvement and counseling). There may be an increased risk for certain cancers (e.g., colon cancer), so appropriate screenings should be conducted.

Irritable Bowel Syndrome Irritable bowel syndrome (IBS) refers to a chronic functional GI condition characterized by exacerbations often associated with stress. IBS includes alterations in bowel pattern and abdominal pain not explained by structural or biochemical abnormalities. IBS is similar to IBD, but in contrast to IBD, IBS is less serious, is noninflammatory, and does not cause permanent intestinal damage (Table 9-6). IBS is more common in women than in men. Its exact cause is unknown, but three theories of its etiology include altered GI motility, visceral hyperalgesia, and psychopathology. IBS is thought to be an intensified response to stimuli that is characterized by increased intestinal motility and contractions. People with IBS may

have a low tolerance for stretching and pain in the intestinal smooth muscle, causing them to respond to stimuli to which people without IBS do not respond. Evolving theories of the pathogenesis include a possible role of inflammation, an alteration in the intestinal microbiota, food sensitivity, and possible genetic predisposition. IBS is associated with other conditions such as fibromyalgia, GERD, depression, and anxiety. Complications of IBS include hemorrhoids, nutritional deficits, social issues, and sexual discomfort.

Clinical Manifestations Clinical manifestations vary from person to person. Stress, mood disorders (e.g., anxiety and depression), food, and hormone changes (e.g., menstruation) often worsen symptoms. These manifestations usually include the following symptoms:

Abdominal distention, fullness, flatus, and bloating Intermittent, abdominal, crampy pain exacerbated by eating and relieved by defecation Chronic and frequent constipation, usually accompanied by pain (i.e., Bristol stool chart type 1 and 2) Chronic and frequent diarrhea, usually accompanied by pain (i.e., Bristol stool chart type 6 and 7) Alternating diarrhea and constipation with or without interspersed normal bowel habits Nonbloody stool that may contain mucus Bowel urgency and tenesmus Sensation of incomplete emptying after a bowel movement Intolerance to certain foods (usually gas-forming foods and those containing sorbitol, lactose, and gluten) Emotional distress Anorexia

Diagnosis and Treatment Diagnosis is based on clinical presentation (TABLE 9-7) and is often made by excluding other GI disorders. Diagnostic procedures consist of a history and physical examination which is generally normal. The diagnosis of IBS is made using the Rome IV criteria. Diagnostic testing is not necessary for the diagnosis of IBS, but tests are performed to exclude other diagnoses. These tests can include stool analysis (including cultures and occult blood), celiac blood panel, C-reactive protein, abdominal X-ray, abdominal CT, abdominal MRI, barium studies (swallow and enema), sigmoidoscopy, colonoscopy, and biopsy. Diagnostic testing should be performed for those patients with concerning symptoms usually not associated with

IBS such as unexplained weight loss, rectal bleeding, age of onset after age 50, nocturnal diarrhea, progressive abdominal pain, laboratory abnormalities (e.g., iron deficiency anemia), or family history of IBD or GI cancer.

TABLE 9-7 Rome IV Criteria

Recurrent abdominal pain on average at least 1 day/week in the last 3 months, associated with two or more of the following criteria: 1. Relieved by defecation 2. Associated with changes in stool frequency 3. Associated with changes in stool form (appearance)

Symptoms That Support Diagnosis of IBS

Abnormal stool frequency (> 3/day or > 3/week) Abnormal stool form (lumpy and hard or watery and loose) Abnormal stool passage (straining, urgency, feeling of incomplete evacuation) Passage of mucus Bloating or feeling of abdominal distention

Treatment focuses on management of symptoms and may vary depending on those symptoms. Initial therapies involve dietary modification with avoidance of gas- producing foods (e.g., beans, bananas, carrots, celery). The FODMAP diet (fermentable oligo-, di-, monosaccharides, and polyols) involves reduction or exclusion of short-chain carbohydrates that are poorly absorbed or that increase osmosis. In some cases, lactose and gluten avoidance may improve symptoms. Maintaining a regular eating pattern and avoiding large meals is recommended. Other strategies involve avoiding triggers, stress management (through techniques such as exercise, meditation, deep breathing, biofeedback, and acupuncture), and support (e.g., group involvement, counseling, and psychotherapy). Pharmacologic strategies for abdominal pain can include antispasmodics and antidepressants. Pharmacologic agents for constipation may include laxatives (e.g., psyllium), chloride channel activators (e.g., lubiprostone [Amitiza]), which works by increasing intestinal fluid and intestinal motility, or guanylate cyclase agonists (e.g., linaclotide [Linzess]) which work by increasing intestinal fluid and intestinal transit. Pharmacologic strategies for diarrhea may include antidiarrheal agents (e.g., loperamide) and bile acid sequestrants. Eluxadoline (Viberzi) is a mu-opioid receptor agonist and delta-opioid receptor antagonist that can be used for IBS related diarrhea. Probiotics can be used, however, their efficacy is uncertain.

Diverticular Disease Diverticular disease refers to conditions related to the development of diverticula. Diverticula (singular, diverticulum) are outwardly bulging pouches of the intestinal wall that develop when mucosa sections or large intestine submucosa layers herniate through a weak point in the muscular layer (e.g., where arteries penetrate

the muscle layer) (FIGURE 9-30). Diverticula may be congenital or acquired. The causes of diverticula development are unknown, but they are thought to be caused by abnormal motility of the colon. In those patients with diverticula, the colon exhibits exaggerated segmental contractions and increased intraluminal pressure. The reasons for the abnormal motility are unclear, but the increased pressure may occur as a result of structural changes in the intestinal wall (e.g., thickened circular muscle layer and luminal narrowing). The incidence increases after age 60. Risk factors for the development of symptoms include a diet low in fiber and high in red meat and fat, obesity, physical inactivity, smoking, and medications (e.g., steroids, opiates, and NSAIDs). Diverticular disease is rare in developing countries where high-fiber diets are typical but is more common in developed countries where processed foods and low-fiber diets are widely consumed. In addition to diet, poor bowel habits (e.g., straining and delaying defecation) can contribute to developing diverticula.

FIGURE 9-30 Diverticula. (A) Exterior of the colon illustrating several diverticula projecting through the wall of the

colon. (B) A closer view of the diverticulum. (C) Interior of the colon, illustrating openings of multiple diverticula. (D) Diverticula of the colon demonstrated by injection of barium contrast material into the colon.

Courtesy of Leonard V. Crowley, MD, Century College.

Meckel diverticulum is a common congenital malformation of the GI tract that results in herniation of all layers of the small bowel wall, not just the mucosa as in diverticular disease. Meckel diverticulum can be described using the rule of 2s—the incidence occurs in approximately 2% of the population; the male-to-female ratio is 2:1; the diverticulum is found 2 feet from the ileocecal valve and is 2 inches long; and approximately 2% develop a complication over their lifetime, typically before the age of 2. Meckel diverticulum usually causes no symptoms. If symptoms occur, they usually consist of GI bleeding, abdominal pain, or perforation signs. Surgery (e.g., small bowel resection and simple diverticulectomy) is performed for those patients with symptoms.

Most cases of diverticular disease are asymptomatic and are discovered incidentally. Diverticulosis describes asymptomatic diverticular disease, usually with multiple diverticula present. Diverticulitis refers to a state in which diverticula have become inflamed. The wall of the diverticula erodes due to the increased pressure and food particles that are thick or hardened. Focal necrosis and perforation, usually microperforations, occur in addition to inflammation. Diverticulitis can be acute or chronic. While some cases of diverticulitis are uncomplicated, several serious complications can occur, such as obstructions, infection, abscess (usually due to a walled-off perforation), fistula, large perforation, peritonitis (e.g., fecal peritonitis), hemorrhage, and shock.

Clinical Manifestations Diverticulitis usually manifests with abdominal tenderness (often in the left lower quadrant). However, cecal diverticulitis is more common in Asian populations and will present with right lower quadrant pain. The pain is constant and may be present for days before the patient seeks care. Other clinical manifestations that may be present include a low-grade fever, abdominal distention, constipation, diarrhea, nausea, vomiting, a palpable abdominal mass, and leukocytosis. While diverticulosis is generally asymptomatic, painless bleeding (hematochezia) that is usually mild and self-limiting can occur, but it can be more severe. Diverticular disease may also present with persistent abdominal pain without inflammation (i.e., smoldering diverticulitis).

Diagnosis and Treatment Diverticula are often noted on diagnostic imaging performed for other purposes such as colonoscopy for colorectal cancer screening. During an episode of acute

diverticulitis, diagnostic procedures consist of a history, physical examination, and an abdominal CT with contrast (preferred) or abdominal ultrasound. Laboratory studies will include a CBC, and a finding of leukocytosis is consistent with acute disease. Complicated acute diverticulitis requires inpatient treatment with management of complications (e.g., obstruction). Other inpatient management will include administration of intravenous antibiotics, pain medications, and intravenous fluids. Bowel rest may be necessary, or oral nutrition should start with clear liquid diet, advancing to a regular diet. Outpatient care will consist of oral antibiotics and modified diet if necessary. With outpatient care, short-term follow-up is important (e.g., repeat evaluation in 2–3 days).

Long-term treatment strategies include consumption of a high-fiber diet, adequate hydration, proper bowel habits (e.g., defecating when urge is sensed and not straining). A low-residue diet (i.e., avoiding foods with seeds, nuts, and corn) is thought to help, but no evidence supports this notion. Consuming nuts, seeds, and corn also do not cause diverticular disease. A colon resection may be necessary for some patients whose symptoms do not resolve.

Cancers Malignancies of the GI system may originate in the GI tract or spread there from other sites. These cancers can lead to altered nutrition as well as impaired elimination depending on their location. Some GI cancers have moderate treatment success rates (e.g., colorectal cancer), whereas others have high mortality rates (e.g., oral and pancreatic cancer). Typical cancer diagnosis, staging, and treatments are usually employed with cancers involving the GI system (see chapter 1 for details on cellular function).

Oral Cancer Oral cancer can occur anywhere in the mouth, but most cases involve squamous cell carcinomas of the tongue and mouth floor (FIGURE 9-31). Approximately 75% of cases can be attributed to use of smoked and smokeless tobacco. Alcohol consumption also significantly increases the risk of developing oral cancer. Combined alcohol and tobacco use can increase this risk by as much as 100 times. Chewing areca nuts (from an areca palm) also increases the of oral cancer. Additional risk factors include viral infections (especially with human papillomavirus), immunodeficiencies, inadequate nutrition, poor dental hygiene, chronic irritation (e.g., from dentures), and exposure to ultraviolet light (as in cancer of the lips).

FIGURE 9-31 Oral cancer.

Courtesy of Sol Silverman, Jr., DDS, University of California, San Francisco/CDC.

Incidence rates of oral cancer have slightly decreased since 1980. Men are twice as likely as women to develop oral cancer. According to the American Cancer Society (2016), oral cancer is the eighth most frequent cancer in men. Prevalence and mortality rates are the highest in Black men; however, overall mortality rates have decreased since 1980.

In its early stages, oral cancer is very treatable. Unfortunately, most cases are advanced by the time the diagnosis is made because the cancer tends to be hidden. Oral cancer has a 5-year survival rate of 63%—a rate that has significantly improved since 1990.

Oral cancer is often preceded by premalignant lesions that appear as a white patch (leukoplakia) or a red patch (erythroplakia) that is usually persistent (e.g., > 3 weeks) and asymptomatic. These lesions then develop into a nodule or an ulcerative lesion. Multiple lesions may be present. These lesions persist, do not heal, and bleed easily. Additional manifestations include a lump, thickening, or soreness in the mouth, throat, or tongue as well as difficulty chewing or swallowing food. Oral cancer often metastasizes to the neck lymph nodes and the esophagus.

Treatment primarily consists of surgery and radiation, but surgery may be difficult depending on the location. Chemotherapy may be added for patients with advanced disease. Speech therapy is often necessary after treatment to improve chewing, swallowing, and speech.

Esophageal Cancer Much like oral cancer, esophageal cancer is usually a squamous cell carcinoma or adenocarcinoma, and it most often affects men. Incidence rates of esophageal cancer have remained steady, but the mortality rates have increased since 1980. According to the American Cancer Society (2016), esophageal cancer is the seventh leading cause of cancer death in men, even though it did not make the list of top 10 cancers in men. Rates are fairly equal across racial and ethnic groups.

The distal esophagus is the most common site at which this adenocarcinoma develops, and the middle esophagus is a more common location for squamous cell carcinoma. Esophageal cancer is associated with chronic irritation (e.g., GERD, achalasia, hiatal hernia, alcohol abuse, and use of smoked and smokeless tobacco), obesity, and Barrett esophagus. Smoking and alcohol abuse are major risk factors for squamous cell carcinoma, but Barrett esophagus is the most common risk factor for adenocarcinoma. These tumors can grow to match the circumference of the esophagus, creating a stricture, or they can grow out into the lumen of the esophagus, creating an obstruction. Complications include esophageal obstruction, respiratory compromise, and esophageal bleeding.

Esophageal cancer is usually asymptomatic in its early stages, delaying its diagnosis and treatment. Because of the usually late diagnosis, the prognosis is poor for patients with esophageal cancer. Clinical manifestations, when present, typically include dysphagia and weight loss. Other signs can include odynophagia, chest pain (not related to eating), hematemesis, hoarseness/cough due to laryngeal nerve compression, and halitosis. Chronic blood loss may cause iron deficiency anemia. Endoscopy with a biopsy is necessary to confirm the diagnosis. Surgery is the treatment of choice, but chemotherapy and radiation are also frequently included in management. Speech therapy will likely be necessary following treatment.

Gastric Cancer Gastric cancer occurs in several forms, but adenocarcinoma (an ulcerative lesion) is the most frequently encountered type. Incidence and mortality rates of gastric cancer in the United States have declined since 1980. Nevertheless, gastric cancer remains extremely prevalent worldwide (it is the fifth most common type of cancer) and is the third most deadly cancer worldwide (WHO, 2015). Japan has particularly high rates of gastric cancer. Gastric cancer is prevalent in men and Asians and Pacific Islanders, but mortality rates are highest among Black men. Gastric cancer has a 5- year survival rate of approximately 29%.

Gastric cancer is strongly associated with increased intake of salted, cured, pickled, preserved (containing nitrates and nitrites), and smoked foods. A low-fiber diet and constipation can increase the risk of developing this cancer because they prolong the time over which the intestinal wall is exposed to these substances. Additional risk factors include family history, H. pylori infections, smoking, alcohol consumption, obesity, pernicious anemia, Epstein-Barr virus (in some populations), chronic atrophic gastritis, gastric ulcers, and gastric polyps. A small percentage (1– 3%) of gastric cancers are familial.

Gastric cancer is asymptomatic, or symptoms may be nonspecific in its early stages, which often delays its diagnosis and treatment. Nonspecific symptoms can include dyspepsia, nausea, decreased appetite, and mild epigastric pain. When present, clinical manifestations include the following symptoms:

Abdominal pain and fullness Epigastric discomfort Palpable abdominal mass Dark stools, possibly melena Dysphagia that worsens over time Excessive belching Anorexia Nausea and vomiting Hematemesis

Premature abdominal fullness after meals Unintentional weight loss Weakness and fatigue

Endoscopy with biopsy confirms the diagnosis. Additionally, barium studies may be necessary. Surgical removal of the stomach (gastrectomy) is the only curative treatment. Endoscopic resection may be done in certain cases (e.g., early stages, no lymph node involvement). Chemotherapy and radiation are also used as curative and palliative measures. H. pylori infection should be treated. Nutritional support (e.g., TPN) and supplements (e.g., vitamin B12 and iron) will be needed before, during, and after treatment. Screening for gastric cancer with contrast radiography and upper endoscopy is being performed in some countries with a high incidence (e.g., Japan and Korea).

Liver Cancer Liver cancer most commonly occurs as a secondary tumor that has metastasized from the breast, lung, or other GI structures (FIGURE 9-32). Incidence and mortality rates of liver cancer in the United States have tripled since 1980. According to the American Cancer Society (2016), liver cancer is the 10th most common cancer in men and the 5th deadliest cancer in men. Worldwide, liver cancer is the 2nd most common cancer (WHO, 2015). Most primary tumors (termed hepatocellular carcinomas) are caused by chronic cirrhosis or hepatitis infection (HBV and HCV). Liver cancer is most prevalent among men as well as Asians and Pacific Islanders. It has a 5-year survival rate of approximately 17%.

FIGURE 9-32 Liver cancer. © Medicine-R/Shutterstock.

Liver cancer may either be asymptomatic or produce mild symptoms initially. Clinical manifestations are similar to those of other liver diseases:

Anorexia Fever Jaundice Nausea and vomiting

Abdominal pain (usually in the upper right quadrant) Hepatomegaly Splenomegaly Portal hypertension Edema, third spacing (accumulation of fluid in tissue or body cavities), and ascites Paraneoplastic syndrome (manifestations and diseases that result from cancer such as hypoglycemia, hypercalcemia, and severe diarrhea) Diaphoresis Weight loss

Treatment strategies vary depending on the primary site and progression of the cancer. Chemotherapy is used systemically when metastasis is evident or may be injected directly into localized tumors. Common sites of metastasis are the heart and the lung. Other areas are the brain, kidney, and spleen. If the tumor is small, a section of the liver may be surgically removed (a procedure called a hepatectomy). If the cancer has spread throughout the liver or has caused significant damage, a liver transplant will be the best option if metastasis has not occurred. Several nontraditional cancer treatment procedures are also available to treat liver cancer. Cryoablation is a procedure that uses extreme cold to destroy cancer cells by injecting liquid nitrogen into the tumor. Radiofrequency ablation uses electric current to heat and destroy cancer cells. Pure alcohol can also be injected into the tumor to dry and eventually kill the cancer cells.

Pancreatic Cancer Pancreatic cancer is an aggressive malignancy—most commonly a ductal adenocarcinoma that arises from exocrine cells. Endocrine tumors (in the islets of Langerhans) are rare. Pancreatic cancer can quickly spread to nearby structures (e.g., stomach, intestines, spleen, liver, and lungs). Its incidence and mortality rates have remained steady since 1980. According to the American Cancer Society (2016), pancreatic cancer is the ninth most common cancer in women, and it is the fourth leading cause of cancer deaths in men and women.

Pancreatic cancer occurs most frequently in men and Blacks. Other risk factors include family history, obesity, chronic pancreatitis, long-standing diabetes mellitus, cirrhosis, alcohol abuse, and tobacco use. Inherited susceptibility may occur in those individuals with non-O blood groups (e.g., type A, AB, or B).

The overall 5-year survival rate for this disease is a mere 7%. This dismal prognosis is due largely to the asymptomatic nature of pancreatic cancer and the lack of a reliable early detection method. Clinical manifestations do not generally develop until the cancer is well advanced and has metastasized, delaying diagnosis and treatment. These manifestations may include the following signs and symptoms:

Upper abdominal (usually epigastric) pain that may radiate to the back (pain worsens as cancer progresses), has insidious onset, is intermittent, and worse with eating or lying supine Jaundice, often with pruritus, dark urine, and clay-colored stools Steatorrhea Indigestion Anorexia Weight loss Depression Malnutrition Hyperglycemia or recent onset of diabetes mellitus Increased clotting tendencies

No effective treatment has been developed for pancreatic cancer. Pancreaticoduodenectomy (Whipple procedure) is recommended for decompression of obstructed ducts. Surgical resection of tumors or total pancreatectomy may be performed, but tumor recurrence rate can be high. Chemotherapy and radiation are often used as palliative treatment or in combination with surgery. Biliary blockages that develop may require repair through surgery or endoscopy. Pain management and nutritional support are often necessary. As with other life-limiting diseases, palliative care is important.

Colorectal Cancer Colorectal cancer (CRC) most often develops from an adenomatous polyp. The large bowel is the most common site for cancer development, with a smaller proportion affecting the rectum. A majority of the tumors are adenocarcinomas. According to WHO (2015), CRC is the fourth most common cancer worldwide. According to the American Cancer Society (2016), CRC is the third most common and most fatal cancer in men and women in the United States, although its rates have been declining since 1980. Incidence and mortality rates are the highest among men and Blacks. The 5-year survival rate for CRC is a robust 65%.

Dietary factors that have been associated with CRC include excessive intake of fat, calories, red meat, processed meat, and alcohol as well as deficient intake of fiber. Other risk factors involve genetics, family history (e.g., familial adenomatous polyposis has a 100% risk of CRC as well as hereditary nonpolyposis CRC), advancing age, obesity, tobacco use, physical inactivity, IBD, and history of abdominal irradiation.

Like many other GI cancers, CRC remains asymptomatic until it is well advanced. Manifestations are also dependent on the location of the tumor (the right side includes the cecum and ascending colon, and the left side includes the descending colon). When present, clinical manifestations may include the following symptoms:

Lower abdominal pain and tenderness Blood in the stool (occult or frank) Diarrhea, constipation, or other change in bowel habits Intestinal obstruction Narrow stools Unexplained anemia (usually iron-deficiency anemia) Unintentional weight loss

Routine screening can dramatically improve prognosis. The 5-year survival rate for colorectal cancer if detected when it is localized to the large intestine is approximately 90%. The U.S. Preventive Services Task Force (2016) recommends regular colorectal screening beginning at 50 years of age for both sexes (earlier if risk factors are present). The American Cancer Society lowered the recommended age for screening to 45 for people at average risks in 2018 (Wolf et. al, 2018). The screening tests and recommended intervals depending on test performed are identified here:

A high-sensitivity fecal occult blood test (which checks for hidden blood in three consecutive stool samples) should be administered every year. A fecal immunochemical test (which is more accurate than the fecal occult blood test) should be administered every year. A fecal immunochemical test for DNA should be administered every 1–3 years. Flexible sigmoidoscopy should be administered every 5 years. CT colonography (i.e., virtual colonoscopy) should be administered every 5 years Colonoscopy (preferred screening test) should be administered every 10 years.

During colonoscopy, adenomatous polyps can be removed (polypectomy). Progression from a polyp to cancer can occur over 10-15 years, but hereditary nonpolyposis can progress over a shorter time (e.g., 3 years). Colonoscopy is also used as a diagnostic test when symptoms are present, and it can be used as a follow-up test when the results of another colorectal cancer screening test are unclear or abnormal. Additionally, early (stage 0) cancer cells can be removed during the colonoscopy.

Cancers stage I through III require extensive surgery (colon resection). Chemotherapy and radiation use vary depending on the cancer stage. The patient may require a temporary or permanent colostomy (usually with lower rectal tumors) because of the colon resection. Because colorectal cancer often reoccurs, lifestyle changes (e.g., diet and physical activity) and follow-up screenings are crucial to long-term survival.

1. 2.

3. 4. 5.

6.

• • • •

BOX 9-3 Application to Practice In which of the following cases would gastrointestinal cancer be a risk and what would be the likely type of cancer?

A 40-year-old man who smokes and has a duodenal ulcer. A 50-year-old woman with long-standing GERD and recent evidence of Barrett esophagus on upper endoscopy. A 60-year-old obese woman with a history of alcohol abuse and chronic pancreatitis. A 25-year-old man who contracted hepatitis A on an international trip. A 60-year-old woman with type 2 diabetes mellitus and a history of long-standing constipation and consuming one or two alcoholic drinks every other day. A 25-year-old with a history of Hashimoto thyroiditis and Crohn disease.

BOX 9-4 Application to Practice Now that we have discussed conditions of the GI system, let us put that knowledge into practice. While working in the clinic, you encounter the following patients. Which patient would be at greatest risk for developing an intestinal obstruction?

An adult diagnosed with cirrhosis of the liver An individual eating a low-fiber, high-fat diet A Jewish patient who smokes and consumes large amounts of caffeine An elderly patient who is on bed rest because of postoperative abdominal surgery

When determining who is at greatest risk, just start counting risk factors—the patient with the most risk factors “wins.” Here, we start with the adult with cirrhosis. This patient has no risk factors for developing an intestinal obstruction. The patient with a low-fiber, high-fat diet may be at risk because consuming low-fiber diet can put individuals at risk for constipation. Keep this patient on the short list. Next, consider the Jewish patient. This patient does not have any risk factors, so eliminate this individual. Finally, the elderly patient has three risk factors—advancing age, immobility, and abdominal surgery. With three risk factors, the elderly patient is at the most risk for developing an intestinal obstruction.

C H A P T E R S U M M A R Y

The GI system is responsible for ingestion, absorption, and removal of food. These functions obtain the essential nutrients, water, and electrolytes the body needs to maintain many physiologic activities and homeostasis. Disorders of the GI tract range in severity from harmless to life threatening. These disorders can be congenital, infectious, structural, or cancerous in nature. Regardless of the pathogenesis, GI disorders often create short- or long-term nutritional deficits or elimination issues that can affect the individual’s overall health. Promoting GI health focuses primarily on dietary strategies that include following a well-balanced diet, reducing alcohol consumption, and maintaining a healthy weight. Other lifestyle factors to promote GI health includes avoiding smoking and engaging in regular physical activity. CRC screening is highly effective and should commence at the age of 50.

R E F E R E N C E S A N D R E S O U R C E S

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Buggs, A., & Dronen, S. (2014). Viral hepatitis. Medscape. Retrieved from http://emedicine.medscape.com/article/775507-overview

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Centers for Disease Control and Prevention (CDC). (2017b). Facts about esophageal atresia. Retrieved from https://www.cdc.gov/ncbddd/birthdefects/esophagealatresia.html

Centers for Disease Control and Prevention (CDC). (2015b). Viral hepatitis surveillance, United States 2014. Retrieved from https://www.cdc.gov/hepatitis/statistics/2014surveillance/pdfs/2014hepsurveillancerpt.pdf

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Gould, B. (2015). Pathophysiology for the health professions (5th ed.). Philadelphia, PA: Elsevier. Heuman, D., Allen, J., & Mihas, A. (2016). Gallstones (cholelithiasis). Medscape. Retrieved from http://emedicine.medscape.com/article/175667-overview#a1

Hoffenberg, E. J., Furuta, G. T., Kobak, G., Walker, T., Soden, J., Kramer, R. E., & Brumbaugh, D. Gastrointestinal tract. In W. W. Hay, Jr., M. J. Levin, R. R. Deterding, M. J. Abzug (Eds.), Current diagnosis & treatment: Pediatrics (24th ed.). New York, NY: McGraw-Hill. Retrieved from http://accessmedicine.mhmedical.com.ezproxy.fiu.edu/content.aspx?bookid=2390&sectionid=189079593

Madara, B., & Pomarico-Denino, V. (2008). Quick look nursing: Pathophysiology (2nd ed.). Sudbury, MA: Jones and Bartlett Publishers.

Professional guide to pathophysiology (3rd ed.). (2010). Philadelphia, PA: Lippincott Williams & Wilkins. Singh, J., & Sinert, R. (2015). Pediatric pyloric stenosis. Medscape. Retrieved from http://emedicine.medscape.com/article/803489-overview#a6

U.S. Preventive Services Task Force. (2016). Colorectal cancer: Screening recommendations. Retrieved from http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/colorectal-cancer- screening2?ds=1&s=colorectal

Valle, J. (2018). Peptic ulcer disease and related disorders. In J. Jameson, A. S. Fauci, D. L. Kasper, S. L. Hauser, D. L. Longo, & J. Loscalzo (Eds.), Harrison’s principles of internal medicine (20th ed.). New York, NY: McGraw-Hill.

Wolf, D. (2015). Cirrhosis. Medscape. Retrieved from http://emedicine.medscape.com/article/185856- overview#a1

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C H A P T E R 1 0

Endocrine Function

L E A R N I N G O B J E C T I V E S

Discuss normal endocrine anatomy and physiology. Differentiate disorders of the hypothalamus and pituitary gland. Explain the pathogenesis, consequences, and complications of diabetes mellitus. Differentiate the types of diabetes mellitus. Differentiate disorders of the thyroid gland. Differentiate disorders of the parathyroid gland. Differentiate disorders of the adrenal glands. Apply understanding of endocrine system alterations in describing various common disorders such as diabetes mellitus, hypothyroidism, hyperthyroidism. Develop diagnostic and treatment considerations for various endocrine disorders.

he endocrine system consists of glands located throughout the body (FIGURE 10-1) that are responsible for producing and secreting a wide range of hormones and chemical transmitters. These hormones serve as chemical

messengers, traveling to various sites to regulate several processes, including 1) growth and development, 2) metabolism, 3) sexual function, 4) reproduction, and 5) mood stability. Hormones influence these processes by binding to receptors on the surface or within their target cells. Only small amounts of these potent substances are required to make a significant impact at the cellular and organism levels. Consequently, subtle fluctuations in hormone levels can disrupt the body’s delicate balance. Disorders of the endocrine system can result from insufficient or excessive amounts of these hormones that alter their specific function. Causes of these disorders vary but include genetic alterations, lifestyle behaviors, and tumors. The severity of these endocrine disorders can range from mild conditions that are easily managed to life-shortening or life-threatening conditions.

FIGURE 10-1 The human endocrine system.

Anatomy and Physiology Hormonal Regulation The endocrine system is a complex messaging and control system that interacts with several body functions. It uses hormones to orchestrate these multifaceted communication and control operations. Endocrine glands located throughout the body produce and secrete these hormones. The term endocrine refers to the act of secreting substances directly into the bloodstream (FIGURE 10-2) rather than in a duct (like the exocrine glands of the gastrointestinal tract). In addition to these structures, reproductive glands (e.g., testes and ovaries) produce hormones (see chapter 8 for more on reproductive function).

FIGURE 10-2 Endocrine release of hormones.

Hormones can be classified or described in regard to their action (e.g., altering serum and glucose levels), source (e.g., anterior pituitary gland), or chemical structure. They can also be divided into four categories based on chemical composition: 1) steroids (e.g., androgens, glucocorticoids, and thyroid hormones), which are lipid soluble; 2) proteins or polypeptides (e.g., insulin and growth hormone), which are water soluble; 3) amines and amino acids (e.g., epinephrine), which are water soluble; and 4) fatty acid derivatives (e.g., prostaglandins).

Hormone release is influenced by the nervous system (e.g., autonomic control of beta cells), other chemical substances (e.g., glucose and sodium), and one endocrine gland influencing another (e.g., the adrenal cortex influences pancreatic secretions). Hormone secretion can also occur in various patterns (e.g., circadian or pulsatile). Release of hormones from their respective glands is primarily controlled by a negative feedback system but may occasionally be controlled by a positive feedback system. In a negative feedback loop, the product (in this case, hormones) of a biochemical process inhibits its own production—the hormone is released only when its levels decline, and production stops when its levels rise (e.g., insulin is released in response to serum glucose levels). In the endocrine system, a positive feedback loop is rare and occurs when the hormone is released when levels are high, and production stops when its levels are low (e.g., the release of oxytocin during childbirth). Tropic hormones regulate endocrine glands to produce other hormones (e.g., thyroid-stimulating hormone). Nontropic hormones (e.g., cortisol) directly stimulate cellular metabolism and other activities.

Once released from the gland, hormones travel through the circulatory system to their target cells in other glands and tissues. Multiple hormone signals continuously interact with these target cells, but these cells respond only to their specific hormone. This selective response is due to protein receptors located in the cell membrane or the cytoplasm. The number of receptors on the target cells and the sensitivity of the receptors to the hormones (i.e., affinity) can change depending on hormone concentration. Upregulation is the process where low hormone levels cause an increase in the number of cell receptors. Conversely, downregulation is the process where high levels of hormone decrease the number of receptors or decrease the cell’s affinity to the hormone. For hormones to cause a reaction, they must be in a free (i.e., unbound) form. Water-soluble hormones (e.g., insulin) are already circulating in free forms while lipid-soluble hormones (e.g., glucocorticoids) are bound to a carrier protein. A lipid-soluble hormone reaches its target cell, dissociates from its carrier protein, and then enters the cell. Once the hormone has acted on the target cells, the liver metabolizes the hormone and the kidneys excrete it to prevent a cumulative effect.

Pituitary Gland and Hypothalamus Roughly the size of a pea, the pituitary gland (i.e., hypophysis) is located at the base of the brain. The gland is located in a depression in the sphenoid bone known as the sella turcica. This gland can be divided into two parts—the anterior (adenohypophysis) pituitary gland and the posterior (neurohypophysis) pituitary gland. The pituitary gland is often referred to as the master gland despite that it mainly functions as an intermediary, receiving input from the hypothalamus and peripheral endocrine glands. Despite its small size, this gland secretes several hormones that influence many different body functions (FIGURE 10-3; TABLE 10-1). The hypothalamus, which is the basal (bottom) portion of the diencephalon, regulates the pituitary gland. The hypothalamus is connected to the pituitary gland through the pituitary stalk (i.e., infundibulum) and connects the nervous and endocrine systems. It contains receptors that monitor hormone, nutrient, and ion levels. When activated, these receptors stimulate neurosecretory neurons in the hypothalamus to synthesize and secrete various types of releasing and inhibiting hormones (Figure 10-2). These hypothalamus hormones, in turn, regulate the hormones produced by the anterior pituitary gland (a relationship known as the hypothalamic-pituitary axis). The hypothalamus hormones travel to the anterior pituitary, and then pituitary capillaries transport the pituitary hormones to the peripheral circulation via the internal jugular veins (i.e., portal circulation). The hypothalamus neurosecretory neurons also synthesize the posterior pituitary hormones—antidiuretic hormone (ADH) and oxytocin. The posterior pituitary hormones, in contrast to the anterior pituitary hormones, travel through a nerve tract and not a circulation portal (Figure 10-2). The posterior pituitary stores and releases ADH and oxytocin, and they are released directly into the systemic circulation. The key neurotransmitters of the nervous system, glutamate (excitatory) and gamma- aminobutyric acid (inhibitory), regulate the posterior pituitary hormones. The posterior pituitary hormones have a direct effect on peripheral tissue (i.e., they bypass target glands).

FIGURE 10-3 The pituitary gland. (A) A cross-section of the brain showing the location of the pituitary and the hypothalamus. (B) The structure of the pituitary gland. Releasing and inhibiting hormones travel via the portal

system from the hypothalamus to the anterior pituitary, where they affect hormone secretion.

TABLE 10-1 Hormones Secreted by the Hypothalamus and Pituitary Gland

Hormone Function

Hypothalamus Anterior pituitary gland

Stimulation Growth hormone–releasing hormone (GHRH): stimulates release Substance P: stimulates secretion

Inhibition Somatostatin: inhibits release

Growth hormone (GH) Stimulates cell growth and fat breakdown. Primary targets are muscle and bone, where GH stimulates amino acid uptake and protein synthesis.

Stimulation Thyrotropin-releasing hormone: stimulates release

Inhibition Somatostatin: inhibits release

Thyroid-stimulating hormone (TSH)

Stimulates release of thyroxine and triiodothyronine.

Stimulation Corticotropin-releasing hormone (CRH): stimulates release

Inhibition Substance P: inhibits synthesis and release

Adrenocorticotropic hormone (ACTH)

Stimulates secretion of hormones by the adrenal cortex, especially glucocorticoids.

Stimulation Gonadotropin-releasing hormone (GnRH): stimulates release Substance P: stimulates secretion

Gonadotropins: follicle- stimulating hormone (FSH) and luteinizing hormone (LH)

Stimulates gamete production and hormone production by the gonads.

Stimulation Prolactin-releasing hormone: stimulates secretion Thyrotropin-releasing hormone: stimulates release Substance P: stimulates secretion

Inhibition Prolactin-inhibiting hormone: inhibits secretion Dopamine: inhibits synthesis and secretion

Prolactin Stimulates breast development during pregnancy and milk production postpartum. Suppresses ovarian function during breastfeeding.

Posterior pituitary gland Antidiuretic hormone (ADH):

Stimulation: glutamate Inhibition: gamma-aminobutyric acid

Melanocyte-stimulating hormone Has a function in promoting secretion of melanin (darkens skin).

Stimulates water reabsorption by nephrons of the kidney.

Stimulation: glutamate Inhibition: gamma-aminobutyric acid

Oxytocin Stimulates breasts to release milk and uterine contractions during birth.

Pancreas

The pancreas is an organ with both exocrine digestive functions and endocrine functions. The pancreas lies underneath the liver and between the two kidneys in the retroperitoneum (the space behind the peritoneum) (FIGURE 10-4). Its endocrine functions are carried out by the islets of Langerhans, which are situated among the many small acini (cell clusters that produce digestive enzymes) in the pancreas. The human pancreas contains approximately 1 million islets of Langerhans, and each islet of Langerhans contains five types of cells: 1) alpha cells, which secrete glucagon; 2) beta cells, which secrete insulin and amylin; 3) delta cells, which secrete somatostatin and gastrin; 4) pancreatic polypeptide cells, which secrete a pancreatic polypeptide (stimulates gastric acid secretion and antagonizes cholecystokinin); and 5) epsilon cells, which secrete ghrelin. See chapter 9 for a discussion of the functions of the pancreas.

FIGURE 10-4 The pancreas. (A) The pancreas produces two hormones, insulin and glucagon, as well as digestive enzymes. (B) Hormones are produced by specialized cells within the islets of Langerhans. (C) The

islets of Langerhans are located among the acini, very small groups of digestive enzyme–producing cells of the pancreas.

C: © Jubal Harshaw/Shutterstock.

The regulation of glucose is reflected in the balance between energy intake and energy use with insulin as a key hormonal regulator. Glucagon is released when serum glucose levels fall, insulin levels drop, or glucose needs increase (e.g., with exercise) (FIGURE 10-5). Glucagon stimulates the breakdown of glycogen to glucose (i.e., glycogenolysis) in the liver, which raises serum glucose levels. Gluconeogenesis (synthesis of glucose) occurs when glucagon stimulates the liver and, to a small extent, the kidneys (renal medulla). Glucagon also decreases the uptake of glucose in skeletal muscle and fat (insulin-sensitive tissue) and promotes the release of amino acids and fatty acids (lipolysis). Sympathetic stimulation causes glucagon release. Conversely, high blood glucose inhibits glucagon release. Insulin is released when serum glucose levels increase. Insulin stimulates cellular uptake of glucose, which in turn decreases serum glucose levels. Amylin is released from the beta cells along with insulin. Insulin also promotes the storage of carbohydrates, fats, and proteins. Amylin has a synergistic relationship with insulin in controlling glucose. Amylin stimulation results in glucose control by suppressing glucagon, delaying gastric emptying, and increasing satiety (feeling of fullness). Somatostatin in the pancreas regulates insulin, glucagon, and pancreatic peptide by inhibiting their secretion. Pancreatic polypeptide is thought to regulate some of the other pancreatic activities (e.g., inhibiting cholecystokinin).

FIGURE 10-5 Glucose metabolism.

Several hormones are secreted in the gastrointestinal tract that affect pancreatic hormones and in turn glucose regulation. These hormones include incretins from the small intestine and ghrelin from the stomach. The key types of incretin hormones are glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. After a meal, the incretins cause insulin release and inhibit glucagon release. Incretins also delay gastric emptying and decrease appetite. Dipeptidyl peptidase 4 is the enzyme causing the breakdown of the incretins. There are medication categories used in the treatment of type 2 diabetes mellitus that target incretin and dipeptidyl peptidase 4.

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Finally, ghrelin stimulates hunger.

Learning Points

Glucose Concepts everal concepts pertain to synthesis of glucose. Understanding the differences is important. Glycogenesis is the formation of glycogen from glucose, and, conversely, glycogenolysis is the breakdown of glycogen to

glucose. Glycogenolysis occurs in the muscle and liver. Gluconeogenesis is the formation of glucose from various chemicals such as pyruvate, and conversely glycolysis is the breakdown of glucose to pyruvate.

Thyroid Gland The thyroid gland (FIGURE 10-6) is located at the base of the neck below the larynx. This gland consists of two lobes, one on either side of the trachea, which are connected by a thin band of tissue (isthmus) that extends across the anterior aspect of the trachea. The thyroid is a highly vascular gland that contains several functional units called follicles. These follicles produce three hormones: 1) thyroxine, or T4; 2) triiodothyronine, or T3; and 3) thyrocalcitonin, or calcitonin.

FIGURE 10-6 The thyroid gland.

Together, T3 and T4 account for 95% of circulating thyroid hormones; they regulate cellular metabolism as well as growth and development. The hypothalamus, through the release of thyrotropin-releasing hormone, stimulates the pituitary gland to produce thyroid-stimulating hormone (TSH) using a negative feedback system. TSH, in turn, drives the thyroid to produce T3 and T4 (i.e., thyroxine). Most of the T4 is produced by the thyroid gland (approximately 90%) while only a small amount (approximately 10%) of T3 is produced by the gland. The remainder of T3 is produced when T4 is converted to T3 in body tissues. The thyroid requires iodine to synthesize these hormones. The thyroid hormones remain attached to a protein known as thyroglobulin until they are released. As with other hormones, the bound thyroid hormones are not active while the unbound (free) form is active. Somatostatin from the hypothalamus inhibits the releases of TSH. With aging, thyroid hormone secretion declines, but the rate of thyroid hormone removal from the bloodstream slows down; therefore, a balance is usually maintained. TSH secretion

is thought to increase with aging; however, determining if this is a normal part of aging or hypothyroidism can be difficult.

Calcitonin, along with parathyroid hormone, regulates serum calcium levels. Calcitonin alters serum calcium levels by inhibiting osteoclast activity (which decreases calcium release from the bone) and stimulating osteoblast activity (which increases calcium deposits in the bone). Calcitonin lowers serum phosphate levels. Calcitonin regulates calcium and phosphate by decreasing renal tubular reabsorption and possibly decreasing gastrointestinal absorption. Calcitonin is also regulated with a negative feedback system and is secreted when serum calcium levels are high.

Parathyroid Glands The parathyroid glands, usually four in number, are located on the posterior surface of the thyroid. Each parathyroid gland secretes parathyroid hormone (PTH). PTH works in the opposite way to calcitonin to regulate serum calcium levels, and PTH is more important than calcitonin in calcium regulation. Specifically, PTH is secreted when serum calcium levels drop. This hormone increases serum calcium levels by increasing osteoclast activity (which increases calcium release from the bone) as well as by increasing absorption of calcium in the gastrointestinal tract and kidneys. PTH conversely decreases serum phosphate levels. Calcium levels are also regulated through the action of PTH on the kidney, PTH stimulates vitamin D, and, together, they increase calcium and phosphate absorption in the intestines. See chapter 6 for a discussion of calcium regulation.

Adrenal Glands The adrenal glands are located on each kidney. Each adrenal gland has an inner portion, or medulla, and an outer portion, or cortex. The hypothalamus influences both portions of the adrenal glands, albeit by different mechanisms.

The adrenal cortex is regulated by negative feedback involving the hypothalamus and adrenocorticotropic hormones; the medulla is regulated by nerve impulses from the hypothalamus. The medulla produces epinephrine (about 30%) and norepinephrine (minor amounts) during times of stress. The majority of epinephrine is released from nerve endings. Epinephrine and norepinephrine mediate the fight- or-flight response of the sympathetic nervous system (FIGURE 10-7). The adrenal catecholamines (e.g., epinephrine and norepinephrine) are also regulated by glucocorticoids and ACTH (increases in both of these cause release of catecholamines).

FIGURE 10-7 Stress response.

The cortex has three separate regions that produce different steroids. The outermost region of the adrenal cortex secretes mineralocorticoids. The principal mineralocorticoid is aldosterone, which acts to conserve sodium and, in turn, water in the body. Aldosterone is primarily regulated by the renin–angiotensin–aldosterone system. The middle region of the adrenal cortex secretes glucocorticoids. The principal glucocorticoid is cortisol, which increases serum glucose levels. Other

glucocorticoids secreted include cortisone and corticosterone. Glucocorticoids have effects on multiple systems such as the metabolic, neurologic, immune, and musculoskeletal systems. The glucocorticoids are released during stress (Figure 10- 7). In addition, cortisol is released in a diurnal (i.e., circadian) pattern. Just before a person awakens, cortisol levels rise, and throughout the day, the levels slowly decline (this pattern is assuming regular sleep–wake patterns). Lastly, the innermost region of the cortex secretes gonadocorticoids, or sex hormones. Male hormones (e.g., androgen) and female hormones (e.g., estrogen) are secreted in minimal amounts in both sexes by the adrenal cortex, but the hormones from the testes and ovaries usually mask their effect. In females, the masculinization effect of androgen secretion may become evident after menopause, when estrogen levels from the ovaries decrease. The innermost layer also secretes mineralocorticoids, aldosterone, and glucocorticoids. See chapters 4 and 6 for more information on aldosterone.

Understanding Conditions That Affect the Endocrine System When considering alterations in the endocrine system, organizing them based on their basic underlying pathophysiology can increase understanding. These concepts focus on inadequate or excessive functioning of the glands. Hormone alterations can be due to 1) inadequate hormones (e.g., decreased production due to missing precursor, inadequate free active hormone, hormone destruction), 2) abnormal delivery (e.g., impaired blood supply), 3) abnormal regulation (e.g., feedback mechanism impaired), and 4) abnormal amount (e.g., ectopic hormone production from a tumor). Production may be adequate, and the regulatory and delivery system may be intact; however, the target gland response may be inappropriate. Inappropriate target gland response is usually a result of problems on the cell surface where receptors are located or problems within the cell. Examples of target gland receptor dysfunction include an inadequate number of receptors and antibodies attacking receptors. Endocrine system disorders can also be categorized by the primary location of the disorder such as hypothalamic or pituitary (e.g., anterior versus posterior) and the target gland affected (e.g., thyroid or adrenal). Once you understand the normal function of the glands and the hormones they produce, it becomes clear that those functions can be either insufficient or exaggerated. In most cases of hypofunctioning, something has destroyed the gland (e.g., tumors or autoimmune conditions). Treatment for hypofunctioning usually centers on hormone replacement. In most cases of hyperfunctioning, something is overstimulating the gland or secreting hormonelike substances (e.g., tumors). Treatment for hyperfunctioning usually centers on giving medications to block hormone production, removing the cause (e.g., a tumor), or removing part or all of the gland.

Disorders of the Pituitary Gland Disorders of the pituitary gland can have significant consequences because of the many hormones and processes this gland influences. Pituitary gland disorders can stem from dysfunction of the hypothalamus or from just the pituitary gland (anterior, posterior, or both). Hypothalamic hormones cause inhibition or release of anterior pituitary hormones. Hypothalamic disorders will, therefore, lead to clinical manifestations that reflect the pituitary hormone altered. Like most endocrine disorders, pituitary gland disorders result in either increased or decreased levels of hormones associated with the gland (Table 10-1). These conditions can be caused by multiple disorders such as tumors (most common), infection, trauma, and necrosis.

Hyperpituitarism Hyperpituitarism is a condition in which the pituitary gland secretes excessive amounts of one or all of the anterior pituitary hormones (Table 10-1). The most common causes are benign pituitary adenomas (primary pituitary carcinoma is rare). The adenomas (i.e., glandular tumors) are usually a result of genetic mutations such as those in multiple endocrine neoplasia type 1 or aryl hydrocarbon receptor- interacting protein. The adenomas usually develop from a cell of origin that secretes hormones (e.g., lactotroph adenoma that is formed from cells that secrete prolactin). Adenomas can form from any cell in the anterior pituitary. The adenomas secrete an excessive amount of hormone of the same type from the cell from which they originated (e.g., an adenoma from somatotroph cells will secrete excessive growth hormone). While the adenoma causes excesses, deficiencies in hormone production can occur. These deficiencies are the result of the destruction or compression of the pituitary gland by the growing adenoma. The tumor can cause pituitary gland infarction, and hemorrhaging can occur into the tumor and gland (apoplexy). While some adenomas can secrete excessive hormones, many are nonfunctional or silent and do not hypersecrete hormones.

Clinical Manifestations Hyperpituitarism is a progressive disorder that can occur suddenly but usually develops slowly. Clinical manifestations vary greatly depending on the hormones affected and the severity of those alterations. The manifestations are usually a result of the expanding adenoma in the small enclosed space where the pituitary is located. Hormonal manifestations can be minimal to absent as many adenomas are nonfunctional. In nonfunctional adenomas, the manifestations are due to the mass and a failing pituitary (i.e., hormone deficiency). Some tumors cause hypersecretion of certain hormones (i.e., the cell origin of the tumor), and manifestations will be a

result of the hypersecretion of a specific hormone (e.g., hyperprolactinemia from a lactotroph adenoma). In summary, manifestations are due to the expanding adenoma and possible hormone excesses or deficiencies.

The size of the adenoma can also influence the presence of manifestations. Microadenoma (< 1 cm) manifestations are more likely to be due to hormone excesses, and macroadenoma (> 1 cm) manifestations are likely to be due to the mass. The mass manifestations usually include headache and visual disturbances (the pituitary gland is located near the optic chiasm). The visual disturbances can include loss of vision, visual field loss, or double vision. The expanding mass can impinge upon cranial nerves that traverse the gland (i.e., cranial nerve III, IV, and parts of V and VI; see chapter 11 on neural function).

Hormonal manifestations will be dependent on whether the tumor secretes excess hormones and the type it is secreting. The types of primary adenomas and the associated hormone excess include:

Lactotroph (i.e., prolactinoma): This causes increased prolactin, further causing hypogonadism in women (e.g., in premenopausal infertility, oligomenorrhea, and galactorrhea) and men (e.g., decreased libido, impotence, infertility, gynecomastia, and galactorrhea). Lactotrophs are among the most common types of adenomas. Somatotroph: This causes increased growth hormone leading to acromegaly (adults) and gigantism (children) (FIGURE 10-8; FIGURE 10-9). Somatotrophs are common types of adenomas.

FIGURE 10-8 A person with acromegaly A as a child, B as a teenager, C as an adult, and D gigantism. A: © Yuliani Andries/EyeEm/Getty Images; B and C: Courtesy of Tanya Angus and Karen Strutynsky

(www.tanyaangus.com); D: © Bettina Cirone/Science Source.

FIGURE 10-9 Dwarfism. © Marion Bull / Alamy Stock Photo.

Corticotroph: This causes increased ACTH, in turn causing central Cushing disease. Gonadotroph: This causes increased LH and FSH, resulting in precocious puberty and ovarian hyperstimulation. These tumors are rare. Thyrotroph: This type of tumor is usually nonfunctioning, and of the tumors that are functioning, which are extremely rare, can cause hyperthyroidism.

Lactotrophic and somatotrophic adenomas can also occur in combination and cause manifestations of prolactin and growth hormone excesses.

Diagnosis and Treatment Diagnosis of hyperpituitarism is often delayed because of its varying presentation. Diagnostic procedures usually include a history and physical examination with vision testing. Diagnostic testing will include magnetic resonance imaging (MRI), which is the best imaging technique for adenomas. A brain computed tomography (CT), usually that is contrast enhanced, can be also be done. Serum prolactin, insulin-like

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growth factor-1 (IGF-1), and cortisol levels are usually measured. All levels will be high depending on the type of adenoma (e.g., high cortisol with a corticotroph adenoma). Other hormone levels such as TSH, FSH, and LH may be evaluated if there are suspicions for imbalances in these hormones.

Treatment strategies depend on the underlying etiology and the hormone affected. Tumors will likely require medications for tumor suppression, surgery, radiation, and chemotherapy, but they often reoccur. Additionally, analogues that inhibit hormone production may be given.

Diagnostic Link

Serum Hormone Levels valuating the pituitary gland and target gland hormones can be useful in determining whether the problem is in the hypothalamus/pituitary or the target gland (e.g., serum ACTH and cortisol). Serum hormone levels

(e.g., cortisol) are usually obtained in the morning (e.g., between 8 a.m. and 10 a.m.). Some serum hormones may require pharmacologic agents to evaluate a response to the stimulation (e.g., metyrapone test reduces cortisol, and ACTH should increase if secretion is intact). Growth hormone effects are dependent on insulin-like growth factors (IGFs) produced in the liver. Therefore, IGFs and GH should be measured. IGF-1 levels are usually constant as they are dependent on GH while circulating GH varies throughout the day. Therefore, IGF- 1 measures may be a better reflection of GH abnormalities.

Hypopituitarism Hypopituitarism is a rare, complex condition in which the pituitary gland does not produce sufficient amounts of some or all (panhypopituitarism) of its hormones. Hypopituitarism usually affects the anterior pituitary hormones (e.g., TSH, growth hormone, ACTH, FSH, LH, prolactin, and melanocyte-stimulating hormone). As a result, the gland or process that the hormone controls is impaired. Hypopituitarism may result from disorders that affect the pituitary or the hypothalamus. Those causes can be divided into tumors within the hypothalamus or pituitary, extrapituitary tumors (i.e., tumors outside the pituitary), and nontumors.

Pituitary Causes Congenital defects (e.g., pituitary hypoplasia or aplasia) and genetic mutations Pituitary surgery or radiation Infections, such as meningitis and tuberculosis Pituitary tumors, such as pituitary adenomas, which are the most common type of tumor associated with hypopituitarism (see the Hyperpituitarism section) Infiltrative disorders, such as hemochromatosis (a condition resulting in excessive iron absorption) or lymphocytic hypophysitis (an abnormal infiltration of lymphocytes and enlargement of the pituitary) Pituitary infarction (Sheehan syndrome), which occurs due to postpartum hemorrhage

Hypothalamic Causes Tumors that originate in the hypothalamus (e.g., benign craniopharyngiomas) or tumors from metastasis (e.g., lung cancer) Infections (e.g., meningitis, tuberculosis) Infiltrative disorders, such as histiocytosis X (an abnormal immune condition that results in tissue damage) or sarcoidosis (an abnormal inflammatory condition that results in tissue damage) Traumatic brain injury Radiation-induced damage (e.g., brain tumor treatment)

Clinical Manifestations Hypopituitarism can result in several manifestations depending on the hormones involved. The severity of these conditions reflects the degree of hormone deficit. Hypopituitarism is a progressive disorder that can occur suddenly (e.g., pituitary hemorrhage) but usually develops slowly (e.g., years after radiation therapy). Clinical manifestations vary greatly depending on the hormones affected and the severity of those alterations. In general, GH, LH, and FSH are more likely to be affected than ACTH or TSH. Manifestations may also be due to the underlying causes, such as a tumor causing compression (e.g., headaches or visual disturbance). Comprehensive discussions of manifestations are found in the individual target gland or hormone sections. General manifestations of hormone deficiency include:

GH deficiency: Delayed growth and development (e.g., weight-to-height ratio increase, immature-appearing face such as undeveloped nasal bridge, frontal protrusion, infantile voice, diminished hair growth) (Figure 10-9) FSH/LH deficiency: Impaired reproductive system (e.g., infertility, amenorrhea, irregular menses, hot flashes) TSH deficiency: Central hypothyroidism with decreased metabolic activity (e.g., fatigue, cold sensitivity, weight gain, constipation) ACTH deficiency: Secondary adrenal insufficiency usually due to cortisol deficiency (e.g., weakness, nausea, anorexia, hypotension). ACTH deficiency is a serious disorder than can be life threatening. ACTH deficiency from pituitary disorders (i.e., secondary adrenal insufficiency) does not cause alterations in aldosterone as seen in ACTH deficiency due to adrenal gland disorder (i.e., primary adrenal insufficiency). ADH deficiency: Excessive urination

Diagnosis and Treatment Diagnosis of hypopituitarism is often delayed because of its variable presentation. Hypopituitarism, even severe deficiencies, may cause few or no clinical

manifestations. Diagnostic procedures usually include a history and physical examination. Diagnostic testing includes measurement of serum hormone levels; findings consistent with hypopituitarism include low ACTH levels. Normally during times of stress, the levels of ACTH rise. To evaluate ACTH reserve, medications such as metyrapone can be administered to evoke a stress response. With pharmacologic provocation, a low ACTH level reflects a lack of a response (i.e., deficiency). Serum GH and IGF levels can be evaluated. Medications can be administered to evaluate whether GH release can be stimulated. Low GH levels with an attempt at stimulation reflect a GH deficiency. Thyroid hormone measurement of TSH, T3, and T4 should be done. With hypopituitarism, TSH levels are suppressed, resulting in low T4 and T3 which is in contrast to thyroid gland where the TSH and thyroid hormones have an inverse relationship (one is up, the other is down). The hypothalamus produces thyrotropin-releasing hormone, which can be measured; however, these laboratory measurements are only available outside of the United States. Men will have LH and testosterone levels evaluated while women will have FSH, LH, and estradiol levels evaluated. With hypothalamic or pituitary disorders, the testosterone and estradiol will be low, and the gonadotropic hormones (i.e., FSH, LH) will be low or normal (reflecting deficiency). Primary disorders of the target glands (i.e., ovarian failure or testicular hypofunction), in contrast to hypothalamic or pituitary disorders, causes high FSH and LH with low estradiol levels (in women), and low testosterone levels with normal LH in men. Additional diagnostic tests for hypopituitarism include pituitary MRI or brain CT and X-rays (to identify any bone abnormalities). See chapter 8 for more on reproductive function.

Lifelong hormone replacement therapy is the cornerstone of treatment. Resolving and treating the underlying cause, such as cancer, is also important when possible. Life-threatening deficiencies, such as those potentially seen in ACTH deficiency, require emergent care. Additional strategies, such as infertility treatments and counseling, depend on the specific hormones affected.

Prolactin Disorders: Prolactinemia Prolactin disorders usually result in high prolactin levels. Deficient levels rarely occur in isolation but instead occur with other hormone deficiencies. Prolactinemia (high prolactin levels) is a result of disorders of the hypothalamus or anterior pituitary. Lactotroph adenomas (i.e., prolactinomas) cause prolactinemia, and they are some of the most common types of pituitary adenomas. Hyperprolactinemia can be caused by interference of the dopamine inhibitory effect on prolactin. Dopamine interference can be due to several medications that are dopamine receptor antagonists (they block dopamine), such as neuroleptics (e.g., antipsychotics including haloperidol and chlorpromazine). Many other medications can increase prolactin levels such as opioids, antihypertensive agents, and H2 antihistamines, but not all the medications

in these categories result in high prolactin levels (e.g., verapamil is the only calcium channel blocker associated with hyperprolactinemia). Genetic mutations can result in a familial hyperprolactinemia. Systemic disorders, such as chronic kidney disease, result in a decreased excretion of prolactin, resulting in high serum levels. The normal range of prolactin is approximately 20 ng/mL. In general, prolactinomas cause the highest elevations of prolactin (e.g., up to 50,000 ng/mL) while most other causes will have smaller elevations (usually not > 200 ng/mL). High prolactin levels can also be due to normal physiologic states, such as pregnancy or from nipple stimulation during breastfeeding.

Clinical manifestations of hyperprolactinemia will include hypogonadism due to inhibition of GnRH. The GnRH inhibition suppresses LH and possibly FSH and, in turn, this suppression usually results in gonadotropic suppression. This suppression in premenopausal women manifests as infertility, oligomenorrhea, and galactorrhea; in men, manifestations include decreased libido, impotence, infertility, gynecomastia, and galactorrhea. Evaluation and treatment are geared toward determining and treating the underlying cause.

Growth Hormone Disorders Growth hormone excesses result in acromegaly in adults and gigantism in children. Growth hormone deficits result in dwarfism (Figure 10-9). The most common causes of growth hormone excesses are adenomas. More than 300 conditions cause short stature. Growth hormone deficiency as one of the causes of dwarfism is generally due to GHRH deficiency as a result of tumors, GHRH receptor mutations, pituitary agenesis (failure of organ development), or panhypopituitarism.

Gigantism is a result of excess GH and IGF-1 causing excess skeletal growth before epiphyseal growth plate closure. The growth is rapid and usually affects stature, causing rapid height increase before weight gain or concurrent with weight gain. The condition is often caused by a tumor (e.g., adenoma), but the condition is rare.

Acromegaly is also a result of excess GH and IGF-1 in adults. The onset is usually around the age of 40–59 years of age. In contrast to gigantism, the progression is usually insidious and slow with most adults having manifestations 12 years prior to diagnosis. The excess growth effects of GH and IGF-1 do not occur in the long bones as the epiphyseal plates have closed. Rather the excessive GH and IGF-1 lead to soft tissue and connective tissue growth and proliferation. Excessive GH and IGF-1 results in the characteristic appearance of a person with acromegaly, which includes:

Soft tissue and skin changes: Skin thickens; patients develop large hands and feet with paresthesias and carpal tunnel syndrome, an enlarged nose as well as a protruding forehead and jaw, teeth that are spread apart, tongue enlargement

(i.e., macroglossia), deepening voice, excessive sweating (i.e., hyperhidrosis), malodor, and sleep apnea as a result of macroglossia. Bones and joints: Knees, ankles, hips, spine, and other joints become hypertrophic leading to back pain and other musculoskeletal disorders (e.g., kyphosis). Organ enlargement: Thyroid (goiter) function can be normal or abnormal; cardiovascular issues (primary cause of death) such as ventricular hypertrophy, hypertension, and cardiomyopathy can occur. Metabolic changes: Fat and carbohydrate metabolism changes result in decrease glucose use, increased glucose production by the liver, and increased insulin production leading to hyperinsulinemia, insulin resistance, and impaired glucose tolerance or diabetes mellitus.

Children with growth hormone deficiency due to congenital disorders usually have growth failure soon after birth, and in neonates, hypoglycemia and seizures can occur. As the child ages, facial features are immature, stature is short, and obesity may be present. Puberty may be delayed, and boys may have microcephalus (i.e., a small penis). Acquired GH deficiency in older children may be due to tumors. GH deficiency in adults is usually due to hypothalamic pituitary tumors.

Diagnosis and treatment of gigantism, acromegaly, and dwarfism is based on determining the underlying cause (e.g., MRI, serum hormone levels) and targeting treatment to the cause (e.g., surgery, medications to suppress hormone secretion).

Antidiuretic Hormone (Vasopressin) Disorders Antidiuretic hormone (ADH) excesses (i.e., vasopressin, arginine, and vasopressin) lead to a disorder known as syndrome of inappropriate antidiuretic hormone secretion (SIADH). Diabetes insipidus (DI) is characterized by low levels of ADH. Both SIADH and DI are a result of posterior pituitary disorders.

In SIADH, water is retained, and total body water increases as a result of the increased levels of ADH. Dilutional hyponatremia and hypo-osmolality occurs as a result of excess total body water. Conversely, urine osmolality increases as a result of urine concentration (particularly with sodium). The excesses may be due to increased ADH secretion/release (pituitary or ectopic) or increased effect. Central nervous system disorders (e.g., stroke, trauma, and psychosis) can cause SIADH. Small cell lung carcinoma is the most common tumor causing ectopic ADH production. Several drug categories are associated with SIADH, such as antidepressants, anticonvulsants, antipsychotics, anticancer drugs, and antidiabetic drugs. Iatrogenic causes include surgery (usually pituitary), hormone administration (e.g., vasopressin for gastrointestinal bleeding), and infections (e.g., HIV and pneumonia).

SIADH should be suspected when hyponatremia (serum levels < 135 mEq/L), hypo-osmolality (serum osmolality < 280 mOsm/kg), and increased urine hyperosmolality (> 100 mOsm/kg) are present. The manifestations are due to hyponatremia and dependent on the rapidity and severity of the sodium decrease. Manifestations are usually the same as from other causes of hyponatremia (e.g., nausea, vomiting, confusion, weakness, and cramping). Treatment is based on the underlying cause and management of the hyponatremia (see chapter 6 for discussion of sodium imbalance.).

DI occurs as a result of insufficient ADH. This deficiency leads to polyuria and polydipsia. Causes can be either due to insufficient secretion of ADH due to hypothalamus or pituitary disorders (i.e., neurogenic or central DI) or as a result of inadequate renal tubule response to ADH (i.e., nephrogenic DI). Nephrogenic DI may be due to genetic or inherited disorders (e.g., vasopressin receptor gene mutation), which are uncommon. Acquired nephrogenic DI occurs when renal tubules are damaged due to drugs such as lithium, loop diuretics, or certain general anesthetics or due to disorders such as bilateral urinary tract obstruction and polycystic kidney disease.

In up to 50% of cases, neurogenic DI is due to idiopathic causes, and autoimmune processes may lead to the destruction of ADH-secreting cells in the hypothalamus. Other causes include hypothalamus or pituitary damage such as trauma, surgery, or hypoxic encephalopathy; benign or malignant tumors; metastatic cancer; infiltrative disorders; and uncommon familial and congenital diseases, such as Wolfram syndrome or congenital hypopituitarism, respectively.

Clinical manifestations of DI include polyuria (urine output 3 L/day in adults or 2 L/m2 in children), nocturia, and polydipsia. The serum osmolality (> 295 mOsm/kg) and sodium (> 145 mEq/L) are high due to the water loss, and these high levels lead to polydipsia. Hypernatremia can worsen if a patient with DI has impaired thirst or inability to drink or if fluids are not replaced.

Treatment will be based on the underlying cause. DI (whether nephrogenic or neurogenic) treatment generally involves reduction of sodium intake (e.g., low- protein, low-sodium diet). Thiazide diuretics may be administered to improve water retention and thereby less water is delivered to ADH sites in the collecting tubules and this reduces urine output. Because of the polyuria, the bladder can easily become dilated, so adequate emptying using double-voiding techniques is recommended. Carbamazepine and chlorpropamide potentiate ADH action and can be considered. Nonsteroidal anti-inflammatory drugs may be beneficial as they inhibit prostaglandin synthesis and, therefore, essentially block the antagonistic action of prostaglandins on ADH. Neurogenic treatment of DI often includes administration of desmopressin (ADH analog).

Diabetes Mellitus Diabetes mellitus (DM) refers to a group of conditions characterized by hyperglycemia (high serum glucose levels) resulting from defects in insulin production, insulin action, or both. Glucose is a vital energy source for the body, but insulin is required for glucose to travel into the cell, where it can be used. Insulin acts like a key that unlocks the cell membrane and allows the glucose to enter. Impaired insulin production or action results in abnormal carbohydrate, protein, and fat metabolism because of the glucose transportation issue. Some cells, such as those in the brain, digestive tract, and skeletal muscles, can use glucose without insulin to some degree. DM can occur in three main forms—type 1, type 2, and gestational diabetes—each with its own pathogenesis (TABLE 10-2).

TABLE 10-2 Comparison of Type 1 and Type 2 Diabetes

Type 1 Type 2

Age Usually in children or young adults Usually after age 40, and incidence increases with age

Onset Generally abrupt More often insidious

Often diagnosed after infection Patients often obese

Diabetic ketoacidosis HHNK

Treatment Insulin Diet, exercise, medication (oral or noninsulin injectables)

Insulin may be required in severe cases

Complications Occur early, often severe Full range of complications may be present at diagnosis

Insulin levels Low or absent Frequently normal or high

Data from: Sheila Grossman (2014). Porth’s Pathophysiology: Concepts of Altered Health States, Wolters Kluwer Health Lippicincott Williams & Wilkins.

An estimated 422 million people worldwide have DM (World Health Organization, 2016). DM is extremely common in the United States—approximately 30.3 million Americans have diabetes and another 84.1 million have prediabetes (more than 1 out of 3 adults) (Centers for Disease Control and Prevention [CDC], 2017). DM incidence is relatively equal across genders, and it is most common in people older than 65 years of age, with nearly 25% of this population having DM. DM is most frequent among Native Americans, Blacks (non-Hispanic), and Latinos (CDC, 2017). In 2017, DM accounted for $327 billion in medical costs in the United States. Although DM was only the seventh most common listed cause of death on U.S. death certificates in 2015, it likely played a role in many more deaths because this disease contributes to several complications (e.g., heart disease, stroke, and kidney disease).

Type 1 Diabetes Type 1 diabetes was previously called insulin-dependent DM and juvenile-onset DM (Table 10-2). These terms are no longer used. Type 1 DM accounts for approximately 5% of all newly diagnosed cases of DM. Type 1 DM develops when the body’s immune system destroys pancreatic beta cells, leading to progressive loss of insulin secretion. To survive, people with type 1 DM must obtain insulin delivered by injection or a pump. This form of DM usually strikes children and young adults (usually less than 20 years of age), although its onset can occur at any age. Type 1 DM accounts for 5–10% of all diagnosed cases in adults (after the age of 30). The exact cause of type 1 diabetes is unknown, but most likely a viral or environmental trigger in genetically susceptible people causes an autoimmune reaction. Initially in the course of the disease, there may be a short period (sometimes 1–2 years) termed the honeymoon phase where there are still residual beta cells producing insulin, but as more and more insulin is needed, as during an infection or puberty, the insulin reserve disappears and insulin becomes near absent to absent.

Type 1 DM is associated with multiple genes with one of the major susceptibility genes found on the human leukocyte antigen region of chromosome 6. This region of the chromosome has genes that encodes for class II major histocompatibility complex, which is involved in the immune response. See chapter 2 for details on immunity.

Many other gene loci are being discovered and evaluated for association with type 1 DM development. While inheritance of certain human leukocyte antigen types increases risk of type 1 DM, up to 80% of patients with type 1 DM do not have an affected relative. With type 1 DM, beta cells are destroyed by the immune system (e.g., cytotoxic CD8 and T lymphocytes), and while there is sparing of other pancreatic cells (e.g., alpha and delta cells), hormonal patterns from these cells are altered. An example of this alteration is the impaired response of glucagon from alpha cells to hypoglycemia in type 1 DM. The reason beta cells are selected and targeted for destruction is unknown. Type 1 DM cannot be prevented.

Type 2 Diabetes Type 2 diabetes was previously called non–insulin-dependent DM and adult-onset DM. These terms are no longer used as some individuals with type 2 DM require insulin, and type 2 DM can occur in any age group. In adults, type 2 DM accounts for approximately 90–95% of all newly diagnosed DM cases. This form of diabetes usually begins as insulin resistance, a disorder in which the body’s cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce insulin. Type 2 DM is associated with advancing age, obesity, family history of DM, history of gestational DM, impaired glucose metabolism, and physical

inactivity. Blacks, Latinos, Native Americans, Asians, Native Hawaiians, and other Pacific Islanders are at particularly high risk for type 2 DM and its complications. Type 2 DM in children and adolescents, although still rare, is being diagnosed more frequently among Native Americans, Blacks, Latinos, Asians, and Pacific Islanders.

The common phenotype in DM is hyperglycemia, but various ethnic groups may have different pathogenesis. As an example, some Asian populations develop type 2 DM while young and with a low body mass index, and some Latino populations have a greater incidence of insulin resistance. Development of type 2 DM is considered multifactorial and polygenic. Multiple genes and environmental influences such as obesity, poor nutrition, and inactivity contribute to the development. A significant risk for type 2 DM is heritable, which is in contrast to the lower familial incidence in type 1 DM risk. As with type 1 DM, several loci are being evaluated for association with DM development.

The pathogenesis of type 2 DM starts with insulin resistance, which refers to insulin’s inability to act upon target tissues (fat, muscle, and liver, which are insulin sensitive tissue). The lack of glucose use causes the liver to produce more glucose in response. Both these processes, lack of use and increased production) lead to hyperglycemia. Hyperinsulinemia occurs as a compensatory response. Ultimately, the beta cells struggle with maintaining the hyperinsulinemic state, so insulin secretion decreases, hepatic glucose production increases, and beta cell failure occurs. Glucagon additionally increases hepatic glucose production due to the inadequate insulin suppression further compounding the hyperglycemia.

The genesis of insulin resistance is unclear, but a known risk factor for type 2 DM development is obesity. Obesity is present in approximately 80% of patients with type 2 DM, and when weight is lost, insulin responsiveness improves. Obesity, particularly when fat is in a central or visceral location, may be related to the development of insulin resistance through various mechanisms. Free fatty acids are extremely high in the plasma of obese individuals and may contribute to impaired glucose uptake and decreased insulin secretion. Adipocytes (cells that store fat) release adipokines such as leptin, adiponectin, resistin, and other chemicals such as tumor necrosis factor-alpha, which stimulate inflammatory activity. These various factors released from adipose tissue may be increased or decreased and contribute to the development of type 2 DM (e.g., leptin is increased while adiponectin is decreased). Adiponectin is one of the adipokines that has been extensively evaluated. Adiponectin is a protective adipokine that reduces free fatty acid and is associated with glycemic control, reduced inflammation, and improved lipid profiles. Low levels of adiponectin are found in obesity. The role of other adipokines, such as leptin and resistin, in diabetes development is still unclear. In type 2 DM, several inflammatory markers (e.g., C-reactive protein, interleukins) are increased. Low- grade systemic inflammation is a characteristic of type 2 DM. Medications, such as thiazolidinediones used for type 2 DM, have an anti-inflammatory property. Receptor

alterations contribute to insulin resistance, specifically postreceptor defects. The mechanism by which insulin secretion decreases is unclear. Amylin, which is

stored in the beta cell and is cosecreted with insulin, may contribute to islet cell destruction through the depositions of amyloid deposits. With beta cell decline, amylin becomes deficient in type 2 DM (and type 1 DM). Pramlintide is an amylin analog that is used in DM treatment to reduce blood glucose. Pramlintide specifically targets postprandial blood glucose levels and slows gastric emptying, promotes satiety, and suppresses abnormal postprandial glucagon rise. Chronic hyperglycemia and inflammatory markers in the islet environment may contribute to impaired islet functioning and destruction. Altered functioning of glucagon-like peptide-1 may reduce insulin secretion.

Gestational Diabetes Gestational DM is a form of glucose intolerance diagnosed during pregnancy (usually the second or third trimester). DM in the first trimester is considered preexisting and pregestational. Metabolic needs increase during pregnancy, and the normal pregnancy state is one of insulin resistance that occurs to ensure the fetus is adequately nourished. Various hormones are secreted by the placenta that are diabetogenic (cause diabetes), including GH, CRH, prolactin, progesterone, and placental lactogen. Gestational DM occurs in women whose pancreas are unable to function effectively to overcome the insulin-resistant state in pregnancy. Gestational DM occurs most frequently among Blacks, Hispanics, and Native Americans. Other risk factors include obesity and a family history of DM. During pregnancy, gestational DM requires treatment (usually lifestyle changes and insulin) to normalize maternal blood glucose levels to avoid fetal complications. Immediately after pregnancy, 5– 10% of women with gestational DM are diagnosed with DM, usually type 2. Women who have had gestational DM have a 40–60% chance of developing DM within 10 years. Children who are born to mothers with gestational DM have an increased risk for development of DM.

Metabolic Syndrome Metabolic syndrome (i.e., insulin resistance syndrome) is a cluster of risk factors that occur together—specifically, hyperglycemia, hypertension, hypercholesterolemia, and increased waist circumference. Metabolic syndrome is not a form of DM but is related to DM because metabolic syndrome increases the risk of cardiovascular disease, DM, and stroke. The diagnostic criteria for metabolic syndrome include the presence of three or more of those risk factors. Treatment strategies focus on lifestyle changes such as weight loss, dietary changes, and physical activity to prevent development of complications.

Clinical Manifestations and Complications The clinical manifestations of DM can range from asymptomaticity to life-threatening diabetic ketoacidosis (DKA). The presentation of type 1 DM or type 2 DM can also vary. Most patients with type 2 DM are asymptomatic, and the diagnosis usually is made during a routine laboratory evaluation or during DM screening. In type 2 DM, symptoms of hyperglycemia are often recalled on retrospect (e.g., upon questioning, the patient may have noted polyuria or paresthesias). Patients with type 2 DM have often had impaired glucose tolerance for years prior to diagnosis. Some patients, upon initial diagnosis, present with complications of DM such as erectile dysfunction. In contrast, in type 1 DM, DKA may be the initial manifestation. Adults with type 1 DM tend to have a more gradual beta cell destruction and a longer period of hyperglycemia symptomaticity in comparison to children. Insulin therapy may not initially be necessary as autoimmune insulin deficiency occurs later. This type of DM is commonly termed latent autoimmune diabetes of adults.

The manifestations of DM, which are a direct result of hyperglycemia, include the following:

Glucosuria (glucose is excreted in the urine to lower serum levels) Polyuria (increased urine output because of the osmotic effects of the glucosuria) Polydipsia (increased thirst because of the dehydration caused by the increased urine output) Polyphagia (increased appetite because of the energy loss as glucose is excreted) Weight loss (from increased fat catabolism) Blurred vision (excessive glucose changes the shape and flexibility of the lens of the eye, decreasing the ability to focus and causing blurred vision) Fatigue (because of a lack of an energy source) Nausea, vomiting, and abdominal pain (associated with sudden onset of type 1 diabetes)

DM can result in an array of acute and chronic complications. Acute complications are related to excessive alterations in blood glucose, either too high or too low, that can be life threatening. Hypoglycemia (low serum glucose level) may result from insufficient dietary intake, increased physical activity, and diabetic pharmacologic therapy (e.g., too intensive, side effect of medication, or excessive use) and is more common with insulin. Hyperglycemia may be a result of excessive dietary carbohydrate intake as well as insufficient or inappropriate diabetic pharmacologic therapy. Two serious complications of DM reflect extreme hyperglycemia—diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic nonketotic state (HHNK). The major causes for the development of DKA and HHNK are insulin deficiency and/or resistance as well as glucagon excess. Often, patients

manifest with varying degrees of clinical manifestations precipitated by hyperglycemia (FIGURE 10-10).

FIGURE 10-10 Major metabolic derangements in diabetes mellitus.

DKA development is usually associated with type 1 DM and is more likely to occur at a young age. HHNK development occurs in patients with type 2 DM and is more likely to occur in older patients. DKA has a higher prevalence in comparison to HHNK, but mortality is higher with HHNK. In DKA and HHNK, the various metabolic abnormalities and the pathogenesis are as follows:

Severe hyperglycemia: HHNK serum glucose levels are usually much higher

(e.g., > 1,000 mg/dL) than in DKA (e.g., < 800 mg/dL). The severe hyperglycemia is a result of impaired glucose use in tissues (muscle and fat) and insulin deficiency. Severe hyperglycemia leads to fatty acid (lipolysis) and protein breakdown (proteolysis). The oxidized fatty acids are delivered to the liver, which results in gluconeogenesis. Insulin also suppresses the effects of glucagon contributing to the hyperglycemia. Counterregulatory hormone release such as catecholamines, which promote glycogenolysis; cortisol, which promotes gluconeogenesis; and GH, which decreases use of glucose in the periphery, oppose the action of insulin. The relatively lower glucose levels in DKA are due to the higher renal excretion of glucose because patients are younger and their glomerular filtration rates (GFRs) are high. Conversely, the osmotic diuresis eventually leads to dehydration and a reduced GFR. The severe hyperglycemia in older adults with HHNK can be a result of preexisting reduced GFR that is more prevalent in older patients. Ketones: The development of ketones is a result of the degradation of fatty acids. When glucose is not used as an energy source, the body begins using fat (where fuel is stored for energy. Initially, the liver uses the energy from fatty acids (small amount) and then releases the remainder into the circulation as ketones. An excessive number of ketones is a characteristic of DKA. The greater the insulin deficiency (e.g., type 1 DM), the greater the need to use fat as an energy source and, therefore, ketone development is higher. To convert carbohydrates to glucose as an energy source, insulin is a requirement. The relative absence of ketone development in HHNK is unclear. However, insulin is thought to be necessary to suppress lipolysis and gluconeogenesis. The amount of insulin needed to suppress lipolysis is much lower than the amount needed to suppress gluconeogenesis. In HHNK, the insulin deficiency is not as severe, leading to less lipolysis and a reduction in ketone formation. Metabolic acidosis: Excessive ketones cause ketoacidosis, an anion gap metabolic acidosis (see chaper 6 on fluid, electrolyte, and acid–base homeostasis). Hyperosmolality and hyponatremia: Hyperglycemia leads to an osmotic diuresis with a resulting elevated plasma osmolality and a dilutional hyponatremia. Most of the urine excreted does not have a higher number of electrolytes, thereby also contributing to a higher plasma osmolality. These alterations are more prevalent in HHNK in comparison to DKA. Potassium: In DKA and HHNK, potassium deficits and excesses are present. The deficits are a result of excess urinary excretion due to the osmotic diuresis. Glycogen and protein breakdown in the cells contribute to potassium loss. DKA and HHNK can also lead to serum hyperkalemia. Insulin deficiency leads to a decrease in the uptake of potassium by the cells. The hyperosmolality causes water to move out of the cell, and potassium levels are increased in the cell. The

H

higher concentration causes potassium to shift out of the cell. The water also drags potassium out of the cell. Inflammation: Various inflammatory cytokines are generated during hyperglycemic crises.

Learning Points

Hypoglycemia ypoglycemia is defined as a low plasma blood glucose level with or without symptoms that may result in harm. A common alert value is usually < 70 mg/dL; however, the actual glycemic threshold that can induce

symptoms (e.g., dizziness and sweating) and activate counterregulatory responses (e.g., glucagon secretion) can vary. If symptoms are present, they are caused by an autonomic response to a low glucose and include tremor, palpitations, anxiety, sweating, hunger, and paresthesias. Symptoms mediated by the actual low glucose (neuroglycopenia) include dizziness, weakness, drowsiness, confusion, and delirium, as well as seizure and coma with extremely low levels. The neuroglycopenic symptoms are more common in older adults or those with long-term diabetes.

Chronic complications are a direct result of long-term excessive glucose levels, especially when DM is not adequately managed. Over time, increased glucose levels contribute to thickening and hardening of vessel walls (much in the same way that the sugar in icing hardens on a cake), causing diffuse ischemia and necrosis. DM complications reflect these circulatory changes. Complications are also the result of the abnormal lipids such as increased triglycerides and reduced protective high- density lipoprotein (see chapter 4 for more on cardiovascular function). Adequate DM management is the best strategy to prevent chronic complications. Vascular complications can affect large vessels and small vessels. Macrovascular complications include atherosclerotic diseases such as coronary artery disease, peripheral artery disease, and cerebral vascular disease. Microvascular complications include retinopathy, nephropathy, and neuropathy. DM complications include:

Coronary artery disease: Myocardial infarction is the most common type of heart disease and the most common cause of death in those with DM. Myocardial infarctions tend to be silent with DM due to diminished sensation from neuropathy. Heart failure is more prevalent in DM. Heart disease death rates are two to four times higher in people with DM. Peripheral artery disease: Diminished blood flow leads to ulcers and gangrene. Approximately 60% of nontraumatic amputations are due to DM. Cerebral vascular disease: Ischemic and lacunar infarcts are the most common types, and occurrence rates are two to four times higher in people with DM. Hypertension: Of the people with DM, 75% also have hypertension. Hypercholesterolemia: Diabetes decreases high density lipoprotein (i.e., good cholesterol) and increases low density lipoprotein (i.e., bad cholesterol) and

triglycerides, increasing the risk of cardiovascular disease. Diabetic retinopathy: This is a leading cause of blindness. Diabetic neuropathy: Diabetic neuropathy (TABLE 10-3) occurs due to diminished nutrients to nerves resulting from decreased blood supply and nerve demyelination. Approximately 70% of people with DM have neuropathy (pain and numbness in the hands and feet). Neuropathy contributes to amputation rates due to unawareness of pain or foot ulcers.

TABLE 10-3 Types of Diabetic Neuropathies

Type Characteristics Clinical Manifestations

Polyneuropathy (diffuse)- involve multiple nerves

Distal Symmetrical Primarily sensory

Pain or loss of sensation (described as numbness and tingling) in extremities most commonly the feet/legs but can involve hands; worse at night; muscle weakness, if present, usually mild; lower extremities reflexes may be absent

Autonomic* Cardiovascular- postural hypotension, arrhythmias Eye- dry eyes, decreased pupillary reaction Mouth- dry mouth Gastrointestinal- gastroparesis, anorexia, early satiety, bloating, diarrhea or constipation Genitourinary- incontinence, urinary retention; in men impotence, ejaculatory and erectile disorder; in women vaginal dryness, impaired orgasm, and low libido Integument- impaired sweating (too much or too little) Hypoglycemia unawareness

Mononeuropathy (focal)- involve single

Asymmetric Commonly affects femoral, sciatic, and peroneal nerves and median and ulnar nerve

Lower extremity nerves affected: Pain in low back or hips and can radiate to thighs and knees; Pain described as deep aching with intermittent stabbing or piercing sensation weakness in legs; muscle atrophy; absent reflexes on affected side Upper extremity nerves affected: Wrist and elbow- arm/hand weakness and decreased sensation in fingers

*partial list of autonomic manifestations

Diagnosis and Treatment Diagnosis is usually made with laboratory evaluation of glucose status. Evaluating glucose status is used for for assessing the effectiveness of DM management (TABLE 10-4). Diagnostic procedures include a history and physical examination. The various glucose tests include fasting blood glucose test, oral glucose tolerance test (most accurate for diagnosis in pregnancy), random blood glucose test, and hemoglobin A1c (HgbA1c; an average of glucose control for the previous 2–3 months).

TABLE 10-4 Diagnostic Procedures and Treatment Goals for Diabetes Mellitus

Criteria for Diagnosis of Prediabetes

HgbA1c 5.7–6.4%

or

Impaired fasting glucose 100–125 mg/dL (fasting plasma glucose)

or

Impaired glucose tolerance 140–199 mg/dL (2-hour post 75 g glucose challenge)

Criteria for Diagnosis of Diabetes

HgbA1c ≥ 6.5%

or

Fasting plasma glucose ≥ 126 mg/dL*

or

2-hour plasma glucose ≥ 200 mg/dL* post 75 g glucose challenge

or

Random plasma glucose ≥ 200 mg/dL with symptoms (polyuria, polydipsia, and unexplained weight loss)

Treatment Goals for the ABCs of Diabetes

HgbA1c

Should be less than 7% for patients in general.

Preprandial capillary plasma glucose 70–130 mg/dL.

Peak postprandial capillary plasma glucose ≤ 180 mg/dL (usually 1–2 hours after the start of a meal). Be alert to the impact of hemoglobin variants on HgbA1c values.

Blood Pressure**

Systolic ≤ 130 mmHg

Diastolic ≤ 80 mmHg

Cholesterol: Lipid Profile

LDL cholesterol ≤ 100 mg/dL

HDL cholesterol

Men ≥ 40 mg/dL

Women ≥ 50 mg/dL

Triglycerides ≤ 150 mg/dL

* Repeat to confirm on a subsequent day unless symptoms are present. Data from American Diabetes Association. (2019). American Diabetes Association standards of medical care. Diabetes Care, 42 (Suppl. 1), S1–S240. ** < 140/90 mmHg target acceptable for those with low cardiovascular risks.

Treatment strategies for DM vary depending on the type, but dietary changes (American Diabetic Association recommendations) and exercise are the first line of treatment. Management also includes glucose self-monitoring, weight loss (if the

patient is overweight), oral or noninsulin injectable hyperglycemia medications (TABLE 10-5), insulin, and complication management. Insulin can be administered as a bolus. Insulin used for a bolus is rapid and short acting. Bolus administration is usually administered around mealtime and can be administered at a fixed dose or based on blood glucose values measured by the patient. Basal insulin is considered a background insulin and the effect is to keep glucose under control during fasting and to maintain a steady state. Basal insulin is intermediate and long acting, and it is usually administered once or twice a day. In addition, bariatric and metabolic surgeries have shown promise as potential cures for DM.

TABLE 10-5 Common Noninsulin Glucose-Lowering Drugs and Mechanism of Action

Medication class Main mechanism of action

Biguanides Decrease hepatic glucose output

Sulfonylureas Stimulate sustained insulin release

Sodium/glucose cotransporter 2 inhibitors—glucoretics Decrease glucose reabsorption in kidneys

Dipeptidyl peptidase-4 inhibitors—incretin enhancers Prolong action of gut hormones Increase insulin secretion Delay gastric emptying

Glucagon-like peptide-1 receptor agonists—incretin mimetics Increase insulin release with food Slow gastric emptying Promote satiety Suppress glucagon

Amylin mimetics Slow gastric emptying Suppress glucagon Promote satiety

Obesity Obesity is a chronic metabolic and endocrine disorder characterized by abnormal or excessive fat accumulation. Obesity is defined as a body mass index (BMI) of 30 kg/m2 or greater. Overweight is defined as a BMI of 25 kg/m2 or greater. The BMI is calculated using weight in kilograms divided by the square of height in meters. Obesity in children is defined as BMI at or above the 95th percentile for age and sex (based on CDC growth charts). The incidence of obesity worldwide has tripled since 1975; 650 million adults are obese, and 381 million persons under the age of 19 are either overweight or obese (WHO, 2019). Obesity is on the rise in the United States with 93.3 million (39.8%) adults affected and 13.7 million (18.5%) children and adolescents affected (CDC, 2018). The incidence is higher in Hispanics and Blacks in both adults and children. Obesity rates increase with aging; however, middle-aged adults (40–59 years) have a slightly higher incidence (approximately 1%) in comparison to adults over 60 years.

Obesity develops as a result of an imbalance between caloric intake (higher) and energy expenditure (lower). The reasons for the imbalance are multifactorial and complex. The various factors involved in obesity development include genetic, epigenetic, physiologic, environmental, behavioral, and sociocultural factors. Heritability of obesity has been demonstrated in twin studies and adoptee studies where the obese adoptees—even twins who were raised in separate environments —had BMIs closer to their biologic parents. While it is well known that obesity is heritable, identifying the genes has been challenging. Genetic loci have been found with BMI and waist-to-hip ratios. The FTO gene on chromosome 16 has demonstrated the strongest link with obesity, with the variant changing adipocytes from an energy-using fat (beige fat) to an energy-storing type of fat (white fat). There are also several single-gene defects causing various disorders associated with obesity such as abnormalities on chromosome 15 that cause Prader-Willi syndrome. This syndrome is associated with obesity, behavioral problems, and cognitive impairments.

Energy expenditure is determined by resting (basal) metabolic processes, which include energy needed for processes such as cellular membrane exchanges and heart, lung, and gastrointestinal function. Most energy expenditure (approximately 70%) is used for these basal metabolic processes even though this is the energy needed during a physically inactive state. The basal metabolic rate is also defined as the minimum number of calories needed to live. About 10% of energy is used to process food (called the thermogenic response), and the remaining 20% is used for activity. Low-energy expenditure such as what occurs in a sedentary lifestyle will cause weight gain. Interestingly, weight gain is associated with an increase in energy expenditure while weight loss results in lower energy expenditure, which can cause many frustrations in weight-loss attempts and in maintenance of weight loss. Energy

expenditure is also influenced by types of food ingested, with some foods expending more energy than others. However, determining the optimum types of food that would increase energy expenditure in attempts to lose weight is complex and not simply measured by food thermogenesis.

Different types of fat in the body will influence energy expenditure. Fat or adipose tissue types include white adipose fat, brown adipose fat, and beige adipose fat. White adipose fat is the most abundant in the body and is responsible for the many functions of fat. Some key functions include the storage of excess calories as an energy reserve. Adipokines (hormones and cytokines) released by adipocytes (fat cells) also regulate metabolism and activate immune processes. Excesses of white fat cause dysregulation of these multiple adipokines. White adipose fat is found deep within the body (visceral fat) and in the periphery as subcutaneous fat. Increases in visceral fat predominantly around the intra-abdominal cavity (belly fat) are associated with increased complications such as cardiovascular and diabetes mellitus risk. With aging, gonadal and growth hormone naturally declines, resulting in an increase in visceral fat in men, while in women, decreases in estrogen (usually due to menopause) and growth hormone contribute to increases in visceral fat. This, in part, may be a reason why fat mass increases during middle age. White fat can become beige fat, which is an energy-expending type of fat. Investigations are underway to determine how to stimulate this conversion so that weight loss can be achieved. Brown fat is considered a good fat and primarily regulates energy usage, particularly maintenance of warmth in newborns, and usage peaks around puberty. Brown fat expends energy like beige fat. The amount of brown fat decreases with age but continues to remain metabolically active and is stimulated with exposure to cold weather. Brown fat is located mainly in the upper torso in the neck and clavicular area. The more active the brown fat, the lower the BMI and body fat percentage. Leaner individuals have more brown fat, and investigations are underway to determine how to increase and stimulate brown fat.

Body weight and fat stores are regulated by the central and peripheral nervous system. The central nervous system receives afferent signals from the periphery regarding food needs and fuel use. In the hypothalamus, there are orexigenic neurons (e.g., neuropeptide Y, melanin-concentrating hormone, and orexin A and B) that when stimulated lead to decreased metabolism and mechanisms to increase calories by promoting appetite and stimulation of eating. In contrast, anorexigenic neurons, when stimulated, increase metabolism and suppress appetite and eating. These opposing neuron activations are necessary for balancing food intake and energy use. The hypothalamus also connects with areas of the cortex that are associated with memory, pleasure, and reward, and these areas can be activated by food and the feeling of satiety. Activation of these areas can override physiologic intake and energy expenditure stimuli leading to overeating, or the desire for only certain foods. The signals that are received by the hypothalamus come from the

periphery via the circulation and the autonomic nervous system. Some of the sensory signals originate in the fat and gastrointestinal tract. Leptin is a key hormone that is primarily secreted by white fat adipocytes; its role is to send signals to the brain regarding the adequacy of energy reserves. When a person overeats, leptin levels increase dramatically, and when the person fasts, levels decrease. Leptin levels are correlated with body fat mass, and the levels increase in proportion to the number of adipocytes. Leptin’s key action is decreasing food intake, but the high levels in obese individuals are ineffective in suppressing appetite. This ineffective response is due to resistance or tolerance to the effects of leptin. The reason for the development of resistance is unclear. There is also a single gene defect that causes leptin deficiency and obesity.

Several gastrointestinal hormones are involved in regulation of food intake. These hormones are either associated with appetite stimulation and increases in food intake (i.e., they are orexins), or they are associated with appetite suppression and inhibit food intake (i.e., they are anorexins). Some of these hormones are listed next.

Increase Food Intake Ghrelin: Ghrelin is produced in the stomach and duodenum, and it stimulates growth hormone and food intake. Levels increase when a person is fasting and decrease after eating. Food types that suppress ghrelin the most are carbohydrates, followed by protein and lipids. Diet and exercise-related weight loss causes increases in ghrelin as a compensatory mechanism, thereby making maintenance of weight loss challenging.

Inhibit Food Intake Glucagon-like-peptide-1: This is an incretin hormone produced in the intestines. Stimulation causes insulin release, slows gastric emptying, and suppresses appetite. Levels may be low in obese individuals. Cholecystokinin: Cholecystokinin is secreted by the intestines. Stimulation causes gallbladder release of bile and release of pancreatic enzymes and insulin and slows gastric emptying. Levels may be low in obese individuals. Pancreatic polypeptide and peptide YY 3-36: These are produced by the pancreatic polypeptide cells; they inhibit gastric motility, cause satiation, and decrease appetite. Levels may be decreased in obesity. Oxyntomodulin: This is a peptide hormone found in the colon that causes appetite suppression. Amylin: Amylin is released from the beta cells and has a synergistic relationship with insulin. Stimulation results in glucose control by suppressing glucagon, delaying gastric emptying, and increasing satiety. Levels may be increased in obesity, but there is resistance to the effects.

Obesity is associated with many complications, particularly cardiometabolic disorders such as dyslipidemia, hypertension, diabetes mellitus type 2, polycystic ovary syndrome, and nonalcoholic fatty liver disease. Several of these disorders are partly the result of the chronic, low-grade inflammatory state created by adipocytes in white fat. Immune cells in the white fat release various inflammatory cytokines (e.g., interleukin-6 and tumor necrosis factor). The inflammatory state is further maintained by various adipokines such as adiponectin (anti-inflammatory), leptin, and resistin (promotes inflammation). Adiponectin levels are decreased, while leptin and resistin levels are increased in obesity. The excess fat of obesity is associated with various biomechanical disorders such as gastroesophageal reflux disease, osteoarthritis, sleep apnea, and urinary incontinence. Various cancers are associated with obesity such as colon, pancreatic, breast, and endometrial cancer. Approximately 40% of all cancers diagnosed are attributed to obesity and overweight (Steele et al., 2017). Reproductive effects include abnormal menses and infertility. Psychosocial problems arising from stigma and low self-esteem are associated with obesity and can cause depression.

Clinical Manifestations Obesity manifestations will be related to the complications that they cause. Some individuals are obese but develop no complications; these individuals are considered metabolically healthy obese. However, not all components of metabolic health are measurable, and the impact may therefore be underestimated. Fat distribution may confer different degrees of risk for obesity-related complications. Those with a greater visceral fat distribution (such persons are commonly referred to as having an apple shape) are at risk for more complications in comparison to those whose fat distribution is in the subcutaneous or buttocks and thigh region (such persons are commonly referred to as having a pear shape).

Diagnosis and Treatment Diagnosis is made based on anthropometric measurements of height and weight and calculation of BMI. BMI limitations include overestimation of body fat in athletes or those with a muscular build and underestimation of body fat in older persons and others who have lost muscle mass. Other diagnostic tools can include the measurement of the waist circumference—usually for those with a BMI less than 35 kg/m2 (above this, waist measurement adds little prediction for risks). In a woman, a high waist circumference is > 88 cm (> 35 inches), and in a man a high waist circumference is > 102 cm (> 40 inches). The waist-to-hip ratio can be calculated to evaluate for body shape and fat distribution. Growth chart percentiles and BMI are used in the diagnosis of obesity in children. Other components of body composition analysis can be done with techniques such as bioelectrical impedance to evaluate

fat mass (which measures the rate at which a low electrical current travels through the body—fat slows this rate), air/water displacement plethysmography, or dual- energy X-ray absorptiometry. A history and physical examination are important to evaluate for complications of obesity. Diagnostic testing is done based on risk and complications associated with obesity and will generally include a lipid profile and electrolyte, glucose, renal function, and liver enzyme analysis.

Treatment strategies center on weight and fat reduction. Lifestyle and behavioral therapies will include healthy eating and physical activity. There are various proposed diet modalities to achieve weight loss such as low-calorie, low-fat/low- calorie, moderate-fat/low-calorie, and low-carbohydrate diets. The most important component of weight loss, however, is not the type of diet but rather adherence to the diet. Adherence can be facilitated with dietary counseling or support groups and behavioral therapy (e.g., self-monitoring with food diaries, stimulus control). If weight loss is not achieved with comprehensive lifestyle strategies, then pharmacologic therapies can be added. The medications available include orlistat (alters fat digestion and increases fecal excretion), lorcaserin (a serotonin agonist that reduces food intake), phentermine/topiramate (which suppresses appetite and increases satiety), naltrexone/bupropion (which suppresses appetite and controls cravings and overeating behaviors), and liraglutide (which has glucagon-like peptide-1 effects). Bariatric surgery is another strategy that is indicated for those with a BMI of 40 kg/m2 or higher and for those with a BMI of 30 to 39.9 kg/m2 with obesity comorbidities or difficulties with controlling their diabetes. There are various techniques for bariatric surgery. The most commonly performed procedures are Roux-en-Y bypass and sleeve gastrectomy. Other techniques include intragastric balloon therapy, vagal blockage, and aspiration therapy.

Disorders of the Thyroid Gland Because of the thyroid hormones’ responsibilities, disorders of the thyroid have a significant impact on metabolic activities. These disorders usually result in either an increase or a decrease in the thyroid hormones. Several etiologies can give rise to these conditions, including tumors, congenital defects, damage (e.g., from surgery, radiation, or infections), and aging. These conditions are usually easily managed with medications and surgery.

Goiter and Thyroid Nodules A goiter refers to an abnormal growth of the thyroid gland. Thyroid nodules are also abnormal growths on the thyroid gland, and they can occur with or without a goiter. A goiter is usually painless but can be painful. Goiters may affect the respiratory and gastrointestinal systems. The enlargement is not necessarily malignant. Goiters can occur in hyperthyroidism, hypothyroidism, and euthyroid thyroid states. Thyroid nodules are common and can be single or multiple. Most nodules are benign; however, up to 15% of nodules are malignant. Thyroid hormone levels are usually normal, but a nodule may produce excess hormone levels, leading to hyperthyroidism.

Iodine deficiency is the most common cause of goiters worldwide. Iodine deficiency leads to decreased T3 and T4 production, and TSH production increases in an attempt to compensate for the low levels of these thyroid hormones. Iodine deficiency in the United States is not common, and goiters in the United States are usually due to the presence of thyroid nodules and autoimmune thyroid disorders. Increased levels of TSH lead to thyroid hyperplasia and hypertrophy. A similar reaction occurs in both hyperthyroidism and hypothyroidism states. Many goiters grow slowly and are asymptomatic. Nodules are usually asymptomatic. Goiters, however, can cause obstructive-type symptoms due to compression of the trachea, and nodules, and, if large enough, may also compress the trachea or esophagus. These symptoms vary and depend on the goiter size and the tracheal diameter. Symptoms such as dyspnea, cough, or a choking sensation can be due to compression. A thyroid ultrasound is usually done to evaluate the thyroid gland and to determine whether a nodule is solid or cystic. With an ultrasound, the size of the nodules can be determined, and cancerous and noncancerous nodule characteristics can be evaluated. After an ultrasound, a fine-needle biopsy is normally done to evaluate if the nodule is benign or cancerous.

Hypothyroidism Hypothyroidism refers to a condition in which the thyroid does not produce sufficient amounts of the thyroid hormones. This endocrine disorder is relatively common (affecting 1 out of 500 Americans) and is more common in women than men.

Hypothyroidism can be congenital (e.g., absent thyroid gland) or acquired as a result of hypothalamus, pituitary, or thyroid (primary hypothyroidism; the most common) dysfunction. Several conditions can result in hypothyroidism. Hypothyroidism risk increases with age, especially in persons older than 50 years.

In many cases, a previous or current inflammation of the thyroid gland (thyroiditis) leaves a large percentage of thyroid cells damaged and incapable of producing sufficient hormone amounts. Causes of thyroiditis include infections, medications such as lithium or amiodarone, and trauma. Trauma that induces thyroiditis can involve vigorous manipulation during surgery or a seat belt injury in a car accident. However, the most common cause of thyroiditis, which can cause thyroid gland failure, is called chronic autoimmune thyroiditis (also called Hashimoto thyroiditis). Chronic autoimmune thyroiditis occurs due to genetic susceptibility and environmental triggers (e.g., pregnancy). In chronic autoimmune thyroiditis, antibodies and T cells destroy thyroid antigen cells. The types of thyroid antigens include thyroglobulin, thyroid peroxidase (TPO), and TSH receptor. Under normal circumstances, the thyroid follicle cells take up thyroglobulin when stimulated by TSH. TPO is the enzyme that oxidizes iodide to iodine, which is necessary for thyroglobulin to yield thyroxine (T4) and triiodothyronine (T3). T4 is deiodinated in the peripheral tissues to form T3. In chronic autoimmune thyroiditis, B cells in the thyroid gland produce IgG-type antibodies to thyroglobulin and TPO. The T cells secrete cytokines, regulate an immune response, and ultimately, destroy the thyroid cells. Thyrotropin receptor antibodies (i.e., thyroid-stimulating immunoglobulin) are present in Graves disease (hyperthyroidism) and chronic autoimmune thyroiditis (atrophic type).

A variant of chronic autoimmune thyroiditis is postpartum thyroiditis. As with chronic autoimmune thyroiditis, there is an autoimmune destruction of the gland. High levels of anti-TPO antibodies are often detected in pregnancy and persist after delivery. Risk factors for development of postpartum thyroiditis include women with type 1 DM, family history, and history of postpartum thyroiditis with prior pregnancies. Postpartum thyroiditis usually occurs within 1 year after childbirth and can also occur after an abortion (e.g., spontaneous or induced). In postpartum thyroiditis, the thyroid gland initially produces large amounts of T3 and T4 as follicular cells are being destroyed. The high levels of thyroid gland hormones result in hyperthyroidism. Eventually, the follicular cells can no longer produce the hormones, and hormone levels decrease. Hypothyroidism occurs and thyroid hormone levels are decreased in response to increased TSH levels. The inflammation of thyroiditis can subside, the gland can begin functioning normally again, and the woman can remain euthyroid. However, hypothyroidism or goiter can remain. Even if the hypothyroidism resolves, the woman is at risk for development of permanent hypothyroidism in the future. The second major cause of hypothyroidism, after chronic autoimmune thyroiditis, is iatrogenic (resulting from medical treatments). The

treatment of many thyroid conditions, such as hyperthyroidism, warrants partial or complete surgical removal of the thyroid gland. If the total remaining thyroid hormone–producing cells are not able to meet the needs of the body, hypothyroidism develops. This result is often the goal of surgery for thyroid cancer. Similarly, goiters and some other thyroid conditions can be treated with radioactive iodine therapy. The aim of the radioactive iodine therapy (for benign conditions) is to kill a portion of the thyroid to prevent goiters from growing larger or developing into hyperthyroidism. Occasionally, the radioactive iodine treatment can damage too many cells, but this consequence is usually preferred over the original problem.

Clinical Manifestations The clinical manifestations of hypothyroidism vary widely, depending on the severity of the hormone deficiency. Generally, clinical manifestations tend to be insidious and develop slowly, often over a number of years. Abrupt manifestations can occur after thyroidectomy or sudden cessation of thyroid hormone replacement therapy. These clinical manifestations reflect the decreased thyroid activity (e.g., metabolism) and deposition of glycosaminoglycans (connective tissue compounds such as chondroitin sulfate) around tissues (TABLE 10-6).

TABLE 10-6 Hypothyroidism and Hyperthyroidism Clinical Manifestations

System Hypothyroidism Hyperthyroidism

General Fatigue, sluggishness Cold intolerance Slow speech Peripheral edema (hands, feet)

Restlessness, nervousness, anxiousness, irritability, impaired concentration Heat intolerance Insomnia

Skin Cool, pale, dry, rough Diminished perspiration Hair: coarse, loss/thinning Nails: brittle

Warm, smooth Diaphoresis Hair: fine, thinning Nails: onycholysis, softening Shins: raised, pigmented papules (pretibial myxedema)

Hematologic Increased bleeding risk Anemia (pernicious—gastric atrophy, iron deficiency)

Head Puffy face, hoarseness Eyes: periorbital edema Nose: rhinitis Mouth: macroglossia Neck: goiter (painful or painless)

Eyes: exophthalmos (FIGURE 10-11) with staring Neck: goiter (painful or painless)

Cardiovascular Decreased heart rate Hypercholesteremia

Increased heart rate Hypertension Atrial fibrillation

Respiratory Dyspnea with exertion Dyspnea with exertion

Gastrointestinal Constipation Weight gain

Diarrhea Weight loss (usually sudden) Increased appetite

Reproductive Abnormal menses (absent, irregular (frequent/infrequent), heavy (more common) Infertility Erectile dysfunction, decreased libido

Abnormal menses (oligomenorrhea, amenorrhea Infertility Erectile dysfunction, decreased libido

Neurologic Depression Carpal tunnel syndrome Decreased deep tendon reflexes

Fine tremor (usually hands)

Musculoskeletal Muscle weakness/cramps, myalgias, arthralgias

FIGURE 10-11 Exophthalmos. A: © Casa nayafana/Shutterstock; B: © SPL/Science Source.

Severe hypothyroidism, known as myxedema coma, is rare. Myxedema coma is more likely to occur in those individuals with longstanding hypothyroidism or poorly controlled hypothyroidism in combination with a precipitating event such as infection or opioid administration. Older women are more commonly affected. When it occurs, myxedema coma can be life threatening. Clinical manifestations include marked hypotension, respiratory depression, hypothermia, hyponatremia, hypoglycemia,

lethargy, and coma.

Diagnosis and Treatment Diagnostic procedures for hypothyroidism include a history, physical examination, serum thyroid hormone levels, and serum TSH. Diagnosis is made based on laboratory results of the thyroid levels and TSH. Primary hypothyroidism (thyroid gland disorder) results in a high serum TSH and low serum-free T4, total T4, and total T3. Conversion of T4 to T3 increases in the early stages of hypothyroidism, so T3 levels may be normal. If the TSH is high and the T3 and T4 are normal, the patient is diagnosed with subclinical hypothyroidism. Central hypothyroidism (pituitary or hypothalamus disorder) results in a low serum TSH and low thyroid hormones. Antithyroid antibodies, particularly anti-TPO and antithyroglobulin, may also be evaluated. Elevated levels indicate chronic autoimmune thyroiditis.

Hypothyroidism is easily managed with thyroid hormone replacement with T4 (e.g., levothyroxine [Synthroid]). The effectiveness of the dose is usually evaluated 6 weeks after initiation of therapy with a TSH measurement. Six weeks is when steady-state TSH levels are expected with replacement therapy. Lower doses are recommended when initiating thyroid-replacement therapy in the elderly to avoid the risk of inducing cardiovascular syndromes. T3 therapy (usually combined with T4) may be attempted for some patients (e.g., those with persistent symptomaticity after thyroidectomy despite adequate T4 replacement), but monotherapy with T4 is almost always sufficient. Hormone replacement for subclinical hypothyroidism is usually recommended when TSH levels are ≥ 10 mU/L. Hormone replacement for patients with values between 4.5 and 10 mU/L is controversial; however, monitoring TSH levels is recommended to evaluate for potential progression to hypothyroidism. Central hypothyroidism is also treated with T4 replacement therapy and other strategies to manage the cause (usually pituitary adenoma).

Hyperthyroidism Hyperthyroidism refers to a condition of excessive levels of thyroid hormones. This overabundance of thyroid hormones results in a hypermetabolic state. The incidence is higher in women than in men. Older age and smoking are risk factors. Hyperthyroidism can result from a variety of conditions, and these disorders can be distinguished using a 24-hour radioiodine uptake scan. The scan is used to measure the amount of radioactive iodine that is taken up by the thyroid gland after oral administration. This test is only for nonpregnant patients. The presence of uptake usually indicates that there is new hormone synthesis. No uptake indicates a destroyed or inflamed thyroid gland, and the thyroid hormones are coming from preformed hormones or an ectopic source. Hyperthyroid disorders are outlined in the

H

following lists.

Normal or High Radioiodine Uptake Graves disease: This disease is an autoimmune condition with TSH receptor antibodies, which stimulate thyroid hormone production; the condition may be precipitated by excessive iodine or medications (e.g., lithium). Thyroid adenomas/toxic multinodular goiter: This adenoma/goiter causes thyroid hyperplasia with cells that produce hormones independent from TSH regulation. Excessive iodine: The excess can occur after administration for scanning or due to iodine-rich medications such as amiodarone.

Near-Absent Radioiodine Uptake Thyroiditis from multiple causes (e.g., radiation, medications such as lithium, amiodarone). Excess thyroid hormone replacement. Ectopic production (e.g., thyroid cancer metastasis)

Clinical Manifestations Hyperthyroidism can mimic other health problems, and its clinical manifestations may be overt, leading to a high suspicion of hyperthyroidism, or they can vary, making diagnosis difficult (Table 10-6).

Older patients tend to have predominant cardiovascular manifestations such as tachycardia or atrial fibrillation, dyspnea, and edema. The manifestations are a result of a hypermetabolic state.

Learning Points

Hyperthyroidism and Hypothyroidism Manifestations ypothyroidism and hyperthyroidism present differently. When considering the clinical manifestations of these disorders, think about what increasing or decreasing thyroid hormones would do in the body. With

hypothyroidism, the hormone levels are decreased and so are all the clinical manifestations (e.g., bradycardia, hypotension, depression, and constipation), with the exception of weight gain. With hyperthyroidism, the hormone levels are increased and so are all the clinical manifestations (e.g., tachycardia, hypertension, anxiety, and diarrhea), with the exception of weight loss.

Thyroid crisis (storm) is a sudden worsening of hyperthyroidism symptoms that may occur with long-term, untreated hyperthyroidism and may be precipitated by such factors as infection, stress, or surgery. Thyroid crisis is rare and is a medical emergency. Thyroid crisis is characterized by high temperature (e.g., 104 to 106° F), tachycardia (> 140 beats per minute), decreased mental alertness, abdominal pain, and an exaggeration of any hyperthyroid manifestations (Table 10-6). Additional

complications of hyperthyroidism include cardiomyopathy, heart failure, and osteoporosis.

Diagnosis and Treatment Diagnostic procedures for hyperthyroidism include a history, physical examination, serum thyroid hormone levels, and serum TSH. With hyperthyroidism, the serum TSH will be low and the T4 and T3 will be high. The T3 increases more than the T4. Central hyperthyroidism will result in a low TSH and normal T3 and T4. This pattern may also be present in subclinical hyperthyroidism. Thyroid-stimulating immunoglobulin will be positive with Graves disease. The anti-TPO antibody may also be positive with Graves syndrome but not as often as in chronic autoimmune thyroiditis (Hashimoto’s thyroiditis). A radioactive iodine uptake test is usually indicated when there is nodular thyroid disease, and results can aid in diagnosing the cause of hyperthyroidism. Hyperthyroidism can usually be easily managed with medication and surgery. Beta blockers can be used to manage symptoms such as tachycardia, anxiety, and heat intolerance. In circumstances where there is increased hormone synthesis (i.e., normal or increased radioiodine uptake disorders) treatments are geared during reducing synthesis. Pharmacologic treatment usually includes radioactive iodine (which shrinks the gland) as well as antithyroid agents, such as methimazole (the primary drug), to decrease hormone production or propylthiouracil which is safe during pregnancy. Surgical removal of the thyroid (thyroidectomy) with subsequent hormone replacement is warranted when the patient does not respond to or tolerate medications. Even with treatment, exophthalmos usually remains. Strategies to improve the discomfort associated with exophthalmos include cool compresses, wearing sunglasses, eye lubricants, and elevating the head of the bed. Increasing caloric and calcium intake is crucial to maintain weight and prevent bone loss. For hyperthyroidism with near-absent radioiodine uptake due to thyroiditis, hormone-synthesis-blocking agents will not be effective since new hormones are not being produced. The treatment, therefore, is symptom control (e.g., via a beta blocker) or anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs.

Disorders of the Parathyroid Glands Parathyroid disorders result in an increase or decrease in PTH. Because of PTH’s effects, disorders of the parathyroid have a significant impact on calcium balance that has a domino effect on other electrolytes (phosphorus and magnesium). Several etiologies can result in these conditions, including tumors, congenital defects, damage (e.g., from surgery, radiation, or infections), and renal failure. These conditions are usually easily managed with medications and surgery. See chapter 6 for a discussion of calcium regulation.

Hypoparathyroidism Hypoparathyroidism refers to a condition in which the parathyroid gland does not produce sufficient amounts of PTH. Hypoparathyroidism, which is uncommon, can be caused by congenital or genetic defects—a lack of one or more of the four parathyroid glands, abnormal PTH synthesis, or mutations of calcium-sensing receptors. It can also be caused by damage following surgery, autoimmune conditions, or metabolic alkalosis. Rare causes of hypoparathyroidism include radiation and infiltrative disorders (e.g., metastasis or hemochromatosis). Hypomagnesemia from multiple causes such as chronic alcoholism or malabsorption suppresses PTH. Correction of the magnesium levels returns PTH levels to normal. PTH deficiency results in hypocalcemia and a subsequent increase in phosphorus levels.

Clinical Manifestations Clinical manifestations reflect electrolyte and pH imbalances, particularly hypocalcemia (see Table 6-6). Hypocalcemia results in an excitatory nerve and muscle response from stimuli.

Acute manifestations will typically include neuromuscular irritability (i.e., tetany) with symptoms such as paresthesias (perioral, hands, and feet), muscle cramping, carpopedal spasms, and seizures along with other manifestations. Acute manifestations can occur after parathyroid or neck surgery (e.g., thyroid surgery). Chronic manifestations that are not present in acute causes include basal ganglia calcifications (cause movement disorders or dementia), cataract development, and skin changes (e.g., dry, coarse, sparse hair, and brittle nails).

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BOX 10-1 Application to Practice Thyroid Function Panel Reference Range

Test Reference range*

TSH 0.450–4.500 mU/mL

Thyroxine (T4), total 4.6–12.0 mcg/dL

Thyroxine (T4), free (direct) 0.7–1.9 mcg/dL

Free thyroxine index (calculated) 4–11

Triiodothyronine (T3), total 80–180 ng/dL

* Reference range may vary from one laboratory to another.

Review the following case and answer the questions.

Case 1: Ms. Jefferson is a 50-year-old woman who comes into the clinic to review her laboratory results from 2 weeks prior. She is in good health and has no complaints. Her laboratory values are normal except for the following:

TSH = 30 mU/L; T4 = 3.0 mcg/dL; free T4 = 0.5 mcg/dL; free thyroxine index = 3.0; T3 = 90 ng/dL

Based on these lab findings Ms. Jefferson is diagnosed with which thyroid disorder? Hyperthyroidism Subclinical hyperthyroidism Hypothyroidism Subclinical hypothyroidism

The lack of symptoms in the type of thyroid disorder Ms. Jefferson has is uncommon. Answer True or False Ms. Jefferson’s thyroid disorder is most likely caused by what?

A pituitary adenoma (i.e., thyrotroph) Chronic autoimmune thyroiditis (i.e., Hashimoto thyroiditis) Autoimmune Graves disease Iodine deficiency

Treatment of Ms. Jefferson’s thyroid disorder will include what? Thyroid hormone replacement with T4 Thyroid hormone replacement with T3 Beta blocker No therapy indicated

Ms. Jefferson asks when she should return to evaluate her thyroid disorder. You should respond: An annual evaluation should be sufficient. Return to have a TSH level done 6 weeks after starting therapy. Six months from now.

Ms. Jefferson asks what are some possible symptoms of her thyroid disorder? Select all that apply. Weight gain Diarrhea Anxiety Palpitations

e. f.

Fatigue Cold intolerance

Diagnosis and Treatment Diagnostic procedures for hypoparathyroidism include a history, physical examination, and serum PTH with serum calcium evaluation. Serum calcium and PTH will be low and serum phosphate levels will be high. Acute manifestations will typically include neuromuscular irritability (i.e., tetany) with symptoms such as paresthesias (perioral, hands, and feet), muscle cramping, carpopedal spasms, and seizures along with other manifestations. Acute manifestations can occur after parathyroid or neck surgery (e.g., thyroid surgery). Chronic manifestations that are not present in acute causes include basal ganglia calcifications (cause movement disorders or dementia), cataract development, and skin changes (e.g., dry, coarse, sparse hair, and brittle nails). Treatment regimens generally include calcium and vitamin D administration. The addition of PTH replacement is rarely necessary and is indicated when calcium levels are not maintained. Other strategies generally focus on correcting electrolyte and pH imbalances such as replacement of magnesium for hypomagnesemia (see chapter 6 for more on fluid, electrolyte, and acid–base homeostasis).

Hyperparathyroidism Hyperparathyroidism refers to a condition of excessive PTH production by the parathyroid gland. Primary hyperparathyroidism is due to parathyroid gland disorders, which are usually caused by adenomas (most common cause), tumors (due to genetic mutations), hyperplasia, or radiation exposure. Secondary hyperparathyroidism is due to chronic hypocalcemia (e.g., kidney disease, decreased intestinal absorption, and chronic vitamin D deficiency). Hyperparathyroidism will result in hypercalcemia. The excessive calcium levels can lead to decreases in phosphorus levels, increases in magnesium levels, and metabolic acidosis. The clinical manifestations of hyperparathyroidism reflect these electrolyte and pH imbalances (see Table 6-5). See chapter 6 for more on fluid, electrolyte, and acid–base homeostasis.

BOX 10-2 Application to Practice

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Differentiating the relationship between serum calcium and PTH levels can be a bit confusing. Understanding the underlying mechanisms for the alterations can assist in interpreting these laboratory values. The following are possible laboratory findings. Answer the following questions.

Explain the mechanism by which the serum calcium and serum PTH is high with primary hyperparathyroidism. Explain the mechanism by which the serum calcium is high and the serum PTH is low with a nonparathyroid disorder such as breast malignancy. Explain the mechanism by which the serum calcium is low and the serum PTH is high with secondary hyperparathyroidism.

Diagnosis and Treatment Diagnostic procedures for hyperparathyroidism include a history, physical examination, serum PTH, and serum calcium evaluation. Serum PTH and calcium will be high with hyperparathyroidism. If the calcium levels are high and the PTH is low, then the high calcium levels may be due to malignancy (usually breast, lung, or multiple myeloma), or excessive calcium or vitamin D intake. Low serum calcium with high PTH is consistent with secondary hyperparathyroidism. Treatment varies depending on the underlying etiology. Tumors will likely require surgery and radiation. Calcitonin may be administered to shift the calcium from the bloodstream to the bones. Calcimimetic agents may be administered to mimic calcium circulating in the blood and, in turn, may lead to decreased PTH production. Bisphosphonates can decrease the loss of calcium from the bone and lessen osteoporosis. Phosphates may be administered to correct phosphorus deficits, which will decrease calcium levels. Increasing fluid intake (either oral or intravenous) will increase renal excretion of calcium. Additionally, magnesium and pH imbalances may need correction (see chapter 6 for more on fluid, electrolyte, and acid–base homeostasis).

Disorders of the Adrenal Glands Adrenal gland disorders may affect one or both areas of the adrenal gland. These disorders result in an increase or a decrease in one or more adrenal hormones. Depending on the hormone affected and the severity of the condition, adrenal gland disorders can have serious consequences. Several etiologies can result in these conditions, including tumors, congenital defects, medications (e.g., corticosteroids), and damage (e.g., from surgery, radiation, or infections). These disorders are usually easily managed with medications and surgery, but they can become life threatening if not managed promptly.

Pheochromocytoma Pheochromocytoma is a rare tumor of the adrenal medulla. The tumor excretes epinephrine and norepinephrine and can be life threatening because of the effects of these hormones (e.g., increased blood pressure and tachycardia). Other tumors that are catecholamine secreting include paragangliomas (extra-adrenal pheochromocytomas), which are clinically similar and treated the same. Pheochromocytoma can occur as a single tumor or as multiple tumors in one or both adrenal glands and is only malignant in 10% of cases. The exact cause is unknown, and the tumors are often sporadic. Some tumors are associated with inherited mutations (e.g., neurofibromatosis type 1 gene). The tumors can occur at any age but are more common in early to middle adulthood for hereditary tumors and older people (40–50 years of age) for sporadic types.

Clinical Manifestations Clinical manifestations reflect the fight-or-flight response and occur in unpredictable attacks that usually last 15 to 20 minutes, but some manifestations can be sustained. The classic triad is the episodic occurrence of headache, diaphoresis, and tachycardia, and while many patients have these symptoms individually, they do not necessarily have all three classic symptoms together. The manifestations include the following symptoms:

Hypertension (sustained or paroxysmal is the most common sign) Tachycardia Profound diaphoresis Mild or severe headaches with variable duration Dysrhythmias Forceful palpitations Chest pain Hyperglycemia

Abdominal pain Anxiety Feeling of extreme fright Pallor Weight loss Difficulty sleeping

Diagnosis and Treatment Diagnostic procedures for pheochromocytoma include a history, physical examination, serum catecholamines (norepinephrine, epinephrine, and dopamine) and metanephrines, as well as urine catecholamines and metanephrines. Metanephrines are metabolites of epinephrine. Radiologic evaluation will include an abdominal and pelvic CT or abdominal and pelvic MRI. An m-iodobenzylguanidine scintiscan (a nuclear scan to confirm pheochromocytoma) can be used if the CT or MRI is negative, and there is continued suspicion or if there are multiple tumors. Genetic testing may be necessary for patients suspected of familial disease. If not promptly treated, pheochromocytoma can lead to hypertensive crisis, stroke, kidney disease, psychosis, and seizures. Surgical removal of the tumor or adrenal gland is the cornerstone of treatment. Administration of antihypertensive medications (e.g., alpha blockers and beta blockers) is often necessary until surgery can be performed. Metastatic pheochromocytoma may require additional treatment, such as radioactive iodine.

Cushing Syndrome Cushing syndrome refers to a condition characterized by excessive amounts of glucocorticoids, specifically cortisol. The most common cause of this excess, called hypercortisolism, is iatrogenic, resulting from ingestion of glucocorticoid medications; however, the incidence is often underreported. When these medications are ingested, they mimic the body’s own hormones. Cushing syndrome can also be caused by excess ACTH production, usually from a pituitary adenoma (the second most common cause of Cushing syndrome), and this state is termed Cushing disease. Cushing disease is ACTH dependent, which refers to ACTH stimulating excess cortisol production while the negative feedback mechanism is impaired. Normal pulsatile cortisol secretion or increased cortisol response during stress is impaired. Cushing disease can occur at any age. An ectopic nonpituitary tumor such as from small cell lung cancer, which is more common in older adults, is another form of ACTH-dependent hypercortisolism. Benign or malignant adrenal gland tumors that secrete cortisol are a form of ACTH-independent hypercortisolism. This condition is the least common cause of Cushing syndrome. Adrenal carcinoma is the cause of 50% of childhood Cushing syndrome.

Glucocorticoids are essential for life but can produce serious effects when present in excessive amounts (FIGURE 10-12). Manifestations can also be the result of androgen deficit or excess. Some tumors secrete only glucocorticoids (e.g., adrenal adenomas) while others can cause excesses in both cortisol and androgens (e.g., adrenal cancer in women). Therefore, the clinical manifestations of Cushing syndrome are a direct result of the excessive amounts of glucocorticoids and possible androgen excess. The clinical manifestations of Cushing syndrome can be metabolic, dermatologic, infectious, cardiovascular, reproductive, musculoskeletal, or neuropsychiatric.

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FIGURE 10-12 Signs and symptoms of Cushing syndrome.

BOX 10-3 Application to Practice A 50-year-old woman with an 8-year history of diabetes mellitus presents with difficulty controlling her blood sugars for the past 2 weeks. Her self-monitoring blood glucose readings have been in the 200s–300s for 2 weeks. She has managed her type 2 DM with diet, exercise, and metformin 1,000 mg twice a day. Her last glycosylated hemoglobin (HgbA1c) level, which was measured 2 months ago, was 6.8%. She has had asthma since age 18. She felt her asthma was getting worse for the past 6 months as she was having increased dyspnea and dry cough. She has managed her asthma with a daily combined long-acting beta-2 adrenergic agonist, an inhaled corticosteroid, and montelukast. She also uses her short-acting beta-2 adrenergic agonist, albuterol, about once a day. She went to her pulmonologist about 2 months ago and was diagnosed with severe asthma. A decision was made to start her on oral prednisone (corticosteroid). The first month she took 5 mg a day with some relief, but the symptoms returned, so her prednisone dose was increased to 10 mg a day. She has been taking the 10 mg dose for 3 weeks. She says her breathing is better, but she feels increasingly tired and like she is gaining weight. See chapter 8 on respiratory function.

Physical examination reveals an anxious woman with blood pressure of 144/92 mmHg, pulse of 90, respiratory rate of 20, and weight of 190 pounds. She is talking in full sentences. Lung sounds are clear bilaterally. No accessory muscles are being used. No cyanosis is present.

Which of the following is the most likely cause of this patient’s loss of glucose control? Inhaled corticosteroid Prednisone therapy Asthma exacerbation Albuterol

All of the following actions are important for this patient to learn regarding glucocorticoid therapy, but which is the most important?

Monitor cuts for healing Take the medication with food Do not stop taking the medication abruptly Contact her healthcare provider if she has any manifestations of infection

Which of the following endocrine conditions is this patient at risk of developing? Hyperthyroidism Pheochromocytoma Addison disease Cushing syndrome

Given this patient’s acute loss of glucose control, which of the following interventions would be ordered for this patient?

Insulin as needed per routine sliding scale (dosing based on blood glucose levels) Increase exercise Decrease caloric intake Decrease prednisone dose

Metabolic Glucose intolerance—insulin resistance from obesity; cortisol stimulation of

gluconeogenesis Delayed growth and development Obesity (especially around the trunk) (FIGURE 10-13)

FIGURE 10-13 Cushing disease before and after treatment. A Before treatment, front and side views of subject, illustrating trunk obesity with relatively thin extremities. B After treatment, illustrating normal body

configuration.

Courtesy of Leonard V. Crowley, MD, Century College.

A fatty pad between the shoulders known as a buffalo hump; fat accumulation in the cheeks known as moon face

Dermatologic Hirsutism (abnormal hair growth); thin hair, oily facial skin, acne due to androgen excess in women (usually adrenal carcinoma); other virilizing signs (e.g., deep voice) if androgen is very high Broad purple striae (marks) on the abdomen, thighs, and breasts Thin skin that bruises easily—catabolic effects of glucocorticoids Skin atrophy—loss of subcutaneous fat Hyperpigmentation due to increased ACTH, which binds to melanocyte- stimulating hormone receptors

Infectious Increased risk and frequency of infections due to glucocorticoid suppression of immune function Delayed wound healing

Cardiovascular Hypertension resulting from multifactorial causes such as increased liver production of angiotensinogen; increased sensitivity to adrenergic agonists Dyslipidemia Edema Hypokalemia

Reproductive Changes in menstruation due to GnRH suppression caused by hypercortisolism Decreased libido Erectile dysfunction

Musculoskeletal Osteoporosis—decreased intestinal calcium absorption, decreased renal calcium reabsorption, decreased bone formation with increased bone resorption Muscle weakness and wasting—catabolic effects of glucocorticoids

Neuropsychiatric Mood changes (e.g., depression, anxiety) and psychosis due to excess cortisol

Diagnostic procedures for Cushing syndrome include a history, physical examination, and serum hormone levels (e.g., cortisol and ACTH). Adrenal and pituitary CT and MRI may be necessary to evaluate for an underlying cause. Other tests are used to further evaluate manifestations or complications of hypercortisolism and can include serum glucose, complete blood count (CBC), blood chemistry, and bone density studies. Treatment varies depending on the underlying cause. Gradual tapering of any glucocorticoids being administered is crucial. If these glucocorticoids are suddenly discontinued, the adrenal gland does not have the opportunity to initiate its own production of hormones, leading to an adrenal crisis. Tumors will likely require surgical removal and radiation. Medications can be used to control cortisol production (e.g., ketoconazole [Nizoral], mitotane [Lysodren], and metyrapone [Metopirone]), control the effects of cortisol (e.g., mifepristone [Korlym]), and decrease ACTH production (e.g., pasireotide [Signifor]). Interventions may be necessary to manage specific complications as they develop (e.g., osteoporosis, DM, and hypertension).

Addison Disease

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Addison disease refers to a deficiency of adrenal cortex hormones (glucocorticoids, mineralocorticoids, and androgens). It can be caused by damage resulting from autoimmune conditions (the most common cause), infections (e.g., tuberculosis, human immunodeficiency virus, fungal infections, and meningitis), hemorrhage, and tumors. Additionally, Addison disease may result from pituitary dysfunction that results in insufficient ACTH levels.

Clinical Manifestations Clinical manifestations reflect the glucocorticoid and mineralocorticoid deficiency and usually develop slowly over weeks to months. Androgen deficiency may be apparent in women only because the testes, not adrenals, are the primary source of androgen in men. The manifestations include laboratory abnormalities and metabolic, dermatologic, cardiovascular, gastrointestinal, reproductive, musculoskeletal, and neuropsychiatric manifestations:

Learning Points

Glucocorticoid Adverse Effects lucocorticoids such as prednisone and prednisolone are medications that are commonly used for various disorders (e.g., asthma, rheumatic disease, lupus, and transplant rejection). The major adverse effects

occur with oral and systemic use. The adverse effects are a result of the inhibition of the hypothalamic- pituitary-adrenal (HPA) function with resulting CRH and ACTH suppression. The suppression causes adrenal atrophy, and cortisol secretion diminishes. The only source of glucocorticoid then becomes the exogenous glucocorticoid. Withdrawal of the exogenous glucocorticoid can lead to adrenal crisis. The occurrence and degree of CRH and ACTH suppression are related to the potency, dose, and duration of glucocorticoid therapy. Minimizing adverse glucocorticoid effects and identifying patients with HPA suppression is important. Various principles of glucocorticoid therapy include 1) use glucocorticoids only if there is objective evidence of benefit; 2) use glucocorticoids only after other therapies have failed; 3) use glucocorticoids with a specific end point in mind and when response can be objectively measured; and 4) administer glucocorticoids in sufficient amounts and duration to get a desired response and for no longer than is necessary. The glucocorticoid should be discontinued if there is no response to glucocorticoid administration, complications arise, or the maximum benefit is achieved. Those patients likely to develop HPA suppression include glucocorticoid use for longer than 3 weeks particularly if greater than 10 mg of prednisone or equivalent daily or the presence of Cushing syndrome manifestations. To avoid HPA suppression, the glucocorticoids should be tapered slowly. Those patients receiving short-term therapy (even if high doses) are not likely to develop HPA suppression. Those patients with long-term low doses are not likely to develop HPA suppression; however, other long-term complications of glucocorticoid use such as osteoporosis can develop.

Laboratory Abnormalities Electrolyte disturbances (particularly hyperkalemia, hyponatremia, and hypochloremia) Hypoglycemia

Metabolic Manifestations Unintentional weight loss due to anorexia or dehydration

Dermatologic Manifestations Patchy hyperpigmentation of areas exposed to light (e.g., face and hands), lips, and oral mucosa Patchy depigmentation (vitiligo) Pallor

Cardiovascular Manifestations Postural hypotension due to mineralocorticoid deficiency

Gastrointestinal Manifestations Nausea and vomiting Abdominal pain Salt craving Diarrhea (can alternate with constipation)

Reproductive Manifestations Decreased axillary and pubic hair (women) Loss of libido (women)

Musculoskeletal Manifestations Myalgia and arthralgia Weakness

Neuropsychiatric Manifestations Mood changes (e.g., depression) and psychosis

Adrenal crisis (i.e., Addisonian crisis) will manifest as shock with hypotension, dehydration, fever, confusion, and other nonspecific manifestations seen in Addison disease (e.g., hyperpigmentation, vitiligo). Adrenal crisis can be precipitated by an acute stressor in someone with Addison disease, acute adrenal gland destruction (e.g., bilateral infarction of the gland), or abrupt withdrawal of glucocorticoid therapy. Adrenal crisis may be the initial presentation of Addison disease.

Treatment of this disease requires lifelong hormone replacement with glucocorticoid and mineralocorticoid therapy. Increases in hormone doses may be required during times of infections, stress, and trauma. The patient should wear a medical alert bracelet and carry extra medication at all times.

C H A P T E R S U M M A R Y

The endocrine system is responsible for producing a wide range of hormones necessary for a variety of processes. Endocrine disorders are often caused by congenital defects, tumors, or gland damage. These conditions vary from harmless to life threatening, and most are managed easily with medications and surgery. Clinical manifestations of these conditions reflect the hormones affected and the degree of deviation. Regardless of the disorder and the severity, lifelong management is necessary to prevent significant complications or death.

R E F E R E N C E S A N D R E S O U R C E S

AAOS. (2004). Paramedic: Anatomy and physiology. Sudbury, MA: Jones and Bartlett Publishers. American Diabetes Association. (2019). American Diabetes Association standards of medical care. Diabetes Care, 42 (Suppl. 1), S1–S240.

Centers for Disease Control and Prevention (CDC). (2017). Diabetes basics. Retrieved from https://www.cdc.gov/diabetes/basics/diabetes.html

Centers for Disease Control and Preventions (CDC). (2018). Overweight and obesity. Retrieved from https://www.cdc.gov/obesity/data/index.html

Chiras, D. (2015). Human biology (8th ed.). Burlington, MA: Jones & Bartlett Learning. Elling, B., Elling, K., & Rothenberg, M. (2004). Anatomy and physiology. Sudbury, MA: Jones and Bartlett Publishers.

Else, T., & Hammer, G. D. (2019). Disorders of the hypothalamus & pituitary gland. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). New York, NY: McGraw-Hill.

Garvey, W. T., Mechanick, J. I., Brett, E. M., Garber, A. J., Hurley, D. L. Jastreboff, A. M, … Plodkowski, R. (2016). American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care for patients with obesity. Endocrine Practice, 22.

Gould, B. (2015). Pathophysiology for the health professions (5th ed.). Philadelphia, PA: Elsevier. Hart, M., & Loeffler, A. (2015). Introduction to human disease: Pathophysiology for health professionals (6th ed.). Burlington, MA: Jones & Bartlett Learning.

Madara, B., & Pomarico-Denino, V. (2008). Pathophysiology (2nd ed.). Sudbury, MA: Jones and Bartlett Publishers.

Nieman, L. K. (2019). Pharmacologic use of glucocorticoids. In K. A. Martin (Ed.), Uptodate. Powers, A. C., Niswender, K. D., & Evans-Molina, C. (2018). Diabetes mellitus: Diagnosis, classification, and pathophysiology. In J. Jameson, A. S. Fauci, D. L. Kasper, S. L. Hauser, D. L. Longo, & J. Loscalzo (Eds.), Harrison’s principles of internal medicine (20th ed.). New York, NY: McGraw-Hill.

Perreault, L. (2019). Genetic contribution and pathophysiology of obesity. In L. Kunins (Ed.), Uptodate Professional guide to pathophysiology (3rd ed.). (2010). Philadelphia, PA: Lippincott Williams & Wilkins. Snyder, P. J. (2018). Diagnostic testing for hypopituitarism. In K. A. Martin (Ed.), Uptodate Steele, C. B., Thomas, C. C., Henley, S. J., Massetti, G. M., Galuska, D. A., Agurs-Collins, T., Puckett, M., & Richardson, L. C. (2017). Vital signs: Trends in incidence of cancers associated with overweight and obesity— United States, 2005-2014. Morbidity and Mortality Weekly Report, 66 (39), 1052.

Sterns, R. H. (2017). Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In J. P. Forman (Ed.), Uptodate.

World Health Organization. (2016). Diabetes. Retrieved from http://www.who.int/mediacentre/factsheets/fs312/en/index.html

World Health Organization. (2019). Overweight and obesity. Retrieved from https://www.who.int/en/news- room/fact-sheets/detail/obesity-and-overweight

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C H A P T E R 1 1

Neural Function

L E A R N I N G O B J E C T I V E S

Discuss normal neural anatomy and physiology. Differentiate congenital neurologic disorders. Differentiate traumatic neurologic disorders. Summarize mechanisms and causes of increased intracranial pressure. Differentiate intracranial bleeding disorders. Differentiate infectious neurologic disorders. Differentiate vascular neurologic disorders. Differentiate types of headache disorders. Differentiate types of seizure disorders. Differentiate chronic degenerative neurologic disorders. Differentiate types of dementia. Differentiate cancers of the nervous system. Summarize structural and functional alterations associated with various mental health disorders. Summarize schizophrenia. Differentiate mood disorders. Differentiate anxiety disorders. Apply understanding of neural system alterations in describing various common disorders such as headaches, dementia, depression, anxiety, spinal cord injuries, and multiple sclerosis. Develop diagnostic and treatment considerations for various neural system disorders.

he nervous system consists of complex structures that control many body functions and cognition. The functions this system manages include: 1) structures such as muscles, glands, and organs; 2) heart rate; 3) blood flow; 4)

breathing; 5) digestion; 6) urination; and 7) defecation. The nervous system is involved in a variety of cognitive functions such as perception, memory, and attention, as well as emotional and behavioral regulation. The nervous system works with other systems to maintain homeostasis by receiving and responding to input from the environment. Disorders of the nervous system include physical and

psychological disorders that may be acute or chronic; regardless of their severity, these conditions often have grave or life-altering effects on the body. Causes of these disorders include congenital defects, trauma, infections, tumors, chemical imbalances, and vascular changes.

Anatomy and Physiology The nervous system is an intricate network of specialized cells and tissue that receive and react to environmental stimuli on physiologic and cognitive levels. To communicate this input, these structures conduct electric impulses between the brain and the rest of the body. The nervous system consists of three main components: the brain, the spinal cord, and the nerves. The brain and spinal cord make up the central nervous system (CNS), and the cranial and spinal nerves make up the peripheral nervous system (PNS).

Central Nervous System The skull and vertebral column house and protect the brain and spinal cord. Additionally, a set of three tough membranes, called the meninges, encase the CNS (FIGURE 11-1). The dura mater is the outer and toughest layer. The arachnoid layer is the middle layer, named for its spider web–like vascular system. The pia mater is the innermost layer that rests directly on the brain and spinal cord. Cerebrospinal fluid (CSF) is a plasmalike liquid that fills the space between the arachnoid and pia mater layers to provide additional cushioning and support to the CNS. The choroid plexus cells in the brain’s ventricles continuously produce the CSF. Approximately 600 mL of CSF is produced per day in adults, and 50 mL is produced in newborns. The composition of CSF is similar to plasma and contains electrolytes (e.g., sodium and potassium), glucose, proteins (e.g., albumin and gamma globulin), and red and white blood cells. There are four ventricles that are interconnected, hollow areas (cavities) of the brain that the CSF fills and where it flows freely between them through openings known as foramens (e.g., foramen of Monro) and aqueducts (e.g., aqueduct of Sylvius) that act as canals. Up to 150 mL (25%) of CSF circulates within the ventricles, and excess CSF drains into the bloodstream.

FIGURE 11-1 The meninges enclose the brain and the spinal cord.

The brain is located within the skull and contains billions of neurons. Neural tissue consists of two basic types of cells—neuroglia and neurons. Neuroglia cells play several important supportive roles in the nervous system. Neuroglial cells are more numerous than neurons. These cells scaffold neural tissue and isolate and protect neuron cell membranes. Additionally, neuroglia cells regulate interstitial fluid, defend the neurons against pathogens, and assist with neural repair.

Neuroglial cells consist of astrocytes, oligodendrocytes, Schwann cells, microglia, and ependymal cells. Each of these cell types has specific functions. Astrocytes form the framework of the brain and spinal cord (central nervous system) and form the blood–brain barrier. Ependymal cells form the epithelial lining of the central nervous system and produce cerebrospinal fluid. The oligodendrocytes are responsible for the development of myelin in the central nervous system. Schwann (neurilemma) cells produce myelin in the peripheral nervous system. Schwann cells also provide metabolic support. Schwann cell transplantation for therapeutic purposes is in a preclinical trial phase. Microglia have phagocytic activities.

Neurons are the fundamental unit of the nervous system; they generate bioelectrical impulses and transmit these signals from one area of the body to another. Neurons occur in several sizes and shapes, but all share similar characteristics. Neurons do not have the ability to divide (except for olfactory neurons, which can divide throughout life); thus, when these cells are lost due to aging or injury, they cannot be replaced. Not all cell death results in loss of functioning. For example, if neurons become damaged in one area of the brain, neurons in other areas can eventually assume responsibility for those functions. In the PNS, severed nerves can regenerate to a point to reestablish connections with the tissue they once supplied. In the brain or spinal cord, severed axons cannot be repaired. Severed spinal cord nerves result in paralysis and loss of sensation below the area of damage. In addition to being unable to divide, nerve cells require a constant supply of oxygen and glucose. This characteristic makes neurons vulnerable to the effects of hypoxia and hypoglycemia. Neurons can begin dying within minutes of these events.

Most neurons have a spherical cell body that houses the nucleus, most of the cytoplasm, and organelles. Neurons contain projections called axons and dendrites that make connections with nearby cells (FIGURE 11-2). Axons transmit impulses away from the cell body (i.e., the soma), whereas dendrites transmit impulses toward the cell body. Dendrites on a neuron are not to be confused with dendritic cells, which are antigen-presenting cells in the immune system. Groupings of soma in the central nervous system are called nuclei (e.g., subthalamic nuclei), while soma collections in the peripheral nervous system are called ganglions (e.g., posterior dorsal root ganglion). However, there is some crossover with terms as the basal

ganglia is a group of CNS soma. When the axon reaches its destination, it often branches into several small fibers that terminate into miniscule bulges, called terminal boutons. These terminal boutons communicate with neurons, muscle fibers, or glands. Axons can communicate with several different neurons or influence one single neuron. Axons may be surrounded by a myelin sheath made of lipids, which increases the rate of impulse transmission to approximately 400 times faster than is possible in unmyelinated nerves (FIGURE 11-3). Schwann cells produce the myelin sheath in the PNS, and oligodendrocytes produce myelin in the CNS; these cells are separated by nodes of Ranvier. Nutrient exchange can occur at the nodes but not where there is myelin. Because of the myelin, impulses move at greater speeds down the axon, jumping from one node to the next, much like stones skipping across water. Bundles of these myelinated nerves are referred to as white matter. Impulses move in a slow, wavelike pattern in unmyelinated nerves. The larger the axon, the faster the impulse transmission. Gaps between the neurons are referred to as synapses. Each of these gaps includes a presynaptic terminal (e.g., a terminal bouton or some similar structure), a synaptic cleft (the space between neurons), and a postsynaptic cell membrane (FIGURE 11-4). The presynaptic and postsynaptic terminals are opposite ends of the nerve. Presynaptic neurons relay impulses toward the synapse, while postsynaptic neurons relay impulses away from the synapse. Throughout life, brain synapse numbers and strength can change, and the ability to do so is termed neuroplasticity or synaptic plasticity.

FIGURE 11-2 A neuron. (A) A scanning electron micrograph of the cell body and dendrites. (B) Collateral branches may occur along the length of the axon. In motor neurons, when the axon terminates, it branches many

times, ending in individual muscle fibers.

A: © Geostock/Photodisc/Getty Images.

FIGURE 11-3 A myelinated nerve. (A) The myelin sheath allows impulses to “jump” from node to node, greatly accelerating the rate of transmission. (B) A transmission electron micrograph of an axon in the cross section,

showing a myelin sheath.

B: © Jose Luis Calvo/Shutterstock.

FIGURE 11-4 The function of neurotransmitters in the synaptic cleft. (A) A scanning electron micrograph showing the terminal boutons of an axon ending on the cell body of another neuron. (B) The arrival of the impulse

stimulates the release of neurotransmitters held in synaptic vesicles in the axon terminals. The neurotransmitter diffuses across the synaptic cleft and binds to the postsynaptic membrane, where it elicits another action

potential that travels down the dendrite to the cell body. (C) A transmission electron micrograph showing the details of the synapse.

A: © Lewis-Everhart-Zeevi/Science VU/Visuals Unlimited, Inc.; C: © T. Reese, DW Fawcett/Visuals Unlimited, Inc.

Electrical impulses of the nervous system are not like the electrical current that powers appliances, which is formed by the flow of electrons. Instead, small ionic changes such as potassium, sodium, and calcium moving across cell membranes generate neural impulses (action potential) (FIGURE 11-5). Usually several potentials, whether excitatory or inhibitory, are necessary for impulse transmission; this concept is known as summation. The plasma side of the neuron membrane has a slight charge at rest, or resting potential, because of the sodium ions concentrated on the outside of the cell. When the neuron is stimulated, protein gates open and sodium flows into the cell. The rapid inflow of positively charged sodium ions increases the charge—a process called depolarization. This is the same process that occurs in the cardiac cells. Immediately following depolarization, the cell membrane returns to its resting state through the rapid outflow of the positively charged potassium ions. When generated, these impulses travel down the nerve to trigger the release of neurotransmitters from vesicles in the presynaptic terminal. The neurotransmitters cross the synaptic cleft, albeit only in one direction, to stimulate an electrical reaction in nearby neurons. The neurotransmitters bind to a receptor on the postsynaptic membrane. Synaptic transmission of the impulse takes a mere millisecond. This electrical reaction passes through those neurons to the next synapse, where the process is repeated. At each synaptic transmission, a small burst of neurotransmitters is released and then removed. Neurotransmitters are either destroyed by enzymes or reabsorbed by the postsynaptic membrane to be recycled for the next transmission. Whereas some neurotransmitters stimulate the action potentials of neurons, other neurotransmitters inhibit action potentials (see TABLE 11-1). Some common neurotransmitters include acetylcholine, norepinephrine, dopamine, and serotonin.

FIGURE 11-5 Action potential. (A) Stimulating the neuron creates a bioelectric impulse, which is recorded as an action potential. The resulting potential shifts from 270 millivolts to 130 millivolts. The membrane is said to be depolarized. This graph shows the shift in potential and the change in the permeability of sodium (Na+) and

potassium (K+) ions, which is largely responsible for the action potential. (B) The influx of sodium ions and the depolarization that occur at the point of stimulation. (C) The impulse travels along the membrane as a wave of depolarization. (D) The efflux of potassium ions restores the resting potential, allowing the neuron to transmit

additional impulses almost immediately.

TABLE 11-1 Substances That Are Neurotransmitters or Neuromodulators

*Increase the release and block the reuptake of norepinephrine. ANS, autonomic nervous system; CNS, central nervous system; GI, gastrointestinal; PNS, peripheral nervous system. Reproduced from Mtui, E., Gruener, G., & Dockery, P. (2016). Fitzgerald’s clinical neuroanatomy and neuroscience (7th ed.). Copyright Elsevier 2016.

The brain is an organ with millions of neurons and an extensive circuitry that allows for thought, emotion, intellect, and receiving and relaying signals from the environment in response to stimuli. The major regions of the brain include the cerebrum (including the cerebral cortex), diencephalon (thalamus and hypothalamus), brainstem (midbrain, pons, and medulla), and cerebellum (FIGURE 11-6). The cerebrum and diencephalon are also part of the structural region known as the forebrain, and the hindbrain encompasses the cerebellum and pons. The midbrain is composed of several nerve tracts and is the portion of the brainstem that connects the forebrain and hindbrain. The cerebrum is the largest of the regions (accounting for 80% of the brain’s total mass) and controls the higher thought processes. A thin layer of gray matter, referred to as the cerebral cortex, surrounds the cerebrum. The gray matter is the area where information is received, integrated, stored, and transmitted. A thick central core of white matter lies beneath the gray matter. This white matter contains bundles of myelinated axons that transmit impulses from the cerebral cortex to the spinal cord, enhancing communication and coordination of activities. The cerebrum is divided into right and left hemispheres by a longitudinal fissure (deep grooves). Although minor shifts of one hemisphere into the other may occur, impinging of one hemisphere on the other can have significant —even life-threatening—effects. Numerous folds, or gyri, increase the surface area of the cerebrum. The grooves in between the gyri are called sulci. At birth, only a minimal set of gyri is present, but these folds increase as the brain develops into adulthood. The right side of the cerebral cortex controls the left side of the body, and the left side of the cerebral cortex controls the right side of the body (term for opposite side of the body is contralateral). As an example, a stroke in the left hemisphere will cause right-sided body symptoms such as hemiparesis.

FIGURE 11-6 The major regions of the brain.

Within each hemisphere of the brain are subdivisions called lobes; each lobe is named for the bone of the skull that covers it (FIGURE 11-7). The frontal lobe facilitates voluntary motor activity and plays a role in personality traits. The parietal lobe receives and interprets sensory input, with the exception of smell, hearing, and vision stimuli. The occipital lobe processes visual information. The temporal lobe plays an essential role in hearing, smell, and memory. Areas within and across these lobes can be classified as three types—motor, sensory, and association. These areas stimulate muscle activity, receive sensory information, and integrate

information and initiate coordinated responses, respectively.

FIGURE 11-7 The lobes of the cerebrum. (A) The cerebral cortex has three principal functions: receiving sensory input, integrating sensory information, and generating motor responses. Special sensory areas handle vision, smell, taste, and hearing. (B) A positron emission tomography (PET) scan reveals the locations of increased

blood flow in the brain during performance of certain tasks.

B: Courtesy of Marcus Raichle, MD, Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine.

The diencephalon includes the thalamus and hypothalamus (FIGURE 11-8). The thalamus receives and relays most of the sensory input, affects mood, and initiates body movements, especially those associated with fear or anger. The subthalamus

participates in motor activities, but the functions of the epithalamus—especially the pineal body—are unclear. The hypothalamus is the most inferior portion of the diencephalon; it regulates many bodily functions (see chapter 10 for more details about endocrine function).

FIGURE 11-8 The regions of the brain and their functions, including the thalamus and hypothalamus.

The brainstem and cerebellum connect the brain to the spinal cord. This structure is crucial for many basic body functions (e.g., maintaining heart rate, blood pressure, and respiration), and injury to the brainstem can easily result in death. The brainstem collaborates with the hypothalamus to regulate these vital activities. In addition to containing control regions, the brainstem serves as the main thoroughfare for information traveling to and from the brain. Of the 12 cranial nerves, 10 exit from the brainstem. The pons (means bridge in Latin) serves as a relay station between the cerebellum and brainstem and contains nerves that regulate sleep and breathing. The midbrain, which is the smallest region of the brain, acts as a sort of relay station for auditory and visual information. It controls the visual and auditory systems and eye movement. The substantia nigra is gray matter located in the midbrain containing a tract that produces dopamine, an important excitatory neurotransmitter involved in motivation and motor control. The medulla (medulla oblongata) is a conduction pathway for ascending and descending nerve tracts. It coordinates heart

rate, peripheral vascular resistance, breathing, swallowing, vomiting, coughing, and sneezing (Figure 11-6).

Most of the many nerve fibers passing through the brainstem have branches that terminate in a region of the brainstem called the reticular formation. The reticular formation acts like a gatekeeper, receiving all incoming and outgoing information. It sends impulses to the cerebral cortex through specialized nerve fibers. These fibers, in turn, make up the reticular activation system (FIGURE 11-9). The reticular formation and the reticular activation system are responsible for alertness during the day, and their ongoing activation can prevent sleeping at night.

FIGURE 11-9 The reticular activation system.

The cerebellum communicates with other regions of the brain to coordinate the

synergistic motion of muscle movement (reflexive, involuntary) and balance as well as cognition. The cerebellum, in contrast to the cerebral cortex, has same side body control, meaning the left cerebellum controls the left side of the body (term for same side of the body is ipsilateral). Deep within the cerebrum, diencephalon, and midbrain is a set of key structures called the basal ganglia. The basal ganglia or basal nuclei play a pivotal role in coordination, voluntary motor movement, and posture, along with cognitive and emotional functions. The basal ganglia includes the substantia nigra along with several other nuclei (e.g., lentiform nuclei and the striatum). Portions of the cerebrum and diencephalon constitute the limbic system (FIGURE 11-10). The limbic system is a set of structures that includes the hypothalamus, amygdala, hippocampus, and thalamus; each structure works to influence instinctive behavior, emotions, motivation, mood, pain, and pleasure. The amygdala is often referred to as the aggression center as stimulation can lead to anger, violence, fear, and anxiety. Benzodiazepines and alcohol affect the amygdala by inhibiting amygdala response and resulting in a mellowing effect and disinhibited behavior. The hippocampus helps in the formation of new memories and is involved in short-term memories becoming long-term memory. Damage to the hippocampus can lead to difficulties forming new memories; however, old memories may remain intact.

FIGURE 11-10 The limbic system. The odd assortment of structures shown in blue is the limbic system. The limbic system is the seat of emotions, such as joy, and instincts; it is home to other functions as well.

The spinal cord, which starts from the medulla oblongata, exits the skull through the opening in the skull, called the foramen magnum. The spinal cord extends through the vertebral canal to the second lumbar vertebra. At this point, the spinal cord transitions into individual nerve roots referred to as the cauda equina. The spinal cord consists of 31 pairs of spinal nerves (part of the PNS) that branch off at regular intervals (FIGURE 11-11).

FIGURE 11-11 The spinal cord.

The central portion of the spinal cord is an H-shaped area of gray matter, which contains nerve cell bodies. White matter consisting of nerve fiber tracts, or pathways, surrounds the gray matter). Ascending fibers, also known as afferent tracts, carry sensory information in the form of action potentials from the periphery back to the brain. Descending fibers, also known as efferent tracts, carry motor impulses in the form of action potentials from the brain to the PNS. The white matter has a variety of tracts that communicate specific ascending or descending input. The tracts are named according to where they start and end. As an example, the corticospinal tract carries impulses from the cortex to the spinal cord, so it is a descending (efferent) pathway. Tracts are grouped into columns based on their locations such as the anterior (ventral), lateral, and posterior (dorsal) columns. Ascending tracts are in all columns while descending tracts are only in the lateral and anterior columns. The following are the various tracts:

Anterior spinothalamic tracts permit sensations of light touch, pressure, tickling, and itching. Lateral spinothalamic tracts allow the sensations of pain and temperature. Spinocerebellar tracts establish the body’s position in relation to the cerebellum. Corticospinal tracts coordinate movements, especially in the hands. Vestibulospinal tracts are responsible for involuntary movements. Reticulospinal tracts are also responsible for involuntary movements.

The spinal reflex arcs refer to the process that creates an unconscious, involuntary response to stimuli (FIGURE 11-12). Most sensory neurons involved in the reflex arc do not pass directly to the brain but rather synapse in the spinal cord. By bypassing the brain the motor neurons can be activated quickly for a response. The brain, however, may receive sensory signals that “something” has occurred and there are times when the brain can prevent a reflex action. An example of this arc can be seen when the patella is gently tapped with a reflex hammer. The tendon stretch reflex is elicited when the patella is tapped, causing quadriceps contraction that results in the lower leg sharply moving forward (called extension) and then backward (called flexion). The flexor reflex is a withdrawal reflex that occurs in response to touching an unpleasant stimulus (e.g., extreme heat) (FIGURE 11-13). This reflex causes the muscles of a limb to withdraw the limb from the source of the stimulus without any conscious action. The tracts of the spinal cord and brain regulate these impulses. Chapter 14 contains detailed information pertaining to the various steps in sensory and motor pathways as they apply in particular to pain transmission.

FIGURE 11-12 Spinal cord nerve tracts.

FIGURE 11-13 The spinal reflex arc. When you accidentally touch a hot pan on the stove, you withdraw your hand before your brain even knows what is happening. This reaction occurs because of a reflex arc. Sensory fibers send impulses to the spinal cord. The sensory impulses stimulate motor neurons in the spinal cord. This stimulation 1) causes muscle contraction in the flexor muscles and 2) inhibits muscle contraction in the extensor muscles, allowing you to withdraw your hand. Nerve impulses also ascend to the brain to let it know what is

happening.

Motor neurons are described as upper motor neurons and lower motor neurons. Upper motor neurons are those pathways located in the CNS (e.g., corticospinal tract neurons). Lower motor neurons describe peripheral neurons that directly influence muscle activity. Upper motor neurons form synapses with interneurons that synapse with lower motor neurons. In general, upper motor neuron damage will lead to contracture and spastic type paralysis (e.g., a stroke damages upper motor neurons) while lower motor neuron injury will result in hypotonic muscles and flaccid type paralysis (e.g., amyotrophic lateral sclerosis).

Peripheral Nervous System The PNS comprises the spinal nerves and cranial nerves. The nerves of the PNS consist of bundles of nerve fibers, with each fiber being part of the neuron. These nerves transport messages to and from the CNS. The nerves end on receptors that respond to a variety of internal and external stimuli. The 31 spinal nerve pairs (8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal) branch directly off the spinal cord to make up the PNS (Figure 11-11). Each spinal nerve pair is named for the vertebral level at which it exits the spinal cord (e.g., C3 is the 3rd cervical nerve and T12 is the 12th thoracic nerve) except that C1 exits below its corresponding vertebrae. Each spinal nerve pair innervates specific areas of the body (FIGURE 11- 14). Ganglia comprise collections of nerve cell bodies outside the CNS. Spinal nerves arise from several small nerves called rootlets along the dorsal and ventral surfaces of the spinal cord (FIGURE 11-15). Approximately six to eight rootlets combine to form each dorsal root and ventral root. These roots, in turn, come together to form the spinal nerve.

FIGURE 11-14 Spinal nerve innervation.

FIGURE 11-15 The dorsal root ganglion.

Each spinal nerve of the PNS comprises two types of nerves—sensory and motor. The sensory nerves, or afferent nerves, carry impulses (regarding information) from the body to the brain. A dermatome is the area of the skin innervated by a given pair of spinal sensory nerves. Each spinal nerve, with the exception of C1, has a specific body surface area from which it obtains sensory information. The motor nerves, or efferent nerves, carry impulses regarding action from the brain to the corresponding muscle receptor, resulting in muscle contraction and movement. Interneurons connect the sensory and motor neurons in the spinal cord.

Sometimes several nerves intersect to form an organized collaboration, or plexus. Four plexuses occur in the body—cervical (located at C1 to C4), brachial (located at C5 to T1), lumbar (located at L1 to L4), and sacral (located at L4 to S4). These plexuses branch into the peripheral nerves that supply sensory and motor functions to many areas of the body. The thoracic nerves are an exception and do not form a plexus; rather, the nerves pass through the intercostal spaces to innervate the thorax.

The brain is responsible for a variety of physiologically vital functions and cognitive activities. It accomplishes these functions in part through the set of cranial

nerves. Twelve pairs of cranial nerves branch directly from the base of the brain (FIGURE 11-16). Some of the cranial nerves carry only sensory fibers (I, II, and VIII), others carry only motor fibers (III, IV, VI, XI, and XII), and a few carry both types of fibers (V, VII, IX, and X). Each nerve travels from the brain through the foramen to its destination.

FIGURE 11-16 The cranial nerves. (S)- sensory

(M)- Motor

(B)- both motor and sensory

Autonomic Nervous System The autonomic nervous system (ANS) controls smooth muscles and is responsible for the fight-or-flight response. The autonomic nervous system is often considered to be part of the PNS; however, components are also located in the CNS (e.g., in the hypothalamus). The autonomic nervous system, which is not under conscious control, affects such activities as heart rate, blood pressure, and intestinal motility. This system has two subdivisions—sympathetic and parasympathetic. The two divisions have an antagonistic effect on each other that aids in maintaining homeostasis (FIGURE 11-17). The sympathetic innervations run from the first thoracic spinal region to the second lumbar spinal region and are responsible for the fight-or-flight response; this response is initiated when a person is startled or faced with danger and is augmented by secretions of the adrenal medulla (FIGURE 11-18). In contrast, the parasympathetic innervations are in the cranial nerve nuclei and the sacral spinal region, and they are responsible for the rest-and-digest response. Neurotransmitters and receptors are important in the autonomic nervous system because sympathetic and parasympathetic innervations will stimulate or inhibit these sites, leading to the physiologic response (TABLE 11-2). The motor portion of the ANS consists of preganglionic, myelinated neurons and postganglionic, unmyelinated neurons. The preganglionic neurons, whether sympathetic or parasympathetic, release acetylcholine, resulting in cholinergic transmission.

FIGURE 11-17 Comparison of the two divisions of the autonomic nervous system.

FIGURE 11-18 Physiologic response to stress.

TABLE 11-2 Types of Autonomic Receptors

The parasympathetic postganglionic neurons (like preganglion neurons) release acetylcholine, and effects are centered on a particular function. The sympathetic postganglionic neurons release norepinephrine, resulting in adrenergic transmission and can result in a generalized, widespread system effect. Some sympathetic postganglionic neurons (e.g., sweat gland innervation) release acetylcholine.

There are different types of cholinergic or adrenergic receptors on effector organs. Cholinergic receptors are nicotinic and muscarinic. At the synapse, acetylcholine is degraded by the enzyme acetylcholinesterase. Adrenergic receptors are beta (β) and alpha (α). At the synapse, norepinephrine is degraded by the enzyme catechol-o-methyl transferase (COMT). Drugs that inhibit this COMT are used to treat Parkinson disease. Acetylcholine and norepinephrine can also be reabsorbed the by the preganglionic neurons. The effects of the neurotransmitter will be dependent on the receptors present on the target organ (may be one or multiple) and the receptor stimulated. As an example, sympathetic stimulation of α-receptors results in vasoconstriction, while stimulation of β-receptors results in vasodilation. Some medications can also stimulate or inhibit these receptors. See chapter 4 for discussion of cardiovascular ANS receptors.

Blood Supply to the CNS The brain receives most of its blood supply from the internal carotid arteries, which form the anterior circulation (FIGURE 11-19). The spinal cord is supplied by vertebral arteries and arteries that branch off the descending aorta. The brain is also supplied by the vertebral arteries, which form the posterior circulation. These various branches interconnect in various ways. The internal carotid artery branches into several arteries; a main one is the anterior cerebral artery that continues as the middle cerebral artery. The vertebral arteries branch into several arteries (e.g., meningeal anterior and posterior inferior cerebellar artery) and then form the basilar artery. The terminal branches of the vertebral and carotid arteries also connect to form the circle of Willis at the base of the brain. The veins of the brain eventually drain into the internal jugular veins. Spinal cord veins are parallel to the arteries and drain via various sinuses.

FIGURE 11-19 Blood supply of the brain.

1. 2.

1. 2.

BOX 11-1 Application to Practice Answer the following questions as they pertain to autonomic receptor activation and expected responses.

Case 1: A patient with chronic obstructive lung disease is prescribed a long-acting antimuscarinic agent. The expected therapeutic effect of this medication is:

Blocks muscarinic receptors in the airway, leading to smooth muscle constriction Blocks muscarinic receptors in the airway, leading to smooth muscle relaxation

Case 2: A patient with chronic obstructive lung disease is prescribed a long-acting beta agonist. The expected therapeutic effect of this medication is:

Stimulates beta-2 adrenergic receptors, resulting in increased heart rate leading to increased oxygenation Stimulates beta-2 adrenergic receptors, resulting in airway smooth muscle relaxation

Case 3: A 60-year-old woman is taking the following medications: lisinopril and metoprolol for hypertension and oxybutynin for an overactive bladder. She is complaining of increased constipation and dry mouth. The symptoms are deemed to be due to medication side effects.

Which of the medications is the likely cause of these symptoms, and why does this medication causes these symptoms?

Case 4: A 55-year-old man is in the intensive care unit in cardiogenic shock after coronary artery bypass surgery. He is unstable as his blood pressure has been very low (e.g., average 80/40 mmHg, average mean arterial pressure of 53) and his heart rate is high (e.g., average between 100 and 120 beats per minute). He is receiving a continuous infusion of Levophed (norepinephrine) and epinephrine as well as metoprolol every 6 hours intravenous push as needed.

Describe the intended therapeutic effects of the three intravenous medications he is receiving on his cardiovascular system.

The blood–brain barrier is an important vascular component of the brain that keeps the neurons from being exposed to potentially harmful substances (e.g., infectious agents and neurotoxins) (FIGURE 11-20). The lipid membrane of the blood–brain barrier is so tightly packed with endothelial cells that penetrating it is like trying to get through a brick wall. Some substances, such as water, carbon dioxide, and oxygen, can easily cross the membrane, while plasma proteins and large lipid molecules are incapable of permeation. Determining how to penetrate the blood– brain barrier for therapeutic purposes to treat CNS disorders, such as Alzheimer disease or depression, is an area of continued research. As an example, drugs can be encapsulated in nanoparticles to protect them from degradation, allowing the drugs to attach to epithelial cells and giving them more time to cross the barrier. The nanoparticles can deliver hydrophobic and protein-based drugs.

FIGURE 11-20 The structure of the blood–brain barrier.

Understanding Conditions That Affect the Nervous System When considering alterations in the nervous system, organizing them based on their basic underlying pathophysiology and common anatomic origin can increase understanding. Conditions of the nervous system are usually complex, affecting many areas of function. For example, these disorders may lead to impaired physical mobility, chronic pain, impairments in thought processes and social interaction, incontinence, risk for injury, and self-care deficit, just to name a few possibilities. Patients experiencing these neurologic conditions often require vigilance to manage the complexity of the situation.

Congenital Neurologic Disorders Congenital defects of the nervous system are often serious, with lifelong consequences. These disorders often have limited treatment options and require long-term management of complications.

Hydrocephalus Hydrocephalus is a condition in which excess CSF accumulates within the ventricles and subarachnoid spaces in the brain. This accumulation leads to dilation of the ventricles and compresses the brain and blood vessels (FIGURE 11-21). The pressure from the excess CSF thins the cortex, causing severe brain damage. The CSF accumulates when the flow of this fluid is disrupted (referred to as noncommunicating or an obstructive hydrocephalus) or when too much CSF is made or not properly absorbed by the bloodstream (referred to as communicating hydrocephalus). Obstructive hydrocephalus is the most common type, while hydrocephalus due to excess production is rare. The obstructions can occur at the aqueduct of Sylvius, the ventricles, or the foramen of Monro. Overlaps can happen, so obstruction and absorption issues can occur together. Hydrocephalus is a common condition that may be present at birth (in an estimated 1 out of 500 births) or develop later in life (another 6,000 children younger than 2 years of age develop it each year) (National Hydrocephalus Foundation, 2014). Risk factors for hydrocephalus at any age include prematurity, pregnancy complications, nervous system tumors, CNS infections, cerebral hemorrhage, and severe head injuries. More than 50% of hydrocephalus cases are due to congenital defects with myelomeningocele being one of the most common causes of congenital hydrocephalus. If left untreated, hydrocephalus is often fatal (60% mortality rate). Adults can also be diagnosed with hydrocephalus, commonly due to enlarged ventricles without increased cerebral pressure, so it is termed normal pressure hydrocephalus. This type of hydrocephalus can be idiopathic or be due to other disorders (secondary). Idiopathic cases in adults are rare and usually occur after the age of 60. The prognosis depends on early treatment and comorbidity.

FIGURE 11-21 Hydrocephalus development. B: © O_Akira/Shutterstock.

Clinical Manifestations Clinical manifestations of hydrocephalus reflect the increased intracranial pressure (ICP). These manifestations vary by age group, underlying etiology, and disease progression. In infants, clinical manifestations are dependent on whether the cranial sutures have fused. If they have not fused, the signs of increased intracranial pressure (ICP) may be absent to mild. The rate of ICP rise (acute) and duration (longer period) will affect clinical manifestations. Those with rapid progression will have earlier manifestations. The clinical manifestations often include the following:

Myth Busters

Some myths surrounding the brain warrant discussion.

Myth 1: The brain is gray. The living, pulsing brain currently residing in your skull is not just a dull, bland, gray organ like the image often depicted in movies; instead, the brain is also white, black, and red. Like many myths, this one has a grain of truth, because much of the brain is gray. Sometimes the entire brain is referred to as gray matter. However, the brain also contains white matter, which comprises nerve fibers that connect the gray matter. The black component is called substantia nigra, which is Latin for black substance. The substantia nigra has a black color because of neuromelanin, a specialized type of pigment. Finally, the brain is red in some areas because of the many blood vessels it contains.

Myth 2: Listening to classical music, especially by Mozart, increases intelligence. How did this myth get started? In the 1950s, a physician named Albert Tomatis claimed he had successfully used Mozart’s music to help people with speech and auditory disorders. In the 1990s, 36 students in a study at the University of California at Irvine listened to 10 minutes of a Mozart sonata before taking an IQ test. The study reported that the students’ IQ scores went up by about 8 points— and thus the Mozart effect was born. Multiple products have been sold based on this assumption. However, the original University of California at Irvine study remains controversial within the scientific community. Other scientists have been unable to replicate the original results, and current scientific evidence does not support the contention that listening to Mozart—or any other classical music, for that matter—increases intelligence. However, some evidence indicates that learning an instrument improves concentration, self-confidence, and coordination. Mozart’s music certainly cannot hurt you, and you might even enjoy it if you try listening to this music; however, you will not get any smarter because of this activity.

Myth 3: You use only 10% of your brain. This myth is probably one of the most well-known legends about the brain. This assumption seems puzzling at first glance. We have the biggest brain in proportion to our bodies of any animal, so why would we not use all of it? Many people have jumped on this idea, writing books and selling products that claim to tap into the other 90%. Believers in psychic abilities use this claim as proof, suggesting that people with these abilities have tapped into the rest of their brains.

In fact, this myth is false. In addition to 100 billion neurons, the brain is full of

other types of cells that are continually in use. Significant neurologic deficits can occur from even minor damage depending on the location, so it is highly unlikely that we could function with only 10% of our brain in use. Brain scans have shown that no matter what we are doing, our brains are always active. Some areas are more active at any one time than others, but unless we have brain damage, no one part of the brain is completely turned off. Thus there is no hidden, extra potential you can tap into, in terms of actual brain space.

Myth 4: Games like sudoku and Brain Age keep your brain young. There is some truth to this myth! Continued mental engagement has benefits, and puzzles can help you get good at a specific skill, such as memorizing grocery lists or hand–eye coordination. Most evidence, however, suggests practicing a task helps you get better only at that particular task. Far better for mental function is physical exercise. Regular physical fitness exercise is especially effective in the elderly, who may suffer from gradual problems with cognitive function such as planning ahead and abstract thinking.

An unusually large head (FIGURE 11-22)

FIGURE 11-22 Hydrocephalus.

© Angela kay Agnew/Shutterstock.

A rapid increase in the head size A bulging fontanelle, or soft spot, on the top of the head Vomiting (often projectile) Dilated scalp veins Prominence of forehead (frontal bossing) Spasticity of the extremities Lethargy Irritability High-pitched cry Feeding difficulties Seizures Eyes that gaze downward (setting-sun appearance) Developmental delays

In older children and adults, the head cannot enlarge because the sutures have closed. Clinical manifestations in these groups may include the following signs and symptoms:

Headache, usually early in the morning when the pressure is highest while the patient is lying down; followed by vomiting Nausea Blurred vision or diplopia (double vision) Sluggish pupil response to light; eyes that gaze downward (setting-sun appearance) Problems with balance, coordination, or gait Extreme fatigue Slowing or regression of development Memory loss Confusion Urinary incontinence Irritability Personality, memory, or cognition changes Impaired performance in school or work

Normal pressure hydrocephalus is a slow-developing disorder, and many of the usual manifestations, such as headache or visual changes, are not typically present. Adults who have normal pressure hydrocephalus will usually have three key manifestations—one must be gait dysfunction, and the other two are cognitive impairment and urinary incontinence. The gait dysfunction is generally characterized

as slow, with small steps, and a wide base. The cognitive impairment can include impaired executive functioning (conceptualization and ability to determine effective behavior), apathy, decreased attention and concentration, and psychomotor slowing. The urinary manifestations may start as urgency and then evolve into incontinence. Because of its symptoms, this disorder can easily be confused with dementia (e.g., Alzheimer disease).

Diagnosis and Treatment Diagnostic procedures for hydrocephalus may be performed during pregnancy or after birth. These procedures consist of a history and physical examination (including head circumference measurement and a comprehensive neurologic assessment). Neuroimaging of various types can include head computed tomography (CT), head magnetic resonance imaging (MRI), skull X-ray, cranial ultrasound, and prenatal ultrasound.

The goal of treatment is to minimize brain damage and reduce or eliminate symptoms by reducing CSF. Blockages are surgically removed, if possible. If the blockage cannot be removed, a shunt may be placed within the brain to allow CSF to flow around the blocked area. The shunt tubing travels to another part of the body, such as the peritoneal cavity (ventriculoperitoneal) or right atrium (ventriculoatrial), where the extra CSF can be drained and absorbed. Shunt replacement may be needed periodically if it becomes blocked or infected or as a child grows. Antibiotic therapy will treat hydrocephalus caused by an infection or if a shunt infection develops. A temporary external ventricular drain can be used to relieve acute pressure. An endoscopic third ventriculostomy can also be performed to relieve pressure without replacing the shunt. Additionally, the area producing too much CSF may be cauterized. Diuretics, such as furosemide and acetazolamide, can be used temporarily if a patient cannot go to surgery. Follow-up examinations generally continue throughout a child’s life to monitor developmental progress and to manage any intellectual, neurologic, or physical problems. Adults with normal pressure hydrocephalus often have symptom improvement after shunting. An interprofessional team can provide emotional support and assistance with the care of those patients who have significant brain damage. The team would be made up of nurses, occupational therapists, educational specialists, social services personnel, and support groups.

Spina Bifida Although rates have been declining over the last 15 years, spina bifida remains the second most common birth defect in the United States, affecting approximately 1 child in every 1,500 births each year (CDC, 2015c). Spina bifida is a neural tube defect that can vary in severity from mild to debilitating. Neural tube development

begins early in pregnancy, starting at the cervical area and progressing toward the lumbar area, and the neural tube usually closes by the 4th week of gestation. In spina bifida, the posterior spinous processes on the vertebrae fail to fuse. This opening permits the meninges and spinal cord to herniate, resulting in neurologic impairment. The lumbar area of the vertebrae is most commonly the site of the defect. Spinal dysraphism is an umbrella term used to describe congenital defects of the spine. In addition to spina bifida, other types of spinal dysraphism include several defects such as a split cord malformation in which the spinal cord develops into two distinct cords; lipomas, which are fatty tumors; or other types of spinal cord tumors, such as dermoid tumors.

The exact cause of spina bifida is unknown, but it is thought to result from genetic and environmental influences. Spina bifida is most common in Hispanic and White populations, with females being more affected than males. Maternal risk factors for development of this defect in a child include family history of neural defects, folate deficiency (thought to be a key factor), certain medications (e.g., antiseizure agents), diabetes mellitus, prepregnancy obesity, and increased body temperature such as that caused by fever, hot tubs, saunas, and tanning beds. Most of these risk factors are likely to cause open spina bifida, while risk factors for the closed types of spina bifida are unclear.

Complications of spina bifida include physical and neurologic impairments as well as hydrocephalus and meningitis. Children with spina bifida are usually of normal intelligence, but they may have learning problems because of the chronic nature of the condition.

Spina bifida occurs in three forms, each varying in severity (FIGURE 11-23):

FIGURE 11-23 Most common types of spina bifida.

1. Spina bifida occulta: Spina bifida occulta is the mildest and most common form. It results in a small gap in one or more of the vertebrae. The spinal nerves and meninges do not usually protrude through the opening, so most children with this form have no clinical manifestations and experience no neurologic deficits. However, other associated anomalies, such as split spinal cord malformation, may be present. The defect may not be evident other than sacrococcygeal skin lesions such as a dimple, birthmark, or tuft of hair over the site. However, those children with other anomalies will have neurologic symptoms, and with some defects, manifestations can be present as the child ages or even become apparent in adulthood, although this is not common.

2. Meningocele: Meningocele is a rare form that involves the same bony defect as in spina bifida occulta, but the meninges protrude through the vertebral opening. The meninges and CSF form a sac on the surface of the infant’s back. Transillumination (shining a light through the tissue) can confirm the absence of nerve tissue in the sac. Because the spinal cord develops normally, neurologic impairment is usually not present, and these membranes can be removed by surgery with little or no damage to nerve pathways. However, infection or rupture of the sac can lead to neurologic impairment.

3. Myelomeningocele: This form, also known as open spina bifida, is the most severe form. In this variant, the spinal canal remains open along several vertebrae in the lower or middle back. The meninges, spinal cord, spinal nerves, and CSF protrude through this large opening at birth and form a sac on the

infant’s back (FIGURE 11-24). Skin covers the sac in some cases. However, tissues and nerves are exposed in most cases, making the infant vulnerable to life-threatening infections. Neurologic impairment (often including paralysis), bowel and bladder problems (e.g., incontinence, urinary tract infections, and constipation), seizures, and other medical complications (e.g., skin conditions and latex allergies) are common.

FIGURE 11-24 Myelomeningocele. © Hugely/Shutterstock.

Clinical manifestations depend on the type and severity of spina bifida. Diagnostic procedures may be performed during pregnancy or after birth. These procedures may include a history, physical examination, check of maternal serum and amniotic fluid alpha fetoprotein levels (high levels indicate a possible neural tube

1. 2. 3. 4.

or other congenital defect), prenatal ultrasound, spinal X-ray, spinal CT, and spinal MRI.

Treatment strategies vary depending on the type and severity. For instance, spina bifida occulta often requires no treatment. Surgery is the mainstay of treatment for the other two types; however, the appropriate timing of the surgery (in utero, immediately after birth, or delayed) remains a topic of debate. Surgery usually includes replacing the meninges and closing the vertebral opening. A shunt may be placed during surgery to control hydrocephalus. Performing the surgical repair in utero may enhance outcomes but will not restore lost neurologic functioning. Additional risk may be incurred with this procedure, including premature delivery and death. If spina bifida is diagnosed before birth, cesarean delivery is preferred to prevent rupture of the sac or damage to any exposed nerves. Long-term support from an interprofessional team (e.g., a nurse, physical therapist, social worker, and an education specialist) will be necessary to limit complications and promote positive outcomes.

BOX 11-2 Application to Practice M.S. is a 26-year-old woman who is pregnant with her first child. Her husband accompanied her to all her prenatal visits. An ultrasound during a routine visit at 34 weeks’ gestation revealed that the baby had hydrocephalus and a myelomeningocele. The parents were initially devastated but remained very excited about the birth of their first child. M.S. was scheduled for a cesarean section at 38 weeks’ gestation, and the couple was anxious about their child’s condition and care following birth.

M.S. delivered a baby boy by cesarean section; he was transferred to the pediatric intensive care unit. On admission to the nursery, the baby’s vital signs and weight were within normal limits, but his head circumference was large. He had bulging fontanelles and a high-pitched cry. The nurse noted a saclike projection in the lumbar region of his spine.

Discuss the rationale for delivering the infant by cesarean section. Discuss the significance of the infant’s clinical manifestations. Discuss the acute and long-term treatment strategies for the infant. Discuss the complications associated with myelomeningocele.

Cerebral Palsy Cerebral palsy (CP) refers to a group of nonprogressive disorders that appear in infancy or early childhood and permanently affect motor movement and muscle coordination. In addition to motor dysfunction, other cerebral functioning may be affected (e.g., cognition and communication). CP usually results from damage to the

cerebellum during the prenatal period (often during childbirth), but it can also occur at any time during the first 3 years of life, when the brain is developing. In addition, this disorder can occur because of brain abnormalities. In the United States, CP is the leading cause of childhood disability, affecting approximately 3–4 out of 1,000 births (CDC, 2016a). CP is more common in males, in Blacks, and in persons of lower socioeconomic status.

Although CP is not curable, the right treatment can make a significant impact on the child’s prognosis; however, these therapies are costly. According to the CDC (2016a), the average lifetime costs (direct and indirect) for one person with CP are estimated to be $921,000 (in 2003 dollars). The estimated lifetime costs (direct and indirect) for all people with CP who were born in 2000 will total $11.5 billion (in 2003 dollars).

CP is a multifactorial disorder, and many risk factors coexist in CP development. Direct causal relationships in the development of CP have not been established. The following factors contribute to the development of CP:

Prematurity—the lower the gestational age, the higher the incidence Low birth weight—the lower the birth weight, the higher the incidence Breech births Multiple fetuses Hypoxia Hypoglycemia (in either the mother or the child) Cerebral hemorrhage Neurologic infections (e.g., meningitis and encephalitis) Head injury Maternal infections during pregnancy (e.g., rubella and varicella) Maternal exposure to toxins during pregnancy (e.g., mercury) Maternal smoking and heavy alcohol use Abnormal placenta Antepartum hemorrhage Severe jaundice

Clinical Manifestations CP is classified according to the movement disorder involved, which reflects the area of the brain affected: spasticity (stiff muscles), dyskinesia (uncontrolled movements), or ataxia (poor balance and coordination). Spasticity is present in 80% of cases. In most patients, one or more movement disorders are present.

Clinical manifestations of CP may or may not be evident at birth, and the average age at diagnosis is 18–24 months. These manifestations vary from mild to severe in their effects. CP may affect the entire body (resulting in quadriplegia) or just one area (resulting in diplegia); it may affect one side or both sides of the body. Clinical

manifestations can change over time as the brain matures. Manifestations may include the following signs and symptoms:

Neurobehavioral Signs Irritability, poor sleep, frequent vomiting, difficult to console and handle, and inadequate visual attention

Developmental Reflexes Persistence or exaggeration of early reflexes (e.g., Moro reflex)

Motor Tone and Posture Tone may be normal, increased (stiff), or decreased (flaccid) Poor head control Mouth—tongue retraction and thrust, grimacing, and abnormal jaw movement Motor milestones delay and varying abnormalities by age (normal developmental milestones up until age 5 can be accessed at www.cdc.gov/ncbddd/actearly/milestones/index.html) By 6 months, inability to roll over or bring hands together or to mouth By 8 months, not sitting, or by 10 months, crawling lopsided or in unusual manner (e.g., hopping on knees) By 18 months, not walking

Spastic Subtype Spastic movements Abnormal reflexes—hyperreflexia and clonus Impaired fine-motor function, difficulty with individual movement, and slow voluntary movements that take a lot of effort Atrophy below the waist Sensory disturbances (e.g., difficulty identifying an object simply by touch) Spastic quadriplegia with associated impairment such as severe intellectual disability, vision issues, and feeding and pulmonary disorders

Dyskinetic Subtype Choreoathetosis, which refers to rapid, irregular, and unpredictable contractions of muscles (individual or groups) Dystonia, which refers to involuntary, sustained muscle contraction leading to twisting and repetitive postures or movements

Ataxic Subtype Ataxic movement, which refers to abnormal, uncoordinated, voluntary movements Slow, jerky, and explosive speech

Complications of CP result because of these clinical manifestations:

Balance and coordination issues Contractures (shortening of a muscle causing severe limitation in movement) Scoliosis Malnutrition Communication issues and speech delays Learning or cognition difficulties Seizures (occur in approximately 50% of patients) Vision and hearing issues Urinary incontinence Constipation Osteoporosis Chronic pain Injury

Diagnosis and Treatment Diagnostic procedures for CP include a history, physical examination (including serial monitoring for developmental milestones), head CT, head MRI, and electroencephalogram (EEG) as well as hearing and vision screening. Treatment strategies focus on maximizing functioning and minimizing complications. Management is long term in nature and requires an interprofessional team (e.g., the primary care provider, nurses, a social worker, a physical therapist, an occupational therapist, a speech therapist, a dietitian, and education specialists). Therapeutic strategies often include the following measures:

Muscle relaxants Botulinum toxin type A (Botox) injections directly into spastic muscles Antiseizure medications Pain management (e.g., massage therapy and analgesics) Physical therapy Occupational therapy Speech therapy Nutritional support Home safety (e.g., remove rugs) Braces and orthopedic devices (e.g., splints) Ambulation devices (e.g., walker and wheelchair) Constipation prevention (e.g., high-fiber diet, adequate water intake, and stool softeners) Glasses and hearing aids Surgical procedures to relieve contractures or to sever nerves of spastic muscles

Support groups (especially for caregivers) Individualized education program

Infectious Neurologic Disorders Nervous system infections can have serious effects by triggering the infectious and inflammatory response. These infections can be caused by a number of bacterial, viral, and fungal pathogens. Regardless of the causative agent, neurologic compromise (either temporary or permanent) can result. Early diagnosis and treatment is imperative for positive outcomes.

Meningitis Meningitis refers to an inflammation of the meninges (membranes surrounding the brain and spinal cord), usually resulting from an infection. The CSF may also become affected. Bacteria, commonly Neisseria meningitides (meningococcus) and Streptococcus pneumoniae (pneumococcus), are causative organisms, as are other bacteria, such as Haemophilus influenzae and drug-resistant S. pneumoniae. Viruses (e.g., enterovirus, West Nile virus, influenza, human immunodeficiency virus [HIV], and herpes) are also a common cause of this infection. Viral meningitis is also known as aseptic meningitis (negative bacterial cultures with meningeal inflammation). The mode of transmission and mechanism by which the organism enters the CNS are dependent on the type of organism and host factors (e.g., if the patient is immunocompromised or has comorbid illnesses). The mode of transmission is generally through respiratory secretions and saliva. Other modes include the oral–fecal route (e.g., enteroviruses) and bites by mosquitoes, ticks, or rabid animals. These infectious agents invade the meninges through the blood or nearby structures (e.g., infective endocarditis) or by direct access (e.g., wounds and iatrogenic devices such as shunts). Additional causes of meningitis include chemical irritants, tumors, fungi, parasites, amoebas, and allergens. The infection or irritant triggers the inflammatory process, leading to swelling of the meninges, increased ICP, localized areas of brain ischemia, and neuronal apoptosis.

Risk factors for developing meningitis include age younger than 25 years, living in a community setting (e.g., a college dormitory), pregnancy, working with animals, and immunodeficiency. Depending on the cause of the infection, meningitis can be self-limiting (as with viral meningitis) or life-threatening (as with acute bacterial meningitis). Complications of meningitis may include permanent neurologic damage, seizures, hearing loss, blindness, speech difficulties, learning disabilities, behavior problems, paralysis, acute renal failure, adrenal gland failure, cerebral edema, septicemia, shock, and death.

Clinical Manifestations Clinical manifestations of meningitis result from the inflammation of the meninges. Initially, these manifestations mimic those associated with an influenza infection

(e.g., fever, chills, and malaise). Viral meningitis manifestations are similar to those of bacterial meningitis; however, they are typically not as severe. The clinical manifestations, which usually arise suddenly, include the following signs and symptoms:

Fever (usually > 100.4º F [38° C]) and chills Mental status changes (e.g., confusion and lethargy) Stiff neck (meningismus or nuchal rigidity) Nausea and vomiting Photophobia Severe headache Agitation Bulging fontanelle Decreased consciousness Opisthotonos (abnormal positioning that involves rigidity and severe arching of the back with the head thrown backward) Myalgias Poor feeding or irritability in children Tachypnea Tachycardia Rash (e.g., petechiae and palpable purpura)

Diagnosis and Treatment Diagnostic procedures for meningitis include a history, physical examination, throat cultures, lumbar puncture with CSF analysis, polymerase chain reaction test, and head CT. Treatment varies depending on the underlying etiology. Strategies may include antibiotics (if the infection is bacterial in origin), antivirals (usually reserved for those cases caused by a herpes virus), hydration, and fever management. Empiric antibiotics can be administered until a determination of a viral or bacterial process can be made. Additional strategies are geared toward managing complications as they develop (e.g., seizures, cerebral edema, and shock). Vaccinations, including those for H. influenzae, pneumococcal, and meningococcal infections, are the cornerstone of meningitis prevention. Meningococcal conjugate vaccines are recommended by the CDC (2019b) for preteens 11–12 years old with a booster given at the age of 16, and it is recommended for other age groups if there are risks (e.g., HIV-positive patients and those actively serving in the military). Serogroup B meningococcal vaccine is recommended for ages 10 and older who are at risk (e.g., outbreak of serogroup B meningococcus and sickle cell disease).

Encephalitis

Encephalitis refers to an inflammation of the brain, and when the spinal cord is involved, it is termed encephalomyelitis. The disorder usually results from an infection. A virus (e.g., coxsackievirus, echovirus, poliovirus, adenovirus, herpes virus, cytomegalovirus, Eastern equine encephalitis virus, West Nile virus, St. Louis virus, measles, or mumps) most frequently causes this infection. Viral exposure occurs through respiratory inhalation of droplets, ingestion of contaminated food or beverages, insect bites (especially mosquitoes and parasites), and skin contact. Encephalitis can also result from bacterial infections such as Lyme disease, tuberculosis, and syphilis. Noninfectious causes of encephalitis include allergic reactions (especially to vaccinations) and autoimmune conditions. The infection or other etiologic process triggers the inflammatory response, which causes vasodilation, increased capillary permeability, and leukocyte infiltration. This inflammatory process can cause nerve cell degeneration and diffuse brain destruction. Encephalitis is classified as either primary or secondary. Primary encephalitis involves a direct infection of the brain and spinal cord. In secondary encephalitis, an infection first occurs elsewhere in the body and then travels to the brain.

Most cases of encephalitis are mild and self-limiting, but in rare cases this condition can be severe and life threatening. Those individuals who are particularly vulnerable to more severe progression of encephalitis include immunocompromised persons (e.g., those with acquired immune deficiency syndrome [AIDS]), young children, older adults, persons living in high-incidence areas, and persons who are frequently outdoors. Complications of encephalitis include cerebral edema, cerebral hemorrhage, and brain damage.

Clinical Manifestations Clinical manifestations of encephalitis result from the meningeal irritation and neurologic damage associated with the inflammatory response. These manifestations are similar to those noted in meningitis but have a more gradual onset. In most cases, clinical manifestations are mild and go undetected. When present, manifestations of encephalitis may include the following signs and symptoms:

Flulike symptoms (e.g., fever, lethargy, and joint pain) Headache Neck rigidity Confusion and hallucinations Personality changes (e.g., flat affect, impaired judgment, and withdrawal from social interactions) Diplopia and photophobia Seizures

Muscle weakness Ataxia Paresthesia or paralysis Loss of consciousness Tremors Abnormal deep tendon reflexes Rash Bulging fontanelle (in infants)

Diagnosis and Treatment Diagnostic procedures for encephalitis include a history, physical examination, head CT, head MRI, EEG, lumbar puncture with CSF analysis, polymerase chain reaction test, and serum viral antibodies. Encephalitis is usually self-limiting, so treatment is largely supportive. Treatment strategies often include the following measures:

Rest Adequate nutrition, including plenty of fluids Respiratory support (e.g., oxygen therapy or endotracheal intubation with mechanical ventilation) for severe cases Reorientation and emotional support Analgesics and antipyretics to relieve headaches and fever Antiviral agents if viral Antibiotic therapy if bacterial Corticosteroids to reduce cerebral edema Antiseizure agents Sedatives to treat irritability and restlessness Physical, speech, and occupational therapy as necessary for any residual neurologic dysfunction

Infection by many of the encephalitis-causative organisms can be prevented. Prevention strategies include vaccinations, wearing protective clothing when outside (e.g., long-sleeve shirts), using mosquito repellant, and eliminating water sources around the home (e.g., standing water in containers).

Zika Virus Disease Infections caused by the Zika virus are a growing worldwide health concern. Zika virus is a flavivirus (in the same family as dengue, yellow fever, and West Nile virus) that is transmitted primarily by mosquitos (Navalkele, Chandrasekar, & Levine, 2016). In 1952, this virus was first discovered in Uganda and the United Republic of Tanzania (WHO, 2016). Since then, several outbreaks—usually involving a mild

illness—have been recorded in Africa, the Americas, Asia, and the Pacific. In 2015, Brazil reported a large outbreak causing more severe neurologic complications. Within a short period of time, cases of Zika virus disease were noted in Florida (tracked to foreign travel to Zika-affected regions), and then the virus spread across the southeast United States. As of September 2016, nearly 3,000 cases of Zika had been diagnosed in the United States. Transmission of the infection in these cases has been attributed to foreign travel (most common), local mosquito spread, sexual transmission, and laboratory exposure (CDC, 2016c). In addition to being carried by mosquitos, the Zika virus can be transmitted from mother to fetus, through sexual contact, via blood transfusion, and organ transplantation.

Clinical Manifestations In most cases, Zika virus infection causes a mild, self-limiting illness. In fact, more than 80% of the cases go unnoticed. The incubation period is thought to be 3–12 days. Most individuals will not experience any manifestations, but even when they do, manifestations are usually mild. Manifestations may include the following signs and symptoms:

Flulike symptoms (e.g., fever, lethargy, and joint pain) Rash—erythematous macules and papules over face, trunk, extremities, palms, and soles Nonpurulent conjunctivitis Muscle and joint pain Weakness and lack of energy Headache Dysesthesia (unpleasant abnormal sense of touch manifested as burning or itching) due to nerve involvement

In rare cases, complications of Zika infection can be severe. The most severe complications occur with maternal–fetal transmission and may include miscarriage and microcephaly (FIGURE 11-25). Additionally, the Zika virus can cause Guillain- Barré syndrome, myelitis, and meningoencephalitis.

FIGURE 11-25 Microcephaly. © Joa Souza/Shutterstock.

Diagnosis and Treatment Diagnostic procedures for Zika virus disease include a history, physical examination, and body fluid examination (e.g., blood, urine, saliva, and semen). The body fluids can be examined with real-time reverse-transcription polymerase chain reaction, which will detect Zika virus RNA and is recommended if the patient experiences symptoms for more than 14 days. While a positive Zika virus RNA confirms the diagnosis, a negative test does not exclude the disease, and an antibody should be conducted. High titers of Zika virus antibodies for IgM just indicate a flavivirus infection (also positive in dengue infection) and is not specific to the type. Treatment is primarily supportive and includes rest, hydration, analgesics, and antipyretics. Aspirin and nonsteroidal anti-inflammatory drugs should not be given until the patient is confirmed as not having a dengue infection as these drugs can cause hemorrhage in dengue. Men and women, whether symptomatic or not, need to refrain from engaging in unprotected sex for a few months after infection (the time frame varies from 8 weeks to 6 months). Prevention is paramount. It includes wearing protective covering, minimizing outdoor exposure, using an insect repellant containing DEET

(N,N-diethyl-meta-toluamide), using condoms, and abstaining from unprotected sex while pregnant if there is risk of exposure (e.g., travel to mosquito transmission areas or if the partner is infected).

Traumatic Neurologic Disorders Traumatic neurologic disorders vary significantly in severity and presentation depending on the location and extent of damage. Even minor injuries to the nervous system can have substantial effects on neurologic functioning. Traumatic injuries to the nervous system can result from a number of events that cause physical damage (e.g., motor vehicle accidents, gunshot wounds, and falls). Commonly, a number of these traumatic conditions overlap and occur concurrently (e.g., subdural hematoma and increased intracranial pressure).

Brain Injuries A traumatic brain injury (TBI) is usually caused by a sudden and violent blow or jolt to the head (called a closed injury) or a penetrating head wound (known as an open injury) that disrupts the normal brain function. However, not all blows or jolts to the head result in a TBI. With such injuries, the brain collides with the skull and any penetrating objects (FIGURE 11-26). These events can bruise the brain, damage nerve fibers, and cause hemorrhaging.

FIGURE 11-26 Comparison of closed and open traumatic brain injury.

According to the CDC (2019a), the main causes of TBI are falls (52%), motor vehicle accidents (20%), struck or hit against an object (28%). Intentional self harm has become the most common cause of death from TBI, surpassing motor vehicle accidents. TBIs range from mild to severe (e.g., from a brief change in mental status or consciousness to an extended period of unconsciousness or amnesia after the injury). Such injuries contribute to a substantial number of deaths and cases of permanent disability annually. According to the CDC (2019a), 2.87 million American sustained a TBI in 2014 and 556,800 died from this injury. The leading cause of TBI leading to emergency room and hospitalizations varied by age and include:

Falls highest in 0-17 year old and over age 55 Being struck by or against an object highest in 5 - 14 year olds Motor vehicle crashes high in adolescents and 15 to 44 year olds

Many TBIs result in a wide range of long-term and potentially life-altering complications such as changes in thinking, sensation, language, or emotions. These injuries can increase the risk for seizures, migraine headaches, chronic traumatic encephalopathy, Alzheimer disease, and Parkinson disease. Multiple mild TBIs can have a cumulative effect and result in neurologic dysfunction, cognitive deficits, and death. This damage can be seen in professional football players and the continuing research related to long-term effects of TBIs experienced by members of this group. These athletes, especially those who encounter routine impacts (e.g., linemen), have higher rates of cognitive deficits (e.g., memory impairment), depression, and possible neurologic diseases (e.g., Alzheimer disease and Parkinson disease).

TBIs are categorized as mild (i.e., concussion), moderate, or severe and can be either closed or open. Closed TBIs often result in a variety of conditions. Concussion describes a momentary interruption of brain function. Concussions usually result from a mild blow to the head that causes sudden movement of the brain, disrupting neurologic functioning. They may or may not lead to a loss of consciousness. Amnesia, confusion, sleep disturbances, dizziness, vertigo, and headaches may follow a concussion (i.e., postconcussive syndrome) for weeks or months; however, most are improved or resolved after one month. Cerebral contusion refers to a bruising of the brain accompanied by rupture of small blood vessels and edema. Most contusions result from a blunt blow to the head that causes the brain to make sudden impact with the skull. The initial area where the brain impacts the skull is referred to as the coup. The brain then rebounds and impacts the opposite side of the skull, causing another area of damage referred to as the contrecoup (Figure 11- 26). Contusions vary in severity depending on the extent of damage (e.g., focal or diffuse axonal injury; cerebral infarction and necrosis), presence of cerebral edema, and increased ICP. Bleeding can occur as a result of vessel injury. The types of bleeding can include epidural, subdural, subarachnoid, and intracerebral hematomas. The presence and severity of residual effects depend on these factors.

Open TBIs can result in serious issues. In addition to the tissue damage from the impact of the brain with the skull, such injuries can cause damage owing to the penetrating object and skull fragments. The skull fractures as the object breaches it. Much like when an egg is broken, the skull usually ends up in multiple pieces when it is struck by an external force. The resulting fracture may take the form of a linear skull fracture (a simple crack), a comminuted skull fracture (several fracture lines), a compound skull fracture (a fracture where the brain tissue is exposed), a depressed skull fracture (displacement of the bone fragments into the brain), or a basilar skull fracture (located at the base of the skull and usually accompanied by CSF leakage). In addition to the brain damage from impact and penetrating objects, open TBIs carry a higher risk for developing infections because they permit direct access to the brain by infectious organisms. As discussed in previous sections, infections of the nervous system can have serious consequences.

Clinical Manifestations Clinical manifestations of TBIs may be vague and develop slowly, or they may be sudden and severe. Symptoms may improve and then suddenly worsen. The outward appearance of the head is not an indication of the injury severity—serious injuries can occur even while the skin and the skull remain intact. When a TBI is suspected, the individual should be asked to give an account of the accident. Not being able to recall details is an indication of a TBI. The Glasgow Coma Scale (FIGURE 11-27) is the most commonly used clinical scale to grade the severity of the TBI. Mild TBI are classified as having a score of 13–15, while 9–12 is a moderate injury, and 8 or less is considered a severe injury. Limitations of the Glasgow Coma Scale include the use of medications that alter cognition (e.g., sedatives and paralytics), substance abuse (e.g., alcohol), and endotracheal intubation. Mild TBI findings were previously discussed. Manifestations of neurologic and cardiopulmonary compromise are likely with moderate to severe TBI. Some of the manifestations may include changes in behavior (e.g., irritability or unusual behavior), restlessness, or lethargy. There may be a loss of consciousness that can be prolonged (e.g., days to weeks), and retrograde amnesia may be present upon awakening. Brainstem injury and increased ICP signs include pupil asymmetry, unilateral or bilateral fixed and dilated pupils, posturing (decorticate or decerebrate; FIGURE 11-28), respiratory depression, irregular breathing pattern, hypertension, and bradycardia. TBI is a common cause of death and disability. For those who survive, neurologic deficits can include impairments such as altered motor movements (e.g., lack of coordination), changes in behavior, altered reasoning, and difficulty with written or verbal communication. The disabilities may be permanent. Some patients may remain in a vegetative or minimally conscious state.

FIGURE 11-27 Glasgow Coma Scale. Reproduced from Teasdale, G. & Jennett, B. (1974). Assessment of coma and impaired consciousness: A

practical solution. The Lancet, 2, 81–84. Copyright (1974), with permission from Elsevier.

C

FIGURE 11-28 Decorticate and decerebrate posturing. (A) Decorticate response: flexion of the arms, wrists, and fingers with adduction in the upper extremities; extension, internal rotation, and plantar flexion in the lower

extremities. (B) Decerebrate response: all four extremities in rigid extension with hyperpronation of the forearms and plantar extension of the feet. (C) Decorticate response on the left side of the body and decerebrate response

on the right side of the body.

Learning Points

Disorders of Consciousness onsciousness is a state of wakefulness and awareness, and both must be present for the patient to be deemed conscious. Wakefulness is mediated by the reticular activating system in the brainstem and is

evaluated with eye opening to command or to stimuli such as pain. Opening eyes is the clinical sign of wakefulness; however, just opening eyes is insufficient for the clinician to determine awareness. The ability to think and perceive indicates awareness and is a result of multiple coordinated activities throughout the brain. Awareness is determined by evaluating a purposeful response to a command, such as squeezing a hand or appropriate (nonreflexive) response to painful stimuli. Disorders of consciousness proceed into three levels— coma, vegetative state, and minimally conscious state. A coma is defined as a lack of awareness and lack of wakefulness. A coma generally lasts up to 3 weeks, after which a person goes into a vegetative state. The vegetative state can be a transition from coma to recovery, but it can also become permanent until death.

The vegetative state is defined as wakefulness without awareness. In TBI, the vegetative state must last more than 1 year to be considered permanent. In nontraumatic brain injury due to anoxic causes, the vegetative state must last 3 months in order to be considered permanent. A person can also transition from a coma to a minimally conscious state or from a vegetative state to a minimally conscious state. In a minimally conscious state, there is wakefulness and intermittent limited purposeful activities (e.g., following simple commands).

Diagnosis and Treatment Diagnostic procedures for TBI consist of a history, physical examination (including using the Glasgow Coma Scale) (Figure 11-27), head CT, head MRI, and ICP monitoring. Treatment strategies vary depending on the severity and the time since injury. Immediate emergency care for TBI focuses on limiting brain damage. Mild injuries usually require no treatment other than rest, analgesics (specifically acetaminophen [Tylenol]) if headache is present, and 24-hour observation in the hospital or at home if there is a reliable caregiver. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen (Motrin), should be avoided because they can increase bleeding risk. Cold compresses can be applied to any outward edema. Moderate to severe brain injuries usually require hospitalization, and patients with such damage often need intensive care. Blood pressure control and cerebral perfusion pressure must be maintained to prevent further injury. Ventilatory management and avoidance of hypoxia and abnormal carbon dioxide levels (high or low) are often necessary as these alterations can aggravate cerebral ischemia. Glucose levels (high or low) can worsen outcomes, so levels need to be maintained within a normal range. Patients with TBIs can display episodes of sympathetic hyperactivity such as tachycardia, hyperthermia, and diaphoresis. These episodes are managed with sedation (e.g., propofol, fentanyl, or midazolam) and

cardiovascular agents (e.g., propranolol or clonidine). Hyperthermia or fever will worsen outcomes, so antipyretics and external cooling devices may be necessary. Intracranial pressure can be managed by elevating the head of the bed to a minimum of 30° and maintaining the head in a neutral position. Osmotic diuretics (e.g., mannitol) or hypertonic saline may be given to reduce cerebral edema. Antiseizure medications may be necessary for prevention and treatment. A barbiturate coma with pentobarbital and thiopental may be necessary if ICP is refractory to other strategies. Therapeutic hypothermia can reduce ICP, but whether outcomes are improved is unclear. Surgery can be performed to remove blood or repair fractures. The rehabilitative phase is usually long and requires physical, speech, and occupational therapy to minimize and/or improve residual neurologic dysfunction.

Prevention strategies for TBIs include wearing a seat belt when driving or riding in a motor vehicle, using appropriate child safety seats, wearing a helmet when appropriate (e.g., when playing sports, riding a bicycle, or skating), making the home safe (e.g., removing tripping hazards, having adequate lighting, and using safety gates), storing firearms in locked cabinets, never driving impaired, and supervising children when playing.

Increased Intracranial Pressure Increased intracranial pressure describes increased volume (fluid or tissue) in the limited space of the cranial cavity. Increased ICP may occur because of a TBI and other conditions that would increase the volume in the skull (e.g., tumor, hydrocephalus, cerebral edema, and hemorrhage). The delicate pressure–volume relationship among ICP; volume of CSF (contributes 10%), blood (contributes 10%), and brain tissue (contributes 80%); and cerebral perfusion is explained by the Monro-Kellie hypothesis (FIGURE 11-29). The Monro-Kellie hypothesis states that the cranial cavity is incompressible, and the volume inside the cavity is fixed (normal ICP is 60–200 mm H2O or 4–15 mmHg) as ICP is a function of the volume and the compliance of each component. The skull and its components (blood, CSF, and brain tissue) create a state of volume equilibrium, such that any increase in the volume of one component must be compensated by a decrease in the volume of another component. This compensation is primarily accomplished by shifts in the CSF and, to a lesser extent, blood volume as brain tissue volume remains relatively constant. These fluids respond to increases in the volume of the remaining components. For example, an area of bleeding into the brain tissue (e.g., epidural hematoma) will be compensated for by the downward displacement of CSF and venous blood. Transient increases in ICP routinely occur with position changes, coughing, or sneezing. These compensatory mechanisms are able to maintain a normal ICP for changes in volume up to a point (approximately 100–120 mL of volume increases).

FIGURE 11-29 Monro-Kellie hypothesis.

In addition to shifting volumes, the brain has two other compensatory mechanisms to maintain tissue perfusion—autoregulation and Cushing reflex. With autoregulation, the blood vessels dilate to increase blood flow and constrict if the ICP is increased. Cushing reflex is a complex cascade of events that results in increased blood pressure. When the mean arterial pressure (average blood pressure) drops below the ICP, the hypothalamus increases sympathetic stimulation. This stimulation causes vasoconstriction, increased cardiac contractility, and increased cardiac output. If unresolved, the increased ICP eventually leads to a trio of effects known as Cushing triad—increased blood pressure, bradycardia, and changes in respiratory pattern (FIGURE 11-30). Baroreceptors in the carotid arteries detect the increase in blood pressure, triggering a parasympathetic response through vagal stimulation that induces bradycardia. Bradycardia may also be stimulated by the increased ICP impinging on the vagal nerve, causing a parasympathetic response. As pressure increases inside the skull, space becomes limited and the brain tissue shifts downward. An irregular respiratory pattern, called Cheyne-Stokes respiration (deeper, faster breathing followed by slower breathing and apneic episodes), and bradypnea typically result from increased pressure on the brainstem due to swelling or from brainstem herniation.

FIGURE 11-30 Vital sign changes with increased intracranial pressure.

Herniation—a feared complication of increased ICP—involves the displacement of brain tissue from a place of high pressure to a place of lower pressure. Several types of herniation are possible (FIGURE 11-31). In transtentorial (central) herniation, the cerebral hemispheres, diencephalon, and midbrain are displaced downward. The pressure created by this type of herniation impairs the cerebral blood flow, CSF, reticular activation system, and respirations. Uncal (uncinate) herniation occurs when the uncus (the hooklike anterior end of the hippocampal gyrus) of the temporal lobe shifts downward past the tentorium cerebelli (the extension of the dura mater that separates the cerebellum from the inferior portion of the occipital lobes). This type of herniation creates pressure on cranial nerve III, the posterior cerebral artery, and the reticular activation system. Cerebellar, or tonsillar (infratentorial), herniation occurs when the cerebellar tonsils (the rounded lobules on the

undersurface of each cerebellar hemisphere) are pushed downward through the foramen magnum. This type of herniation compresses the brainstem and vital centers, causing death. Cerebellar herniations can also go upwards due to pressure.

FIGURE 11-31 Types of herniation.

Regardless of the cause, increased ICP past the point of compensation compresses cerebral blood vessels and other structures as it shifts the brain’s

contents. Eventually, brain tissue dies. Increased ICP is a life-threatening situation that requires prompt treatment. If left unresolved, it causes declining neurologic function, leading to death.

Clinical Manifestations The clinical manifestations of increased ICP vary depending on the patient’s age and reflect the effects of the rising pressures:

Decreasing level of consciousness (results from pressure on the brainstem and cerebral cortex) Vomiting, often projectile (results from pressure on the medulla) Increasing blood pressure with increasing pulse pressure (the difference between systolic and diastolic pressure) (results from Cushing reflex) Bradycardia (response to the increasing blood pressure) Papilledema (results from increased pressure exerted by CSF, which causes swelling around the optic disk) Fixed and dilated pupils (results from pressure on cranial nerve III) Posturing (Figure 11-28)

Two manifestations of increased ICP are unique to infants:

1. Separated sutures 2. Bulging fontanelle

Manifestations in older children and adults include the following symptoms:

Behavior changes Severe headache (results from stretching of the dura and walls of the large blood vessels) Lethargy Neurologic deficits Seizures

Diagnosis and Treatment Diagnostic procedures for increased ICP consist of a history, physical examination (including completing the Glasgow Coma Scale), head CT, head MRI, and ICP monitoring. Increased ICP requires prompt diagnosis and treatment for optimal patient outcomes. Treatment strategies vary depending on the underlying etiology, and attempts should be made to resolve the source of the increased pressure if possible (e.g., remove a tumor or blood). Additional strategies are similar to those for

TBIs and may include respiratory support (e.g., oxygen therapy or endotracheal intubation with mechanical ventilation), semi-Fowler positioning, draining excess CSF, osmotic diuretics or hypertonic saline, corticosteroids (used for CNS infections and brain tumors), seizure precautions (e.g., low lighting and minimal stimulation), antiseizure agents, sedatives, stool softeners (because straining increases ICP), antiulcer agents (for those patients at high risk for stress ulcers), thermoregulation, blood pressure control, and glucose management. Rarely, surgical removal of a skull segment (decompressive craniectomy) may be performed.

Hematomas Secondary brain damage can be caused by additional injurious factors such as hemorrhaging. A hematoma is a collection of blood in the tissue that develops from ruptured blood vessels. Hematomas, which can develop immediately or slowly because of a TBI or surgery, are classified by their location (FIGURE 11-32).

FIGURE 11-32 Types of hematomas. (A) Beneath the dura but outside the brain (subdural hematoma). (B) Within the substance of the brain tissue (intracerebral hematoma). (C) Outside the dura and under the skull

(epidural hematoma).

Epidural hematomas result from bleeding between the dura and skull, usually caused by an arterial tear (e.g., the middle meningeal artery at the skull base is a common location). Because of the location, epidural hematomas do not cross

sutural margins. These bleeds are more common in adolescents and young adults as a result of trauma (e.g., accidents and assaults). Skull fractures are present in most patients with an epidural hematoma. Clinical manifestations of epidural hematomas include marked neurologic dysfunction that usually develops within a few hours of injury. The typical symptom pattern of an epidural hematoma is a brief loss of consciousness, followed by a short period of alertness, then deterioration over a period of hours manifested as headache, vomiting, confusion, aphasia, seizures, and hemiparesis, and loss of consciousness again. This pattern may not appear in all people. Subdural hematomas develop between the dura and the arachnoid, and are frequently caused by a small venous tear and, in fewer cases, an arterial rupture (FIGURE 11-33). In contrast to epidural hematomas, these bleeds can cross sutural margins but not dural attachments. Because they are usually the result of a venous tear, these types of hematomas generally develop slowly. Subdural hematomas follow several patterns. With acute subdural hematomas, manifestations of neurologic deficits present within 24 hours of an injury. Manifestations are similar to other those of other head injuries (e.g., headache and vomiting) and a lucid interval may also appear followed by deterioration and coma. This type of hematoma progresses rapidly and has a high mortality. With subacute subdural hematomas, ICP increases over a period of about a week after the injury. With chronic subdural hematomas, manifestations develop several weeks (usually 2 weeks or longer) after the injury because of a slow leak. The manifestations with chronic subdural hematoma appear insidiously, can be transient, and fluctuate. The manifestations include headache, light-headedness, sleepiness, and personality changes (e.g., apathy). Chronic subdural hematomas are more common in elderly adults because of the brain atrophy that occurs with age, which gives the hematoma more space to develop. Atrophy is also prevalent with chronic alcohol abuse or in those with prior TBIs.

FIGURE 11-33 Midline shift associated with right-sided subdural hematoma. Courtesy of Dr. Jason W. Schroeder, MD.

Intracerebral hematomas result from bleeding in the brain tissue itself. These types of hematomas are caused by contusion or shearing injuries but, more commonly, result from hypertension or vascular abnormalities (a common cause in children). Intracerebral hematomas are a common cause of hemorrhagic stroke. A subarachnoid hemorrhage results from bleeding in the space between the arachnoid and the pia. This type of hemorrhage is often due to the rupture of an intracranial aneurysm or vascular malformations while trauma is a less common cause. The primary clinical presentation is a severe headache that has a sudden onset and is worse near the back of the head or wherever the aneurysm is located. The headache is often described as the worst headache of the patient’s life and is often the only symptom.

In all types of hematomas, the bleeding leads to localized pressure on nearby tissue and increases ICP. Blood may coagulate and form a solid mass. The

I

hematoma becomes encapsulated by fibroblasts, and blood cells within the capsule lyse. The fluid from the hemolysis exerts osmotic pressure, drawing more fluid into the capsule. This edema increases the size of the mass, applying pressure on the surrounding tissue and increasing ICP. Bleeding can trigger vasospasms, worsening ischemia. Additionally, increasing ICP can result in herniation. Chronic subdural hematomas can also expand and cause a recurrent bleed referred to as an acute- on-chronic bleed.

Diagnosis and Treatment Diagnostic procedures for all types of hematomas and hemorrhaging consist of a history, physical examination (including completing the Glasgow Coma Scale), head CT, head MRI, cerebral angiogram, and intracranial pressure monitor. Treatment strategies depend on the location and bleeding severity. No treatment may be required in mild cases in which the volume is small and the bleeding has ceased. For many patients, surgical removal of the blood through a burr hole or a craniotomy is required. In some cases, however, removal of the blood may not be possible. In these situations, patients may experience significant residual neurologic deficits that require physical, speech, and occupational therapy. Strategies similar to those used for TBIs and increased ICP (e.g., respiratory management, seizure precautions, and thermoregulation) may be required.

Learning Points

Head Injury mmediately following a head injury, some key actions should be avoided:

Do not apply direct pressure to a bleeding site; cover the wound with sterile gauze. Do not wash a head wound that is deep or bleeding profusely. Do not remove any object sticking out of a wound. Do not move the person unless it is absolutely necessary. Do not shake the person if he or she seems dazed. Do not remove a helmet if you suspect a serious head injury. Do not pick up a fallen child with any sign of a head injury. Do not drink alcohol within 48 hours of a serious head injury.

Spinal Cord Injuries Spinal cord injuries (SCIs) result from direct injury to the spinal cord or indirectly from damage to surrounding bones, tissues, or blood vessels. SCIs are most common in Whites and in males (National Spinal Cord Injury Statistical Center, 2016). The average age for experiencing an SCI has increased from 29 years in the 1970s to 42 years today. SCIs are often caused by motor vehicle accidents, falls, violence, and sports injuries. Minor injuries to the spinal cord can occur because of weakening

vertebral structures (e.g., rheumatoid arthritis or osteoporosis). Direct damage can occur if the spinal cord is pulled, pressed sideways, or compressed (FIGURE 11-34). Such damage may occur, for example, if the head, neck, or back twists abnormally during an accident or injury. A fracture, dislocation, ligament tear, or intervertebral disc disruption or herniation may accompany the SCI. The cord can also be partially or completely transected as a result of penetrating injuries (e.g., gunshot or knife wounds).

FIGURE 11-34 Spinal cord injuries.

The primary injury occurs when there is direct impact to the cord. After the injury, a cascade of secondary events ensues, leading to further injury. The proposed