Literature review paper - Dental
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PeriodontalMedicine.PDF
Periodontal Medicine
Periodontal Medicine Louis F. Rose, DDS, MD Professor of Surgery and Medicine MCP Hahnemann School of Medicine Philadelphia, Pennsylvania and Clinical Professor of Periodontics University of Pennsylvania School of Dental Medicine Philadelphia, Pennsylvania
Robert J. Genco, DDS, PhD Distinguished Professor and Chair of Oral Biology State University of New York Buffalo, New York
D. Walter Cohen, DDS Chancellor-Emeritus MCP Hahnemann University of Health Sciences Dean-Emeritus University of Pennsylvania School of Dental Medicine Philadelphia, Pennsylvania
Brian L. Mealey, DDS, MS Chief of Periodontics Chief of Dental and Professional Services US Air Force Hospital Eglin Air Force Base Fort Walton Beach, Florida
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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs.
James D. Beck, PhD Kenan Professor Department of Dental Ecology University of North Carolina at Chapel Hill Chapel Hill, North Carolina
Sebastian G. Ciancio, DDS Professor and Chair, Department of
Periodontics and Endodontics Clinical Professor of Pharmacology, State
University of New York at Buffalo School of Dental Medicine
Buffalo, New York
D. Walter Cohen, DDS Chancellor-Emeritus, MCP Hahnemann
University of Health Sciences Dean-Emeritus, University of Pennsylvania
School of Dental Medicine Philadelphia, Pennsylvania
Joel Epstein, DDS, MSD Faculty of Dentistry, University of
British Columbia Department of Oral Medicine,
University of Washington, Seattle Department of Dentistry,
Vancouver General Hospital Dentistry, B.C. Cancer Agency Vancouver, Canada
Robert J. Genco, DDS Distinguished Professor and Chair of
Oral Biology, School of Dental Medicine, State University of New York at Buffalo
University Dental Associates Buffalo General Hospital Buffalo, New York
Michael Glick, DMD Professor, Department of Oral Medicine Director, Programs for Medically Complex
Patients, University of Pennsylvania Philadelphia, Pennsylvania
Sara G. Grossi, DDS, MS Clinical Director, Periodontal Disease
Research Center Department of Oral Biology School of Dental Medicine State University of New York at Buffalo Buffalo, New York
Carl W. Haveman, DDS, MS Staff, University Hospital Assistant Professor Department of General Dentistry The University of Texas Health Science
Center San Antonio, Texas
Palle Holmstrup, PhD, DrOdont Professor of Periodontology University of Copenhagen School of Dentistry Department of Periodontology Copenhagen, Denmark
Marjorie Jeffcoat, DMD University of Alabama School of Dentistry University of Alabama at Birmingham Birmingham, Alabama
Contributors
vi Contributors
Kenneth S. Kornman, DDS, Ph.D. University of Texas Health Science Center
at San Antonio San Antonio, Texas Harvard University Boston, Massachusetts
Brian Mealey, DDS, MS Chief of Periodontics Chief of Dental Professional Services US Air Force Hospital Eglin Air Force Base, Florida Clinical Assistant Professor Department of Periodontics University of Texas Health Science Center San Antonio, Texas
Robert E. Mecklenburg, DDS, MPH Coordinator, Tobacco and Oral Health
Initiatives, Tobacco Control Research Branch, National Cancer Institute
Potomac, Maryland
Michael G. Newman, DDS University of California School of Dentistry Section of Periodontics Pacific Palisades, California
Steven Offenbacher, DDS Professor and Director Center for Oral and Systemic Diseases University of Carolina School of Dentistry Chapel Hill, North Carolina
Spencer W. Redding, DDS, MEd Staff, University Hospital Professor, Department of General Dentistry The University of Texas Health Science
Center at San Antonio San Antonio, Texas
Louis F. Rose, DDS, MD Professor of Surgery and Medicine MCP Hahnemann School of Medicine Clinical Professor of Periodontics University of Pennsylvania School of
Dental Medicine Philadelphia, Pennsylvania
Terry D. Rees, DDS, MSD Periodontics Department Baylor College of Dentistry Dallas, Texas
Frank A. Scannapieco, DMD, PhD Department of Oral Biology School of Dental Medicine Associate Professor State University of New York at Buffalo Buffalo, New York
Harold C. Slavkin, DDS Director, National Institute of Dental and
Craniofacial Research Laboratory Chief, Craniofacial Developmental Biology National Institute of Arthritis,
Musculoskeletal, and Skin Disease Bethesda, Maryland
Barbara J. Steinberg, DDS Professor of Surgery and Medicine MCP Hahnemann School of Medicine Clinical Assistant Professor of Oral Medicine University of Pennsylvania School of Dental Medicine Philadelphia, Pennsylvania
Edwin J. Zinman, DDS, JD Former Lecturer, University of California
at San Francisco San Francisco, California
To my beautiful granddaughter, Cameron Sara, who has brought so much love and joy into my life. To my mother-in-law, Helen Aberbach, whose love and kindness will remain with me for- ever. And to my wife, Claire, and children, Michael, David, and Hedy, whose unconditional love and support have allowed me to pursue my professional dreams.
Louis F. Rose
To D. Walter Cohen, Henry Goldman, Nicholas Marfino, James English, Fred Karush, and Art Ellison. These mentors instilled in me their intense appreciation for the role of the host in mod- ulating oral diseases, and for the effect of oral disease on the rest of the body.
Robert J. Genco
To the late Russell Ross, DDS, PhD, one of the most distinguished scientists of the Twentieth Century.
D. Walter Cohen
To my loving wife Carla, who has supported me in every endeavor and has given me the most beautiful family a man could ever have. I also devote this undertaking to the honor of my mother, Jeanne C. Mealey, who taught me the value of a challenge, who showed through her personal example the gains derived from sacrifice, and who demonstrated that love and devotion overcome all difficulties.
Brian L. Mealey
Over the past 70 years, a number of astute clinicians in the field of dental medicine have observed and recorded the relationship between periodontopathies and systemic manifestations of disease. The influence of systemic conditions on the oral environment, and especially the periodontium, has long been recognized and supported by scientific evidence. However, an evidence base for the influence of periodontal diseases on overall systemic health has only recently begun to be estab- lished. Fascinating research has eroded the tradition-bound concept that oral infections such as periodontitis are simply local entities whose effects are limited to the oral tissues. While the clini- cal observations of many practitioners have long suggested that periodontal diseases can have widespread systemic effects, only recently has rigorous scientific investigation supported this con- cept. The information in this text has not been collected in this format previously, and one of the goals of the authors is to offer the material to physicians, dentists, and other health-care profes- sionals collaborating in treatment of patients with periodontal disease who may also have systemic involvement. This will allow the practicing clinician to enhance the medical-dental interface when evaluating a patient and will contribute to a continuing dialogue between the dentist and physician. We are hopeful that this information will stimulate new collaborations between physicians and dentists and serve as a basis for further studies to help improve the total health of our society. This effort should also prove useful to medical and dental students as well as those in residency train- ing and post-doctoral studies.
Bridging the gap between the dental and medical professions will provide better education, research and patient care. Our purpose is to provide existing evidence that supports and strength- ens the association and relationships between periodontal diseases and systemic diseases/condi- tions. The information presented will demonstrate the practical application in day to day practice.
Our sincere gratitude to the many excellent contributors to this volume and sincere appreci- ation to their families who sacrificed to make this a timely and valuable publication. We applaud Mr. Brian Decker for inspiring the authors to assemble this material in an effective and expedi- tious manner and the support provided by his excellent editorial staff. Our heartfelt thanks to the various federal agencies, corporations and foundations, who had the courage and creativity to sup- port the numerous studies that are reported in this volume.
Dr. Genco would like to thank his colleagues at the University of Buffalo, School of Dental Medicine, who have supported and contributed to our efforts in this emerging science, particu- larly Lou Goldberg for unfailing support of our efforts in periodontal medicine. He thanks his wife, Sandra, for her patience with his hectic schedule which intensified during the editing of the text. She was a wonderful sounding board for ideas about the importance of good health. He also wishes to thank Rose Parkhill for her unceasing efforts in preparing materials, editing, and per- forming other tasks that are so essential in making such a book possible.
The Editors August, 1999
Preface
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii
CHAPTER 1 Periodontal Disease and Systemic Disease . . . . . . . . . . . . . . . . . . . . . . . . . 1 D. Walter Cohen, DDS, Harold C. Slavkin, DDS
CHAPTER 2 Risk Factors for Periodontal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Robert J. Genco, DDS, PhD
CHAPTER 3 Clinical History and Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Louis F. Rose, DDS, MD, Barbara J. Steinberg, DDS
CHAPTER 4 Role of Genetics in Assessment, Risk, and Management of Adult Periodontitis . . . . . . . . . . . . . . . . . . . . . . . . . 45 Kenneth S. Kornman, DDS, PhD, Michael G. Newman, DDS
CHAPTER 5 Cardiovascular Diseases and Oral Infections . . . . . . . . . . . . . . . . . . . . . . 63 Robert J. Genco, DDS, PhD, Steven Offenbacher, DDS, James Beck, PhD, Terry Rees, DDS, MSD
CHAPTER 6 Relationships between Periodontal and Respiratory Diseases . . . . . . . . . . . 83 Frank A. Scannapieco, DMD, PhD
CHAPTER 7 Tobacco Use and Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Robert E. Mecklenburg, DDS, MPH, Sara G. Grossi, DDS, MS
CHAPTER 8 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Brian Mealey, DDS, MS
CHAPTER 9 Periodontal Medicine and the Female Patient . . . . . . . . . . . . . . . . . . . . 151 Joan Otomo-Corgel, DDS, MPH, Barbara J. Steinberg, DDS
CHAPTER 10 Osteopenia, Osteoporosis and Oral Disease . . . . . . . . . . . . . . . . . . . . . . 167 Sara G. Grossi, DDS, MS, Marjorie K. Jeffcoat, DMD, Robert J. Genco, DDS, PhD
Contents
x Contents
CHAPTER 11 HIV Infection and Periodontal Diseases . . . . . . . . . . . . . . . . . . . . . . . . 183 Michael Glick, DMD, Palle Holmstrup, PhD, Dr. Odont
CHAPTER 12 Periodontal Disease and Periodontal Management in Patients with Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Joel B. Epstein, DMD, MSD, FRCD(C)
CHAPTER 13 Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants . . . . . . . . . . . . . . . . . . . . . . . 205 Terry D. Rees, DDS, MSD
CHAPTER 14 Bleeding Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 Spencer W. Redding, DDS, MEd, Carl W. Haveman, DDS, MS
CHAPTER 15 Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Sebastian G. Ciancio, DDS
CHAPTER 16 Medicolegal Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Edwin J. Zinman, DDS, JD
CHAPTER 1
PERIODONTAL DISEASE AND SYSTEMIC DISEASE D. Walter Cohen, DDS Harold C. Slavkin, DDS
Health sciences are in the midst of major transi- tions. The scientific and technologic paradigms of dentistry, medicine, nursing, and pharmacy are changing as well as the management and financing of health care, the demographics of the United States, the patterns of disease, and even the public’s expectations for “quality of life.” Marked variations in disease occurrence and survival exist among dif- ferent subgroups of the population of the United States. Some of these are attributable to factors such as age, gender, ethnicity, sexual orientation, geographic locations, and socioeconomic status. This chapter describes the scientific advances and responsibilities for health professionals, to help them revisit how we address the connections between a number of oral microbial infections and major systemic diseases and how we manage the oral complications of systemic diseases.
On a macro level, scientific and technologic advances are defining new paradigms for dentistry, medicine, nursing, and pharmacy to which tradi- tional theory may not apply. Improved under- standing of human biology at the molecular level is rapidly advancing and may make invasive surgery, intensive care units, and long-term home care, for example, far less necessary in the not too distant future. Costly and often clinically inadequate interventions may soon be replaced by the postge- nomic products of gene-based diagnostics and therapeutics, innovations from bioengineering and biomaterials, and progress toward understanding individual, family, and community behaviors.
Advances over infectious diseases have been hindered by changes in the patient population. Increasingly older and medically compromised patients, including immunosuppressed ones, now constitute a significant proportion of the seriously
infected population. Health professionals use immunosuppressive drugs in patients to prevent the rejection of transplants, and patients can become immunosuppressed as a consequence of many of the treatments for neoplastic and inflammatory diseases. Some infections, most notably those caused by the human immunodeficiency virus (HIV), immuno- compromise the host in and of themselves. Lesser degrees of immunosuppression are associated with many other infections, such as influenza, viral meningitis, and a number of sexually transmitted diseases, such as syphilis. The microenvironment of immunosuppression can induce the prominence of once obscure microbes, such as Pneumocystis carni, Cryptosporidium parvum, Mycobacterium avium, and Candida albicans.
There is growing evidence that a number of complex human diseases are caused or profoundly influenced by opportunistic infections, such as in Legionnaire’s disease, Lyme disease, gastric ulcer and gastric cancers, a number of other malignan- cies, cardiovascular disease, low-birth-weight pre- mature babies, and osteoarthritis. As a conse- quence, there has been a resurgence of interest in oral microbial ecology, so-called “biofilms,” mucosal immunity, and systemic diseases through- out the human lifespan. This renewed interest is taking place at a time when advances in epidemi- ology, microbiology, immunology, molecular biol- ogy and cell biology have enabled meaningful questions regarding oral infections and systemic diseases to be addressed.
This chapter introduces the theme of oral infection associated with systemic diseases and highlights the rapidly expanding understanding of microbial ecology, mucosal immunity, and com- plex human diseases.
2 Periodontal Medicine
ORAL INFECTION AND SYSTEMIC DISEASE: A PARADIGM SHIFT
The adult human body consists of 1013 somatic cells, and 1014 normal or commensal mirobes. These commensal bacteria reside on the surfaces of teeth and/or prosthetic implants within complex ecosystems termed “biofilms,” and they reside on the surfaces of the mucosal epithelia that line the oral cavity, respiratory tract, esophagus, gastroin- testinal tract, and urinary tract. Under a variety of conditions, some of these microorganisms become opportunistic and are associated with local or sys- temic infections, such as Hemophilus influenza, Streptococcus pneumonia, Neisseria meningitis, and Staphylococcus aureus infection.
The oral cavity contains almost half the com- mensal bacteria in the human body; approximately 6 billion microbes representing 300 to 500 species reside in the oral cavity. The oral microbial ecosys- tem is remarkably dynamic. During human devel- opment, viruses, bacteria, and yeast are transmitted from mother to child and, in addition, microbes are transmitted from caretaker to child, from spouse to spouse, and can be also acquired from the environment.
The oral microbial ecology is extremely sensi- tive to the potential insults that confront the human hosts throughout their lifespan. From fetal life through senescence, the oral cavity is continu- ously challenged by opponunistic infections on the one hand and the oral complications of systemic diseases and disorders on the other. These dynam- ic interactions between hosts and pathogens are the essence of a paradigm shift in oral medicine. There is growing evidence that oral bacteria contribute to systemic disease. One of the best documented examples is the involvement of the gram-positive Streptococcus sanguis and Streptococcus oralis in infective endocarditis.
An association between oral infections and systemic diseases has been suspected for centuries. The effect of oral health on the rest of the human body was proposed by the Assyrians in the sev- enth century BC. In the 18th century, a Pennsyl- vania physician named Benjamin Rush was quot- ed as remarking that arthritis could be treated in some people after they had infected teeth extract- ed. Over the past decade, a growing body of sci- entific evidence suggests an exquisite association between oral infection (eg, viruses, bacteria, yeast) and systemic diseases (eg, atherosclerosis, cardio- vascular disease, cerebrovascular disease, prematu- rity and low birth weight, and pulmonary diseases
and disorders) and also between systemic diseases (eg, arthritis, diabetes, HIV infection, and osteo- porosis) and oral, dental, and craniofacial diseases and disorders.
Transmissible and opportunistic microorgan- isms are responsible for dental caries. Transmissible and opportunistic microorganisms are also respon- sible for periodontal diseases. In the case of peri- odontal diseases, the microbial-induced infection presents a substantial infectious burden to the entire body. Further, specific microorganisms with- in the microbial ecology associated with the disease process release toxins that invoke an inflammatory response. Bacteria, bacterial toxins, localized tissue response cytokines, and other inflammatory medi- ators enter the vascular circulation and may acti- vate a systemic response. The subsequent patho- genesis of the disease process reflects gene–gene and gene–environment interactions. Nested in a complex interaction of host susceptibility, external exposures, and life-style behaviors, the manage- ment of health and disease will require interdisci- plinary education, strategies, and health-care deliv- ery. These scientific and technologic advances are creating new paradigms.
ANATOMIC PRIMER OF THE PERIODONTIUM
The following provides an anatomic primer of the periodontium to facilitate the reader’s understand- ing of this chapter and those to follow. The perio- dontium includes those tissues that invest and sup- port the tooth—the gingiva, the cementum cover- ing the root surfaces of each tooth, the periodontal ligament that attaches the tooth root surface to the adjacent alveolar bone process that supports each tooth, and the alveolar bone. The gingiva covers the structures that comprise the attachment appa- ratus (cementum, ligament, and adjacent alveolar bone). The gingiva is divided into free and attached gingiva. The free gingiva extends from the base of the gingival sulcus to the gingival margin. The tissues extending from the bottom of the sul- cus to the mucogingival junction are those that comprise the attached gingiva. Apical to the mucogingival junction, the alveolar mucosa is con- tinuous with the mucous membrane of the lip, cheek, and the floor of the mouth.
The adult dentition presents the gingival mar- gin located on the enamel surface approximately 0.5 to 2.5 mm coronal to the cervical line of each tooth. The gingival margin is rounded and is adja-
Periodontal Disease and Systemic Disease 3
cent to the opening of the gingival sulcus, which is normally 2 to 4 mm in depth. Placing of a cali- brated instrument, such as a periodontal probe, into the gingival sulcus provides the clinician with a measurement referred to as the probing depth.
The term “pocket” is used to describe the histopathology in the soft and possibly the under- lying bony tissues, reflecting an inflammatory response to oral infection. “Pocket” is used to dif- ferentiate from the healthy gingival sulcus. The gingival sulcus contains fluid. The gingival sulcus fluid in disease reflects inflammation as measured by the levels of cytokines and tissue necrosis factor. Pocket depth and pocket levels of cytokine bio- markers can be used to monitor health and disease.
There are two major forms of periodontal dis- ease (Table 1–1). One is gingivitis, in which the most apical portion of the junctional epithelium is on the enamel, or at or near the cementoenamel junction (Table 1–2). Periodontitis occurs when the periodontal ligament, the connective tissues that attach the tooth to the Alveolar Bone is destroyed by the inflammatory process. This is associated with apical migration of the junctional epithelium onto the root surface beyond the cementoenamel junction. Periodontal disease occurs in the presence and absence of systemic conditions (Table 1–3). For example, gingivitis may occur simply associated with dental plaque, in which case it is called marginal gingivitis. It may also occur as a result of systemic involvement such as gingivitis in AIDS patients and hyperplas- tic gingival conditions associated with intake of drugs such as phenytoin, cyclosporine, nifedipine, and the dihydropyridines.
Periodintitis occurs as two major forms: adult and juvenile or early onset. The adult form may occur in the presence or absence of systemic com- plications. Juvenile forms are usually associated with abnormalities in neutrophil functions.
Structure of the Periodontium
The gingival tissues are covered with keratinized and parakeratinized epithelia. The gingival epithe- lium has three components: oral, sulcular, and junctional. The underlying dermis or connective tissue beneath the gingival epithelium connects the gingiva to the tooth root cementum and the adja- cent alveolar process (Figure 1–1). The gingiva is firm and is tightly attached to the tooth and the alveolar process by the supra-alveolar connective tissue fibers. The gingival tissues are covered with oral epithelium which is usually keratinized.
The lining of the gingival sulcus is sulcular epithelium which resembles the oral epithelium but is not keratinized. The base of the sulcus is formed by the junctional epithelium, which consists of a thin layer of epithelium that joins the gingival con- nective tissue to the tooth surface (Figure 1–1). In recently erupted teeth, the junctional epithelium extends from the bottom of the gingival sulcus to the apical border of the enamel tooth surface. The thickness of epithelial tissue varies from 15 to 30 cells in the vicinity of the gingival sulcus to as few as 1 cell at its apical extension. The junctional epithelim is not keratinized. The sulcular and junc- tional epithelia form the critical anatomic location at which bacterial biofilms of the subgingival microbiota interact with host defense mechanisms.
Supra-alveolar Connective Tissue
The dermis of the gingiva coronal to the alveolar crest comprises the supra-alveolar connective tissue and consists of fibers, cells, blood vessels, and nerves, in a rich dense connective tissue. The princi- pal cell is the gingival fibroblast, which produces the main elements of the connective tissue. There are also undifferentiated mesenchymal cells, macro- phages, and mast cells. Types I and III collagen, elastin, and fibronectin, along with proteoglycans, assemble into the reticular fibers that are observed beneath the basement membrane adjacent to the epithelium, and they are also seen in the connective tissue stroma associated with blood vessels. The greatest part of the gingival connective tissue are the collagen fibers; some are arranged in distinct bun- dles with a definite orientation. There are bundles that run around the tooth in a ring-like pattern and are referred to as circular fibers. Interdentally, there are bundles that run from the cementum of one tooth to another and are called the trans-septal fibers. Other fibers may not be in a distinct pattern. The dentogingival fibers are bundles that arise from
TABLE 1–1. Diseases of the Periodontal Tissues
I. Gingival diseases and conditions A. Gingivitis (no systemic involvement) B. Gingivitis and gingival changes with systemic
involvement
II. Periodontal Diseases and Conditions A. Periodontitis in adults (no systemic involvement) B. Periodontitis in juveniles C. Periodontitis with systemic involvement D. Occlusal traumatism
4 Periodontal Medicine
the cementum and run parallel to the sulcus. Anoth- er group runs at right angles to the root surface; yet another group emerges from the cementum, passes over the alveolar crest, and blends with the mucope- riosteum of the gingiva, and these fibers are called dento-peristeal fibers.
Blood Supply of Gingiva
The gingival tissues are rich in blood vessels, which have their origins from the supraperiosteal vessels originating from the lingual, mental, buccinator, and palatine arteries. These vessels give off branches along the facial and oral surfaces of the alveolar process. Branches of the alveolar arteries may penetrate the interdental septa or from the coronal parts of the periodontal ligament. Numerous capillaries are seen immediately below the basement membrane of the sulcular, junctional, and oral epithelium.
Clinical Criteria of Healthy Gingiva
Healthy gingiva is usually pink in color, well adapt- ed to the teeth, with a stippled surface texture, and bound tightly to the underlying alveolar process and the roots of the dentition (Figure 1–2). The gingival sulcus varies in depth from 1 to 3 mm and shows no signs of bleeding when probed. Histolog- ically, it has been shown that a small number of lymphocytes and plasma cells are observed in the connective tissue of the gingiva under the sulcular epithelium in health gingiva as elsewhere in the gas- trointestinal tract.
Attachment Apparatus
Attachment of the tooth to the alveolus consists of numerous bundles of collagenous tissue (principal fibers) arranged in groups in between, which is loose connective tissue together with blood vessels, lymph vessels, and nerves. This attachment appa- ratus functions as the investing and supporting mechanism for the tooth. It comprises the cemen- tum of the tooth, the periodontal ligament, and the alveolar process. The periodontal ligament is the tissue that surrounds the roots of the tooth and attaches it to the bony alveolus. Cementum is the hard tissue covering the anatomic roots of the teeth. The alveolar process is made up of the alve- olar bone and supporting bone and the outer cor- tical bone. The alveolar bone that lines the tooth socket is termed the lamina dura. In addition to its supportive function, the dentoalveolar unit has sensory, nutritional, and formative roles to play.
TABLE 1–2. Gingival Diseases and Conditions
A. Gingivitis 1. Marginal gingivitis 2. Acute necrotizing ulcerative gingivitis (ANUG)
B. Gingivitis and other gingival changes with systemic involvement
1. Gingival changes associated with sex hormones a. “Pregnancy” gingivitis b. Gingivitis associated with oral contraceptives c. Gingivitis associated with other hormonal
alterations (eg. Polycystic ovaries, puberty, and menopause)
2. Gingival changes associated with diseases of the skin and mucous membranes
a. Pemphigus b. Cicatrical pemphigoid c. Bullous pemphigoid d. Lichen planus e. Psoriasis f. Desquamative gingivitis g. Lupus erythmatosus h. Erythma multiforme i. Idiopathic gingival fibromatosis j. Recurrent aphthous stomatitis
3. Gingivitis in generalized systemic diseases a. Diabetes b. Acute leukemia c. Thrombocytopenia d. Hemophilia e. Sturge-Weber syndrome f. Wegener’s granulomatosis g. Sclerosis h. Hypodrenocorticism i. Vitamin C deficiency j. AIDS k. Sarcoidosis
4. Infective gingivostomatitis a. Herpetic gingivostomatitis b. Herpes zoster c. Herpangina d. Syphilis e. Candidiasis f. Actinomycosis g. Histoplasmosis
5. Drug-associated gingival changes a. Systemic medications
i. Phenytoin (Dilantin) ii. Sodium valproate iii. Cyclosporine iv. The dihydropyridines: nifedipine
(Prodardia) and nitrendipine b. Compounds with local effects
i. Caustic compounds ii. Heavy metals
Periodontal Disease and Systemic Disease 5
Cementum
Cementum is the calcified tissue that covers the roots of the teeth and is deposited during tooth formation. There are two types of root cementum: acellular and cellular. The acellular type is clear and structureless and is formed by cementoblasts, which do not become embedded in it as they do when the cellular type is formed. Those collagen fibers that become embedded in the cementum are known as Sharpey’s fibers (Figure 1–3). Most of the root is covered by acellular cementum, with cellular cementum forming on the apical portions of the root. Cellular cementum is bone-like, with the cementocytes embedded in it. Cementum is unlike bone in that it does not remodel throughout life. Incremental lines of cementum deposition are seen with the aging of the individual. These dark- staining lines also reflect the activities or function of the tooth, with cementoblasts continuing to line the cemental surface throughout life and compen- sating for the physiologic movements of the tooth within the attachment apparatus.
Alveolar Process
The alveolar process consists of osseous tissue, and the alveolar bone is the portion that lines the tooth socket. It is thin compact bone containing small openings through which blood vessels, nerves, and lymphatics pass. The alveolar bone contains the embedded ends of the connective tis- sue fibers of the periodontal ligament known as Sharpey’s fibers (see Figure 1–3). The supporting bone is the cancellous bone between the alveolar bone and the cortical plates. This supporting bone or spongiosa makes up the greatest part of the interdental septum but is much more active than cementum, showing areas of resorption and depo- sition. It is composed of a network of osteocytes and extracellular matrix. The calcified portion consists of apatite crystals. Alveolar bone is deposited next to the periodontal ligament by the osteoblasts and is reinforced by the supporting bone. Larger vessels are found in the inter-radicu- lar bony process and branches from them to enter the periodontal ligament through the numerous openings in the cribiform plate.
Periodontal Ligament
The fibers of the periodontal ligament that attach the tooth to the alveolar bone are arranged in groups according to their direction, with the alve-
TABLE 1–3. Periodontal Diseases and Conditions
A. Periodontitis in adults 1. AAP Classification I, II, III, IV 2. Epidemiologic; moderately and rapidly pro-
gressing periodontitis 3. Clinical based on treatment; refractory and
recurrent 4. Clinical based on history; recurrent acute
necrotizing ulcerative periodontitis and postlo- calized juvenile periodontitis
B. Periodontitis in juveniles 1. Localized juvenile periodontitis 2. Generalized juvenile periodontitis
C. Periodontitis with systemic involvement 1. Periodontitis in primary neutrophil disorders
a. Agranulosytosis b. Cyclic neutropenia c. Chediak-Higashi syndrome d. Neutrophil adherence abnormalities e. Job’s syndrome f. “Lazy leukocyte” syndrome g. Neutrophil functional syndrome
2. Periodontitis in systemic diseases with sec- ondary or associated neutrophil impairment a. Diabetes mellitus type I b. Diabetes mellitus type II c. Papillon-LeFevre syndrome d. Down’s syndrome e. Inflammatory bowel disease: Crohn’s disease f. Preleukemic syndrome g. Addison’s Disease h. AIDS
3. Other systemic diseases associated with changes in the structures of the periodontal attachment apparatus a. Ehlers-Danlos syndrome (VIII) b. Histiocytosis (Cosinophilic granuloma) c. Sarcoidosis d. Scleroderma e. Hypophosphatasia f. Hypoadrenocorticism g. Hyperthyroidism
D. Miscellaneous conditions affecting the periodontium 1. Periodontal abscesses 2. Periodontal cysts 3. Ankylosis 4. Root resorption 5. Periodontal-pulpal communicating lesions 6. Pericoronal abscesses 7. Dentinal hypersensitivity 8. Retained roots 9. Bony sequestration 10. Infections associated with fractured roots, or
anatomic defects 11. Neoplasms of the attachment apparatus
E. Occlusal traumatism
6 Periodontal Medicine
olar crest fibers running from the alveolar crest to the cementum. The horizontal fibers pass in a per- pendicular fashion from tooth to bone. Most of the fibers are in the oblique group, which run from the alveolus in an apical direction to the cemen- tum. The apical fiber group surrounds the apex of the root. In multirooted teeth, the fibers running from the inter-radicular crest to the furcation are called the inter-radicular fibers.
The ligament is made up of collagen fibers, which are arranged in bundles (see Figure 1–3). Research suggests that there is a high turnover of
collagen in the ligament. It has been observed that the fibers on the cementum side are numerous and relatively thin; they tend to spread out and are interwoven into a network that makes up the greatest width of the ligament. On the bone side, the fiber bundles are fewer in number and are of greater diameter than on the cementum side.
The ligament contains a network of blood ves- sels and lymph vessels as well as nerve bundles. These vessels are closer to the alveolar side of the lig- ament and connect with larger vessels in the marrow spaces through the perforations in the alveolar bone.
The cellular components of the periodontal ligament include fibroblasts, cementoblasts, osteoblasts, osteoclasts, and epithelial cell rests.
Regenerative Capacity
The attachment apparatus has been shown to regen- erate in certain surgical therapies. The periodontal ligament behaves as a double periosteum, giving rise to the cells that form cementum, bone, and connec- tive tissue as well as numerous growth factors. This capability is of great value to the clinician who is seeking to restore lost supporting tissues.
ORAL INFECTION, SYSTEMIC DISEASE,AND THE GENETIC PARADIGM
The host’s reaction to invading microbes (viruses, bacteria, yeast) involves a rapidly amplifying polyphony of signals and responses that may spread beyond the invaded tissue. Fever or hypothermia, tachypnea, and tachycardia often herald the onset of the systemic response to micro- bial invasion and may be described as bacteremia (viable bacteria in the blood), fungemia (viable yeast in the blood), or septicemia (systemic illness caused by the spread of microbes in the blood).
Commensal bacteria living on tooth and mucosal epithelial cell surfaces create an interactive system, in which the host synthesizes and secretes various immunoglobulins and antibacterial pep- tides that control this remarkable eucaryotic/ procaryotic ecosystem.
Molecular medicine and dentistry are defined as the use of genotypic analysis (DNA testing) to enhance the quality of health care, including presymptomatic identification of predisposition to disease, preventive interventions, selection of phar- macotherapy, and the design and fabrication of gene-based diagnostics and therapeutics.
Figure 1–1. Histology of the healthy periodontium. E = enamel; C = cementum of the root surface; CEJ = cemento- enamel junction; D = dentin; OE = oral epithelium; SE = sulcular epithelium; JE = junctional epithelium; GCT = gin- gival connective tissue; AB = alveolar bone; PDL = peri- odontal ligament. In health, the junctional epithelium form- ing the base of the sulcus termiantes at or near the cemento- enamel junction (CEJ). Gingival connective tissue fibers and the fibers of the periodontal ligament insert into root surface cementum. In inflammatory periodontal disease, the con- nective tissue attachment is destroyed, allowing the juction- al epithelium to migrate apically. Alveolar bone is also destroyed. The overall effect is a deepening of the gingival sulcus (“pocket”) and a loss of support for the tooth.
E
JE
GCT
GCT
AB
PDL
SE
C
D
CEJ
OE
C
Periodontal Disease and Systemic Disease 7
Genomic progress continues to change the practice of dentistry and medicine. Gene-based diagnostics for viral, bacterial, and yeast infections as well as the numerous clinical applications through- out the human lifespan are continuing to enhance health care. Gene testing for inherited diseases as well as for predisposition to diseases or disorders has enormous potential benefits to improve health care. During 1998, more than 30,000 human genes were isolated, sequenced, and mapped to specific loca- tions on one of the 23 pairs of human chromo- somes. By the year 2003, the complete nucleotide sequence of the approximately 100,000 structural and regulatory genes that comprise the human genetic lexicon will be completed. In tandem, the genomes of many significant microbes and animals are also being deciphered, including those of virus- es, bacteria, yeast, parasites, plants, animals (eg, fruit fly, zebrafish, mouse, rat), and data from these genomes are being used to revolutionize our think- ing about biology, health, and disease. Completion of the microbial genomes of opportunistic viral, bacterial, and yeast species (putative pathogens) as well as the human genome may provide even faster progress in the diagnostics and therapeutics related to oral infections, systemic diseases, and the oral complications of systemic diseases.
Perhaps with the sole exception of trauma, essentially all human diseases are genetic. Genetic dentistry and medicine are based on the paradigm that changes or mutations in individual genes or alleles result in inherited diseases. For example, mutations in the amelogenin gene located on the human X and Y chromosomes can produce X- linked dominant or recessive amelogenesis imper- fecta; mutations in the fibroblast growth factor receptor 2 gene can produce Crouzon syndrome as well as other craniofacial syndromes with cran- iosynostosis; or mutations in a number of tran- scription factors that regulate development can pro- duce craniofacial malformations. These and other scientific discoveries are rapidly defining single- gene mutations, mapping these individual genes in their precise positions on human chromosomes, and are being used to diagnose inherited clinical phenotypes throughout the human lifespan. More- over, these advances in human molecular genetics are identifying candidate genes for developing tar- geted gene-mediated therapeutic approaches to many clinical problems.
Gene mutations define not only the virulence of microbes (viruses, bacteria, yeast, and parasites) but also the fidelity of the human immune system. Of course, microbial as well as human genes are
extremely sensitive to environmental “stress” and can and do mutate or change resulting in multidrug and/or antibiotic resistance. The genetic variance within microbial genomes, such as that of Candida albicans, may be closely aligned with the host changes associated with immunologically compro- mised patients. The HIV viral genome is another particularly useful model for considering viral muta- tion frequency within the human population.
Moreover, genes are also the foundation of even more complex human diseases. First, multiple mutations that are acquired can produce cancers. We now appreciate that all cancers are genetic and that most cancers are not inherited but rather result from acquired multiple mutations. Oropha-
Figure 1–2. Clinical appearance of healthy gingival tissue in a 60 year old female. The gingival tissues are pink and firm. No areas of redness or inflammation are seen. The depth of the gingival sulcus ranges approximately from 1 to 3 mm and does not bleed following probing.
Figure 1–3. Periodontal ligament between the root surface and the alveolar bone. Collagen fibers of the periodontal lig- ament are arranged in bundles. These fibers (Sharpey’s fibers) connect the cementum on the root surface to the alve- olar bone. The collagen fibers are destroyed by proteases dur- ing inflammatory periodontal disease, allowing the epitheli- um of the pocket to migrate apically.
8 Periodontal Medicine
ryngeal cancer is the sixth most common neoplas- tic disease; one American dies every hour of oral cancer. The major “risk factors” for oral cancer are tobacco products and alcohol.
Second, we are beginning to understand that variations or polymorphisms in multiple genes con- fer susceptibility or resistance to chronic and dis- abling diseases and disorders, such as osteoporosis, periodontal diseases, and temporomandibular dis- eases and disorders. In these examples, multiple genes and multiple gene–environment and gene– gene interactions are associated with the molecular pathophysiology of the disease process. For example, single nucleotide polymorphisms (SNPs) in such genes as IL-1a, IL-1b, IL-1 receptor, IL-2, IL-6, IL-10, IL-12, and TNF a in various combinations and in juxtaposition to a number of risk factors may explain genetic susceptibility to periodontal diseases and/or associations with cardiovascular diseases.
The human genome consists of 100,000 genes, and each gene is likely to be represented in the pop- ulation with 10 variant alleles. To comprehensively cover the entire human genome and have the capac- ity to identify SNPs, 1 million SNPs will be required. The recent consortia by the federal gov- ernment and the private sector in SNPs, sufficient to cover the entire human genome, will significantly accelerate the progress toward defining the multiple genes associated with complex human diseases.
These microbial and human genomic databas- es will provide remarkable opportunities for the identification, design, and production of a new generation of biomarkers for diagnostics and for the development of innovative therapeutics such as drugs and vaccines to improve human health and advance periodontal medicine.
SUMMARY
There is growing evidence that a number of com- plex human diseases are associated with oppor- tunistic infections in periodontal medicine. As a consequence, there has been a resurgence of interest in oral microbial ecology, mucosal immunity, and associations with systemic conditions, such as pre- maturity and low birth weight, pulmonary diseases, cardiovascular diseases, and cerebrovascular dis- eases. This renewed interest in periodontal medi- cine is taking place at a time when dramatic advances in the fields of microbiology, immunolo- gy, molecular biology, and cell biology have allowed in-depth exploration of microbial genomics, oral infections, the human genome project, host immu-
nity, and a variety of systemic diseases and disor- ders. The following chapters will highlight the many advances and opportunities for improved health care in the 21st century.
SELECTED REFERENCES
Oral Infections and Systemic Disease: A Paradigm Shift
Andrews WW, Goldenberg RL, Hauth JC. Preterm labor: emerging role of genital tract infections. Infect Agent Dis 1995;4(4):196–211.
Drangsholt MT. A new causal model of dental diseases associated with endocarditis. Annals of Periodon- tology 1998;3(1):184–196.
Davenport ES, Williams ECS, Sterne JAC, Sivanpatha- sundram V, Fearne JM, Curtis MA. The east lon- don study of maternal chronic periodontal disease and preterm low birth weight infants: study design and prevalence data. Annals of Periodontology 1998;3(1)213–221.
Herzberg MC, Meyer MW. Dental plaque, platelets, and cardiovascular diseases. Annals of Periodontol- ogy 1998;3(1):151–160.
Kinane DF. Periodontal diseases’ contributions to car- diovascular disease: an overview of potential mech- anisms. Annals of Periodontology 1998;3(1): 142–150.
Limeback H. Implications of oral infections on systemic diseases in the institutionalized elderly with a spe- cial focus on pneumonia. Annals of Periodontology 1998;3(1)262–275.
Loesche WJ, Schork A, Terpenning MS, Chen YM, Kerr C, Dominguez BL. The relationship between dental disease and cerebral vascular accident in elderly united states veterans. Annals of Periodon- tology 1998;3(1):161–174.
Mealey BL. Periodontal implications: medically com- promised patients. Annals of Periodontology 1996;1(1)256–321.
Nishimura F, Takahashi K, Kurihara M, Takashiba S, Murayama Y. Periodontal disease as a complication of diabetes mellitus. Annals of Periodontology 1998;3(1)20–29
Offenbacher S. Periodontal disease: pathogenesis. Ann Periodontol 1996;1(1):821–78.
Page RC, Beck JD. Risk assessment for periodontal dis- ease. Int Dent J 1997;47:61–87.
Petit MDA, Van Steenbergen TJM, Degraaff J, et al. Transmission of Actinobacillus actinomycetemcomi- tans in families of adult periodontitis patients. J Periodontal Res 1996;28:335–45.
Periodontal Disease and Systemic Disease 9
Salvi GE, Beck JD, Offenbacher S. Pge2, Il-1a, and TNF-a responses in diabetics as modifiers of peri- odontal disease expression. Annals of Periodontol- ogy 1998;3(1)40–50.
Scannapieco FA, Papandonatos GD, Dunford RG. Associations between oral conditions and respirato- ry disease in a national sample survey population. Annals of Periodontology 1998;3(1):251–256.
Slavkin HC. Infection and immunity. J Am Dent Assoc 1996;127:1792–6.
Slavkin HC. Emerging and re-emerging infectious dis- ease. J Am Dent Assoc 1997;128:108–13.
Slavkin HC. And we all lived happily ever after: under- standing the biological controls of aging. J Am Dent Assoc 1998;129:629–33.
Slavkin HC. Chronic disabling diseases and disorders. J Am Dent Assoc 1997;128:1583–9.
Slavkin HC. Diabetes, clinical dentistry and changing paradigms. J Am Dent Assoc 1997;128:638–44.
Slavkin HC. Notes on a silent disease. J Am Dent Assoc 1996;127:801–5.
Slavkin HC. An update on HIV/AIDS. J Am Dent Assoc 1996;127:1401–4.
Slavkin HC. The war on oral cavity and pharyngeal can- cer. J Am Dent Assoc 1996;127:517–20.
Slavkin HC. First encounters: transmission of infectious oral diseases from mother to child. J Am Dent Assoc 1997;128:773–8.
Soskolne WA. Epidemiological and clinical aspects of periodontal diseases in diabetics. Annals of Peri- odontology 1998;3(1):3–12.
Von Troil-Linden F, Alahuusua S, Wolf J, et al. Perio- dontitis patient and the spouse: periodontal bacte- ria before and after treatment. J Clin Periodontol 1997;2:893–9.
Winn DM, Diehl SR, Horowitz AM, et al. Scientific progress in understanding oral and pharyngeal can- cers. J Am Dent Assoc 1998;129:713–8.
Yuan A, Luh KT, Yang PC. Actinobacillus actino- mycetemcomitans pneumonia with possible septic embolization (letter). Chest 1994;105:646.
Zijlstra EE, Swart GR, Godfroy FJM, Degener JE. Peri- carditis, pneumonia and brain abscess due to a combined actinomyces-actinobacillus actino- mycetemcomitans infections. J Infect 1992;25: 83–87.
Anatomic Primer of the Periodontium
Armitage GC. Periodontal diseases: diagnosis. Annals of Periodontology 1996;1(1)37–215.
Genco RJ, Goldman HM, Cohen DW. Contemporary periodontics. St. Louis, MO: The C.V. Mosby Company; 1990.
Page RC. The pathobiology of periodontal diseases may affect systemic diseases: inversion of a paradigm. Annals of Periodontology 1998;3(1)108–120.
Oral Infections, Systemic Disease, and the Genetic Paradigm
Amer A, Singh G, Darke C, Dolby AE. Association between HLA antigens and periodontal disease. Tissue Antigens 1988;31:53–58.
Backman B. Inherited enamel defects. In: Chadwick DJ, Cardew G, editors. Dental enamel. London: John Wiley & Sons Ltd; 1997. p. 175–96.
Baum BJ, Atkinson JC, Baccaglini L, et al. The mouth is a gateway to the body: gene therapy in 21st cen- tury dental practice. CDA J 1998;25:455–60.
Bodmer W, McKie R. The book of man: the Human Genome Project and the quest to discover our genet- ic heritage. New York: Scribner Publishers; 1995.
Boughman JA, Halloran SL, Roulston D, Schwartz S, Suzuki JB, Weitkamp LR, Wenk RE, Wooten R, Cohen MM. Autosomal dominant form of juvenile periodontitis: it’s localization to chromosome 4 and linkage to dentinogenesis imperfecta and Gc. Jour- nal of Craniofacial Genetic Development Biology 1986;6:341–350.Porter R. The greatest benefit to mankind. New York: W.W. Norton & Company; 1997.
Chambers DA. DNA: the double helix: 40 years, prospective and perspective. New York: New York Academy of Sciences; 1995.
Cohen MM Jr. Molecular biology of craniosynostosis with special emphasis on fibroblast growth factor receptors. In: Cohen MM Jr, Baum BJ, editors. Studies in stomatology and craniofacial biology. Amsterdam: IOS Press; 1997. p. 307–30.
Field MJ. Dental education at the crossroads. Washing- ton, D.C.: National Academy Press; 1995.
Finch CE, Pike MC. Maximum lifespan predictions from the Gompertz mortality model. J Gernotol 1996;51(3):3183–94.
Hart TC, Marazita ML, McCanna KM, Schenkein HA, Diehl SR. Reevaluation of the chromosome 4q candidate region for early onset periodontitis. Human Genetics 1993;91:416–422.
Kevles BH. Naked to the bone. New Brunswick, New Jersey: Rutgers University Press; 1997.
Kornman KS, Page RC, Tonetti MS. The host response to microbial challenge in periodontitis: assembling the players. Periodontology 2000 14:33–53, 1997
Kornman KS, di Giovine FS. Genetic variations in cytokine expression: a risk factor for severity of adult periodontitis. Annals of Periodontology 1998;3(1)325–338.
10 Periodontal Medicine
Mealey BL. Periodontal implications: medically com- promised patients. Ann Periodontol 1996;1(1): 256–321.
Schwartz WB. Life without disease. Berkeley: Universi- ty of California Press; 1998.
Slavkin HC. Possibilities of growth modification: nature versus nurture. In: MacNamara R, editor. Ann Arbor, Michigan: University of Michigan Press. 1999. [In press]
Slavkin HC. Understanding human genetics. J Am Dent Assoc 1996;127:266–7.
Slavkin HC. Clinical dentistry in the 21st century. Compendium 1997;18(3):212–8.
Slavkin HC. Basic science is the fuel that drives the engine of biotechnology: a personal science transfer vision for the 21st century. Tech Health Care 1996; 4:249–53.
Slavkin HC. Advice to coaches of students in one of the youngest sciences. J Dent Edu 1998;62:226–9.
Toteson DC, Adelstein SJ, Carver ST. New pathways to medical education. Cambridge, Massachusetts: Harvard University Press; 1994.
CHAPTER 2
RISK FACTORS FOR PERIODONTAL DISEASE Robert J. Genco, DDS, PhD
Periodontal diseases, now recognized as bacterial infections, are among the most common, chronic diseases of humans, affecting 5 to 30% of the adult population in the age group of 25 to 75+ years. Periodontal diseases are also among the most important causes of pain, discomfort, and tooth loss in adults.1–3 While a significant portion of the population is susceptible to periodontitis, there are those that are relatively resistant to the severe forms of periodontal disease. This leads to the hypothesis that there are susceptibility factors or risk factors that modulate susceptibility or resistance of indi- viduals to destructive periodontal disease.
In addition to being a major cause of discom- fort, disfigurement, and tooth loss in the popula- tion, emerging evidence suggests that periodontitis increases the risk for certain systemic diseases such as heart disease,4 low birth weight,5 respiratory dis- ease,6 and possibly other conditions.7 It is clear then that prevention and treatment of periodontal disease are necessary to maintain periodontal health; without periodontal health, general health is often compromised. Present day concepts of management of periodontal disease include prima- ry and secondary prevention, treatment of existing disease to resolve the periodontal infection, and modification of adverse risk factors which increase susceptibility to initial or re-infection with peri- odontal organisms. The goals of this chapter, there- fore, are to provide the reader with (1) an under- standing of the microbial etiology and pathogene- sis of periodontal infection, (2) detailed knowledge of factors which increase the risk of periodontal disease, and (3) information to be used in assessing individual patients to determine their risk profile or risk level for development of periodontal infec- tion. Information on modification of risk is found in other chapters of this book.
ETIOLOGY
Concepts of the etiology of periodontal disease have changed markedly in the last four decades. Several specific subgingival oral bacteria including Porphyromonas gingivalis, Actinobacillus actino- mycetemcomitans, Prevotella intermedia, Bacteroides forsythus, and perhaps others such as Campylobacter rectus, Fusobacterium nucleatum, and spirochetes are associated with severe forms of periodontal disease.8
In addition, a group of pathogens not normally found in the oral cavity, except as transients, has been associated with periodontal disease, including Enterobacteriaceae, Pseudomondacea, Klebsiella spp and Acinetobacter as well as others such as Staphylo- coccus aureus, and Candida albicans.9 Periodontal diseases, therefore, are infections in which severe forms of the disease are often associated with spe- cific bacteria that colonize the subgingival area in spite of the host’s protective mechanisms. Many of these bacteria have potent virulence factors such as cytotoxins for mammalian phagocytes produced by A. actinomycetemcomitans, a potent array of pro- teases produced by P. gingivalis, and the ability to invade epithelial cells exhibited by A. actino- mycetemcomitans and P. gingivalis.10 Recently, P. gin- givalis has also been shown to invade the endothe- lial cells which may explain, in part, the link between periodontal disease and heart disease.11
Studies have linked specific therapies to specif- ic infections in periodontal disease. For example, van Winkelhoff12 found that amoxicillin with metronidazole was useful in controlling periodon- tal infection when A. actinomycetemcomitans was found in plaque samples. Further, microbiologic tests have been developed and are useful in the assessment of periodontal infection and the selec- tion of appropriate therapies.
12 Periodontal Medicine
PATHOGENESIS
The periodontal pathogens have virulence factors which cause direct damage. However, it appears that a significant contribution to tissue destruction in periodontal disease comes from an imbalance in host protective and destructive mechanisms induced by periodontal infection.13 Host hyper- responsiveness or reactivity is induced by peri- odontal infection and includes activation of neu- trophils, which migrate to the area of periodontal infection, and induction of antibodies, both of which appear to be protective. On the other hand, extracellular matrix components of the gingiva and periodontal ligament are destroyed and alveolar bone is resorbed mainly through induction of matrix metalloproteinases.14 This leads to connec- tive tissue destruction and production of proin- flammatory cytokines, such as IL-1,15 resulting in alveolar bone resorption. These cytokines can cause activation of fibroblasts, which then produce major metalloproteinases that destroy the extracel- lular matrix. In addition, proinflammatory cytokines such as IL-1, IL-6, and TNF-a lead to activation of osteoclasts, which leads to bone resorption. A full description of cytokines and prostaglandins in immune hemostasis and tissue destruction in periodontal disease is reviewed by Gemmell and colleagues.16
Briefly, the pathogenesis of periodontal disease could be thought of as a pathway, including direct toxic effects on cells from proteases and toxins pro- duced by bacteria, to triggering of cells by mitogens and antigens. This initially results in a wave of neu- trophil chemotaxis and antibody production, which is protective, leading to reduction of the infecting flora. However, several of the periodontal bacteria can evade the neutrophil-protective response by killing neutrophils, inhibiting their function, or digesting antibody and complement. The next wave is the induction of mononuclear cells such as resident macrophages and fibroblasts to produce matrix metalloproteinases, reactive oxy- gen species, and proinflammatory cytokines, which results in connective tissue destruction and bone resorption. The organisms then eventually appear to be controlled by antibodies that neutralize the toxins and by phagocytes that remove them from the site of infection causing the disease to go into remission. Episodes of periodontal disease exacer- bation and remission follow blooms of the organ- ism once the immune response subsides and allows the organism to propagate again, resulting in a repeat of the cycle and recurrence of periodontitis.
It is clear then that host factors play a major role in the pathogenesis of periodontal disease. Exogenous factors such as smoking, which alter immune function and tissue repair, or endogenous or intrinsic factors such as genetic predisposition to hyperproduction of cytokines, low production of antibody, or depressed neutrophils can lead to marked changes in the disease process. These fac- tors then modify the host response to periodontal infection, altering susceptibility to infection by periodontal organisms.
ASSESSMENT OF RISK FACTORS
A risk factor for periodontal disease is a character- istic, an aspect of behavior, or an environmental exposure that is associated with destructive peri- odontitis.17 Numerous factors are modifiable while others cannot be easily modified. The term “risk factor” often implies a modifiable condition; how- ever, this is not always the case. Those risk factors that cannot be modified are often called determi- nants or background factors. The term “risk indi- cator” is used to describe a possible or putative fac- tor associated with the disease often identified from case-control or cross-sectional studies. True risk factors that are associated with disease are con- firmed in longitudinal and interventional studies and by the existence of a biologically plausible mechanism for their actions.18
There are several study designs that are useful in the assessment of risk factors for diseases that are considered multifactorial diseases, such as peri- odontitis. Table 2–119 presents a series of study designs ranging from anecdote, to case reports, to case series, to randomized controlled trials that constitute evidence of increasing strength for risk factors. The anecdotes, case reports, and case series provide the weakest evidence for association of risk with disease; however, they are important because they often provide the basis for generating important hypotheses.
The next line of evidence concerning the association between a potential risk factor or risk indicator and disease is provided by case-control studies. Case-control studies can identify risk indicators but often are not able to assess the role of important confounding factors. For this, cross- sectional, population-based studies are necessary because they describe large populations and allow a more rigorous assessment of confounders or co-risk factors by multivariate statistical analysis. Cross- sectional studies are important because they can
Risk Factors for Periodontal Disease 13
lead to identification of risk indicators that are rea- sonable or plausible correlates of disease.
Longitudinal studies are necessary to provide strong evidence that a risk indicator or a putative risk factor is indeed a true risk factor. Risk indica- tors are not always confirmed as risk factors in lon- gitudinal studies. Although longitudinal studies provide strong evidence, they are often difficult to carry out for periodontal disease because periodon- titis is a slowly progressing disease, and the defini- tion of a new case is by no means clear. However, longitudinal studies are necessary to resolve the temporal sequence of putative risk factors as they are associated with disease. A true risk factor should precede the development of disease.
Analysis of risk is ultimately directed to improv- ing the health of the population. Evidence for effi- cacy of the elimination or suppression of a risk fac- tor in modulating or reducing disease often is gained from randomized controlled trials in which inter- vention is rigorously tested. It is important that the mechanism of action of risk factors is biologically plausible to understand how the risk factor exerts its influence on the disease. Also, knowing the mode of action may allow development of effective risk inter- vention strategies that intercept or modulate the effects of the risk factor on disease.
Accurate and precise measurement of peri- odontitis can be carried out by assessing several
surrogate variables for periodontal disease, such as estimate of alveolar bone destruction by measure- ment of radiographs, clinical attachment loss, and gingival inflammation including bleeding on prob- ing and probing pocket depth. In large scale clini- cal epidemiologic studies, relative attachment lev- els are often measured from an arbitrary but fixed point, such as the cemento-enamel junction, and are better indicators of destructive periodontitis than probing depths.20 Ideally, both attachment loss and radiographic measurement of alveolar bone loss in epidemiologic studies are carried out. Measurement of alveolar bone loss may be more sensitive than attachment loss in assessing risk fac- tors. This, in fact, has been observed by Grossi and co-workers.21,22
Establishment of a definition for a periodontal case is often arbitrary. Various cut-off points for attachment loss, bone loss, and pocket depth have been suggested but none is universally agreed upon. Perhaps the best approach would be to assess the extent and severity of disease in the population and determine cut-off points or case definitions appropriate for the population. Lack of a clear-cut definition of a case of periodontitis has hindered longitudinal studies that attempt to define inci- dence or occurrence of new cases, and often pro- gression of periodontal disease is used. For exam- ple, the rate of periodontal attachment loss using
TABLE 2–1. Hierarchy of Evidence for Risk Factors*
Hypothesis Hypothesis Interpretation and Study Design Generating Testing Health Policy Implication
1. Anecdote X case report Suggests a relationship case series
2. Case control X X Evidence for risk indicator
3. Cross-sectional X X Evidence for risk indicator
4. Longitudinal (cohort) X Evidence for risk factor
5. Interventional X Evidence for risk factor modulation • RCT of treatment effects in
high vs. low risk groups • RCT in which risk factor is X Strongest evidence for specific
modified interaction to apply to population
*Adapted from Ibrahim M. Epidemiology and health policy. Rockville (MD): Aspen Systems Corporation; 1985. RCT = randomized controlled trial. Table reprinted with permission from the Journal of Periodontology.
14 Periodontal Medicine
repeated measures and the establishment of step- wise thresholds—based on factors that contribute to error including pocket depth, tooth type, and tooth location—for each individual patient and for examiners have also been used with success to assess risk factors.23
RISK ASSESSMENT STUDY DESIGN AND ANALYSIS OF DATA
Correlation or univariate analysis is often seen in older studies of risk, especially in case-control or small cross-sectional studies. The weakness of such analysis resides in the inability of a single correla- tion analysis to develop comprehensive models of disease since only one or, at most, a few potential risk factors can be analyzed at one time. Also, uni- variate analysis does not allow for adjustments for confounding or co-risk variables or factors. Power- ful, modern statistical analyses using multiple regression models, linear discriminate analysis, and multivariate logistic regression have provided the necessary tools to assess the role of risk factors in periodontal disease. These analyses often make adjustments for confounding factors and are useful in assessing risk. The unit of study in epidemiolog- ic assessment of risk is necessarily the patient. However, data often come from multiple sites in the same patient and hence lead to complex statis- tical issues. For example, there is often a lack of independence of multiple observations in the same patient, and several approaches to the assessment of relationships between site-specific variables and statistical models assessing risk of periodontal dis- ease have been described.24–26 Recently, general estimating equations that allow the use of a broad range of regression models that take into account and adjust for the dependence between observa- tions in the same individuals have been described and are in wide use.27
Ultimately, however, association studies for risk usually require that there be a concordance of several well-executed studies on different popula- tions. In addition, it is important that the risk factor show some type of dose response; the more the exposure to the risk factor, the worse is the disease. Furthermore, it is important that longi- tudinal studies show that there is a logical occur- rence of the risk factor prior to the development of disease. Finally, for decisions on the clinical importance of the risk factor, it is necessary for the intervention studies to show that modifica- tion of the risk factor will result in modification
of the disease. It is the confluence of these multi- ple experimental approaches that leads to confi- dence in assigning a risk factor to a disease and thereby taking the next step, which is implemen- tation of risk factor modification in practice and in public health.
BACKGROUND FACTORS OR DETERMINANTS
Age
Studies of periodontal disease prevalence, extent, and severity show more disease in older age groups compared with younger groups.1,21,22,27–29
Several studies also show that there is greater dental plaque and more severe gingivitis in elder- ly persons compared with younger individuals, suggesting age-related effects.29 Most studies, however, show that periodontal disease is more severe in the elderly because of the cumulative destruction over a lifetime, rather than an age- related intrinsic deficiency or abnormality that affects susceptibility to periodontal infection. For example, an analysis of the epidemiologic data from the National Health and Nutrition Surveys (NHANES) in the United States con- cluded that when oral hygiene status was consid- ered, age was not an important factor in deter- mining periodontal disease.29
A longitudinal study addressing the cumula- tive nature of periodontal attachment loss suggests that, at least up to age 70 or 75 years, the rate of periodontal destruction has been the same throughout adulthood.30 Several other longitudi- nal studies came to the same conclusion.31–33 How- ever, Ismail and colleagues34 from the Tecumseh study found that age was a significant factor in a multivariate model relating greater attachment loss to age. However, it is instructive to note that in this study, the age range of individuals was >65 or 70 years, the maximum age in most of the other stud- ies. It appears that age, per se, is not an intrinsic risk factor, at least until the age of 70 or 75 years. It is still unknown whether the deterioration of host-protective mechanisms or the acceleration of host-destructive mechanisms affects susceptibility to periodontal disease beyond age 70 or 75 years. Indeed, there may be an increased risk of perio- dontal disease associated with advanced age; per se, however, this does not appear to be manifested before age 70 or 75 years. Further work is needed to resolve this issue.
Risk Factors for Periodontal Disease 15
Race
Assessment of risk factors related to race, socioeco- nomic status, and poverty have been unsuccessful in making associations with periodontal disease. For example, in recent studies where periodontal status was adjusted for oral hygiene and smoking, the asso- ciation between lower socioeconomic status and more severe periodontal disease was not seen.21,22
In a study of risk indicators for African Ameri- can and Caucasian Americans, there were more indi- cators related to socioeconomic status for the former than for the latter. For example, Prevotella intermedia was a risk indicator for African Americans, but not for Caucasian Americans. However, when persons from both races belong to the same socioeconomic group, differences in periodontal disease often dis- appeared.21,22,35 Further studies are necessary to look at the relative role of race and ethnicity, which may be tied to genetic factors in Asians, Native Americans, Hispanics, and other racial and ethnic groups in the American population.
Gender
Periodontal disease is regularly reported to be more prevalent or more severe in men than in women at comparable ages.1,21,22,36 Men exhibit poorer oral hygiene and report fewer visits to the dentist than do women.37 However, when correcting for oral hygiene, socioeconomic status, visits to the dentist, and age, being male is still associated with more severe disease when either attachment loss or bone height is used as a measure of periodontal disease.21,22
Assessment of the effects of hormones, partic- ularly the female hormone estrogen, which likely protect against destructive periodontal bone loss, may help us understand the small but definite increase in periodontal disease seen in men.
SYSTEMIC RISK FACTORS AND RISK INDICATORS
Two groups of systemic factors are associated with periodontal disease.38 One group includes smoking and diabetes mellitus, for which there is consider- able evidence based on cross-sectional, longitudi- nal, intervention, and mechanism studies, and it is reasonable to call these true risk factors. Certainly, modification of these factors is important in the management of periodontal disease.
The second set of factors associated with peri- odontal disease is related to an earlier stage of devel-
opment and understanding and are probably best called risk indicators at this point. These include osteopenia and osteoporosis; stress, distress, and coping; dietary factors including calcium and vita- min C; and genetic factors. There are also a group of immune system diseases such as AIDS; primary and secondary neutrophil disorders, such as con- genital neutropenia and drug-related agranulocyto- sis; and diseases affecting host response, such as Papillon-Lefèvre syndrome, Ehlers-Danlos syn- drome, and hypophosphatasia, which are associated with more severe disease in juveniles and likely sig- nificantly increase the risk for periodontal disease.
Tobacco Use
In spite of the long history of the association between tobacco smoking and periodontal dis- ease,39–41 the observation that greater levels of plaque and calculus in smokers may have account- ed for the association failed to convince the com- munity of the importance of smoking and peri- odontal disease risk. However, in 1983, Ismail and co-workers analyzed smoking and periodontal dis- ease and found that smoking remained a major risk indicator for periodontal disease after adjusting for potential confounding variables, such as age, oral hygiene, and socioeconomic status.42
In recent studies,21,22 smoking was shown to be a strong risk indicator for periodontal disease with an odds ratio of 2.0 to 5.0 when using clini- cal attachment loss as a measurement. Odds ratios of 1.5 to 7.0 were achieved when using alveolar bone loss as a measure of periodontal disease in these studies. These studies were adjusted for age, gender, socioeconomic status, plaque, and calcu- lus, and hence strongly implicate cigarette smoking per se as a major risk indicator for periodontal dis- ease. Grossi and co-workers21,22 also found a direct and linear dose response between level of smoking (pack years) and destructive periodontitis, support- ing the contention that smoking is a risk factor for periodontal disease (Figure 2–1). Longitudinal studies have confirmed that current smokers exhib- ited greater disease progression as compared with nonsmokers.43 Attachment loss is also directly related to serum cotinine levels.44 A longitudinal study of the association between smoking and tooth loss over a 10-year period was carried out in 273 individuals.45 Younger individuals who smoked more than 15 cigarettes per day had the highest risk. In this study, the odds ratio for asso- ciation of smoking with periodontitis, adjusted for age and gender, for current smokers relative to
16 Periodontal Medicine
those who never smoked, was 3.3, and for former smokers versus those who never smoked, the odds ratio was 2.1. These longitudinal studies provide convincing evidence, along with other lines of evi- dence, that tobacco use is a major risk factor for periodontal disease.
Although direct intervention studies of peri- odontal disease in smokers who have quit smoking have not been carried out, other studies show that periodontal therapies are less effective in smokers than in nonsmokers, and recurrence of disease is more likely in smokers after periodontal thera- py.44–53 Also, smoking cessation appears to yield clinical benefits.21,22,52,54–56 In these reports, the periodontal status of former smokers is comparable with that of nonsmokers. In the study by Grossi and colleagues,52 there was no relationship to time of cessation of smoking (although cessation times of less than 1 year were not observed), which sug- gests that smoking cessation for as little as 1 year results in healing after periodontal therapy compa- rable with that in a nonsmoker.
The mechanisms by which cigarette smoking affects the periodontal tissues are quite diverse. Smoking causes constriction of the blood vessels of the gingiva57 and has deleterious effects on leuko- cyte function.58 Smoking also has been shown to suppress serum antibody levels to certain periodon- tal bacteria.59–60 The effect may be specific since smoking suppresses production of the IgG2 class of immunoglobulin both in patients with periodonti- tis and in those with normal periodontium.59–60
Smoking also may have direct effects on tissues. For example, cytotoxic substances can penetrate the
epithelium and may exert deleterious effects on fibroblasts.61 Smoking also decreases intestinal absorption of calcium and may thereby affect osteoblast function and increase bone loss in other- wise healthy postmenopausal women.62,63 Postsur- gical healing may be interfered with by absorption of the toxic substances in tobacco smoke by the root surfaces.51,64 Recently, two studies have shown the adverse effects of smoking on the subgingival flora.65,66 While there is no evidence that the use of smokeless tobacco increases susceptibility to peri- odontal disease, smokeless tobacco may affect gin- gival inflammation by affecting levels of IL-1b and PGE in gingival tissues.67,68 Although there is no direct evidence, it is likely that cigar and pipe smoking will have effects similar to cigarette smok- ing if the exposures are comparable. It is clear that there are many mechanisms by which the compo- nents of tobacco smoke can deleteriously affect periodontal tissues.
Diabetes Mellitus
There is a large body of evidence supporting the association between diabetes mellitus and peri- odontal diseases. There is remarkable consistency in finding either greater prevalence, severity, or extent of at least one manifestation of periodontal disease in the overwhelming majority of these studies. Studies of children and adolescents with type 1 diabetes and a group of similar ages with- out diabetes found greater periodontal disease in the diabetics as compared to the controls.69–77
However, Goteiner and colleagues78 did not find such a relationship. In another group of studies, subjects between the ages of 15 and 35 years with type 1 diabetes were assessed and, essentially, all the studies found greater periodontal disease in the diabetics.79–84 A set of studies of insulin- dependent diabetics, presumably mostly type 1, in adults 20 to 70 years of age, also found greater periodontal disease in diabetics as compared with controls.85–88
A series of studies of type 2 diabetic subjects also has been reported, and the investigators reported greater periodontal disease in the diabet- ics than in the controls.89–95 In a longitudinal study,89 the increased relative risk of advanced peri- odontal disease in the diabetics was found to be 2.6 (95% CI 1.0 to 6.6). A further study of the same population by Taylor and colleagues96 showed that type 2 diabetes was a significant risk factor for pro- gression of alveolar bone loss with an odds ratio of 4.2 (95% CI 1.8 to 9.9).
40
30
20
10
0 Healthy
Pa ck
ye ar
± S
E
Low Moderate Level of Probing Attachment Loss
High Severe
Figure 2–1. The relationship of more severe periodontal disease as assessed by increasing levels of probing attachment loss, with increasing exposure to cigarette smoking (expressed as packyears) is depicted. (Figure is reprinted with permission from Grossi SG, Zambon JJ, Ho AW, et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994; 65:260–7.)
Risk Factors for Periodontal Disease 17
There are a series of studies that do not sepa- rate type 1 and type 2 diabetes and, in general, these also support an association of diabetes with periodontal disease.21,97,98 In the study by Grossi and colleagues,21 the estimates of association between diabetes and attachment loss severity had an odds ratio of 2.3 (95% CI 1.2 to 4.6). Hence, it is clear from case-control, cross-sectional, and longitudinal studies that diabetes is a significant risk factor for periodontal disease.
Randomized controlled trials of the effects of therapy on both periodontal disease and diabetes status have also provided evidence that treatment of periodontal disease can be successfully carried out in diabetics. Furthermore, resolution of peri- odontal infections in diabetics can contribute to the management of glycemic control in type 1 or type 2 diabetes (see Chapter 8).52,99,100 The study by Aldridge and colleagues99 did not show a ben- eficial effect but the two studies by Grossi and col- leagues52,100 did show a beneficial effect. Perhaps it is significant that in the Grossi studies, systemic doxycycline was used. Miller and colleagues101 also used systemic doxycycline and mechanical therapy and found an effect on glycemic control, pointing to the possible effect of antibiotics in this benefi- cial response.
Further rigorous, controlled studies of treat- ment of periodontal disease in diabetics are needed to confirm the extent to which treatment not only resolves periodontal infection but enhances glycemic control. Further studies also are needed to assess the extent to which control of the diabetes status is related to control of periodontal disease status. Case reports as well as clinical experience do support this contention. However, randomized controlled trials are needed to fully assess the extent to which glycemic control in diabetics will prevent or minimize periodontal destruction.
Acquired Immune Deficiency Syndrome and Other Immunodeficiencies
Systemic diseases, especially those that compro- mise the host’s ability to fend off infections, often lead to more severe periodontal disease. There are studies that describe severe forms of destructive periodontal disease in acquired immune deficiency syndrome (AIDS) patients, resulting in necrotizing ulcerative lesions, often affecting the alveolar bone. Furthermore, a “linear” form of gingivitis has also been described in AIDS patients. A wide variety of oral lesions have been described in persons infect- ed with HIV,102 the etiologic agent for AIDS. Sev-
eral reviews of the oral manifestations of HIV infection have been published recently.103–105
Oral Candidiasis Oral candidiasis is an infection of the oral tissues by yeasts of the genus Candida, and its association with severe underlying disease has been noted for many years.106 Oral candidiasis is rarely seen in previously healthy individuals107 and is often seen as part of the acute HIV syndrome.108 It can also be a common problem when CD4 lymphocyte counts fall.109 There are four clinical variants of oral candidiasis including pseudomembranous, erythematous, hyperplastic, and angular cheili- tis.110 Both the pseudomembranous and erythema- tous forms of candidiasis appear to be important predictors of progression of HIV infection.107–111
Oral Hairy Leukoplakia Oral hairy leukoplakia is an oral lesion that was first reported in the early days of the AIDS epidem- ic.112–113 In HIV-positive persons, oral hairy leuko- plakia predicts more rapid progression to AIDS.109
Oral hairy leukoplakia is associated with the Epstein-Barr virus and generally occurs infrequent- ly among immunocompetent individuals.114–115
Non-Hodgkin’s Lymphoma Non-Hodgkin’s lymphoma and Kaposi’s sarcoma are two AIDS-associated malignancies that can occur in the mouth. Because it involves the gingivae, non-Hodgkin’s lymphoma is frequently mistaken for common periodontal or dental infections.116
Linear Gingival Erythema Periodontal disease in AIDS patients often pre- sents in several forms. A gingival lesion known as linear gingival erythema (formerly known as HIV-gingivitis) has been described in HIV-infected individuals.117–118 It is characterized by a red band on the marginal and attached gingiva, and does not resolve with routine dental curettage and prophylaxis.109
Necrotizing Ulcerative Periodontitis Necrotizing ulcerative periodontitis (formerly known as HIV periodontitis) also can occur in HIV-infected individuals. It is characterized by painful, ulcerative, bleeding lesions of the gingiva which often are rapidly destructive and involve the deep periodontal tissues and alveolar bone.109–119
Necrotizing ulcerative periodontitis may be gener- alized or localized and may lead to tooth loss and bone sequestration.
18 Periodontal Medicine
Neutrophil Disorders
Severe periodontal disease may also occur in patients with neutrophil abnormalities, and many of these conditions are reviewed by Van Dyke and col- leagues.120 Patients with neutrophil defects that are either quantitative (neutropenia) or qualitative (adherence, chemotaxis, microbicidal functional activity) often suffer from oral mucosal ulcerations, gingivitis, and periodontitis. Severe oral disease occurs with both primary and secondary neutrophil abnormalities. The primary neutrophil disorders characterized by severe periodontal disease include neutropenia (chronic or cyclic), leukocyte adhesion deficiency (LAD), and Chédiak-Higashi syndrome. Neutrophil abnormalities that occur secondary to underlying systemic disease and those that are also associated with severe periodontal disease include diabetes, Papillon-Lefèvre syndrome, Down syn- drome, hyperimmunoglobulin-E recurrent infec- tion syndrome (HIE or Job’s syndrome), inflamma- tory bowel disease, Crohn’s disease, preleukemic syndrome, AIDS, and acute myeloid leukemia.121
Drugs which induce agranulocytosis, including some drugs used to treat cancer, can result in mucositis or periodontal disease. Other conditions such as acatalasia, alpha-1 antitrypsin deficiency, and Ehlers-Danlos syndrome are also described in which periodontal disease is more severe, some of which may well involve neutrophil abnormalities.
Hence, it appears that neutrophil disorders that are either primary neutrophil dyscrasias, sec- ondary to systemic diseases, or result from chemo- therapy are often associated with severe periodon- tal disease. Hence, neutrophil dysfunction is a risk factor for periodontitis, most likely as it lowers the host resistance to periodontal infection by subgin- gival microflora.
Osteoporosis
Osteoporosis is one of the most important health concerns in the United States. It affects over 20 million people, most of whom are women, and causes nearly two million fractures per year. Osteo- porosis is a physiologic, gender-, and age-related condition resulting from bone mineral content loss. It is a disease characterized by low bone mass and fragility, which in turn may lead to increase in fractures. Primary osteoporosis includes post- menopausal osteoporosis, age-related osteoporosis, and idiopathic osteoporosis. Secondary osteoporo- sis is that caused by an identifiable agent or disease. The rate of bone mineral density (BMD) loss is
approximately two times greater in women than in men, and postmenopausal osteoporosis is a hetero- geneous disorder that begins after natural or surgi- cal menopause and leads to fractures within 15 to 20 years from the cessation of ovarian function.
Cortical bone loss is, on average, 0.3 to 0.5% per year until menopause. At menopause, 2 to 3% loss per year occurs for the next 8 to 10 years. Tra- becular bone is lost at a greater rate, with 4.8% being lost per year in the 5 to 8 years following menopause. This loss occurs when an imbalance is caused by more bone resorption than formation. Calcium balance, vitamin D metabolism, estro- gens, and aging are interrelated factors in the cau- sation of osteoporosis.
Osteoporosis has long been suspected as a sys- temic risk factor for loss of oral bone, including loss of the alveolar process associated with peri- odontal infection. From assessment of osteoporosis in the jaws by dual photon absorptiometry,122–126 it was found that reduction in total skeletal mass is directly related to reduction in mandibular density in osteoporotic women.127–128 Studies by Kribbs and Chesnut129 and Henrikson and Wallenius130
showed that mandibular BMD correlated with skeletal BMD. Ortman and colleagues131 found a significantly higher percentage of women with severe alveolar ridge resorption than men, which may be related to the findings of Humphries and colleagues132 showing that age-related loss of BMD in an edentulous adult mandible is important in females but not in males.
As shown by Daniell133 and Krall and col- leagues,134 who conducted a study of estrogen replacement after menopause and tooth retention in 488 women, osteoporosis is clearly related to tooth loss. Estrogen users had more teeth than did nonusers, and the duration of estrogen use indepen- dently predicted the number of remaining teeth.
Several studies have shown a relationship between periodontal disease and osteoporosis. For example, Von Wowren,124 in a case control study of 12 female patients with osteoporotic fractures com- pared with 14 normal women, found significantly more loss of periodontal attachment in osteoporot- ic women than normal women. Groen and col- leagues135 found edentulism and severe periodontal disease among 38 patients, who exhibited severe radiographic evidence of osteoporosis. Wactawski- Wende and colleagues136 found a relationship between alveolar crestal bone height as a measure of periodontal disease and skeletal osteopenia. It appears that osteopenia, measured as BMD of the trochanter and total femur, was related to both
Risk Factors for Periodontal Disease 19
greater probing attachment loss and greater alveolar crestal height loss. Although these studies point to the possibility that osteopenia may be a risk factor for periodontal disease, further studies are clearly needed, especially large-scale studies in which mul- tiple risk factors affecting both osteoporosis and periodontal disease are taken into consideration. Furthermore, longitudinal studies are necessary to establish if skeletal bone loss and mandibular BMD precede the development of periodontal disease. Finally, intervention studies are needed to evaluate the extent to which reduction or prevention of osteopenia—through nutritional supplements, estrogen use, or use of bone-sparing agents such as alendronate—will affect periodontal disease.
Dietary Factors
Studies of diet and periodontal disease, based on our knowledge of the pathogenesis of periodontal disease and the role of bone metabolism in inflam- matory responses, may well lead to uncovering other important dietary factors that increase the risk for periodontal disease or decrease the ability of the periodontal tissues to heal. Clinical recommen- dations regarding diet or use of nutritional supple- ments must be based on randomized controlled tri- als of diet or nutritional supplements, and these have not yet been done with respect to periodontal disease for calcium, vitamin C, or other nutrients.
Calcium Nishida and co-workers evaluated the role of dietary calcium intake as a contributing factor to the risk for periodontal disease.137 They evaluated a large study of the United States population from NHANES data. In the NHANES III data set, which involved subjects assessed from 1988 to 1992, it was found that both men and women in the younger age group (20 to 39 years) and men in the middle-age group (40 to 59 years) who ingested lower levels of calci- um in their diet showed increased risk for periodon- tal disease. The odds ratio for increased risk for peri- odontal disease associated with lower dietary levels of calcium for those 20 to 39 years of age was 1.84 (95% CI 1.36 to 2.48); for women aged 20 to 39 years, it was 1.99 (95% CI 1.34 to 2.97). For mid- dle-aged men, the odds ratio was 1.9 (95% CI 1.4 to 2.54). These odds ratios were obtained after adjusting for gingival bleeding, tobacco consump- tion including smoking cigarettes or cigars and chewing tobacco, and alcohol consumption. Nishi- da and colleagues137 also showed that women in the younger age group (20 to 39 years) had lower total
serum calcium levels and that those with the lower serum calcium levels showed a significantly higher risk of periodontal disease (odds ratio 6.1; 95% CI 2.35 to 15.84). These analyses of over 12,000 sub- jects representative of the United States population suggest that reduced dietary calcium intake and reduced total serum calcium levels are associated with increased risk for periodontal disease. Fur- ther studies on other populations carried out in a longitudinal fashion, with consideration for dietary calcium supplementation, as well as inter- vention studies, are necessary to fully determine if low dietary calcium is indeed a true risk factor for periodontal disease.
Vitamin C Several studies suggest that vitamin C plays a role in maintaining the health of the gingiva.138 In fact, severe forms of vitamin C deficiency can cause a gingivitis known as “scorbutic” gingivitis.
A recent analysis of the NHANES III (1988 to 1992) study assessed the relationship between dietary vitamin C and periodontal disease.139 In this study, a representative sample of 12,419 indi- viduals in the United States, 20 to 90+ years of age, were analyzed. Those taking less dietary vitamin C showed an increased risk of periodontal disease, especially among current tobacco users (odds ratio 1.28; 95% CI 1.04 to 1.59); the odds ratio for for- mer users was 1.21 (95% CI 1.02 to 1.43) com- pared with those who did not smoke. These results suggest that reduced dietary vitamin C intake, especially in smokers and former smokers, increas- es the risk for periodontal disease. Further studies are needed, especially longitudinal studies, to determine if lower dietary intake of vitamin C pre- cedes the development of periodontal disease.
Stress and Psychological Disorders
Stress and psychological disorders have been sug- gested to be related to oral diseases including tem- poromandibular disorders, dental caries, salivary dysfunction, and periodontal disease in HIV infec- tion. Little definitive data exist, however, with respect to the role of stress on oral diseases. An evaluation of mental health, family interaction, and life events of infants and toddlers with caries by Wendt and colleagues140 found that there was considerable stress in most of the families. Howev- er, there was not a typical family pattern in which infants developed caries.
In studies of acute necrotizing ulcerative gin- givitis, stress and emotional factors have been iden-
20 Periodontal Medicine
tified as risk indicators since the early 1950s.141–142
Recently, the role of psychosocial factors in adult periodontitis has been assessed. For example, Marcenes and Sheiham143 showed that among the 135 subjects studied, those who faced greater work-related mental demand had greater peri- odontal disease as assessed by probing depth. Mon- teiro da Silva and colleagues144 carried out a case- control study comparing 50 patients with severe periodontitis, 50 patients with chronic adult peri- odontitis, and 50 controls. They found that the subjects with severe periodontitis had higher levels of psychosocial maladjustment than the other two groups. Specifically, the severe periodontitis group presented increased depression and loneliness com- pared with the other groups. Linden and col- leagues145 studied 23 dental patients over 5 years. They found that loss of periodontal attachment was greater in those with increasing age, lower socioeconomic status, lower job satisfaction, and type A personalities, suggesting a relationship between progression of periodontitis and psy- chosocial measures. These studies are interesting in that they suggest the hypothesis that periodontal disease is associated with psychological stress.
Recently, in a cross-sectional epidemiologic study, 1,426 adults were evaluated for stress, distress, and coping as related to periodontal disease severi- ty.146–147 The large study group allowed for adjust- ment for presently known confounders, such as age, gender, smoking status, systemic health, dental care, and oral hygiene practices. Furthermore, this study addressed not only stress but also measures of dis- tress and coping. To estimate stress, the Life Events Scale148 and the Daily Strain Scale149 were used. To measure distress, the Brief Symptom Inventory of Derogatis and Cleary was used.150 Coping styles were assessed using the COPE Inventory.151
The associations between psychosocial factors and periodontal disease status were evaluated, and it was found that individuals who suffered from high levels of clinical attachment loss had higher scores on the financial strain scales compared with periodontally healthy individuals, after adjusting for age, gender, and cigarette smoking (p = .008). A similar significant difference was found for indi- viduals with high levels of financial strain and greater loss of alveolar bone height compared with those in the low financial strain group. Stepwise ordinal logistic regression analysis showed that financial strain was associated with significantly greater clinical attachment loss (odds ratio 1.70; 95% CI 1.09 to 2.65), and with alveolar bone loss (odds ratio 1.68; 95% CI 1.20 to 2.37), after
adjusting for age, gender, and cigarette smoking. Hence, it appears that stress, likely chronic stress as would be associated with financial strain, is a risk indicator for periodontal disease.
When coping behaviors were evaluated for those with high financial strain, it was found that those who were high emotion–focused copers, a form of inadequate coping, had a higher risk of having more severe attachment loss and alveolar bone loss compared with those with low levels of financial strain. However, subjects with high levels of financial strain and reported high levels of prob- lem-focused coping, a form of adequate or good coping, have no more periodontal disease than those with low levels of financial strain. From this study, it appears that psychosocial measures of stress associated with financial strain are significant risk indicators for periodontal disease in adults. Fur- thermore, this study suggests that adequate coping behaviors may reduce stress-associated risk for peri- odontal disease. Adjustment for oral hygiene status and previous dental care did not change the associ- ations significantly, suggesting that other at-risk health behaviors did not account for the findings.
The mechanism(s) by which stress may moder- ate periodontal disease is presently unknown. How- ever, there are at least two pathways that stress can affect in infectious disease: the biologic model and the behavior model.147 Stress effects on periodontal disease may be biologically moderated through the hypothalamic-pituitary-adrenal (HPA) axis to pro- mote the release of corticotropic-releasing hormone from the hypothalamus and glucocorticoids from the adrenal cortex. Glucocorticoids may inhibit or reduce periodontal destruction. The effects of psy- chosocial stress also may occur through behavioral changes which affect at-risk health behaviors such as smoking, poor oral hygiene, and poor compli- ance with dental care. Any evaluation of the role of stress in periodontal disease should take into con- sideration at-risk health behaviors as well as the bio- logic effects transmitted through the HPA axis.
Genetic Factors
Genetic factors affect most oral conditions. These will be discussed as (1) abnormalities of the teeth, affecting size, shape, and number of teeth, defects in enamel and dentin, and abnormalities in the dental pulp; (2) genetic abnormalities affecting the orofacial complex; and (3) genetic factors associat- ed with periodontal disease.
Orofacial genetic abnormalities include cheru- bism, osteoporosis, osteogenesis imperfecta, cleido-
Risk Factors for Periodontal Disease 21
cranial dysplasia, craniofacial dysostosis, man- dibulofacial dysostosis, Pierre-Robin syndrome, Marfan’s syndrome, Ehlers-Danlos syndrome, Down syndrome, trisomy 21, hemifacial hypertro- phy, clefts of the lip and palate, and the fragile X syndrome. In some of these conditions, such as Ehlers-Danlos syndrome and Down syndrome, severe periodontitis may occur.
Genetic Aspects of Localized Periodontal Disease Localized juvenile periodontitis (LJP) has a familial aggregation and hence has been long thought to be a genetically determined condition. Melnick and col- leagues152 suggested an X-linked transmission; how- ever, Saxén,153 Long and colleagues,154 and Beaty and colleagues155 proposed an autosomal mode of inher- itance of juvenile periodontitis. Hart and col- leagues156 and Saxby157 also proposed autosomal modes of transmission. Hart points out, however, that juvenile periodontitis may be a heterogeneous group of diseases and, indeed, some rare X-linked forms may exist. Hart and colleagues158 convincing- ly argue that the predominance of evidence suggests that most cases of juvenile periodontitis are inherited in an autosomal manner. Additional studies are needed to provide definitive evidence of the specific genetic contributions to juvenile periodontitis.
Specific traits associated with juvenile peri- odontitis that may have genetic backgrounds include abnormalities in neutrophil function. For example, Van Dyke and colleagues159 studied 22 families in which the probands suffered from local- ized juvenile periodontitis. The families included a total of 44 affected individuals: 25 female and 19 male patients, including the probands. Among the siblings, exclusive of probands, the proportion of affected females (0.41) was the same as that of males (0.41). In 19 of the 22 families, neutrophil abnormalities were observed while in the other 3 families, there were no subjects with neutrophil abnormalities, suggesting heterogeneity. However, the predominant number of cases of juvenile peri- odontitis appear to have neutrophil chemotactic and possibly other disorders. Others have also reported neutrophil chemotactic disorders in fam- ilies with juvenile periodontitis, in which the affected children have the neutrophil defect, but not the unaffected children.160
Recent studies have shown genetic polymor- phisms to be associated with neutrophil function in subjects with juvenile periodontitis.161–162 For example, Gwinn and colleagues161 found a poly- morphism in the f-met-leu-phe receptor, a receptor for chemotactic factors produced by bacteria. This
polymorphism is found in most juvenile periodon- titis patients and few normal controls. Wilson and Kalmar162 found Fc receptor polymorphisms also associated with poor binding of IgG2 Fc to neu- trophils to be much more common in LJP patients than in matched controls.
The search for genetic polymorphisms in can- didate genes has been successful in the two studies, reported above, in neutrophil chemotactic recep- tors and Fc opsonic receptors. Further studies of candidate genes for polymorphisms may explain some of the subjects’ increased susceptibility to periodontal infection in LJP.
Attempts to associate human leukocyte anti- gens (HLA) with juvenile periodontitis are con- flicting. For example, Cullinan and colleagues163
showed that the segregation patterns of HLA in LJP were not conclusive. Similar findings were reported by Saxén and Koskimies.164 However, in a population-based study, Reinholdt and col- leagues165 showed that LJP patients have a higher prevalence of HLA-A9, HLA-A28, and HLA- BW15 than the general population, suggesting an association between HLA markers and the gene(s) for localized juvenile periodontitis.
Genetic Aspects of Adult Periodontitis Periodontal diseases are common, with mild forms affecting 75% of adults in the United States,1 and bacteria are generally thought to be the initiating etiologic agents. However, the host response trig- gered by pathogenic bacteria largely determines the course and severity of the disease. Host responses may affect initial colonization and infection and the growth of the organisms. They may also affect the immune and inflammatory response to the peri- odontopathic bacteria, which, in turn, determines the severity and rate of progression of the disease.166
Three approaches to the study of genetic influ- ences have been carried out in adult periodontitis. One approach is linkage analysis, that is, to associ- ate periodontal disease with inherited disease markers, such as blood groups or HLA. The second approach is through twin studies, and the third and most recent approach is to assess genetic polymor- phisms in candidate genes.
Human Leukocyte Antigen Associations Early studies showed negative association of adult periodontal disease with HLA-A2.167–169 Klouda and colleagues170 and Amer and colleagues171
showed an increase in HLA-A9 in patients with periodontal disease, which may be related to the reported increased frequency of HLA-A9 as well as
22 Periodontal Medicine
other HLA types by Reinholdt and colleagues165 in juvenile periodontitis. Further studies of HLA linkage are needed to resolve the issue of HLA association in adult periodontal disease.
Twin Studies Twin studies were carried out on 26 sets of twins aged 12 to 17 years, in which 7 pairs were mono- zygotic and 19 dizygotic.172 No differences were found in gingival recession, gingival crevice depth, gingival bleeding, calculus, or plaque. Michalowicz and colleagues173 studied 120 pairs of adult twins, including 62 pairs of monozygotic twins reared together, 25 pairs of same-sex dizygotic twins reared together, and 33 pairs of monozygotic twins reared apart. They found that alveolar bone height was significantly affected by genetic factors. A sec- ond study from this group174 studied 110 pairs of adult twins, including 66 monozygotic and 33 dizygotic twins reared together and 14 monozy- gotic twin pairs raised apart. They found a genetic influence on gingivitis, probing depth, attachment loss, and plaque. These studies are provocative, leading to hypotheses relating to genetic factors in periodontal disease. However, the authors point out that the data must be viewed cautiously. For example, changes in alveolar bone height may be genetic due to anatomic variation and may or may not be related to periodontal disease per se.
Corey and colleagues175 studied 116 monozy- gotic and 233 dizygotic pairs and compared their periodontal disease history. They found that the proband-wise concordance rates were 0.38 for monozygotic twins, and only 0.16 for dizygotic twins. These results provide further evidence that genetic factors make an important contribution to adult periodontal disease.
Genetic Polymorphisms Genetic polymorphisms have been associated with adult periodontitis. For example, Kornman and colleagues176 studied genetic polymorphisms in the proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-a). They report a specific periodontitis-associated IL-1 geno- type, comprising a variant in the IL-1B gene associ- ated with high levels of IL-1 production. This geno- type was associated with severe periodontitis only in nonsmokers. In smokers, severe periodontal disease was not correlated with any of the tested genotypes. Tests for this combined genotype are commercially available and may be of value in understanding risk for periodontal disease, especially in nonsmokers. Further studies with larger populations including
controls with no periodontal disease as well as pop- ulations of various racial and ethnic groups are needed to fully evaluate polymorphisms.
Van Schie and colleagues177 report an Fcg receptor polymorphism pattern associated with periodontitis. They compared 105 adults with moderate to severe periodontitis with 132 age- and race-matched controls without periodontitis. The FcgRIIA-H/H131 and FcgRIIIB-NA2/NA2 geno- type was elevated in patients compared with con- trols (18.8% versus 3.8%) while the combined FcgRIIA-R/H131 and FcgRIIIB-NA2/NA2 geno- type was reduced in the periodontitis group (6.3%) compared with the controls (22.9%). This association observed between the combined FcgRIIA and FcgRIIIB genotype and moderate to severe periodontitis suggests that reduced opsonization associated with this combined geno- type impairs phagocytosis of pathogenic bacteria in individuals carrying these receptors. This may be an important risk factor in adult periodontitis. However, further studies with different racial pop- ulations and with larger populations are needed to better account for possible confounding factors to fully assess the role of this risk indicator.
Hence, it appears that candidate gene poly- morphisms are a useful approach in assessing genetic factors in both adult and juvenile forms of periodontal disease. Future efforts along these lines may reveal a set of important genes in periodonti- tis in which genetic polymorphisms affect the function of the molecules encoded for by these genes and thereby increase susceptibility or resis- tance to periodontal infections. It is likely that genetic polymorphisms will explain risk for peri- odontal disease in subsets of the population. In the future, a larger battery of such polymorphisms may be useful to understand genetic influences on risk for periodontal disease.
EFFECTS OF MEDICATIONS AND PERIODONTAL DISEASE
Phenytoin
Sodium 5,5-phenylhydantoin has been used for 50 years in the treatment of grand mal epilepsy and also has been used for management of other neuro- logic disorders. Overgrowth of the gingiva is one of the most troublesome side effects of phenytoin.178
A gross increase in gingival size is due to a dramat- ic expansion of the connective tissue component. The growth is not a true fibrosis but a gingival over-
Risk Factors for Periodontal Disease 23
growth since it results from neither hypertrophy nor hyperplasia. Treatment consists of replacing phenytoin with an alternative drug such as carba- mazepine or sodium valproate, conservative peri- odontal therapy to reduce the inflammatory com- ponent of enlargement, and surgery, if necessary.
Cyclosporine
Cyclosporine has been used in the United States since 1984 for the prevention of rejection phenom- ena following solid organ and bone marrow trans- plantation. It is also used in other countries in the treatment of type 2 diabetes mellitus, rheumatoid arthritis, psoriasis, multiple sclerosis, malaria, sar- coidosis, and some other diseases with an immuno- logic basis. Cyclosporine selectively suppresses sub- populations of T lymphocytes interfering with pro- duction of interleukins, especially interleukin-1. Gingival overgrowth has been associated with cyclosporine.179 Histopathologically, cyclosporine- induced gingival overgrowth is associated with apparent fibroplasia, redundant collagenous ele- ments, epithelial thickening as well as secondary inflammation. Reduction of dental plaque and low drug dosages may discourage the gingival over- growth associated with the use of cyclosporine. Fur- thermore, cyclosporine substitute drugs appear to have little or no effect on the gingivae.
Dihydropyridines: Nifedipine and Nitrendipine
Nifedipine (Procardia) is a substituted dihydropro- lidine widely used since 1978 in the treatment of angina pectoris and postmyocardial syndrome. Nifedipine is a calcium ion blocker which induces gingival overgrowth.180 Histologically, there is thickened epithelium, elongation of epithelial rete ridges, redundant connective tissue, and abundant fibroblasts. Inflammation may be reduced with good plaque control, and scaling and root planing; however, often periodontal surgery is required for treatment.
Another commonly used calcium antagonist in cardiology is verapamil hydrochloride (Calan). Verapamil hydrochloride has not been associated with gingival enlargement or fibrosis elsewhere in the body.
Heavy Metals
Pigmentation of the gingiva or other mucosa results when heavy metals, primarily heavy metal
sulfides, are present in the body. Oral manifesta- tions of mercury, lead, and bismuth intoxication are well described; however, the presence of such manifestations has decreased significantly as expo- sure to heavy metals by way of occupational haz- ards and metal-containing drugs has declined. Bis- muth line is seen as a blue-black, easily discernible, diffuse pigmentation of marginal gingiva. Lead poisoning results in a line with grayish pigmenta- tion typically located a few millimeters apical to the gingival margin. A mercury line on the gingiva resulting from deposition of mercurial salts, main- ly mercuric sulfide, may be deposited in the gingi- va. Cases of true allergy to mercury present in the silver amalgam dental restorations are rare.181 The role of lead and other heavy metals in the risk for periodontal disease has not been studied but is pos- sible since these metals have major biologic effects, and their ingestion is increasing in our society.
LOCAL RISK FACTORS: PERIODONTAL MICROFLORA
There are over 400 genera and species of microor- ganisms that have been identified in the oral flora of man. Only a few members of the subgingival periodontal microflora, however, have been identi- fied as candidate pathogens for the initiation and progression of periodontal disease. In a large epi- demiologic study, Grossi and co-workers21,22 tested a panel of candidate pathogen microorganisms, many of which have been implicated as periodon- tal pathogens from animal, virulence, and case- control human studies. This panel included Acti- nobacillus actinomycetemcomitans, Bacteroides forsythus, Campylobacter rectus, Capnocytophaga species, Eubacterium saburreum, Fusobacterium nucleatum, Porphyromonas gingivalis, and Prevotella intermedia. Of this panel, only two, P. gingivalis and B. forsythus, were associated with increased risk for attachment loss as a measure of periodontal dis- ease, after adjustment for age, plaque, smoking, and diabetes.21 The same two organisms were also identified as risk indicators for periodontal alveolar bone loss.22 Epidemiologic studies of Beck and co- workers182 suggested that specific bacteria such as P. gingivalis and P. intermedia play a role in peri- odontal disease in older adults. They found in their study of older adults that the difference in the prevalence of periodontal disease between African Americans and Caucasian Americans is explained in part by the prevalence of P. gingivalis and P. intermedia. In a longitudinal study of 886 patients,
24 Periodontal Medicine
Wolff and colleagues183 found that P. gingivalis, A. actinomycetemcomitans, P. intermedia, Eikenella corrodens and F. nucleatum were found in higher numbers in areas of increasing probing depths with relative risks between 2.7 and 4.0. A very strong association has been found between the presence of A. actinomycetemcomitans and periodontal disease in localized juvenile periodontitis.184–185
The presence and level of spirochetes have been associated with increased risk of periodontal dis- ease;186 however, this finding has to be tempered by the observation that spirochetes are also elevated when patients have poor oral hygiene.187 Haffajee and co-workers188 found that P. intermedia, C. rectus, B. forsythus, and Peptostreptococcus micros were pre- dictors of future periodontal progression in patients who were already affected by adult perio- dontitis. Listgarten189 found that the absence of A. actinomycetemcomitans, P. intermedia, and P. gin- givalis served as an indicator of periodontal health to a greater extent than their presence being a marker for future disease. He suggests that they have a high negative predictive value. The importance of specif- ic bacteria in periodontal destruction is highlighted by the finding that the quantity of total plaque accu- mulation is only correlated weakly with destructive periodontal disease.21,22,190 Further studies are neces- sary to determine the extent to which other organ- isms (eg, A. actinomycetemcomitans) may play a role in juvenile forms of periodontal disease.
Oral Hygiene, Plaque, and Calculus
Microbial dental plaques have been strongly asso- ciated as causative agents for gingivitis; however, the association of supragingival plaque with peri- odontitis is not clear. For example, in the studies by Grossi and colleagues,21,22 they are not found to be risk factors for periodontal disease. In treat- ment studies, such as that by Axelsson and col- leagues,191 it was shown that patients who main- tain excellent hygiene measures and who undergo scaling and root planing every 2 to 3 months for 9 years, and twice annually for an additional 6 years, had very little clinically detectable periodontal disease. Thus, it is clear that periodontitis can be prevented and established periodontitis arrested by control of microbial deposits. Supragingival plaque may provide a favorable environment for coloniza- tion with specific subgingival flora and indirectly affect the pathogenic subgingival flora.192–193
Therefore, the association that has been docu- mented above for the specific flora is a direct one in terms of risk factors.
Calculus and its relationship to periodontitis is complex. Calculus developing in certain sites, such as the lower incisal areas, in patients receiv- ing regular dental care does not result in signifi- cant periodontal disease.194 On the other hand, studies report a high correlation between measures of calculus and measures of periodontal disease and since they coexist, it is difficult to determine that calculus per se is a risk factor for periodontal disease. Calculus is likely a deposit that forms after periodontal disease develops and likely con- tributes to progression of periodontitis by provid- ing a nidus for microbial plaque accumulation and persistence.
Bleeding on Probing
Surprisingly, gingival bleeding on probing appears to have weak predictive value for future periodontal breakdown.195–196 However, the repeated absence of bleeding upon probing is associated with no disease progression.197–198 In these studies, it was found that setting level of bleeding upon probing at 50% is predictive for future periodontal disease with a relative risk of 3, after adjusting for smoking, microbial dental plaque accumulation, diabetes, and baseline flora.
Preexisting Periodontal Disease
Perhaps one of the most strongly associated risk factors for future periodontal breakdown is pres- ence and severity of periodontal disease assessed by attachment loss or alveolar bone loss at base- line.32,34,188–189,199–203 In a study of 79 patients with established periodontitis who were monitored every 3 months for 1 year, Machtei and co-work- ers203 found that individuals with baseline pocket depth ³3.2 mm were at greater risk for future bone loss 1 year later (relative risk: 2.97; 95% CI 1.02 to 8.70). A multivariate analysis of this study also found that smokers were at increased risk for fur- ther attachment loss when compared to nonsmok- ers (relative risk: 5.41; 95% CI 1.50 to 19.5) and that subjects who harbored B. forsythus at baseline were at seven times greater risk for increased pock- et depth (relative risk: 7.84; 95% CI 1.74 to 35.3). This study confirms that pre-existing periodontal disease is among the true risk factors for develop- ment of periodontal disease.
Lack of regular dental therapy has also been suggested as a risk factor for periodontal disease in studies using univariate analyses. However, with multivariate analysis, most studies showed that pre-
Risk Factors for Periodontal Disease 25
vious dental therapy is not a risk factor when one considers existing levels of disease, such as existing pocket depth or existing gingivitis in the model.21,22
Individual Tooth Risk Factors
Several factors have been proposed to affect the risk of further periodontal disease on individual teeth. These include
1. occlusion, especially functional malocclusion such as bruxism;
2. excessive occlusal stress, which may be prima- ry if the tooth has excessive stress with inade- quate support, or secondary if the tooth is under even normal stress and has inadequate support; and
3. teeth with pulpal infections that show periapi- cal lesions; these have greater chance of future loss of attachment than those with no pulpal
infection. More study of the role of occlusion in periodontal disease is needed.
CLINICAL APPLICATION OF RISK FACTOR ANALYSIS
Table 2–2 lists important risk indicators and risk factors for periodontal disease and summarizes their strength of association. On the basis of the strength of the association, those factors that appear to be true risk factors for periodontal dis- ease in adults include the subgingival periodontal pathogens P. gingivalis and B. forsythus, diabetes mellitus, male gender, smoking, and pre-existing periodontal disease. Putative risk factors or risk indicators at this time include genetic factors; osteoporosis; stress, distress, and coping; and dietary factors such as low calcium intake. Further studies are necessary to determine the extent to
TABLE 2–2. The Strength of Association of Local and Systemic Factors with Destructive Periodontal Disease
Case Report Case-Control Cross-Sectional Longitudinal Factor Studies Studies Studies Studies Intervention Studies
Specific bacteria P. gingivalis Yes Yes Yes Yes Yes B. forsythus Yes Yes Yes Yes Yes P. intermedia Yes Yes Yes Yes Yes
Gender Male Yes NR Yes NR NR
Age Yes Yes Yes No (to 7th decade) NR Diabetes mellitus
Type 2 Yes Yes Yes Yes Yes (treatment reduces glycosylated hemoglobin)
Type 1 Yes Yes Yes NR NR Smoking NR Yes Yes Yes Yes (smokers heal poorly) Osteoporosis Yes Yes Yes NR NR Stress, distress, Yes Yes Yes NR NR
coping PMN disorders Yes Yes NR Yes (case series) NR Genetic factors NR Yes NR NR NR
(IL-1 polymorphisms)
Dietary calcium NR Yes Yes NR NR Preexisting Yes Yes Yes Yes Yes
periodontal disease
NR = not reported, or not relevant; PMN = polymorphonuclear. Adapted from Genco RJ. Current view of risk factors for periodontal diseases. J Periodontal 1996;67(Suppl):1041–9.
26 Periodontal Medicine
which these risk indicators are true risk factors for periodontal disease.
DETERMINING A PATIENT’S RISK PROFILE
Determination of patient-based as well as site- based risk factors for periodontal disease is a neces- sary component of the evaluation and diagnosis of our patients. Identification of risk factors for each patient, and their management should be part of the treatment plan.
RISK FACTOR MODIFICATION IN CLINICAL MANAGEMENT
Periodontal diseases are infections and, by and large, are treated with anti-infective therapy, and residual defects are restored by regenerative therapy. The third mode of therapy, modification of risk, is becoming more and more important as indicated by studies that show that if risk factors are not mod- ified, periodontal healing is compromised, especial- ly in patients who smoke.52,204 It would seem that smoking cessation is indicated for optimal peri- odontal healing as well as for other general health reasons. Diabetics who respond successfully to peri- odontal therapy also have a reduction in glycated hemoglobin, particularly if they are treated with tetracycline.100 Several other studies have shown similar results. Hence, management of periodontal disease, that is, modification of risk factors, is part of contemporary treatment of periodontal disease and is supported by intervention studies.
SUMMARY
In this chapter, those factors associated with increased risk for periodontal disease, functioning as systemic factors or as local factors, are described, and data supporting these factors as true risk fac- tors are provided. A model for the assessment of risk for the development of periodontal disease in patients with no or moderate periodontal disease is provided. Furthermore, the concept of risk management, that is, modification of risk factors as part of periodontal therapy, in those at high risk is presented.
REFERENCES
1. Miller AJ, Brunelle JA, Carlos JP, et al. Oral Health of United States Adults: National Findings.
Bethesda, MD: National Institute of Dental Research; 1987. NIH Publication No. 87-2868.
2. Hugoson A, Jordan T. Frequency distribution of individuals aged 20–70 years according to sever- ity of periodontal disease. Commun Dent Oral Epidemiol 1982;10:187–92.
3. Brown LJ, Löe H. Prevalence, extent, severity and progression of periodontal disease. Periodontol 2000 1993;2:57–71.
4. Genco RJ. Periodontal disease and risk for myocar- dial infarction and cardiovascular disease. Car- diovasc Rev Rep 1998;19(3):34–40.
5. Offenbacher S, Katz V, Gertik G, et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol 1996;67:1103–13.
6. Scannapieco FA, Papandonatos GD, Dunford RG. Associations between oral conditions and respi- ratory disease in a national sample survey popu- lation. Annals Periodontol 1998;3:251–6.
7. Scannapieco FA. Periodontal disease as a potential risk factor for systemic diseases [position paper]. J Periodontol 1998;69:841–50.
8. Haffajee AD, Socransky SS. Microbial etiological agents of destructive periodontal diseases. Peri- odontol 2000 1994;5:78–111.
9. Slots J, Feik D, Rams TE. Age and sex relationships of superinfecting microorganisms in periodontitis patients. Oral Microbiol Immunol 1990;5:305–8.
10. Njoroge T, Genco RJ, Sojar HT, et al. A role for fim- briae in Porphyromonas gingivalis invasion of oral epithelial cells. Infect Immun 1997;65:1980–4.
11. Genco CA, Odusanya BM, Potempa J, et al. A pep- tide domain on gingipain R which confers immunity against Porphyromonas gingivalis infec- tion in mice. Infect Immun 1998;66:4108–14.
12. van Winkelhoff AJ, Tijhof CJ, de Graaff J. Micro- biological and clinical results of metronidazole plus amoxicillin therapy in Actinobacillus actin- omycetemcomitans-associated periodontitis. J Periodontol 1992;63:52–7.
13. American Academy of Periodontology. The patho- genesis of periodontal diseases [informational paper]. J Periodontol 1999;70:457–70.
14. Reynolds JJ, Meikle MC. Mechanisms of connec- tive tissue matrix destruction in periodontitis. Periodontol 2000 1997;14:144–57.
15. Honig J, Rordorf-Adam C, Siegmund C, et al. Increased interleukin-1b concentration in gingi- val tissue from periodontitis patients. J Perio- dontal Res 1989;24:362–7.
16. Gemmell E, Marshall R, Seymour G. Cytokines and prostaglandins in the immune hemostasis and tissue destruction in periodontal disease. Periodontol 2000 1997;14:112–43.
Risk Factors for Periodontal Disease 27
17. Last JM. A dictionary of epidemiology, 2nd ed. New York, NY: Oxford University Press; 1988.
18. Beck JD. Methods of assessing risk for periodonti- tis and developing multi-factorial models. J Periodontol 1994;65:468–78.
19. Ibrahim M. Epidemiology and health policy. Rockville, MD: Aspen Systems Corporation; 1985.
20. Goodson JM. Selection of suitable indicators of periodontitis. In: Bader JD, editor. Risk assess- ments in dentistry. Chapel Hill, NC: University of North Carolina Dental Ecology; 1990. p. 69.
21. Grossi SG, Zambon JJ, Ho AW, et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994;65:260–7.
22. Grossi SG, Genco RJ, Machtei EE, et al. Assess- ment of risk for periodontal disease. II. Risk indicators for alveolar bone loss. J Periodontol 1995;66:23–9.
23. Carlos JP, Wolfe MD, Kingman A. The extent and severity index: a simple method for use in epi- demiologic studies of periodontal disease. J Clin Periodontol 1986;13:500–5.
24. DeRouen TA. Statistical methods for assessing risk of periodontal disease. In: Bader JD, editor. Risk assessments in dentistry. Chapel Hill, NC: University of North Carolina Dental Ecology; 1990. p. 239–44.
25. Hujoel PP, Loesche WJ, DeRouen TA. Assessment of relationships between site-specific variables. J Periodontol 1990;61:368–72.
26. DeRouen TA, Mancl L, Hujoel P. Measurement of association in periodontal diseases using statisti- cal methods for dependent data. J Periodontal Res 1991;26:218–29.
27. Marshall-Day CD, Stevens RG, Quigley LF Jr. Periodontal disease prevalence and incidence. J Periodontol 1955;26:185–203.
28. Schei O, Waerhaug J, Lövdal A, Arnö A. Alveolar bone loss as related to oral hygiene and age. J Periodontol 1959;30:7–16.
29. Abdellatif HM, Burt BA. An epidemiological investigation into the relative importance of age and oral hygiene status as determinants of peri- odontitis. J Dent Res 1987;66:13–8.
30. Machtei EE, Dunford R, Grossi SG, Genco RJ. Cumulative nature of periodontal attachment loss. J Periodontal Res 1994;29:361–4.
31. Papapanou PN, Wennström JL, Grondahl K. A 10- year retrospective study of periodontal disease progression. J Clin Periodontol 1989;16:404– 11.
32. Albandar JM, Rise J, Gjermo P, Johansen JR. Radi- ographic quantification of alveolar bone level changes. A 2-year longitudinal study in man. J Clin Periodontol 1986;13:195–200.
33. Wennström JL, Serino G, Lindhe J, et al. Peri- odontal conditions of adult regular dental care attendants. A 12-year longitudinal study. J Clin Periodontol 1993;20:714–22.
34. Ismail AI, Morrison EC, Burt BA, et al. Natural history of periodontal disease in adults: findings from the Tecumseh periodontal disease study. 1959–1987. J Dent Res 1990;69:430–5.
35. Russell AL. Geographical distribution and epidemi- ology of periodontal disease. Geneva: World Health Organization; (WHO/DH/33/34), 1960.
36. U.S. Public Health Service. National Center for Health Statistics. Periodontal disease in adults, United States 1960–1962. PHS Publication No. 1000, Series 11, No. 12, Washington, DC: Government Printing Office; 1965.
37. U.S. Public Health Service. National Center for Health Statistics. Basic data on dental examina- tion findings of persons 1–75 years; United States, 1971–1974. DHEW Publication No. (PHS) 79-1662, Series 11, No. 214, Washing- ton, DC: Government Printing Office; 1979.
38. Genco RJ. Current view of risk factors for peri- odontal diseases. J Periodontol 1996;67(Suppl): 1041–9.
39. Pindborg JJ. Tobacco and gingivitis. I. Statistical examination of the significance of tobacco in the development of ulceromembranous gingivi- tis and in the formation of calculus. J Dent Res 1947;26:261–4.
40. Frandsen A, Pindborg JJ. Tobacco and gingivitis. III. Difference in action of cigarette and pipe smoking. J Dent Res 1949;28:464–5.
41. Solomon HA, Priore RL, Bross IDJ. Cigarette smoking and periodontal disease. J Am Dent Assoc 1968;77:1081–4.
42. Ismail AI, Burt BA, Eklund SA. Epidemiologic pat- terns of smoking and periodontal disease in the United States. J Am Dent Assoc 1983;106: 617–23.
43. Machtei EE, Hausmann E, Dunford R, et al. Lon- gitudinal study of predictive factors for peri- odontal disease and tooth loss. J Clin Periodon- tol 1999;26:374–80.
44. Gonzalez YM, De Nardin A, Grossi SG, et al. Serum cotinine levels, smoking and periodontal attachment loss. J Dent Res 1996;75:796–802.
45. Holm G. Smoking as an additional risk for tooth loss. J Periodontol 1994;65:996–1001.
46. Preber H, Bergström J. Occurrence of gingival bleeding in smoker and nonsmoker patients. Acta Odontol Scand 1985;43:315–20.
47. Preber H, Bergström J. The effect of non-surgical treatment on periodontal pockets in smokers
28 Periodontal Medicine
and nonsmokers. J Clin Periodontol 1985;13: 319–23.
48. Preber H, Bergström J. Effect of cigarette smoking on periodontal healing following surgical thera- py. J Clin Periodontol 1990;17:324–8.
49. Kaldahl WB, Kalkwarf KL, Patil KD, Molvar MP. Relationship of gingival bleeding, gingival sup- puration and supragingival plaque to attach- ment loss. J Periodontol 1990;61:347–51.
50. Tonetti MS, Pini-Prato G, Cortellini P. Effect of cigarette smoking on periodontal healing fol- lowing GTR in infrabony defects. A prelimi- nary retrospective study. J Clin Periodontol 1996;22:229–34.
51. Preber H, Linder L, Bergström J. Periodontal heal- ing and periopathogenic microflora in smokers and non-smokers. J Clin Periodontol 1996;22: 946–52.
52. Grossi SG, Skrepcinski FB, DeCaro T, et al. Respons- es to periodontal therapy in diabetics and smok- ers. J Periodontol 1996;67(Suppl):1094–102.
53. Kaldahl WB, Kalkwarf KL, Patil KD, et al. Long- term evaluation of periodontal therapy. II: Inci- dence of sites breaking down. J Periodontol 1996;67:103–8.
54. Bergström J, Eliasson S, Preber H. Cigarette smok- ing and periodontal bone loss. J Periodontol 1991;62:242–6.
55. Haber J, Wattles J, Crowley M, et al. Evidence for cigarette smoking as a major risk factor for peri- odontitis. J Periodontol 1993;64:16–23.
56. Haber J, Kent RL. Cigarette smoking in a peri- odontal practice. J Periodontol 1992;63:100–6.
57. Baab DA, Oberg PA. The effect of cigarette smok- ing on gingival blood flow in humans. J Clin Periodontol 1987;14:418–24.
58. Palmer RM. Tobacco smoking and oral health: review. Br Dent J 1988;164:258–60.
59. Haber J, Brinnell C, Crowley M, et al. Antibodies to periodontal pathogens in cigarette smoking. J Dent Res 1993;72(Special Issue): Abstract 1126.
60. Tew JG, Zhang J-B, Quinn S, et al. Antibody of the IgG2 subclass, Actinobacillus actinomycetem- comitans, and early-onset periodontitis. J Perio- dontol 1996;67(Suppl):317–22.
61. Raulin L, MacPherson J, McQuade M, Hanson B. The effect of nicotine on the attachment of human fibroblasts to glass and human root sur- faces in vitro. J Periodontol 1988;59:318–25.
62. Krall EA, Dawson-Hughes B. Smoking and bone loss among postmenopausal women. J Bone Min Res 1991;6:331–7.
63. Daniell HW. Osteoporosis of the slender smoker. Arch Intern Med 1976;136:298–304.
64. Cuff MJ, McQuade MJ, Scheidt MJ, et al. The presence of nicotine on root surfaces of peri- odontally diseased teeth in smokers. J Periodon- tol 1989;60:564–9.
65. Zambon JJ, Grossi SG, Machtei EE, et al. Cigarette smoking increases the risk for subgingival infec- tion with periodontal pathogens. J Periodontol 1996;67(Suppl):1050–4.
66. MacFarlane G, Herzberg M, Wolff L, Hardie N. Refractory periodontitis associated with abnor- mal polymorphonuclear leukocyte phagocytosis and cigarette smoking. J Periodontol 1992;63: 908–13.
67. Poore TK, Johnson GK, Rheinhardt RA, Organ CC. The effects of smokeless tobacco on clinical parameters of inflammation and gingival crevic- ular fluid prostaglandin E2, interleukin-1a, and interleukin-1b. J Periodontol 1995;66:177–83.
68. Johnson GK, Poore TK, Rayne JB, Organ CC. Effect of smokeless tobacco extract on human gingival keratinocyte levels of prostaglandin E2 and inter- leukin-1. J Periodontol 1996;67:116–24.
69. Ringelberg ML, Dixon DO, Francis AO, Plummer RW. Comparison of gingival health and gingival crevicular fluid flow in children with and with- out diabetes. J Dent Res 1977;56:108–11.
70. Faulconbridge AR, Bradshaw WC, Jenkins PA, Baum JD. The dental status of a group of dia- betic children. Br Dent J 1981;151(8):253–5.
71. Cianciola LJ, Park BH, Bruck E, et al. Prevalence of periodontal disease in insulin-dependent dia- betes mellitus (juvenile diabetes). J Am Dent Assoc 1982;104:653–60.
72. Harrison R, Bowen WH. Periodontal health, den- tal caries, and metabolic control in insulin- dependent diabetic children and adolescents. Pediatric Dent 1987;9:283–6.
73. Novaes AB Jr, Pereira ALA, de Moraes N, Novaes AB. Manifestations of insulin-dependent diabetes mellitus in the periodontium of young Brazilian patients. J Periodontol 1991;62:116–22.
74. de Pommereau V, Dargent-Pare C, Robert JJ, Brion M. Periodontal status in insulin-dependent dia- betic adolescents. J Clin Periodontol 1992;19 (Pt. 1):628–32.
75. Pinson M, Hoffman WH, Garnick JJ, Litaker MS. Periodontal disease and type 1 diabetes mellitus in children and adolescents. J Clin Periodontol 1995;22:118–23.
76. Firatli E, Yilmaz O, Onan U. The relationship between clinical attachment loss and the dura- tion of insulin-dependent diabetes mellitus (IDDM) in children and adolescents. J Clin Periodontol 1996;23:362–6.
Risk Factors for Periodontal Disease 29
77. Firatli E. The relationship between clinical peri- odontal status and insulin-dependent diabetes mellitus. Results after 5 years. J Periodontol 1997;68:136–40.
78. Goteiner D, Vogel R, Deasy M, Goteiner C. Peri- odontal and caries experience in children with insulin-dependent diabetes mellitus. J Am Dent Assoc 1986;113:277–9.
79. Kjellman O, Henriksson CO, Berghagen N, Andersson B. Oral conditions in 105 subjects with insulin-treated diabetes mellitus. Svensk Tandlakaretidskrift 1970;63:99–110.
80. Sznajder N, Carraro JJ, Rugna S, Sereday M. Peri- odontal findings in diabetic and nondiabetic patients. J Periodontol 1978;49:445–8.
81. Galea H, Aganovic I, Aganovic M. The dental caries and periodontal disease experience of patients with early onset insulin dependent dia- betes. Intl Dent J 1986;36:219–24.
82. Rylander H, Ramberg P, Blohme G, Lindhe J. Prevalence of periodontal disease in young dia- betics. J Clin Periodontol 1987;14:38–43.
83. Guven Y, Satman I, Dinccag N, Alptekin S. Salivary peroxidase activity in whole saliva of patients with insulin-dependent (type 1) diabetes melli- tus. J Clin Periodontol 1996;23:879–81.
84. Cohen MM. Transforming growth factor beta and fibroblast growth factors and their receptors: role in structural biology and craniosynostosis. J Bone Min Res 1997;12:322–31.
85. Glavind L, Lund B, Löe H. The relationship between periodontal state and diabetes dura- tion, insulin dosage and retinal changes. J Perio- dontol 1968;39(6):341–7.
86. Hugoson A, Thorstenson H, Falk H, Kuylenstierna J. Periodontal conditions in insulin-dependent diabetics. J Clin Periodontol 1989;16:215–23.
87. Thorstenson H, Hugoson A. Periodontal disease experience in adult long-duration insulin- dependent diabetics. J Clin Periodontol 1993; 20:352–8.
88. Tervonen T, Karjalainen K. Periodontal disease related to diabetic status. A pilot study of the response to periodontal therapy in type 1 dia- betes. J Clin Periodontol 1997;24:505–10.
89. Nelson RG, Shlossman M, Budding LM, et al. Periodontal disease and NIDDM in Pima Indi- ans. Diabetes Care 1990;13:836–40.
90. Shlossman M, Knowler WC, Pettitt DJ, Genco RJ. Type 2 diabetes and periodontal disease. J Am Dent Assoc 1990;121:532–6.
91. Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in non-insulin dependent diabetes melli- tus. J Periodontol 1991;62:123–30.
92. Morton AA, Williams RW, Watts RLP. Initial study of periodontal status in non-insulin-dependent diabetics in Mauritius. J Dent 1995;23:343–5.
93. Novaes AB Jr, Gutierrez FG, Novaes AB. Periodon- tal disease progression in type II non-insulin- dependent diabetes mellitus patients (NIDDM). Part I. Probing pocket depth and clinical attach- ment. Brazilian Dent J 1996;7:65–73.
94. Taylor GW, Burt BA, Becker MP, et al. Non-insulin dependent diabetes mellitus and alveolar bone loss progression over two years. J Periodontol 1998;69:76–83.
95. Taylor GW, Burt BA, Becker MP, et al. Glycemic control and alveolar bone loss progression in type II diabetes. Ann Periodontol 1998;3(1):30–9.
96. Taylor GW, Burt BA, Becker MP, et al. Severe peri- odontitis and risk for poor glycemic control in subjects with non-insulin-dependent diabetes mellitus. J Periodontol 1996;67:1085–93.
97. Dolan TA, Gilbert GH, Ringelberg ML, et al. Behav- ioral risk indicators of attachment loss in adult Floridians. J Clin Periodontol 1997;24:223–32.
98. Szpunar SM, Ismail AI, Eklund SA. Diabetes and periodontal disease: analyses of NHANES I and HHANES [abstract 1605]. J Dent Res 1989; 68(Special Issue):383.
99. Aldridge JP, Lester V, Watts TL, et al. Single-blind studies of the effects of improved periodontal health on metabolic control in type 1 diabetes mellitus. J Clin Periodontol 1995;22:271–5.
100.Grossi SG, Skrepcinski FB, DeCaro T, et al. Treat- ment of periodontal disease in diabetics reduces glycated hemoglobin. J Periodontol 1997;68: 713–9.
101.Miller LS, Manwell MA, Newbold D, et al. The relationship between reduction in periodontal inflammation and diabetes control: a report of 9 cases. J Periodontol 1992;63:843–8.
102.Clearinghouse on oral problems related to HIV infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus. Classification and diagnostic criteria for oral lesions in HIV infection. J Oral Pathol Med 1993;22(7):289–91.
103.Greenberg MS. HIV-associated lesions. Dermatol Clin 1996;14:319–26.
104.Greenspan D, Greenspan JS. HIV-related oral dis- ease. Lancet 1996;348(9029):729–33.
105.Phelan JA. Oral manifestations of human immun- odeficiency virus infection. Med Clin North Am 1997;81:511–31.
106.Samaranayake LP, Holmstrup P. Oral candidiasis and human immunodeficiency virus infection. J Oral Pathol Med 1989;18:554–64.
30 Periodontal Medicine
107.Klein RS, Harris CA, Small CB, et al. Oral can- didiasis in high risk patients as the initial mani- festation of the acquired immunodeficiency syndrome. N Engl Med J 1984;311(6):35–48.
108.Tindall B, Carr A, Cooper DA. Primary HIV infec- tion: clinical, immunologic, and serologic aspects. In: Sande MA, Volberding PA, editors. The medical management of AIDS. Philadel- phia: WB Saunders; 1995. p. 105–29.
109.Glick M, Muzyka BC, Lurie D, Salkin LM. Oral manifestations associated with HIV-related dis- ease as markers for immune suppression and AIDS. Oral Surg Oral Med Oral Pathol 1994; 77:344–9.
110.Daniels TE. Oral candidiasis and HIV infection. In: Greenspan JS, Greenspan D, editors. Oral manifestations of HIV infection. Chicago, IL: Quintessence; 1995. p. 80–4.
111.Dodd CL, Greenspan D, Katz MH, et al. Oral can- didiasis in HIV infection: Pseudomembranous and erythematous candidiasis show similar rates of progression to AIDS. AIDS 1991;5(11): 1339–43.
112.Greenspan D, Greenspan JS, Conant M, et al. Oral “hairy” leukoplakia in male homosexuals: evi- dence of association with both papillomavirus and a herpes-group virus. Lancet 1984;2:831–4.
113.Greenspan D, Greenspan JS, Lennette ET, et al. Oral viral leukoplakia—a new AIDS-associated condition. Adv Exp Med Biol 1985;187:123–8.
114.Eisenberg E, Krutchkoff D, Yamase H. Incidental oral hairy leukoplakia in immunocompetent persons. A report of two cases. Oral Surg Oral Med Oral Pathol 1992;74:332–3.
115.Felix DH, Watret K, Wray D, Southam JC. Hairy leukoplakia in an HIV negative, nonimmuno- suppressed patient. Oral Surg Oral Med Oral Pathol 1992;74(5):563–6.
116.Epstein JB, Silverman S Jr. Head and neck malig- nancies associated with HIV infection. Oral Surg Oral Med Oral Pathol 1992;73:193–200.
117.Lamster I, Grbic J, Fine J, et al. A critical review of periodontal disease as a manifestation of HIV infection. In: Greenspan JS, Greenspan E, edi- tors. Oral manifestations of HIV infection. Chicago, IL: Quintessence; 1995. p. 247–56.
118.Winkler JR, Robertson PB. Periodontal disease associated with HIV infection. Oral Surg Oral Med Oral Pathol 1992;73:145–50.
119.Winkler JR, Grassi M, Murray PA. Clinical description and etiology of HIV-associated peri- odontal diseases. In: Robertson PB, Greenspan JS, editors. Perspectives on oral manifestations of AIDS: diagnosis and management of HIV-
associated infections. Littleton (MA): PSG Pub- lishing; 1988.
120.Van Dyke TE, Levine MJ, Genco RJ. Neutrophil function in oral disease. J Oral Pathol 1985;14: 95–120.
121.Sofaer JA. Genetic approaches to the study of peri- odontal disease. J Clin Periodontol 1990;17(7 Pt. 1):401–8.
122.Phillips HB, Ashley FP. Relationship between peri- odontal disease and a metacarpal bone index. Br Dent J 1973;134:237–9.
123.Von Wowren N. Dual-photon absorptiometry of mandibles: in vitro test of a new method. Scand J Dent Res 1985;93:169–77.
124.Von Wowren N, Klausen B, Kollerup G. Osteo- porosis: a risk factor in periodontal disease. J Periodontol 1994;65:1134–8.
125.Von Wowren N, Kollerup G. Symptomatic osteo- porosis: a risk factor for residual ridge reduction of the jaws. J Prosthet Dent 1992;67:656–60.
126.Von Wowren N, Storm TL, Olgaard K. Bone min- eral content by photon absorptiometry of the mandible compared with that of the forearm and the lumbar spine. Calcif Tissue Int 1988; 42:157–61.
127.Kribbs PJ, Smith DE, Chesnut CH. Oral findings in osteoporosis. Part I: Measurement of mandibular bone density. J Prosthet Dent 1983; 50:576–9.
128.Kribbs PJ, Smith DE, Chesnut CH. Oral findings in osteoporosis. Part II: Relationship between residual ridge and alveolar bone resorption and generalized skeletal osteopenia. J Prosthet Dent 1983;50:719–24.
129.Kribbs PJ, Chesnut CH, III. Osteoporosis and dental osteopenia in the elderly. Gerodontology 1984;3:101–6.
130.Henrikson P, Wallenius K. The mandible and osteoporosis—a qualitative comparison between the mandible and the radius. J Oral Rehab 1974;1:67–74.
131.Ortman LF, Hausmann E, Dunford RG. Skeletal osteopenia and residual ridge resorption. J Pros- thet Dent 1989;61:321–5.
132.Humphries S, Devlin H, Worthington H. A radi- ographic investigation into bone resorption of mandibular alveolar bone in elderly edentulous adults. J Dent 1989;17:94–6.
133.Daniell H. Postmenopausal tooth loss. Contribu- tions to edentulism by osteoporosis and cigarette smoking. Arch Intern Med 1983;143:1678–82.
134.Krall EA, Dawson-Hughes B, Hannan MT, et al. Postmenopausal estrogen replacement and tooth retention. Am J Med 1997;102:536–42.
Risk Factors for Periodontal Disease 31
135.Groen JJ, Menczel J, Shapiro S. Chronic destruc- tive periodontal disease in patients with prese- nile osteoporosis. J Periodontol 1968;39:19–23.
136.Wactawski-Wende J, Grossi SG, Trevisan M, et al. The role of osteopenia in oral bone loss and peri- odontal disease. J Periodontol 1996;67:1076–84.
137.Nishida M, Grossi SG, Dunford RG, et al. Role of dietary calcium and the risk for periodontal dis- ease. J Periodontol 1999. [Submitted]
138.Rubinoff AB, Latner PA, Pasut LA. Vitamin C and oral health. J Canadian Dent Assoc 1989;55: 705–7.
139.Nishida M, Grossi SG, Dunford RG, et al. Dietary vitamin C and the risk for periodontal disease. J Periodontol 1999. [Submitted]
140.Wendt LK, Svedin CG, Hallonsten AL, Larsson IV. Infants and toddlers with caries. Mental health, family interaction, and life events with infants and toddlers with caries. Swed Dent J 1995; 19(1-2):17–27.
141.Moulton R, Ewen S, Thieman W. Emotional fac- tors in periodontal disease. Oral Surg Oral Med Oral Pathol 1952;5:833–60.
142.Melnick SL, Roseman JM, Engel JD, Cogen RB. Epidemiology of acute necrotizing ulcerative gingivitis. Epidemiol Rev 1988;10:191–211.
143.Marcenes WS, Sheiham A. The relationship between work stress and oral health status. Soc Sci Med 1992;35:1511–20.
144.Monteiro da Silva AM, Oakley DA, Newman HN, et al. Psychosocial factors in adult onset rapidly progressing periodontitis. J Clin Periodontol 1996;23(8):789–94.
145.Linden GJ, Mullally BH, Freeman R. Stress and the progression of periodontal disease. J Clin Periodontol 1996;23(7):675–80.
146.Genco RJ, Ho AW, Grossi SG, et al. Relationship of stress, distress, and inadequate coping behav- iors to periodontal disease. J Periodontol 1999. [In press]
147.Genco RJ, Ho AW, Kopman J, et al. Models to evaluate the role of stress in periodontal disease. Ann Periodontol 1998;3(1):288–302.
148.Dowrenwend BS, Drasnott L, Ashenasj AR, Dowrenwend BP. Exemplification of a method for scaling life events: the PERI life events scale. J Health Soc Beh 1978;19:205–9.
149.Pearlin LI, Schooler C. The structure of coping. J Health Soc Behav 1978;19:2–21.
150.Derogatis LR, Cleary PA. Confirmation of the dimensional structure of the SCL-90: a study in construct validation. J Clin Psychol 1977;33: 981–9.
151.Carver CS, Scheier MF, Weintraub JK. Assessing
coping strategies: a theoretically based approach. J Pers Soc Psychol 1989;56:267–83.
152.Melnick M, Shields ED, Bixler D. Periodontosis. A phenotypic and genetic analysis. Oral Surg Oral Med Oral Pathol 1976;42:32–41.
153.Saxén L. Heredity of juvenile periodontitis. J Clin Periodontol 1980;7:276–88.
154.Long JC, Nance WE, Aring P, et al. Early onset periodontitis. A comparison and evaluation of two proposed modes of inheritance. Genet Epi- demiol 1987;4:13–24.
155.Beaty TH, Boughman JA, Yang P, et al. Genetic analysis of juvenile periodontitis in families ascertained through an affected proband. Am J Hum Genet 1987;40:443–52.
156.Hart TC, Marazita ML, Gunsolley JA, et al. No female preponderance in juvenile periodontitis after correction of ascertainment bias. J Perio- dontol 1991;62:745–9.
157.Saxby MS. Juvenile periodontitis: an epidemiolog- ical study in West Midlands of the United King- dom. J Clin Periodontol 1987;14:594–8.
158.Hart TC, Marazita ML, Schenkein HA, Diehl SR. Re-interpretation of the evidence for X-linked dominant inheritance of juvenile periodontitis. J Periodontol 1992;63:169–73.
159.Van Dyke TE, Schweinebraten M, Cianciola LJ, et al. Neutrophil chemotaxis in families with local- ized juvenile periodontitis. J Periodontal Res 1985;20:503–14.
160.Page RC, Vandesteen GE, Ebersole JL, et al. Clini- cal and laboratory studies of a family with a high prevalence of juvenile periodontitis. J Peri- odontol 1985;56:602–10.
161.Gwinn MR, Sharma A, De Nardin E. Sequence analysis of chemotactic receptor DNA in LJP [abstract 130]. J Dent Res 1998;77(Special Issue B):648.
162.Wilson ME, Kalmar JR. FcgRIIa (CD32): a potential marker defining susceptibility to localized juvenile periodontitis. J Periodontol 1996;67:323–31.
163.Cullinan MP, Sachs J, Wolf E, Seymour GJ. The distribution of HLA-A and -B antigens in patients and their families with periodontitis. J Periodontal Res 1980;15:177–84.
164.Saxén L, Koskimies S. Juvenile periodontitis—no linkage with HLA-A antigens. J Periodontal Res 1984;19:441–4.
165.Reinholdt J, Bay I, Svejgaard A. Association between HLA-antigens and periodontal disease. J Dent Res 1977;56:1261–3.
166.Kornman KS, Page RC, Tonetti MS. The host response to the microbial challenge in periodon- titis: assembling the players. Periodontol 2000 1997;14:33–53.
32 Periodontal Medicine
167.Kaslick RS, West TL, Chasens AI. Association between ABO blood groups, HL-A antigens and periodontal diseases in young adults: a fol- low-up study. J Periodontol 1980;51:339–42.
168.Kaslick RS, West TL, Chasens AI, et al. Association between HL-A2 antigen and various periodon- tal diseases in young adults. J Dent Res 1975; 54(2):424.
169.Teraski PI, Kaslick RS, West TL, Chasens AI. Low HL-A2 frequency and periodontitis. Tissue Antigens 1975;5:286–8.
170.Klouda PT, Porter SR, Scully C, et al. Association between HLA-A9 and rapidly progressive peri- odontitis. Tissue Antigens 1986;28(3):146–9.
171.Amer A, Sing G, Drake C, Dolby AE. Association between HLA antigens and periodontal disease. Tissue Antigens 1988;31:53–8.
172.Ciancio SC, Hazen SP, Cunat JJ. Periodontal obser- vations in twins. J Periodontal Res 1969;4:42–5.
173.Michalowicz BS, Aeppli DP, Kuba RK, et al. A twin study of genetic variation in proportional radiographic alveolar bone height. J Dent Res 1991;70:1431–5.
174.Michalowicz BS, Aeppli D, Virag JG, et al. Peri- odontal findings in adult twins. J Periodontol 1991;62:293–9.
175.Corey LA, Nance WE, Hofstede P, Schenkein HA. Self-reported periodontal disease in a Virginia twin population. J Periodontol 1993;64:1205–8.
176.Kornman KS, Crane A, Wang H-Y, et al. The inter- leukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997; 24:72–7.
177.Van Schie RC, Grossi SG, Dunford RG, et al. Fcg receptor polymorphisms are associated with periodontitis [abstract 129]. J Dent Res 1998; 77(Special Issue B):648.
178.Hassell T. Epilepsy and oral manifestations of phenytoin therapy. Basel, Switzerland: S. Karg- er; 1981.
179.Adams D, Davies G. Gingival hyperplasia induced by cyclosporine-A. A report of two cases. Brit Dent J 1984;157(3):89–90.
180.Lucas RM, Howell LP, Wall BA. Nifedipine- induced gingival hyperplasia: a histochemical and ultrastructural study. J Periodontol 1985; 56:211–5.
181.Finne K, Goransson K, Winckler L. Oral lichen planus and contact allergy to mercury. Intl J Oral Surg 1982;11(4):236–9.
182.Beck JD, Koch GG, Zambon JJ, et al. Evaluation of oral bacteria as risk indicators for periodonti- tis in older adults. J Periodontol 1992;63:93–9.
183.Wolff LF, Aeppli DM, Pihlstrom BL, Anderson L.
Natural distribution of five bacteria associated with periodontal disease. J Clin Periodontol 1993;20:699–706.
184.Dzink JL, Tanner ACR, Haffajee AD, Socransky SS. Gram-negative species associated with active destructive periodontal lesions. J Clin Periodon- tol 1985;12:648–59.
185.Mandell RL. A longitudinal microbiological inves- tigation of Actinobacillus actinomycetemcomitans and Eikenella corrodens in juvenile periodontitis. Infect Immun 1984;45:778–80.
186.Listgarten MA, Levin S. Positive correlation between the proportions of subgingival spiro- chetes and motile bacteria and susceptibility of human subjects to periodontal deterioration. J Clin Periodontol 1981;8:122–38.
187.Dahlén G, Manji G, Baelum V, Fejerskov O. Puta- tive periodontopathogens in “diseased” and “non-diseased” persons exhibiting poor oral hygiene. J Clin Periodontol 1992;19:35–42.
188.Haffajee AD, Socransky SS, Dzink JL, et al. Clini- cal, microbiological, and immunological fea- tures of subjects with refractory periodontal dis- eases. J Clin Periodontol 1988;15:390–8.
189.Listgarten MA, Slots J, Nowotny AH, et al. Inci- dence of periodontitis recurrence in treated patients with and without cultivable Actinobacil- lus actinomycetemcomitans, Prevotella intermedia, and Porphyromonas gingivalis. A prospective study. J Periodontol 1991;62:377–86.
190.Haffajee AD, Socransky SS, Dzink JL, et al. Clini- cal, microbiological, and immunological fea- tures of subjects with destructive periodontal diseases. J Clin Periodontol 1988;15:240–6.
191.Axelsson P, Lindhe J, Nystrom B. On the preven- tion of caries and periodontal disease: results of a 15-year longitudinal study in adults. J Clin Periodontol 1991;18:182–9.
192.Smulow JB, Turesky SS, Hill RG. The effect of supragingival plaque removal on anaerobic bac- teria in deep periodontal pockets. J Am Dent Assoc 1983;107:737–42.
193.Müller H-P, Hartmann J, Flores-de-Jacoby L. Clin- ical alterations in relation to the morphological composition of the subgingival microflora fol- lowing scaling and root planing. J Clin Perio- dontol 1986;13:825–32.
194.Anerud A, Löe H, Boysen H. The natural history and clinical course of calculus formation in man. J Clin Periodontol 1991;18:160–70.
195.Claffey N, Nylund K, Kiger R, et al. Diagnostic predictability of scores of plaque, bleeding, sup- puration and probing depth for probing attach- ment loss. J Clin Periodontol 1990;17:108–14.
Risk Factors for Periodontal Disease 33
196.Badersten A, Nilveus R, Egelberg J. Scores of plaque, bleeding, suppuration, and probing depth to predict probing attachment loss. 5 years observation following nonsurgical therapy. J Clin Periodontol 1990;17:102–7.
197.Lang NP, Adler R, Joss A, Nyman S. Absence of bleeding on probing is an indicator of periodon- tal stability. J Clin Periodontol 1990;17:714–21.
198.Lang NP. Clinical markers of active periodontal disease. In: Johnson NW, editor. Risk markers for oral diseases, Vol. 3. Periodontal Disease, Cambridge: Cambridge University Press; 1991. p. 179–202.
199.Grbic JT, Lamster IB, Celenti RS, Fine JB. Risk indicators for future clinical attachment loss in adult periodontitis. Patient variables. J Perio- dontol 1991;62:322–9.
200.Haffajee AD, Socransky SS, Lindhe J, et al. Clini-
cal risk indicators for periodontal attachment loss. J Clin Periodontol 1991;18:117–25.
201.Axelsson P, Lindhe J. Effect of controlled oral hygiene procedures on caries and periodontal disease in adults. J Clin Periodontol 1978;5:133–51.
202.Haffajee AD, Dzink JL, Socransky SS. Effect of modified Widman flap surgery and systemic tetracycline on subgingival microbiota of peri- odontal lesions. J Clin Periodontol 1988;15: 255–62.
203.Machtei EE, Dunford R, Hausmann E, et al. Lon- gitudinal study of prognostic factors in estab- lished periodontitis patients. J Clin Perio- dontol 1997;24:102–9.
204.Grossi SG, Zambon JJ, Machtei E, et al. Effects of smoking and smoking cessation on healing after mechanical periodontal therapy. J Am Dent Assoc 1997;128:599–607.
CHAPTER 3
CLINICAL HISTORY AND LABORATORY TESTS Louis F. Rose, DDS, MD Barbara J. Steinberg, DDS
PATIENT EVALUATION
Medical emergencies can occur in any patient; however, they are most prevalent in geriatric or medically compromised patients. There is a rapid- ly growing segment of the population whose phys- ical or psychosocial problems may complicate den- tal treatment. The elderly or medically compro- mised patient who is frequently taking one or more medications such as steroids, anticoagulants, car- diac drugs, or immunosuppressive agents may require special consideration before undergoing dental treatment. As ever-increasing numbers of such individuals seek dental care, it becomes the responsibility of the dentist to avoid adverse thera- peutic interactions and to deal with medical emer- gencies when they occur.1–5
Careful study has shown that the compromised patient is actually in the majority, with more than 50% of 4,365 patients recently surveyed giving a history of more than one significant medical prob- lem.6 Sophisticated surgical manipulation and medical intervention have made possible the ambu- latory treatment of patients with cardiovascular, endocrine, and degenerative diseases-disorders that just a few years ago would have meant confinement or death. Medical advances, along with increasing public awareness of dental health, probably explain the increased numbers of elderly and chronically ill patients seeking dental treatment.
With an increasing likelihood of medical emer- gencies in this population, the practising dentist and auxiliary staff are responsible for identifying patients with a potential for medical risk by obtain- ing a comprehensive pretreatment physical evalua- tion.7–9 This evaluation is performed to determine patients’ physical and emotional status and how well they will tolerate a specific dental procedure.5
Little and King, in 1971,10 presented the rea- sons for an evaluation of general health in the den- tal office, and these are summarized as follows:
1. To identify patients with undetected systemic disease that could be a serious threat to the life of the patient or whose condition could be complicated by dental treatment
2. To identify patients who are taking drugs or medications that could adversely interact with drugs prescribed, that would complicate den- tal therapy, or that may serve as a clue to an underlying systemic disease the patient has failed to mention
3. To provide information for the dentist to modify the treatment plan for the patient in light of any systemic disease or potential drug interactions
4. To enable the dentist to select and communi- cate with a medical consultant concerning the patient’s possible systemic problems
5. To help establish a good patient-doctor rela- tionship by showing patients the clinician’s interest in them as individuals and concern for their overall well-being
Information obtained from a comprehensive health evaluation may prevent a medical emer- gency. A well-conceived evaluation of the patient includes the following: (1) recording a complete medical history; (2) recording appropriate findings on physical examination; (3) when indicated, ordering and interpreting necessary laboratory studies; and (4) initiating medical consultation or referral as needed.5
In addition, to detect changes in general health that may affect dental treatment, the med- ical evaluation must be updated every time the
36 Periodontal Medicine
patient is seen during maintenance therapy (eg, every 3 to 6 months) and at appropriate intervals during protracted active therapy.
MEDICAL HISTORY
History-taking is a technique for eliciting subjec- tive information. These data are organized logical- ly to portray the patient’s physical and emotional status. Diagnosis of a specific medical disorder may require consultation. Medical history puts physical examination into perspective by supplying infor- mation that should alert the examiner to suspected abnormalities.3 Even in a life-threatening situation, once the immediate threat has been contained, a history should be obtained from the patient, if pos- sible, or from a relative or friend if the patient is unable to respond.
Two basic methods for obtaining a medical his- tory are the questionnaire and the personal inter- view. At first, it might seem that a great deal of time and trouble could be saved if we were to have each patient complete a printed questionnaire and then have the answers coded. There are, however, several problems with this approach. For instance, a “no” answer may mean the patient never had the symp- toms or the disease or that the question is not understood or is thought to be irrelevant since the patient only wants to have a tooth restored or extracted. On the other hand, a personal history elicited through dialogue allows for observation of patients and their reactions to questions. This often provides more important information than the answer itself. The personal dialogue allows the prac- titioner to evaluate the patient’s mental status in a nonthreatening atmosphere. The patient who is afraid or uninterested will respond quite differently from the one who is self-confident and truly con- cerned about oral health.
A questionnaire can be used in conjunction with the dialogue to obtain a more complete med- ical history. The questionnaire may help a patient recall frequently used medications and various symptoms that indicate disease. It can also assist the dentist in determining which areas to emphasize and further explore when conducting the dialogue. The questionnaire completed by the patient in pri- vacy can also alleviate embarrassment in answering questions concerning habits, addictions, or sexually transmitted diseases, all of which are important components of a complete medical history.
A comprehensive medical history helps the dentist evaluate present health status, past medical
history, allergies, medications, and pertinent famil- ial and social history as well as conduct a review of body systems. The following information may be elicited under each area of the medical history.1,11,12
Present Health Status
The patient should be asked the date and results of the last complete physical examination. If the patient states, for example, that they have diabetes, it is important to determine the date of the initial diagnosis, the degree of success in controlling the disease, and the therapeutic regimen as well as the date, type, and results of the last blood glucose study. If the patient has not had a recent physical examination, it may be advisable to make a recom- mendation for an examination, especially if the patient is in a high-risk group. The patient’s per- ception of their present health status may be an important indication of their psychological make- up and potential compliance with treatment.
Past Medical History
The date, diagnosis, and treatment rendered at sig- nificant hospitalizations for illnesses during child- hood and adult life will help evaluate the patient’s past medical history and clearly indicate whether their average state of health has been one of normal vigor or chronic illness.
Allergies
The patient should be asked about allergies or reac- tions to any foods, medications, or environmental factors. Specifically, aspirin, local anesthetics, antibi- otics, and any other potential allergens that may be used in dental therapy should be mentioned.
Medications
In questioning about medications, it is imperative to determine the brand and/or generic name of the drug, why and by whom it was prescribed, the dosage, and the length of time the medication has been taken. Patients may not include medications used for allaying anxiety or for inducing sleep, such as tranquilizers and sedative-hypnotic drugs. An effective way of obtaining this information is to ask patients if they ever have to take anything to help them rest, relax, or sleep. Also, some women will not include oral contraceptives or supplemental hormones, either of which may affect oral tissues.
Clinical History and Laboratory Tests 37
Review of Systems
The review of body systems (see Table 3–1) is the main component of the interview approach to his- tory-taking. It provides additional data about each system and reveals symptoms not already elicited that may indicate a previously treated or undiag- nosed disorder. The review of systems helps to refresh the patient’s memory, thus preventing any inadvertent oversight.
Family History
Family history is taken to determine if there is a familial predisposition to diseases or if there are diseases in which inheritance is an important fac- tor. For example, a patient with a strong family his- tory of diabetes mellitus, with no apparent signs or symptoms of the disease, should be evaluated peri- odically since clinical manifestations may appear later in life. Also, those with a history of diabetes may have a greater risk for developing infections such as periodontal disease. The dentist should inquire specifically about a family history of dia- betes, cancer, heart disease, high blood pressure,
seizure disorders, mental disorders, and other dis- eases that may be familial.
Social History
Social history may assist in determining the patient’s response to the demands and conflicts of modern society. In addition, it may help explain untoward reactions to health problems and to the therapeutic recommendations. For example, the alcoholic patient may be unwilling to follow recommenda- tions about diet and oral hygiene. Also, the alcoholic patient is an anesthetic risk and may develop pro- longed and profound hypotensive episodes sec- ondary to certain anxiety and pain-control drugs. Social history should include the patient’s occupa- tion and any associated health hazards, marital sta- tus, diet, and use of alcohol, tobacco, or other drugs. Possible exposure to various infectious diseases, such as hepatitis B, herpes, or acquired immunodeficien- cy syndrome (AIDS), should be determined. Social history is therefore important in assessing whether a patient is in a high-risk group, for example, those with alcoholism, drug addiction, or contagious infections such as herpes, hepatitis, tuberculosis, or
TABLE 3–1. Review of Systems
Skin Itching, rash, ulcers, excessive dryness, pigmentary change, changes in hair or nails, hair loss
Eyes Vision, inflammation, diplopia, blurring
Ears, nose, throat Hearing, earache, epistasis, sore throat, hoarseness, sinus pain
Respiratory Cough, sputum (describe quantity, color, odor, blood), wheezing, infections, exposure to system tuberculosis, prior chest radiographic examination
Heart Chest pain, palpitation, dyspnea, orthopnea, swelling of ankles, history of rheumatic fever, rheumatic heart disease, “heart attack,” high blood pressure, murmur
Gastrointestinal Appetite, nausea, vomiting, dysphagia, heartburn, indigestion, food intolerance, abdominal system pain, jaundice, hepatitis
Genitourinary Dysuria, nocturia, polyuria, hematuria, frequency, difficulty starting stream, sexually transmitted system diseases, kidney infection
For women: • Menstrual history: last menstrual period and previous menstrual periods, dysmenorrhea • Menopause: age of occurrence, hot flashes • Obstetric history: pregnancies, miscarriages, living children
Extremities • Vascular: varicose veins, phlebitis • Joints: pain, stiffness, swelling of joints • Muscles: weariness, pain, tenderness, cramps
Nervous system Syncope, convulsions, headache, lightheadedness, vertigo, tremor, paralysis, paresthesias, anesthesia
Psychiatric “Nervousness,” irritability, depression, history of previous “nervous breakdown,” family history of mental illness
Blood Bleeding tendency, excessive bruising, anemia, known exposure to radiation or toxic agents
38 Periodontal Medicine
AIDS. Direct confirmation of these conditions often requires testing and consultation.
Medical Summary and Recommendations
Positive findings should be summarized and recom- mendations recorded. This will enable the dentist and the dental staff to quickly review a patient’s med- ical status at each visit and facilitate the diagnosis and treatment of any medical emergency that may arise.
Initially, the medical history form described here represents one of the most accurate methods for determining the physical and emotional status of the patient, the patient’s tolerance for specific proce- dures, and the presence of any medical risk factors. In essence, this form aids in the decision to proceed with dental treatment with relative safety or to seek medical consultation before beginning therapy.13,14
In conclusion, a comprehensive medical histo- ry is an important procedure that dentists must adopt and routinely use to ensure that their patients are receiving the optimum benefit from all available health resources. A form for recording the medical history has been suggested by the Ameri- can Dental Association. (Figure 3–1)
INTERPRETATION OF CLINICAL LABORATORY STUDIES
On occasion, the patient’s medical history and phys- ical examination warrant laboratory tests to confirm a diagnosis or to uncover incidental findings sepa- rate from the chief complaint.15–17 Depending on the dentist’s background and experience in inter- preting such tests, the patient will be referred direct- ly to either a clinical laboratory or a physician for appropriate examination, tests, and opinion. With the first alternative, the dentist assumes responsibil- ity for the interpretation and then refers the patient to a physician for confirmation and treatment, if indicated. With the second alternative, the physi- cian assumes all responsibility for preparing the patient and evaluating the findings. Table 3–2 lists some commonly used clinical laboratory tests.
Complete Blood Count
The complete blood count (CBC) will routinely include hemoglobin (HgB), hematocrit (Hct), red blood cell (RBC) count, and white blood cell (WBC) count, with a differential WBC count and a statement on the adequacy of platelets.
Hemoglobin Hemoglobin is the oxygen carrier of the blood. It is decreased in hemorrhage and anemias and increased in hemoconcentration and polycythemia. The normal range is 14 to 18 g/dL of blood in men and 12 to 16 g/dL of blood in women.
Hematocrit Hematocrit reflects the relative volume of cells and plasma in the blood. In anemias and after blood loss, it is lowered and is elevated in polycythemia and dehydration. The normal Hct range is 40 to 54% for men and 37 to 47% for women, or rough- ly three times the HgB value.
RBC Count The RBCs contain HgB. An increase in RBCs may indicate hemoconcentration or polycythemia. A decrease in the number of RBCs may be indicative of blood loss or one of the anemias.
WBC Count White blood cells are important in the bodily defense against invading microorganisms. An increase in the WBC count is seen in leukemias, bacterial infections, infectious mononucleosis, and certain parasitic infections as well as after exercise and emotional stress. A decrease in the WBC count is seen in aplastic anemia, lupus erythe- matosus, acute viral infections, and drug and chemical toxicity. A normal WBC count is 5000 to 10,000/mm3.
There are several kinds of WBCs that can be identified microscopically; such identification is called the differential. It is important to know whether the proportions of these cells have changed since they may be indicative of a particu- lar type of ailment.
1. Neutrophils (50 to 70%) are increased in most bacterial infections. An increase in the number of immature neutrophils is frequently found in acute infections. This is the so-called “shift to the left.”
2. Eosinophils (1 to 4%) are increased in allergic conditions and parasitic infections.
3. Basophils (0 to 1%) may be increased in some blood dyscrasias.
4. Lymphocytes (25 to 40%) are noted to be increased in measles and in several bacterial or chronic infections.
5. Monocytes (4 to 8%) may be increased during recovery from severe infections and Hodgkin’s disease.
Clinical History and Laboratory Tests 39
Figure 3–1. Medical history form, side 1.
40 Periodontal Medicine
Figure 3–1. Medical history form, side 2.
Clinical History and Laboratory Tests 41
Blood Glucose
Blood glucose tests are performed to evaluate glu- cose metabolism. Basic tests for disorders of blood glucose are the fasting blood sugar test, the glucose tolerance test, and the random blood sugar test. The normal range for blood glucose is 70 to 100 mg/dL of serum.
Blood Urea Nitrogen
Blood urea nitrogen (BUN) is used as a screening test for kidney function; however, it is not entirely specific. An increased value may be seen in exten- sive kidney disease, congestive heart failure, and dehydration. Protein intake may also directly affect BUN values. If renal disease is suspected, a more reliable assessment is the serum creatinine test. The ratio of BUN to creatinine is 10:1. The normal range for BUN is 8 to 23 mg/dL of blood.
Serology
There are a variety of serologic tests for the screen- ing of syphilis. All are nonspecific tests and may give both false-positive and false-negative results. Interpretation of these serologic tests requires cor- relation with the patient’s history and clinical find- ings. Normally, results of these tests are negative; if results are positive, confirmation with the fluores- cent treponemal antibody-absorption test (FTA- abs) or the microhemagglutination treponemal pallidum test (MHA-tp) is indicated.
Screening Tests for Hemorrhagic Disorders
Bleeding Time Bleeding time is the time required for hemostasis to occur in a standard wound of the capillary bed. Bleeding time varies with vascular and platelet abnormalities. The normal range is 1 to 7 minutes.
Platelet Count Platelets are decreased in thrombocytopenic pur- pura. In myeloproliferative disease, platelets are increased. The normal platelet count is 150,000 to 400,000/mm3.
Prothrombin The prothrombin (PT) test is an indirect test of the clotting ability of the blood. This test gives an indication of prothrombin deficiency arising from liver disease, fibrinogen deficiency, and lack of or
TABLE 3–2. Normal Values
Test Normal Values*
Blood chemistry Albumin 3.8–5.0 g/dL Bilirubin
• direct <0.3 mg/dL • indirect 0.1–1.0 mg/dL • total 0.1–1.2 mg/dL
Calcium 9.2–11.0 mg/dL 4.6–5.5 mEq/L
Creatinine 0.6–1.2 mg/dL Glucose 70–110 IU/L Lactate dehydrogenase 25–100 IU/L Phosphatase, alkaline
• child 20–150 IU/L at 30°C • adult 20–90 IU/L at 30°C
Transferases • aspartate amino 16–60 U/mL at 30°C
(SGOT) • alanine amino (SGPT) 8–50 U/mL at 30°C
Urea nitrogen 8–23 mg/dL Hematology
Leukocyte count (WBC) 5000–10,000/mm3
5–10 ´ 103/µL • neutrophils
– segmented 50–70% – band 0–5%
• lymphocytes 25–40% • monocytes 4–8% • eosinophils 1–4% • basophils 0–1%
Erythrocyte count (RBC) • male 4.5–6.2 million/mm3
4.6–6.2 ´ 106/µL • female 4.2–5.4 million/mm3
4.2–5.4 ´ 106/µL Hemoglobin
• male 13.5–18.0 g/dL • female 12.0–16.0 g/dL
Hematocrit • male 40–54% • female 37–47%
RBC indices • mean corpuscular 27–31 pg
hemoglobin • mean corpuscular 80–96 µm3
volume • mean corpuscular 32–36%
hemoglobin concentration
Platelet count 150,000–400,000/mm3
150–400 ´ 103/µL Bleeding time (Ivy) 1–7 min Partial thromboplastin time ² 45 sec (variable) Prothrombin time 12–14 sec
*There may be interlaboratory variations.
42 Periodontal Medicine
inability of the body to use vitamin K. The normal range is 12 to 14 seconds, depending on the type of thromboplastin used. In treatment with Coumadin, the physician will attempt to keep the prothrombin time at 2 to 2 1/2 times the normal value (see “Test to Monitor Oral Anticoagulants”).
Partial Thromboplastin Time The partial thromboplastin time (PTT) test is designed to help the clinician recognize mild to moderate deficiencies of the intrinsic clotting fac- tors. This test is necessary because PT entirely bypasses the intrinsic clotting system. Another use for PTT is to demonstrate a circulating anticoagu- lant in plasma. The normal PTT is 45 seconds or less; however, because there are wide variations in technique, the normal range for PTT varies some- what between laboratories.
Test to Monitor Oral Anticoagulants
The international normalized ratio (INR) is the ratio of a patient’s PT to the mean PT value deter- mined by using a given thromboplastin, and this ratio is raised to the power of the international sensitivity index (ISI) that is provided by the reagent manufacturer. By using the INR, the degree of anticoagulation achieved by warfarin therapy may be compared, regardless of the thromboplastin used. Use of the INR allows PT results to be compared among clinical laboratories around the world, resulting in better patient man-
agement. It must be emphasized that the purpose of the INR is to monitor patients taking oral anti- coagulants; it is not intended to be used for initial evaluation of the hemostatic system or thrombot- ic conditions. Anticoagulation to a target INR of 3.0 should be made before patients with cardiac valve prosthesis undergo dental procedures involv- ing the risk of bleeding.
MEDICAL RISK ASSESSMENT
Having completed all the components of the phys- ical evaluation and a thorough oral examination, the dentist must gather all the information and determine if the patient is capable, physiologically and psychologically, of tolerating in relative safety the stresses involved in the proposed dental treat- ment. Is there a greater risk (of morbidity or mor- tality) than normal during the dental therapy? If the patient decides to go ahead with the treatment in spite of the risk of being medically compro- mised, then appropriate modifications in the planned dental treatment must be considered to minimize the risk.18
To categorize dental patients from the stand- point of medical status, each patient should be assigned an appropriate medical risk category rec- ommended by the American Society of Anesthesi- ologists. This is commonly referred to as the ASA physical status classification system and is summa- rized in Table 3–3.
TABLE 3–3. Medical Risk Categories*
ASA Classification Dental Consideration
Physical status 1 A patient without systemic disease; Routine dental therapy without modification a normal healthy patient
Physical status 2 A patient with mild systemic disease Routine dental therapy with possible treatment
limitations or special considerations (eg, duration of therapy, stress of therapy, prophylactic consideration, possible sedation, and medical consultation)
Physical status 3 A patient with severe systemic disease Dental therapy with possible strict limitations that limits activity but is not incapacitating or special considerations
Physical status 4 A patient with incapacitating systemic Emergency dental therapy only with severe limitations or disease that is a constant threat to life special considerations
*Adopted in 1962 by the American Society of Anesthesiologists (ASA)
Clinical History and Laboratory Tests 43
DENTAL HISTORY
Significant items of the past dental history that should be recorded at this visit include previous restorative, periodontic, endodontic, or oral surgi- cal treatment; reasons for loss of teeth; untoward complications of dental treatment; attitudes toward previous dental treatment; experience with orthodontic appliances and dental prostheses; and radiation or other treatment for oral or facial lesions.19 General features of past treatment, rather than specific, detailed, tooth-by-tooth descriptions are needed at this time. In the case of radiation or other treatment for oral or facial lesions, exact information regarding the date and nature of the diagnosis, the type and anatomic location of treat- ment, and the name, address, and telephone num- ber of the physicians and/or dentists involved as well as the facility (hospital, clinic) where the treat- ment was given, must be recorded. Likewise, clear details of any previous untoward complications of dental treatment must be recorded.
REFERENCES
1. Genco R, Goldman H, Cohen DW. Contempo- rary periodontics. St Louis, MO: The CV Mosby Publishing Co.; 1990.
2. Rose LF. Diagnosis and management of medical emergencies in the dental office. Univ PA School Dent Med 1977;3.
3. Rose LF. Medical history as a dental procedure. Dent Dimens 1977; Jan–March;13.
4. Rose LF, Hendler BH. Medical emergencies in dental practice. Chicago: Quintessence Publish- ing Co.; 1981.
5. Rose LF, Steinberg BJ, Hendler BH. Physical eval- uation. Alpha Omegan 1984;77(4):17.
6. Colton JA, Kafrawy, AH. Medications and health histories; a survey of 4,365 dental patients. J Am Dent Assoc 1979;98:713.
7. Hendler BH, Rose LF. Common medical emergen- cies; a dilemma in dental education. J Am Dent Assoc 1975;91:575.
8. Malamed SF. Handbook of medical emergencies in the dental office. St. Louis, MO: The CV Mosby Publishing Co.; 1982.
9. McCarthy FM. Emergencies in dental practice. 2nd ed. Philadelphia: W.B. Saunders Company; 1972.
10. Little JW, King OR. The significance of physical diagnosis, patient history, data and medical screening in the dental office. Am Dent 1972;3:31.
11. Bates G. A guide to physical examination. Philadel- phia: J.B. Lippincott Co.; 1974.
12. Halsted CL, et al. Physical evaluation of the dental patient. St. Louis, MO: The CV Mosby Pub- lishing Co.; 1982.
13. Brasher WJ, Rees TD. The medical consultation: its role in dentistry. J Am Dent Assoc 1977;95:961.
14. Redding SW, Rose LF. The consultation: a means of communication between dentists and physi- cians. Gen Dent 1979;Sept/Oct p.54.
15. Rose LF. Hospital dental practice. Dent Clin North Am 1975;19(4).
16. Sonis ST, Sandinski JJ. Physical and laboratory diagnosis. Dent Clin North Am 1974;18(1).
17. Zambito RF. Hospital dental practice: a manual. New York: Medical Examination Publishing; 1978.
18. Little JW, et al. Dental management of the med- ically compromised patient. 5th ed. St. Louis, MO: The CV Mosby Publishing Co.; 1997.
19. Kerr DA, Ash MM, Millard DH. Oral diagnosis. 6th ed. St. Louis, MO: The CV Mosby Publish- ing Co.; 1983.
CHAPTER 4
ROLE OF GENETICS IN ASSESSMENT, RISK, AND MANAGEMENT OF ADULT PERIODONTITIS Kenneth S. Kornman, DDS, PhD Michael G. Newman, DDS
PERIODONTAL DISEASE
Periodontitis, a chronic multifactorial disease in adults, is caused mainly by gram-negative microor- ganisms, such as Porphyromonas gingivalis, Prevotel- la intermedia, and Actinobacillus actinomycetemco- mitans. The most common form of periodontitis is adult periodontitis, which has been reported to affect more than 30% of the population, with severe disease reported in 7 to 13%.1 Adult peri- odontitis is characterized by an interaction between the host immunoinflammatory response and gram-negative bacteria. With periodontal dis- ease, plaque microorganisms adjacent to the gingi- va stimulate host cells, resulting in the production of molecules that play an important role in activat- ing and regulating the immunoinflammatory response. Microbial substances such as lipopolysac- charide (LPS) activate host cells (ie, fibroblasts, macrophages, and polymorphonuclear leukocytes [PMNs]) to secrete proinflammatory cytokines such as interleukin-1 beta (IL-1b) and tumor necrosis factor alpha (TNF-a).2
Clinical evidence has demonstrated that not all individuals have the same response to similar amounts of plaque accumulation. There are patients with moderate and advanced disease who have very little plaque while other patients with lit- tle disease have large amounts of plaque. Most importantly, large studies that have assessed the relationship of plaque quantity, as well as the pres- ence of specific bacteria, to the severity of peri- odontitis indicate that a substantial part of the
variation in clinical severity of disease may be explained by factors other than the bacterial chal- lenge. It should be emphasized that this statement in no way means that bacterial plaque is unimpor- tant—in fact, it is quite the contrary. Bacterial plaque is absolutely essential for the initiation and progression of periodontitis. However, it now appears that once the bacteria are present, the amount of periodontitis that a patient develops is due to factors related to the body’s response to the bacterial challenge. One reason for the differences in how patients respond to plaque, manifest dis- ease, and respond to treatment is that there are dif- ferent types of plaque. Some types of plaque are more virulent than others.3–5 Although a few labo- ratories have offered microbial analysis of subgin- gival plaque samples for many years, the value of plaque sampling in nonresponding patients is of growing interest as some research groups have started to clarify how the resulting information can be integrated into clinical practice.
The presence of bacteria is necessary for peri- odontal disease to occur; however, this presence alone does not predict the presence or severity of periodontitis. The differences in disease severity observed among individuals cannot be explained solely by the presence of different quantities or types of bacteria.6 For the presence, absence, or level of specific microbes believed to be periodon- tal pathogens, the correlation coefficients are in the range of 0.3 to 0.4 in current multivariate models of periodontitis that incorporate microbial factors. These findings indicate that less than 20% of the
46 Periodontal Medicine
variability in periodontal disease expression can be explained by the levels of specific microbes. It has been shown that specific elements of host suscepti- bility, such as an individual’s systemic disease state and immune response, are important factors in dis- ease expression.7,8
Genetics and Clinical Presentation of Periodontal Disease
It has long been observed that unusual forms of periodontitis, such as disease affecting young indi- viduals (early onset periodontitis), “run in fami- lies.” The evidence for a genetic influence on early- onset periodontitis has been well reviewed in recent years.7,9,10 Since it was believed that adult periodontitis was totally determined by bacterial plaque, less effort was devoted to exploring a genetic influence. In addition, the genetic influ- ence in an adult-onset chronic disease is difficult to study since so many factors change during the course of the disease and it is more difficult to study families with adult-onset disorders than those with diseases affecting children.
Early studies reported significant differences in gingivitis among different ethnic groups.9 Howev- er, the finding of familial aggregation or ethnic dif- ferences in a disease does not prove a genetic com- ponent because a common familial environment or the variable environments of different ethnic groups may bring about these findings.11 However, in recent years, new studies demonstrated substan- tial genetic influences on adult periodontitis. In particular, studies in twins indicate that a signifi- cant part of the variance in clinical and radio- graphic measures of adult periodontitis may be explained by genetic factors.12–14 The combination of two observations—(1) the recognition that much of the clinical expression of periodontitis was not explainable solely by the bacterial parame- ters, and (2) studies in twins—led to renewed interest in finding specific genetic factors that influence the severity and therapeutic responses of the most common form of periodontitis.
Types of Genetic Disorders
Genetic diseases can be divided into three major categories: chromosomal disorders, Mendelian dis- orders, and non-Mendelian disorders.
Congenital Chromosomal Disorders Congenital chromosomal disorders are caused by an abnormal dose of normal genes (not abnormal
genes) because of a deficiency or excess of chromo- somal material. Chromosomal abnormalities occur in approximately 1 per 160 live births.15 The majority of these abnormalities are sporadic, involving an extra chromosome due to nondis- junction of meiosis during egg or sperm forma- tion. A minority of abnormalities result from chro- mosomal rearrangements (ie, translocation), which may be inherited or sporadic. Down syndrome (trisomy 21), which is caused by the presence of an extra chromosome 21, is a classic example of a chromosome abnormality.15
Mendelian Disorders Mendelian disorders are caused by a mutation in a single gene and, therefore, are also referred to as single-gene (or major gene effect) disorders. The inheritance patterns of Mendelian disorders may be described in terms of the classic patterns of how certain traits, such as autosomal dominant or autosomal recessive disorders, are transmitted through successive generations. An autosomal dominant disorder is caused by a mutation of a gene located on one of the autosomes (chromo- somes 1 to 22). Individuals usually have two alle- les (copies) of each autosomal gene. With autoso- mal dominant disorders, individuals may have one “normal” copy of a gene and one “abnormal” copy of the same gene. In dominant disorders, if one of the two copies of the gene is abnormal that is suf- ficient to cause disease. There is a 50% chance that each offspring of an affected individual will receive the dominant gene from an affected par- ent. Offspring who receive a normal copy of the gene (and also have a normal copy from the other parent) will not develop the disease or pass it on to their offspring.15
There are several general features of autosomal dominant disorders that may disguise the inheri- tance pattern, such as delayed age of onset, pleiotropism, and variable expression (Table 4–1).15 Genetic disorders are not necessarily clini- cally evident at birth, and delayed age of onset is found in the majority of common adult diseases. Pleiotropism refers to the multiple effects of a sin- gle gene. Several common disease associations may be explained by pleiotropism, such as the increased incidence of both insulin-dependent diabetes mel- litus (IDDM) and autoimmune thyroid disease in the same patient and family, suggesting a common immunogenetic basis for both disorders. Variable expression refers to the differences in the severity and/or extent of disease manifestation among affected individuals.15
Role of Genetics in Assessment, Risk, and Management 47
With autosomal recessive disorders, two alleles of an abnormal gene are necessary for disease expression. Affected individuals are homozygous for the disease gene (homozygotes). Individuals that have a single dose of the normal gene and a single dose of the abnormal gene (heterozygotes) are considered carriers. Although autosomal reces- sive disorders can occur at any time during an indi- vidual’s life, they more frequently occur during infancy or childhood.15
A mutation at a single gene locus can produce a gene product that predisposes an individual to a disease. A single dose of a mutant allele (heterozy- gote) is often associated with disease susceptibility whereas a double dose of a mutant allele (homozy- gote) is associated with direct development of a more severe form of the disease.15
Some single-gene disorders occur with enough frequency to make a significant contribu- tion to a common disease or a subgroup of a com- mon disease. For example, the heterozygous state for familial hypercholesterolemia occurs with a frequency of approximately 1 per 500 in the pop- ulation. Gene carriers have a high probability of developing atherosclerosis. In addition, this gene is found in the heterozygous state in 5 to 10% of men age 60 years or younger who experience myo- cardial infarcts.15
Non-Mendelian Disorders Most common adult-onset diseases have a genetic component that cannot be explained by either a chromosomal abnormality or a major gene effect. In particular, the genetic influence of non- Mendelian disorders does not fit the typical inher- itance patterns within families. For example, in cardiovascular disease, there is an unusual major gene disorder called hypercholesterolemia. Indi- viduals with this Mendelian disorder will have severe cardiovascular disease at a very early age. Most cardiovascular diseases, however, do not involve hypercholesterolemia but seem to be familial and to have genetic influences. These non-Mendelian disorders are undoubtedly multi- factorial; they are caused by a combination of genetic and environmental factors. The genetics of these disorders is complicated by several factors: (1) a similar clinical condition may be the result of different disorders and different genetics (genetic heterogeneity); (2) the clinical condition may be polygenic—many additive genes, each of which produces a small effect; and (3) the clinical condi- tion may not be evident unless two different genetic factors are present (multilocus).
COMMON DISEASES GENERALLY INVOLVE BOTH GENETIC AND ENVIRONMENTAL FACTORS
From a population genetics point of view, a com- mon disease is defined as an arbitrary frequency of approximately 1 affected individual per 1,000 in the population.15 King and associates defined the genetic basis of a common disease as “the presence of a genetically susceptible individual, an individ- ual who may or may not develop the disease, depending on the interaction of factors such as other genes, diet, activity, environmental expo- sures, or even some degree of random biologic vari- ation such as occurs in the immune system and may be operative during development.”15
There is no absolute distinction between com- mon and single-gene diseases because a single-gene mutation may not cause disease until the carrier of the gene is exposed to a specific environmental agent. For example, an individual with the b-glob- ulin gene polymorphism that leads to sickle cell anemia will have different clinical disease experi- ences at sea level and at high altitudes, where the oxygen is more limited. The actions of several genes are involved in most common diseases, and sometimes a few genes can be identified as playing a major role in susceptibility. Individuals with dif- ferent genetic backgrounds have different suscepti- bilities; therefore, the etiologies of common dis- eases are usually genetically heterogeneous, that is,
Table 4–1. Autosomal Dominant Disorders
Common Autosomal Dominant Disorders Familial hypercholesterolemia Familial combined hyperlipidemia
Features that may disguise this inheritance pattern Delayed age of onset
Adult polycystic kidney disease: cysts are not evident until the second or third decade of life
Pleiotropism Marfan syndrome: a single abnormal gene can produce changes in the great vessels, eyes, heart, and skeleton: probably through an alteration in a structural protein common to these tissues
Variable Expression Mitral valve prolapse: in a single family, affected members may have significant rhythm distur- bances or mitral insufficiency whereas other fami- ly members have only an audible click on physical examination with no other symptoms
48 Periodontal Medicine
different genetic mechanisms lead to the same clin- ical endpoint. In addition, not everyone who is genetically susceptible will develop the disease. These points suggest that some individuals may have increased susceptibility whereas others will have reduced susceptibility.
The majority of common diseases fall between having a purely genetic cause and a purely envi- ronmental cause; they are the result of an interac- tion between genetic and environmental factors. In addition, some mechanisms of genetic susceptibil- ity involve the actions of genes that control envi- ronmental response, such as the histocompatibility (human leukocyte antigen [HLA]) complex on chromosome 6. The involved HLA genetic pattern identifies individuals who will have a specific immunologic response when exposed to various environmental agents.
The clinical manifestation of the gene(s) that an individual possesses is called “the phenotype.” Com- plex phenotypes, such as cardiovascular disease, cluster in certain families but they do not exhibit simple Mendelian inheritance patterns and may have many genetic and environmental causes. By this definition, most chronic, common disorders are considered to be complex. The complexity origi- nates from the fact that multiple genetic and envi- ronmental factors may interact with each other in unpredictable ways; the association between the phenotype and any single factor by itself may not be perceptible. With nonlinear interactions (including genotype by environment interactions), clinical expression may not be accurately predicted from understanding the individual effects of each of the component factors considered alone, no matter how well the separate components are understood.16
Common Genetic Variations (Polymorphisms)
Gene polymorphisms are a mechanism by which individuals may have variations within the biolog- ically normal range. In a population, a genetic polymorphism is present when variant forms of a gene at a given locus exist with a frequency of more than 1 to 2%. One of the more well-studied exam- ples of gene polymorphisms relates to enzymes involved in normal metabolism. Estimates indicate that approximately 30% of all enzyme gene loci are polymorphic, and approximately 7% of the popu- lation is heterozygous at each enzyme locus.15 Poly- morphisms in enzyme genes produce alternative active forms of an enzyme that are shown to differ from the standard enzyme, using electrophoresis,
isoelectric focusing, or other methods of separa- tion. There are frequently subtle differences in enzyme activities between products of different alleles of the polymorphic genetic factor. These dif- ferences may result in subtle differences in genetic susceptibility to a disease.
Studies have shown that stable immune phe- notypic characteristics, including cytokine produc- tion, antibody titer, and monocyte function, may result from specific genetic polymorphisms. For example, studies have focused on the role of genet- ics in an individual’s susceptibility to disease by showing that individuals with an unusual genetic variant in the chemokine receptor CCR5 demon- strate a striking resistance to human immunodefi- ciency virus (HIV) infection.7
Influence of Genetic Susceptibility on Different Characteristics of a Disease
The underlying genetic characteristics of a patient’s immune system (a patient’s “resistance”) deter- mine, in part, how a patient will react to bacterial challenges. Individuals are not equally susceptible to many common diseases, mainly due to differ- ences in their genetic constitutions. Genetic varia- tion is important for classifying diseases, diagnos- ing and managing patients with common disor- ders, defining the etiology of common diseases, and evaluating family members of patients. The genetic basis of common diseases, including coro- nary artery disease, obstructive lung disease, and periodontitis, has several similar factors. These fac- tors include clinical appearance in midlife, a fami- ly component, and onset of the underlying patho- genesis, which may begin as early as adolescence.17
Almost all common disorders have a familial com- ponent, which suggests that the distribution of these diseases is not random, and certain individuals are at high risk.15
There are different types of genetic suscepti- bility—susceptibility to a disease, differences in the natural history of a disease, and different ther- apeutic responses. Susceptibility to the disease itself is the most direct type and may be consid- ered the most important type because it puts an individual and some family members at increased risk of developing the disease. The advantages of assessing this type of susceptibility include being able to identify individuals at risk before disease onset and the potential benefits of preclinical intervention. Susceptibility is usually a complex issue with common diseases. The actions of sever- al genes are usually involved with common dis-
Role of Genetics in Assessment, Risk, and Management 49
eases but few genes can be identified as playing a major role in the disease. Different genetic back- grounds create different susceptibilities, encourag- ing the opportunity for different etiologies to lead to the same clinical expression of a disease (ie, dif- ferent species of bacteria can cause pneumonia or periodontal disease).
Individuals may have susceptibility to differ- ences in the natural history of a disease; they may be more likely to follow a particular clinical course for a disease. After initiation of the disease process, the genetic make-up of the affected individual can influence the course of the disease in terms of severity and complications. Clinicians with the ability to identify these susceptibilities can, in turn, identify individuals at risk for specific complica- tions and apply specific interventions or different therapies. A single genetic factor that significantly changes the clinical course of a disease may have great practical importance for the clinical manage- ment of the disease.
Individuals may also exhibit susceptibility to different therapeutic responses, which is common- ly found to exist as a genetic subtype of the disease. In addition, individuals may exhibit genetic sus- ceptibility to complications of a specific therapy or variations in their response to therapy. Reductions in poor therapeutic responses or unwanted drug complications could be achieved by an improved ability to recognize this type of susceptibility.
Host Immune Response to Microbial Infection
There are many genetic loci that have been associ- ated with the immune response of the host to microbial infection. Certainly, the most well-stud- ied genetic factor is the major histocompatibility complex (MHC) on chromosome 6, which defines the HLA system that is involved in many interactions between the cells of immune response. The MHC genetics have been associated with increased susceptibility to various microbial infections, including tuberculosis, HIV, and cer- tain parasitic diseases. Recently, a polymorphism in the gene that produces a specific receptor (chemokine receptor CCR5) on the surface of monocytes has been shown to produce strong resistance to HIV-1 infection, even with frequent exposure to the virus.18,19
Both CD32 and CD16 are receptors on immunoinflammatory cells for the Fc fragment of immunoglobulin G (Fc-gamma). Variants of genes that code for the Fc-gamma receptor produce a
receptor that results in reduced phagocytic capaci- ties, which provide a mechanism for heritable sus- ceptibility to microbial infections. Genetic variants in Fc-gamma receptors have been associated with both early-onset periodontitis20 and recurrent adult periodontitis.21
ROLE OF GENETICS IN PERIODONTAL DISEASE
Periodontal diseases have many of the characteris- tics of complex diseases, such as the temporal nature of the disease, difficulty in measuring and classifying disease phenotypes, and complex inter- actions between the host and microbial, environ- mental, and genetic factors, which make genetic studies difficult.7
Several immune response traits have been asso- ciated with clinical forms of periodontitis, and the underlying genetic determinants are known for some of these factors. It will be important to identi- fy the genetic factors that imply significant clinical risk. A gene can be considered as possibly having a causative or modifying role in periodontitis if the physiologic processes determined by the gene have been associated with disease presence or severity.7
As previously mentioned, some mechanisms of genetic susceptibility involve the actions of genes that control environmental response, such as the HLA complex on chromosome 6. The chromo- some 6 HLA region contains several genes involved in the immune response, and the TNF-a gene maps to this region. It has been shown that genetic polymorphisms in the 5' region of the TNF-a gene are involved in the response to an infectious challenge; these polymorphisms may be important in some forms of periodontitis.7
As previously discussed, the initiation of peri- odontitis requires the accumulation of specific bac- teria. However, studies of the quantity and types of bacteria have not fully explained the differences in disease severity seen among adults. After disease initiation, there is a correlation between some markers of periodontitis and the host immunoin- flammatory response; yet, none of these markers could be used to predict in advance an individual’s susceptibility to disease. In addition, there has not been a reliable mechanism for determining the course of the disease to identify patients who require more aggressive therapy.1
Why are there clinical differences in the preva- lence and severity of adult periodontitis? The answer is that there is a strong genetic component
50 Periodontal Medicine
to the disease. A patient’s resistance to periodontal disease is influenced by genetics, and this has been determined from a variety of sources: studies of twins, laboratory studies of antibodies, natural his- tory studies, and cytokine genetics studies.17
For many years, clinical and laboratory studies found substantial variability in the severity of peri- odonitits, even with high plaque challenges. Löe and colleagues conducted a study on the natural history of periodontal disease in man over a 15- year period.22 The study group consisted of Sri Lankan men (age range 14 to 31 years) who did not follow any conventional oral hygiene measures. They exhibited large amounts of plaque, calculus, and stain on their teeth, and almost all the gingival units were inflamed. Among this group, three sub- populations were identified on the basis of inter- proximal loss of attachment and tooth mortality rates: (1) individuals with rapid progression of periodontal disease (approximately 8%), (2) those with moderate progression of periodontal disease (about 81%), and (3) individuals with no progres- sion of periodontal disease beyond gingivitis (approximately 11%) (Figure 4–1). The group exhibiting rapid progression had a mean loss of attachment of approximately 9 mm at age 35 years, which increased to approximately 13 mm at age 45 years, with an annual rate of destruction of 0.1 to 1.0 mm. In individuals exhibiting moderate pro- gression, the mean loss of attachment was approx- imately 4 mm at age 35 years and 7 mm at age 45 years, with an annual rate of destruction between
0.05 and 0.5 mm. The mean loss of attachment in individuals with no progression of disease was 1 mm at age 35 years, with an annual rate of destruc- tion between 0.05 and 0.09. Most in the study group were caries free; therefore, essentially all the missing teeth were the result of periodontal dis- ease. Based on modern views of susceptibility, the results of this study show that there may be indi- viduals who are less susceptible to disease.
Studies of Twins
The most convincing demonstration of a genetic influence on adult periodontitis came from studies of twins. Comparison of concordance rates of dis- ease (ie, if both twins in a pair are affected, the con- cordance rate is 100%) in monozygotic or dizygotic twins is the classic method for determining whether familial patterns of disease are the result of common genetic or common environmental factors. Mono- zygotic twins are genetically identical whereas dizy- gotic twins are no more genetically alike than sib- lings. When the concordance rate is higher in monozygotic twins compared with dizygotic twins, especially same-sex dizygotic twins, a significant part of the familial agreement is caused by genetic factors. When the concordance rate is equal, the familial agreement is mainly determined by envi- ronmental factors. With monozygotic twins, it is sometimes difficult to separate heredity from envi- ronment as these twins tend to select similar envi- ronments, probably because of their genetic iden- tity. Examples of diseases in which the concor- dance rate is higher in monozygotic twins com- pared with dizygotic twins include coronary heart disease, diabetes, and peptic ulcer disease. The con- cordance rate in monozygotic twins is rarely 100%, suggesting an environmental or random component to these disorders, in addition to a genetic component. When 100% concordance is observed in monozygotic twins, genetic factors are of great importance in the specific environment in which the twins were studied.15
Michalowicz and colleagues conducted a study to examine the relative contribution of environ- mental and host genetic factors to the clinical fac- tors of periodontal disease in adult twins.12 The study group included 77 monozygous twins (63 pairs were reared together and 14 pairs were reared apart) and 33 dizygous twins. Probing depth, clin- ical attachment loss, gingivitis, and plaque were assessed from the Ramfjord index teeth, and boot- strap sampling was used to estimate and provide confidence limits of between-pair and within-pair
35
30
25
20
15
10
5
0
15 20 25 30 40 45
Number of missing
teeth Rapid Moderate None
Age in years
8%
81%
11%
Figure 4–1. Sri Lanka: tooth loss. (Data from Löe H, Anerud A, Boysen H, Morrison E. Natural history of periodontal dis- ease in man. Rapid, moderate, and no loss of attachment in Sri Lankan laborers 14 to 46 years of age. The curves show the number of teeth lost in each of the three groups that were based on the rate of disease progression. The numbers in boxes (8%, 81%, 11%) show the percentage of the study population in that specific disease-progression group. J Clin Periodontol 1986;13:431–45.)
Role of Genetics in Assessment, Risk, and Management 51
variances, heritability, and intraclass correlations. A significant genetic component was identified for plaque, gingivitis, probing depth, and attachment loss based on ratios of within-pair variances or her- itability estimates. Heritability estimates showed that between 38 and 82% of the population vari- ance for the clinical factors of disease studied can be attributed to genetic factors.12 Another study by Michalowicz and colleagues estimated the genetic variance for alveolar bone height in adult twins.13
Panoramic radiographs were obtained from 62 pairs of reared-together monozygous twins, 25 pairs of same-sex, reared-together dizygous twins, and 33 pairs of reared-apart monozygous twins. Mesial and distal bone heights were determined as a proportion of tooth length. By averaging these proportions from all measurable teeth, a full- mouth bone score was determined for each twin. Calculations of the between-pair and within-pair variances were made for each twin group. Results showed that the population variances (between- pair and within-pair) of the monozygous and dizy- gous twins were similar, validating a basic assump- tion of the twin model. In addition, intraclass cor- relations and heritability estimates were calculated for the reared-together monozygous (0.70) and dizygous twins (0.52), as well as the reared-apart monozygous twins (0.55). The results of this study indicate that there is significant genetic variance for proportional alveolar bone height in the popula- tion.13 In addition, comparisons of reared-together and reared-apart adult monozygous twins showed that early family environment had no substantial influence on probing depth and attachment loss measures in adults.23
Although there was strong evidence for some genetic influence on the severity of adult peri- odontitis, there was not, until the past few years, clear evidence of a specific genetic factor that may explain genetic susceptibility to periodontitis. Increased understanding of the biology of peri- odontal disease and new understandings of genetic factors that influence responses to bacterial chal- lenges guided the search for candidates that may explain the genetic influences on periodontitis.
Candidate Genes in Adult Periodontitis
Recent reviews have discussed some of the key can- didate genes that may be of value, given current knowledge, in the search for genetic influences on periodontitis.7 The key is to identify genetic factors that are strong enough to significantly influence the clinical outcomes of disease. In general, a gene
may be considered a candidate for a significant modifying role in periodontitis if the physiologic processes determined by the gene have been associ- ated with the presence or severity of disease. It should be emphasized that genetic variations that dramatically alter major protective mechanisms are unlikely to be involved in common chronic dis- eases such as periodontitis. Patients with such major defects are likely to suffer serious childhood problems and complications from various infec- tious diseases. The most likely candidates for a genetic influence in adult periodontitis are, there- fore, genetic variants that produce a subtle change in the magnitude of biologic processes.
The most prominent candidates for a genetic influence on adult periodontitis include factors that produce variations in the relative ability of antibod- ies and PMNs to kill bacteria and factors that change the relative magnitude of inflammatory processes.
Genetic variations in the quantity of antibody and in the magnitude of PMN binding of antibody (Fc-gamma receptors) have been described and have been associated with early-onset periodontitis. One study associated genetic factors involved in Fc- gamma receptors with recurrence of adult peri- odontitis in Japanese patients.21 Studies in U.S. adults have not supported these observations.24
The strongest biochemical associations with the severity of periodontitis have been reported for prostaglandin E2 (PGE2), IL-1 and TNF-a, and the enzymes that destroy collagen (matrix-metallo- proteinases). Genetic variations in these compo- nents should be reasonable candidates for influ- ences on adult periodontitis. There are currently no data to indicate that variations in the genes for PGE2 or for matrix-metalloproteinases influence the severity of periodontitis. Variations in the TNF-a genes were tested for association with severity of periodontitis and showed no association with disease.1 At present, data indicate that IL-1 gene variations are involved in the clinical severity of periodontitis in adults.
Role of IL-1 in Adult Periodontitis
Chemicals in the tissues that provide communica- tions between cells are generally referred to as cytokines. One cytokine, IL-1, plays a critical sig- naling role in many different systems in the body and has been strongly implicated in the progres- sion and severity of adult periodontitis.
The cytokines IL-1a, IL-1b, and TNF-a are important mediators of inflammatory responses and appear to play a central role in the pathogene-
52 Periodontal Medicine
sis of many chronic inflammatory diseases.25,26 It is now well documented that their biologic activities in vivo are sufficient to produce local inflamma- tion and destruction of connective tissue and bone.27 The cytokine IL-1 is one of the first chem- ical mediators activated following any external stimulus, such as a bacterial challenge. As an early response factor, it activates other nonspecific and protective mechanisms, including recruitment of PMNs and activation of blood clotting. It also acti- vates specific protective mechanisms and is involved in wound healing and bone and connec- tive tissue metabolism.
Higher production of these cytokines has also been associated with response to infection, where local induction of IL-1 and TNF facilitates the elimination of the microbial invasion. However, classic studies also report that in some infectious conditions very high levels of monocytic cytokines are produced and initiate a cascade of concomitant events, such as tissue catabolism, vascular reactivi- ty, and hypercoagulation, with damaging effects on the host.28,29
Elevated tissue and gingival fluid levels of IL- 1b in particular have been repeatedly associated with the severity of periodontitis.30–35 The rela- tionship between IL-1 and periodontitis has been extensively reviewed by Offenbacher.8 Although the inflammatory process automatically increases the local tissue levels of IL-1, stable differences between people in cytokine production rates have been reported.36,37
Genetic Variations in the IL-1 Genotype and Increased Levels of IL-1
Three IL-1 genes (IL-1A, IL-1B, and IL-1RN) clus- ter on chromosome 2q13. Interleukin-1A and IL-1B encode the proinflammatory proteins IL-1a and IL-1b, and IL-1RN encodes IL-1ra, a related pro- tein that functions as a receptor agonist. Several genetic polymorphisms have been identified in the genes of the IL-1 cluster. In recent studies, severe adult periodontal disease in nonsmokers38 was cor- related with a composite genotype in the IL-1 gene cluster that includes at least one copy of allele 2 of the IL-1A-889 polymorphism and at least one copy of allele 2 of the +3953 polymorphism of the IL-1B gene. The IL-1A (–889) locus is in > 99% linkage disequilibrium (eg. the two are inherited together) with a polymorphism at the IL-1A (+4845) locus which is currently used in the laboratory in place of IL-1A (–889) in the composite genotype test for severity of adult periodontitis.
A study by di Giovine and colleagues showed that peripheral blood monocytes from individuals with at least one copy of allele 2 at IL-1B (+3953) produced up to four times more IL-1 in response to the same bacterial challenge than those who were genotype negative.39 Individuals inherit one copy of the IL-1 gene from each parent. Individu- als who had two copies (homozygous) of the most common IL-1B (+3953) polymorphism (allele 1) produced a certain amount of IL-1b (5.2 ng/mL) when stimulated by the bacterial component LPS. Individuals who were homozygous for the poly- morphism associated with periodontitis (allele 2) produced approximately four times more IL-1b than normal (19.9 ng/mL) (Figure 4–2). And indi- viduals with one copy of allele 1 and one copy of allele 2 of the IL-1B (+3953) polymorphism (het- erozygous), produced approximately twice as much IL-1b (12.4 ng/mL).39
Patients with the composite IL-1 genotype have higher levels of IL-1 in the gingiva than those observed in genotype-negative patients. Recent studies have determined the levels of IL-1a and IL-1b in gingival biopsies and the levels of IL-1b in gingival crevicular fluid (GCF).40 The IL-1 genotype positives had higher levels of IL-1b in GCF, with the greatest differences between geno- type-positive and genotype-negative patients in sites of minimal probing depth (Figure 4–3). Tissue levels of IL-1b were also higher and levels of IL-1a were marginally higher in genotype-positive patients. These findings were dramatic and indi- cate that IL-1 genotype-positive patients will have higher levels of IL-1 in periodontal tissues when there is a bacterial challenge. Related observations were made in a pilot study by Jotwani and col- leagues who examined the response of periodontal- ly healthy patients to plaque accumulation. This study found that IL-1 genotype-positive patients, but not the genotype-negative patients, had a sig- nificant increase in GCF IL-1b after 3 days with- out oral hygiene.41
Genetic Variations in IL-1 Genotype and Increased Severity of Adult Periodontitis
The first report of an association between the IL-1 genotype and severity of adult periodontitis was published in 1997.1 Since that time, other studies that confirm these findings have been reported.
In the first report the study population includ- ed only adults with no known history of early-onset disease and most likely included patients with both adult periodontitis and refractory periodontitis. The
Role of Genetics in Assessment, Risk, and Management 53
association between severe periodontitis and the genetic polymorphism in the IL-1 genes was present only when smokers were excluded, which confirmed the importance of smoking as a risk factor for peri- odontitis. This was the first study that identified a genetic polymorphism that corresponds with a phe- notypic immune response variable (IL-1 produc- tion) in adult periodontitis patients.1 The IL-1 genotype identified in this study appears to be a marker of a strong biologic change that results in severe periodontitis, without regard to the amount of bacterial challenge. This does not mean that bac- teria are not important in the disease process—quite the contrary. The first findings indicate that the sig- nificant association between the IL-1 genotype and severity of periodontitis did not require any adjust- ments for the amount of bacterial plaque. The com- bination of having either the specific genotype or smoking accounted for the majority (86%) of severe cases of periodontitis. The IL-1 genotype was a very strong predictor of severe periodontitis in nonsmok- ers age 40 to 60 years (odds ratio 18.90) (Figure 4–4). Among similar-aged individuals with mild periodontitis, 84% were genotype negative.1
It is noteworthy that the association between the genetic polymorphism in IL-1 genes with severe periodontitis was only evident when smokers are excluded. These data support the importance of other environmental factors, such as smoking, as a risk factor for periodontitis.34,103 The association of severe periodontitis with smoking and the IL-1 genotype suggests that both factors play an impor- tant role in the pathogenesis and clinical course of adult periodontitis.
Other studies have confirmed these early observations. McDevitt and colleagues found sim- ilar associations between the IL-1 genotype and adult periodontitis (Figure 4–5).42 McGuire and Nunn have reported an increased susceptibility to tooth loss after periodontal therapy in IL-1 geno- type-positive patients.43 Recently, Gore and col- leagues (1998) reported a significant association between the IL-1b polymorphism and severity of disease.44 In this study, the composite genotype (IL-1A plus IL-1B) did not offer advantages over just the IL-1B markers. Such differences among the studies are not surprising as genetic studies usually have small numbers of subjects.
The above studies were performed primarily in Caucasians. One obvious question is, what is the role of the IL-1 genotype in other ethnic groups? In most of the populations that have been tested, this genotype occurs in approximately 30% of individ- uals.1 Although it is expected that the IL-1 geno-
type will have the same relationship to disease in all populations, the IL-1 genotype may be found less frequently in some populations than in Caucasians. It is also possible that other genetic factors may play a role in other ethnic groups. At present, it has been reported that IL-1 genotype positivity is found in approximately 30% of Caucasians1 and Hispan- ics.45 It has been reported that genotype positivity is much less common in the Chinese population.46
Studies are in progress to determine the prevalence of the IL-1 genotype in other populations.
Figure 4–3. IL-1 is higher in the periodontal tissues of PST® positives. (Data from Engebretsson SP, Lamster IB, et al. The influence of interleukin-1 (IL-1) gene polymor- phisms on expression of IL-1b, and tumor necrosis factor alpha (TNFa) in periodontal tissue and gingival crevicular fluid. J Periodontol 1999;70:567–73.
Gingival crevice fluid IL-1ß pg/uL
Sites < 4mm probing depth
200
150
100
50
0** p < .05
Genotype positive
Genotype negative
**
Figure 4–2. Amount of IL-1 produced by patients who are homozygous (2.2) or heterozygous (1.20 for the allele for adult periodontitis . (Data from diGiovine FS, Cork MJ, Crane A, et al. Novel genetic association of an IL-1b gene variation a + 3953 with IL-1b protein production and psori- asis [abstract]. Cytokine 1995;7:606.)
ng/mL IL-1ß 20
18 16 14 12 10 8 6 4 2 0
1.1 1.2 2.2 Genotypes of the IL-1ß (+3953) locus
54 Periodontal Medicine
The association between the IL-1 genotype and disease severity was unclear when heavy smokers were included in the data analysis. What does this mean? It is well documented that smoking, by itself, is a strong risk factor for more severe periodontitis. It is therefore reasonable to expect that some IL-1
genotype-negative patients who are heavy smokers will be susceptible to more severe periodontitis. This will certainly confuse the data analysis of research studies unless this factor is taken into account in the analysis. One study that involves periodontal treat- ment shows a synergistic risk when a patient is both a smoker and is IL-1 genotype positive.43 At pre- sent, it seems reasonable to expect that, as with risk factors for cardiovascular disease, multiple factors such as IL-1 genotype and smoking convey increased risk of more severe disease. It is likely that larger studies will help to define the magnitude of interactions between smoking and the IL-1 geno- type as well as other risk factors.
Genetic Variations in IL-1 Genotype and Response to Treatment
It seems reasonable to assume that if the IL-1 geno- type is associated with more severe disease, the genotype may also influence response to therapy. New data from McGuire and Nunn validate that assumption.43 Over several years, McGuire and Nunn conducted studies to determine the effec- tiveness of clinical parameters in developing an accurate prognosis.47,48 In their first study, the authors evaluated 100 treated periodontal patients under maintenance care for 5 years to determine
% subjects who are PST ®
positive
Mean bone loss (mm)
80
60
40
20
0 < 1.5 1.5–2.49 ³ 2.5
Figure 4–5. Most nonsmoker patients with severe bone loss were PST® positive. (Data from McDevitt M, Wang H-Y, Knobelman C, et al. IL-1 genetic association with perio- donitits in clinical practice. J Periodontol 1999. [in press])
% of subjects with ³ 30%
mean bone loss Genotype pos Genotype neg
35–40 41–45 46–50 51–55 56–60 >60 Age
35
30
25
20
15
10
5
0
Figure 4–4. The periodontitis genotype defines a different disease susceptibility in adults. Age 35–60; odds ratio: 18.9; p < .001. The cumulative frequency distribution of non-smokers with ³ 30% mean bone loss (severe) at different ages. The bars represent the cumulative percentage of subjects who had severe disease by the indicated age. Genotype positive (N=63). Reprinted with permission from J Clin Periodontol 1997;24:72–7.
Role of Genetics in Assessment, Risk, and Management 55
the relationship between assigned prognoses and the clinical criteria commonly used in developing a prognosis.47 Using multiple logistic regression models, it was shown that improvement or wors- ening in prognoses was strongly associated with initial tooth malposition, probing depth, furcation involvement, and smoking, when adjusted for ini- tial prognosis. It was found that initial mobility decreased the probability of improvement in prog- nosis whereas good oral hygiene increased the probability of improvement in prognosis; however, neither of these factors was shown to be significant in worsening the prognosis. On the other hand, smoking doubled the probability of worsening of prognosis at 5 years and decreased the probability of improvement by 60%. According to the authors, the results of this study suggest that some clinical factors used in the assignment of prognoses are clearly associated with changes in a patient’s clinical condition over time.
In their second study, McGuire and Nunn eval- uated tooth loss in 100 treated periodontal patients under maintenance care to determine the effective- ness of commonly taught clinical parameters used in assigning an accurate prognosis for tooth survival.48
Using a Cox proportional hazards regression model, it was found that initial furcation involvement, probing depth, percent bone loss, mobility, and smoking were associated with an increased risk of tooth loss. Data from the study showed a relation- ship between the assigned prognosis and tooth loss. The worst survival rate occurred in teeth with the worst prognosis but the commonly taught clinical parameters used in the traditional way for assigning prognosis do not adequately explain this relation- ship. In addition, the initial prognosis did not ade- quately predict survival of the tooth or explain the condition of the tooth. The results of this study indicate that when assigning prognosis, some clini- cal parameters should be weighted more heavily than other clinical parameters.
The latest study by McGuire and Nunn (Figure 4–6) determined that the significant predictors of tooth loss in periodontal patients who were moni- tored for 14 years after active therapy were heavy smoking (increased risk for tooth loss of 2.88; meaning that heavy smokers had a 288% increased risk of losing teeth after therapy as compared to non-smokers or light smokers) and the IL-1 geno- type (increased risk for tooth loss of 2.66).43 If patients were both heavy smokers and IL-1 geno- type positive they were 7.7 times more likely to lose teeth after periodontal therapy than all other patients. It should be noted that even in IL-1 geno-
type-positive patients, conventional periodontal therapy and good maintenance care allowed the suc- cessful retention of most teeth.
Studies so far have shown evidence that IL-1 polymorphism analysis can provide valuable insight into an individual patient’s likely response to vari- ous interventions. However, additional studies are necessary to provide greater insight into the rela- tionships between genetic factors and periodontal and restorative therapy. This genetic marker is not diagnostic; it is a prognostic test that is used to identify individuals who have a much higher sus- ceptibility to adverse reactions to plaque.49
The finding of the association between the IL-1 polymorphism and an increase in IL-1b production and more severe periodontal disease is consistent with the current model of how genetic factors influ- ence common chronic diseases. If this model is applied to periodontitis, it would involve a disease- initiating factor, which would most certainly be a specific bacterium (ie, P. gingivalis, Bacteroides forsythus, and A. actinomycetemcomitans), and modi- fiers of disease mechanisms that explain the clinical severity, including certain systemic diseases, smok- ing, psychosocial stress, and the IL-1 genotype.6
Clinical Application
Despite the general overall improvement in peri- odontal health, periodontitis is still the number one
Increased risk of
tooth loss*
PST® positive
Heavy smoker
PST® plus smoking
8
7
6
5
4
3
2
1
0
Figure 4–6. IL-1 genotype and heavy smoking were the pri- mary predictors of tooth loss after periodontal therapy. *An increased risk of 2 indicates that the patient is two times more likely to lose teeth than patients without that risk fac- tor. (Data from McGuire MK, Nunn ME. Prognosis versus actual outcome. IV. The effectiveness of clinical parameters and PST genotype in accurately predicting prognosis and tooth survival. J Periodontol 1999;70:49–56.
56 Periodontal Medicine
cause of tooth loss in adults. In the United States alone, over 50 million people have the disease. The cost to society in both human and economic terms is great. The indirect expenses of replacing teeth lost due to periodontitis are much higher than the direct periodontal expenditures. Patients, insurance payers, and clinicians are seeking accurate treat- ment and better preventive approaches. The genet- ic aspects of the disease have been understood and accepted with increased enthusiasm because of the tremendous strides made in molecular biology. These new insights are beginning to find their way into practical translation and use by clinicians.
This section will briefly describe how to inte- grate information on the genetic basis of periodon- titis into the overall framework of the patient’s diagnosis and treatment plan. Certain characteris- tics of genetic information make it different from almost any other kind of patient specific data the dental professional deals with. These include scien- tific, ethical, inheritance, and practical considera- tions unique to information about heredity. How- ever, although different, genetic information may be viewed as (just) another type of medical infor- mation about patients and their relatives.
Use of Genetic Information in Clinical Practice
The literature in the past 5 years has had increasing amounts of space devoted to presentations of data postulating an important role for genetics in the pathogenesis of adult periodontitis. Although much of this information has been well accepted, its trans- lation into clinically useful practice has been very slow, primarily because there have been no com- mercially available methods that could be used by dentists wanting to know if their patient had a spe- cific periodontitis-implicated genotype.
Most professional organizations have devel- oped comprehensive guidelines for diagnosis, risk assessment, and prevention of periodontitis through measures aimed at reducing the risks of disease initiation or disease progression. Dentists, dental hygienists, and their patients would like to have as much useful information as possible in order to guide decision making for periodontal treatment planning. Faced with the challenge of ascertaining all relevant risk factors and then trying to put the information together with patient pref- erences, the clinician manages, organizes, and syn- thesizes all the data to produce the best possible treatment plan. The goal is to personalize the plan and make it as accurate and predictive as possible.
Although scientific evidence and clinical experi- ence have improved the accuracy and power of tra- ditional methods, the ability to predict the prog- nosis and outcome for individual patients and individual sites has been limited.
To best appreciate how genetic information fits into the current concepts of disease, it is impor- tant to describe the scientific and clinical model of periodontitis etiology and pathogenesis that is cur- rently accepted by the vast majority of clinicians. Importantly, the new genetic features of the disease do not replace existing elements of the paradigm and, in fact, provide clarification for many of its uncertainties.
Paradigm for Microbiologic Periodontal Disease
The main conceptual framework for the etiology of periodontitis is based on the belief that peri- odontitis is an infection caused by plaque (Figure 4–7). The assumptions of the model are:
1. Periodontitis begins as gingivitis. 2. In a large portion of the adult population
(35%), gingivitis converts to periodontitis. 3. Approximately 10% of affected individuals
will develop severe forms of the disease. If left untreated, periodontitis may progress to become more severe.
4. Plaque must be present for disease progression but the presence or the identification of spe- cific bacteria is not predictive of periodontitis severity on an individual-site basis.
5. Intrinsic factors (genetics) and extrinsic factors (such as oral hygiene) account for the clinical variability of disease manifestation.
6. Adult periodontitis is a common, multifactor- ial, chronic disease.
Since there are important differences in the combination of factors causing disease, it follows that the treatment for different groups of patients with periodontitis should not be the same. Other- wise, there is the possibility that some patients will get too much treatment while some others do not get what they need. If 10% of patients with peri- odontitis will develop severe disease, then the other 90% will have only mild to moderate disease. How can patients be identified as to their risk for future severity of their disease? Are there tests or any other information that will help the clinician improve the accuracy of the predictions about the patient’s future status? These are critical questions that interest all
Role of Genetics in Assessment, Risk, and Management 57
parties involved. Patients want the best treatment, clinicians want to provide efficient therapy, and insurance payers want to focus resources. Genetic susceptibility to the resident periodontal flora is one of the factors that determine the actual clinical pre- sentation of disease. Assessment of other risk factors, such as smoking and systemic health, are always included in the development of a comprehensive treatment plan but practical methods available to the clinician to determine the types of bacteria at an individual periodontal site are limited.
Clinical Perspective
The practical use of genetic information offers the potential to change periodontitis treatment. Genet- ic predisposition to the onset of periodontitis means that some patients can be identified even before dis- ease begins. This improves the chances of successful prevention. Genetic heterogeneity associated with disease also extends to treatment responsiveness. Distinguishing patients who are of good responders from those who are poor responders will allow more precise chemotherapeutic interventions because drug targets will be more precise. For example, there may be different response patterns to a specific anti- inflammatory drug, depending on the nature of the individual patient’s cell receptors compared with those of another patient. Pharmaceutical companies are devoting vast resources to this endeavor that has been referred to as pharmacogenomics.
Available techniques, tests, diagnostic proce- dures, and guides to treatment have either been weakly applicable on a patient-by-patient basis, or, they have been impractical in terms of cost-effec- tiveness, and time management.
The main barrier to widespread use of current technology is its poor record in predicting the patient’s future periodontal status. Clinical and bio- logic evaluations can tell the clinician about the cur- rent status of the patient’s periodontium but these signs, symptoms, and clinical judgments have rela- tively weak prognostic value. By focusing attention on both the etiology and modifiers of periodontitis, rather than on “fixing” the results of disease, practi- tioners can anticipate, manage, and prevent disease much more effectively. For example, smoking, dia- betes, family history, and other factors known to increase the risk and susceptibility to periodontitis are important to consider because they can influ- ence the patient’s response to therapy. Patients with more risk usually need more care. Optimum treat- ment implies managing the multiplicity of issues, etiologies, preferences, and physical, emotional, and inherited risk and susceptibility factors.
Ethical Considerations
The sensitivity of genetic information underscores the importance of understanding the often dis- cussed and highly debated issues dealing with genetic information. For most dental personnel,
• More aggressive therapy – surgery – antimicrobials
• More frequent recall/ maintenance
• Less aggressive therapy • Less frequent recall/
maintenance
• Smoking cessation • More frequent recall/
maintenance
Increased risk for severe disease
Lower risk for severe disease
Increased risk for severe disease
Genotype positive
Nonsmoker
Pathogenic bacteria present
Genotype negative
Smoker
Figure 4–7. Clinical utility of genetic testing.
58 Periodontal Medicine
genetic information is distinguished from other patient information because it is potentially pre- dictive, permanent, and associated with blood rel- atives. Many of the most important issues are sum- marized in Table 4–2.
Genetic Counseling
There are two factors involved in disease risk: numerical risk and the burden or severity of the disease. Well-defined mathematical rules for pre- dicting risk are not available for many multifactor- ial (non-Mendelian) disorders. In this instance, clinicians rely on empiric observations, epidemio- logic data, and a variety of studies about recurrence risks. From nongenetic studies, approximate pre- dictions and generalization can be inferred and direct application to the individual is limited. On the other hand, genetic prognosis is concerned with the prognosis for the affected individual and outlining disease risks for their different relatives.
During genetic counseling, the risks for a disease and the potential options for dealing with the risks are discussed with the individual and often with family members at risk. With diseases that are treatable, such as periodontitis, it has been shown that early intervention improves the outcome. For many common disorders, the process of family- based screening can be of value. After the initial genetic risks are determined, these risks can be more clearly defined by performing additional studies in patients and family members who are at risk.15 Family linkage and association data are being generated for many of the genetic markers associated with periodontitis. These data will assist the counselor in describing the level of risk to the patient and family members.
For common diseases, the physician and dentist will have responsibility for counseling patients about the implications of genetic susceptibility. Genetic counselors may also be involved in this process, especially in the setting of large medical institutions.
TABLE 4–2. Summary of Genetic Information Issues for the Clinician*
Representative Issues Discussion
No distinctions between 1. For all diseases, whether or not there are reasonable treatments or preventive genetic information and options, presymptomatic, predictive genetic testing can introduce sensitive other forms of medical/ medical/genetic information. The feature of this category of information that dental information makes it sensitive is that it is subject to misinterpretation by patients, providers,
insurers, and employers. In essence, this type of medical information is no different from other types of confidential medical facts about an individual, for example, whether or not a patient is HIV positive or negative.
2. In cases such as presymptomatic testing, the clinician must realize that the actual information about a patient’s genetic make-up will, itself, impact the lives/mental health of otherwise healthy people.
3. Genetic information is not limited to the individual tested; the information is about the individual’s germline/family and thus may have consequences beyond treatment planning decisions for the tested patient.
Clinical utility 1. There is a general consensus that genetic testing should not be withheld until enough data have been compiled to know exactly what a genetic test result means for all individuals in the general population, ie, it is not necessary to know the exact relationship between genotype and phenotype for the target marker(s). Effective treatments (therapeutics and even gene therapies) may be developed before all the complexities of interactions among genes/gene sequences and genetic and environmental variables are known.
2. Genetic testing should be introduced when • there is sufficient analytical validity (in essence, the test reliably determines
the presence of the target marker(s) in the laboratory); • there is sufficient clinical utility (there is a clinical benefit for patients, which
also is a prerequisite for reimbursement); and • patient safeguards (to ensure only informed, voluntary testing) are adhered to.
*Adapted from: M. Malinowsky, 1999.
Role of Genetics in Assessment, Risk, and Management 59
Periodontal Disease-Specific Issues and Comments 1. Genetic tests for common diseases are not usu-
ally considered to be classic “diagnostic tests,” and they do not eliminate the need for an accurate diagnosis and treatment plan.
Comment: Risk assessment, including the use of genetic susceptibility testing, is an addi- tional step, but not a substitute for a full diag- nostic evaluation.
2. Common diseases are multifactorial, and because of this, genetic test results provide one piece of information needed to form a diagno- sis, prognosis, and treatment plan.
Comment: Most often, the diagnosis of a common disease is based on the identification of signs and symptoms associated with well- established criteria. Signs of periodontitis include plaque, changes in gingival color, ini- tial attachment loss, probing depth, bleeding on probing, and suppuration. Negative genet- ic susceptibility test results by themselves do not rule out future occurrence of disease or disease activity because one of the other con- tributing factors may contribute to the observed pathology. Similarly, positive test results do not mean that disease is inevitable.
3. Another important facet of genetic test results specific to periodontitis has to do with the implications to people biologically related to the tested individual.
Comment: Depending on the nature of the genetic association, offspring, siblings, parents, and others may carry genes that could put these people at increased disease risk. In the case of adult periodontitis, this information may be helpful in establishing treatment recommenda- tions and preventive approaches. The decision to be tested for periodontitis susceptibility should be made by the individual patient.
4. Essential scientific characteristics of genetic susceptibility tests must meet the highest
level of validity, as well as addressing ethical considerations.
Comment: Before deciding to use genetic testing as part of patient assessment and treat- ment planning, the clinician must ensure that the test itself embodies certain attributes dis- cussed in previous sections and summarized in Table 4–3. All five characteristics and consider- ations must be checked before the test is used.
Genetic Testing in Dentistry
Genetic testing for the IL-1 genotypes in dentistry was begun in 1997 with the introduction of the PST test (PST®, Interleukin Genetics, Inc., San Antonio, TX). Its primary use is to provide addi- tional information about a patient’s susceptibility to adult periodontitis. Since it measures the absence or presence of specific markers of the patient’s inflammatory response to plaque, one of the key components of the pathogenesis of peri- odontitis, its clinical utility is very high. Control of inflammation is a key component of many of the treatment goals in esthetic, restorative, and recon- structive dentistry. The currently available genetic susceptibility test meets the five characteristics and conditions listed in Table 4–3.
The primary use for information about a patient’s risk for disease initiation or progression is the modification and individualization of therapeu- tic interventions. Both the nature and the timing of therapy may be altered as a result of knowing a patient’s risk for future disease. What the benefits of knowing a patient’s risks for disease, including their genetic susceptibility to periodontitis, are and who should be tested are two common questions often asked by practitioners and patients. The section below discusses some essential factors about risk assessment. Knowing about these factors will pro- vide a context for determining how the genetic sus- ceptibility risk factor fits in the overall approach to treating and preventing periodontal disease and its relevance to restorative dentistry.
TABLE 4–3. Required Characteristics for Genetic Susceptibility Tests Associated with Common Diseases
1. The genotype must be associated with disease occurrence and, if possible, the mechanism known to be an integral part of the pathogenesis of the disease.
2. Analytical sensitivity and specificity must be determined, ie, how accurate the laboratory test and methods are in their ability to detect the genetic marker, if it is truly present.
3. Appropriate clinical validity must be ascertained: eg, odds ratio, for disease with and without the genetic marker. 4. The benefits and risks from test results must be known. 5. Treatment initiation or change as a result of the information derived from the test must be available.
60 Periodontal Medicine
Risk Factor Determination
The term “risk” is generally used to imply the probability that an unfavorable or unwanted out- come may occur in the future. Many studies have been conducted to identify the factors that increase an individual’s risk for developing periodontal dis- ease.50,51 The findings from these studies have identified the following as risk factors for peri- odontitis: smoking, diabetes mellitus, advancing age, poor oral hygiene status, microbial deposits, inheritance, bleeding on probing, specific patho- genic bacteria in the subgingival flora, and previ- ous disease experience and severity. Some risks are strongly linked to disease causation (ie, pathogenic bacteria in the subgingival flora), others may be background factors that enhance susceptibility (ie, advancing age), and some may suggest increased risk for future disease (ie, bleeding on probing). Patient decisions about treatment must be based on accurate information, including individual preferences, estimates of the patient’s prognosis, expected side effects and benefits, and efficiency of the proposed treatment alternatives.38 Although the data regarding risk factors are very good, the degree of patient variability and treatment respon- siveness demonstrates the need for more research.
Patient Selection and Potential Benefit(s) of Genetic Susceptibility Testing
The list below describes some potential types of patients and the benefits that may be derived from the decision to determine the patient’s genotype.
1. Patients with early signs of periodontal disease. Testing can be done to better determine the appropriate level of therapy and maintenance and to potentially minimize further disease progression and tooth loss.
2. Periodontal maintenance patients. Individuals with continuing signs of disease will potential- ly benefit from understanding their risk for future disease. This information should be combined with other risk factors (eg, smoking and diabetes) to determine who might benefit from more or less aggressive treatment. The information may also help to determine the level of periodontal and inflammatory risk prior to restorative or implant therapy.
3. Patients who are resistant to accepting treatment recommendations. If a patient is found to be genetically positive, the information may motivate him or her to reduce as many of the
controllable risks as possible. This may be accomplished through better home care, more frequent dental visits, smoking cessation, pocket reduction, or any other recommended therapy. For patients who are found to be genetically negative, the information can still be used to motivate them to control other risk factors (such as smoking) and increase their chances of staying healthy.
4. New periodontal patients as part of an initial examination and objective measure of their risk for disease progression and patients who have a familial history of periodontitis or who have relatives who are genotype positive. Some patients may be tested after initial therapy, especially if they are not responding well.
5. Biologic family members of genotype-positive patients or patients with severe periodontal disease for prevention or early intervention.
6. Patients with advanced periodontal disease to provide information that, when combined with other risk factors, can be used to optimize therapy and determine who needs aggressive treatment and/or maintenance to minimize further disease progression and tooth loss.
7. Patients who are candidates for complex restorative procedures to enhance the success and maintain- ability of the case by considering the overall risk profile of the patient in the treatment, mainte- nance, and follow-up plan. Marginal inflamma- tion and bleeding are risk factors associated with gingival recession. Patients who are “inflamma- tion prone” due to their genetically variable response to plaque can use this information to motivate them to improve their oral hygiene.
8. Adult orthodontic patients as part of an initial screening for periodontal health status and risk assessment. If a patient is seen to be at risk for developing severe periodontal disease on the basis of genetic test results and/or other risk factors or already has periodontal disease, he or she may benefit from more frequent periodon- tal maintenance during orthodontic treatment.
CONCLUSION
With the discovery of a specific genetic factor that places individuals at a greater risk for the develop- ment of periodontitis or more severe forms of the disease, clinicians can tailor treatment for individual patients, resulting in more effective therapy. In addi- tion, by identifying genotype-positive patients before disease initiation, clinicians may be able to prevent
Role of Genetics in Assessment, Risk, and Management 61
the development of periodontitis in some patients with the use of standard preventive measures.
There is little doubt that on the basis of risk and susceptibility factors, the practice of periodon- tics, will require a change of approach for dentistry and for the patients and public it serves. Risk and predisposition assessment will be used more often as first priority decision-making guides in diagnos- tic and therapeutic algorithms. Because clinicians can now identify and monitor periodontal risk con- siderably earlier than before, there is an opportuni- ty for maximizing benefit/cost ratios. Early detec- tion enhances appropriate treatment planning, whether it is prophylactic, medical, or surgical.
Acknowledgement
The excellent drafting and editorial assistance of Kathy Barnes and Elaine Robertson were very much appreciated in the preparation of this chapter.
REFERENCES
1. Kornman KS, Crane A, Wang H-Y, et al. The inter- leukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997; 24:72–7.
2. Roberts FA, Hockett RD Jr, Bucy RP, Michalek SM. Quantitative assessment of inflammatory cytokine gene expression in chronic adult perio- dontitis. Oral Microbiol Immunol 1997;12(6): 336–44.
3. Haffajee AD, Socransky SS. Microbial etiological agents of destructive periodontal diseases. Peri- odontology 2000 1994;5:78–111.
4. Tanner AC, Kent R, Maiden MFJ, Taubman MA. Clinical, microbiological and immunological profile of health, gingivitis and putative active periodontal subjects. J Periodontal Res 1996;31: 195–204.
5. Zambon JJ. Periodontal diseases: microbial factors. Ann Periodontol 1996;1:879–925.
6. Kornman KS, di Giovine FS. Genetic variations in cytokine expression: a risk factor for severity of adult periodontitis. Ann Periodontol 1998;3(1): 327–38.
7. Hart TC, Kornman KS. Genetic factors in the pathogenesis of periodontitis. Periodontology 2000 1997;14:202–15.
8. Offenbacher S. Periodontal diseases: pathogenesis. Ann Periodontol 1996;1:821–78.
9. Hassell TM, Harris EL. Genetic influences in caries and periodontal diseases. Crit Rev Oral Biol Med 1995;6(4):319–42.
10. Hart TC. Genetic risk factors for early-onset peri- odontitis. J Periodontol 1996;67:355–66.
11. Alaluusua S, Asikainen S, Lai C. Intrafamilial transmission of Actinobacillus actinomycetem- comitans. J Periodontol 1991;62:207–10.
12. Michalowicz BS, Aeppli D, Virag JG, et al. Peri- odontal findings in adult twins. J Periodontol 1991;62(5):293–9.
13. Michalowicz BS, Aeppli DP, Kuba RK, et al. A twin study of genetic variation in proportional radiographic alveolar bone height. J Dent Res 1991;70(11):1431–5.
14. Corey LA, Nance WE, Hofstede P, Schenkein HA. Self-reported periodontal disease in a Virginia twin population. J Periodontol 1993;64:1205–8.
15. King RA, Rotter JI, Motulsky AG. The approach to genetic bases of common diseases. In: King RA, Rotter JI, Motulsky AG, editors. The genetic basis of common diseases. New York: Oxford University Press Inc.; 1992.
16. National Institutes of Health. Genetic architecture of complex phenotypes. Released on the Inter- net, June 8, 1998.
17. Newman M. Genetic, environmental, and behav- ioral influences on periodontal infections. Com- pend Contin Educ Dent 1998;19(1):25–31.
18. Dean M, Carrington M, Winkler C, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 struc- tural gene. Hemophilia Growth and Develop- ment Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 1996;273(5283):1856–62.
19. Huang Y, Paxton WA, Wolinsky SM, et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med 1996;2(11): 1240–3.
20. Wilson ME, Bronson PM, Hamilton RG. Immunoglobulin G2 antibodies promote neu- trophil killing of Actinobacillus actinomycetemco- mitans. Infect Immun 1995;63(3):1070–5.
21. Kobayashi T, Westerdaal NA, Miyazak A, et al. Relevance of immunoglobulin G Fc receptor polymorphism to recurrence of adult periodon- titis in Japanese patients. Infect Immun 1997; 65(9):3556–60.
22. Löe H, Anerud A, Boysen H, Morrison E. Natural history of periodontal disease in man. Rapid, moderate and no loss of attachment in Sri Lankan laborers 14 to 46 years of age. J Clin Periodontol 1986;13(5):431–45.
23. Michalowicz BS. Genetic and heritable risk factors in periodontal disease. J Periodontol 1994;65(5 Suppl):479–88.
62 Periodontal Medicine
24. Socransky SS, Haffajee AD, Cugini MA, et al. Microbial complexes in subgingival plaque. J Periodontol 1998;25:346–53.
25. di Giovine FS, Duff GW. Interleukin-1—the first interleukin. Immunol Today 1990;1:13–20.
26. Beutler B, Cerami A. The biology of cachectin/ TNF-a primary mediator of the host response. Ann Rev Immunol 1989;7:625–55.
27. Probert L, Plows D, Kontogeorgos G, Kollias G. The type-i interleukin-1 receptor acts in series with tumor-necrosis-factor (TNF) to induce arthritis in TNF-transgenic mice. Eur J Immunol 1995;25:1794–7.
28. Jacob CO. Tumor-necrosis-factor-alpha in autoim- munity—pretty girl or old witch. Immunol Today 1992;13:122–5.
29. Vassalli P. The pathophysiology of tumor necrosis factors. Ann Rev Immunol 1992;10:411–52.
30. Lee HJ, Kang IK, Chung CP, Choi SM. The sub- gingival microflora and gingival crevicular fluid cytokines in refractory periodontitis. J Clin Periodontol 1995;22:885–90.
31. Liu C-M, Hou L-T, Wong M-Y, Rossomando EF. Relationships between clinical parameters, interleukin-1B and histopathologic findings of gingival tissue in periodontitis patients. Cytokine 1996;8:161–7.
32. Preiss DS, Meyle J. Interleukin-1 beta concentra- tion of gingival crevicular fluid. J Periodontol 1994;65:423–8.
33. Stashenko P, Fujiyoshi P, Obernesser MS, et al. Levels of interleukin-1b in tissue from sites of active periodontal disease. J Clin Periodontol 1991;18:548–54.
34. Yavuzyilmaz E, Yamalik N, Bulut S, et al. The gin- gival crevicular fluid interleukin-1 beta and tumour necrosis factor-alpha levels in patients with rapidly progressive periodontitis. Aust Dent J 1995;40:46–9.
35. Cavanaugh PF Jr., Meredith MP, Buchanon W, et al. Coordinate production of PGE2 and IL-1b in the gingival fluid of adults with periodontitis: its rela- tionship to alveolar bone loss and disruption by twice daily treatment with ketorolac trometham- ine oral rinse. J Periodontal Res 1998;33(2): 75–82.
36. Pociot F, Molvig J, Wogensen L, et al. A Taq1 poly- morphism in the human interleukin-1 beta (IL- 1b) gene correlates with secretion in vitro. Eur J Clin Invest 1992;22:396–402.
37. Cox A, Duff GW. Cytokines as genetic modifying factors in immune and inflammatory diseases. J Pediatr Endocrinol Metab 1996;9:129–32.
38. Newman MG, Korman KS, Holtzman S. Associa- tion of clinical risk factors with treatment out- comes. J Periodontol 1994;65:489–97.
39. di Giovine FS, Cork MJ, Crane A, et al. Novel genetic association of an IL-1b gene variation a +3953 with IL-1b protein production and pso- riasis [abstract]. Cytokine 1995;7:606.
40. Engebretsson SP, Lamster IB, Herrera-Abreu M, et al. The influence of interleukin-1b gene poly- morphism on expression of IL-1b, and tumor necrosis factor alpha in periodontal tissue and gingival crevicular fluid. J Periodontol 1999;70: 567–73
41. Jotwani R, Avila R, Kim BO, Cutler CW. The effects of an antiseptic mouthrinse on subclinical gingivitis in IL-1 genotype-positive and -negative humans [abstract]. J Dent Res 1998; 77(B):921.
42. McDevitt M, Wang H-Y, Knobelman C, et al. IL- 1 genetic association with periodontitis in clini- cal practice. J Periodontol 1999. [In Press]
43. McGuire MK, Nunn ME. Prognosis versus actual outcome. IV. The effectiveness of clinical para- meters and PST genotype in accurately predict- ing prognosis and tooth survival. J Periodontol 1999;70:49–56.
44. Gore EA, Sanders JJ, Pandey JP, et al. Interleukin- 1B +3953 allele 2. Association with disease sta- tus in adult periodontitis. J Clin Periodontol 1998;25:781–5.
45. Caffesse RG, R de La Rosa M, G de La Rosa M. PST genotypes in a periodontally healthy popula- tion treated for mucogingival surgery [abstract]. J Dent Res 1998;77(B):872..
46. Wu Y, Wang H-Y, di Giovine FS, Armitage GC. Low prevalence of IL-1A and IL-1B polymor- phisms in a Chinese population [abstract]. J Dent Res 1998;77(B):738.
47. McGuire MK, Nunn ME. Prognosis versus actual outcome. II. The effectiveness of clinical para- meters in developing an accurate prognosis. J Periodontol 1996;67(7):658–65.
48. McGuire MK, Nunn ME. Prognosis versus actual outcome. III. The effectiveness of clinical para- meters in accurately predicting tooth survival. J Periodontol 1996;67(7):666–74.
49. Newman MG. Genetic risk for severe periodontal disease. Compend Contin Educ Dent 1997; 18(9):881–4.
50. Genco RJ. Assessment of risk of periodontal dis- ease. Compend Contin Educ Dent 1994;18 (Suppl):S678–83.
51. Page RC, Beck JD. Risk assessment for periodontal diseases. Int Dent J 1997;47:61–87.
CHAPTER 5
CARDIOVASCULAR DISEASES AND ORAL INFECTIONS Robert J. Genco, DDS, PhD, Steven Offenbacher, DDS, James Beck, PhD, Terry Rees, DDS, MSD
The relationship between oral infections and car- diovascular disease is well known, particularly with respect to orally derived bacteremias as a source of organisms that infect damaged heart valves causing bacterial endocarditis. Recently, evidence has emerged relating periodontal infections to coro- nary artery disease and stroke.
This chapter will discuss how oral infections are related to bacterial endocarditis, coronary artery disease, and stroke. Etiologic associations, case-control studies, mechanisms, and interven- tion studies, where appropriate, as well as manage- ment of periodontal patients at risk for infective endocarditis and arteriosclerosis will be presented. The main goal of this chapter, therefore, is to pro- vide a basis of knowledge relating oral infections, especially periodontal disease, to cardiovascular diseases, with clinical management guidelines out- lined, where appropriate.
THE PERIODONTAL PATIENT AT RISK FOR INFECTIVE ENDOCARDITIS
Cardiovascular diseases affect over 43 million indi- viduals in the United States, with a marked increase among the geriatric population.1–3 Since this population group is increasing in number and since more elderly individuals are dentate than in the past, there is also an increased incidence of periodontal disease in this patient group. This, coupled with recent evidence linking severe, gener- alized periodontitis with coronary artery disease, suggests that the periodontist must be prepared to provide safe yet effective therapy to patients with various types of heart conditions.4,5 Patient man-
agement requires a thorough medical history and physical examination, evaluation of vital signs, and medical consultation, when indicated.6–12 In most instances, guidelines for periodontal management of patients with cardiovascular diseases are well established. One area, however, remains strongly controversial, with many experts voicing markedly different opinions; that is dental management of individuals with valvar heart disease.13–17
Infective endocarditis (IE) is a microbial infec- tion of a native or prosthetic cardiac valve or sur- rounding cardiac tissue. It may be caused by a vari- ety of microorganisms, including bacteria, fungi, rickettsiae, or chlamydia. The clinical course of IE may be classified as acute (duration of less than 6 weeks) or subacute (duration of more than 6 weeks). The two most common microorganisms associated with community-acquired IE are Strep- tococcus viridans and Staphylococcus aureus, either of which may, on occasion, be normal commensals in the oral cavity.18 The biologic load of these organ- isms may be markedly increased in the presence of oral infection such as chronic periodontitis.14,19,20
Other causative microorganisms for IE include enterococci, which are occasionally found in the oral cavity, or gram-negative HACEK micro- organisms (Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella, and Kingella), some of which, especially A. actinomycetemcomitans and Eikenella corrodens, are putative periodontal pathogens. Other perio- dontal pathogens which have been occasionally associated with IE include Capnocytophaga and Lactobacillus species. Nosocomial IE is most com- monly caused by antibiotic-resistant S. aureus infection.15,21–23
64 Periodontal Medicine
The increased use of heroin or other intra- venously injected illicit drugs has further expanded the spectrum of causative organisms to include Can- dida albicans and other common skin-related microorganisms such as S. aureus.22–24 Additionally, an increasing number of patients receive intravenous shunts or fistulas during hospitalization or have them permanently placed; either of these may serve as a source for systemic sepsis caused by a variety of microorganisms. For example, sepsis may be a spe- cial problem for individuals receiving renal hemodialysis or for those with diabetes mellitus that use indwelling devices for administration of insulin. A growing number of patients suffer from acquired immunodeficiency syndrome or other immunosup- pressant disorders, and many individuals are pre- scribed drugs that induce immunosuppression.25
Most IE occurs in individuals with no known valvar lesions although the majority of patients in this group usually have predisposing factors such as coronary artery disease, alcoholism, intravenous drug abuse, or long-term hemodialysis.25
Individuals with cardiac valve prostheses are especially susceptible to IE although those with native valvar damage and even those with undam- aged heart valves may develop endocarditis. Infec- tive endocarditis may occur spontaneously or as a result of focal sites of infection. Blood-borne path- ogenic microorganisms may lodge directly on heart valves or on the endocardium near anatomic car- diac defects.
The incidence of IE has remained constant for several years although the epidemiology has changed. In the past, the most common cause of IE in young individuals was rheumatic fever (RF). In contrast, RF and IE are now more common among older individuals, especially those over 60 years of age with chronic heart disease or mitral valve prolapse due to calcifications of one or more of the valves or associated tissues.22,23,25,26
Acute IE may result from bacteremias associat- ed with virulent strains of microorganisms. Signs and symptoms may include abrupt onset of fever, cutaneous and oral petechiae, and focal dermal gangrene. These features may be accompanied by intravascular coagulation, which markedly increas- es the risk for emboli and metastatic infection of any body organ.23
Subacute IE may begin insidiously and persist for months. Affected individuals complain of fever, night sweats, myalgias, arthralgias, malaise, anorex- ia, and easy fatigability.1 In the past, clubbing of the last digits of the fingers or the presence of Osler’s nodes on the hands were frequent signs of the pres-
ence of the disease. Today, however, earlier diagno- sis has resulted in diminished occurrence of these signs. Patients with subacute IE are also at risk for emboli and abnormalities in the function of many organs, including the spleen and kidney. Cerebral emboli may induce stroke or seizures, altered levels of consciousness, or other neurologic manifesta- tions. Cardiac changes are consistent with underly- ing valvar or congenital heart defects and may lead to congestive heart failure.22,23
Diagnosis of endocarditis is based on the pres- ence of classic symptoms: a persistent bacteremia or fungemia and the presence of a heart murmur associated with valvar dysfunction. Transthoracic and transesophageal echocardiography are very accurate in the identification of anatomic heart changes associated with endocarditis. Differential diagnosis may include acute rheumatic fever and altered heart function associated with dysfunction of organs other than the heart.23
Infective endocarditis has a high morbidity and mortality, and therefore prevention is highly desirable. Preventive regimens include measures to reduce the potential for significant bacteremia from the oral cavity, the skin, the upper respirato- ry tract, and the gastrointestinal or urinary tract.14–16,27 The following section will discuss den- tal management of individuals at risk for IE, par- ticularly bacterial endocarditis (BE) related to oral infection and/or therapeutic manipulation of mouth tissues.14–16,23,27
VALVAR HEART DISEASE
Valvar heart disease is a significant cause of cardiac morbidity in individuals of all ages despite a sig- nificant decline in the incidence of rheumatic dis- ease in the developed countries. The patient with valvar disease may be especially susceptible to IE. The most common valvar anomalies include mitral regurgitation, often associated with mitral valve prolapse; aortic stenosis resulting from congenital deformity of the aortic or bicuspid valve; or senile valvar calcification. Aortic regurgitation may be associated with dilatation of the aorta as well as a defective aortic valve. Thus, valvar heart disease may result from diverse pathologic process- es.8,22,28,29 Valvar calcification may be associated with congenitally acquired heart defects, mitral valve regurgitation due to mitral valve prolapse, aortic or bicuspid valve stenosis, or senility. These calcifications of the valvar leaflets or their associat- ed chordae tendineue cordis or papillary muscles
Cardiovascular Diseases and Oral Infections 65
can lead to turbidity and back-flow of blood, plac- ing the patient at risk for heart failure and/or IE. Valvar disease tends to be progressive over time because degenerative changes may be superim- posed on an initial abnormality.22,23
Several conditions are commonly associated with valvar stenosis or regurgitation. Rheumatic fever results from streptococcal sepsis, and it occa- sionally induces an autoimmune phenomenon, in which antibodies against the streptococcal antigen cross-react with valvar tissue. The initial lesion of rheumatic heart disease is edema of valvar tissues. However, progressive fibrosis, calcification, and scarring may subsequently lead to valvar stenosis or incompetence.22 Previous episodes of endocarditis may also predispose the affected individual to fur- ther valvar damage and a recurrence of IE. Despite increased use of antibiotics, RF continues to be the most common cause of mitral valve stenosis world- wide but its importance is diminishing in the developed countries due, in part, to early diagnosis and treatment.22
The incidence of valvar disease has increased in the geriatric population due to RF, valvar calci- fications with regurgitation, mitral valve prolapse, or valvar stenosis.22,30 As discussed earlier, an increasing number of elderly individuals are den- tate yet experience a general reduction in immune response.22,23,25,26
Heart transplantation or ischemic heart disease may induce degenerative calcification, rupture, or scarring of perivalvar tissue, any one of which may be associated with valvar regurgitation and an increased risk for IE.31 Degenerative calcification is a common cause of aortic stenosis in the elderly or in individuals with chronic renal dysfunction while calcification of the mitral annulus in the elderly (especially women) can also induce mitral regurgita- tion or stenosis.22,31–34 Other causes of valvar steno- sis include radiation therapy, the use of serotonin agonists such as methysergide, or previous use of fenfluramine and phentermine in combination.22
Kawasaki disease is an acute febrile disease com- plex of unknown etiology. It features conjunctival congestion, dryness of lips, skin, and the oral cavity, cervical lymphadenopathy, and cardiovascular changes, including coronary thromboarteritis, mitral valve insufficiency, and myocardial ischemia.35,36
Congenital heart anomalies may induce car- diac blood turbulence and permanent valvar dam- age even after surgical repair. Therefore, patients with certain congenital defects should be consid- ered at lifetime risk for IE although the risk may be low (Tables 5–1 and 5–2).14, 22
Mitral valve prolapse (floppy valve syndrome) is characterized by idiopathic loss of the fibrous and elastic tissue of the mitral valve leaflets or the chordae tendineae cordis. It is found in several heritable con- nective tissue disorders, especially Down syndrome, Ehlers-Danlos syndrome, and Marfan syndrome.35 It is also common in the general population, especially in young women, the elderly (especially men), and those affected by psychiatric conditions such as panic disorder, severe depression, or anorexia ner- vosa.22,25,37–40 Therefore, any such history suggests a possible need for medical consultation and requires a
TABLE 5–1. Cardiac Conditions Requiring Prophylaxis for Dental Treatment
High Risk • Prosthetic cardiac valves, including bioprosthetic
and homograft valves • Previous infective endocarditis • Complex congenital cardiac malformations • Systemic pulmonary shunts (surgically constructed)
Moderate Risk • Rheumatic heart disease, Kawasaki disease, connec-
tive tissue disorders and, other conditions associated with valvar dysfunction, even after valvar surgery
• Hypertrophic cardiomyopathy – Mitral valve prolapse with valvar regurgitation – Most other congenital cardiac malformations,
except as listed below in Table 5–2
Modified from Dajani AS, Taubert KA, Wilson W, et al. Pre- vention of bacterial endocarditis. Recommendations by the American Heart Association. Circulation 1997;96:358–66.
Table 5–2. Cardiac Conditions not Requiring Endocarditis Prophylaxis
• Isolated secundum atrial septal defect • Surgical repair of secundum atrial septal defects,
ventricular septal defects, or patent ductus arteriosus after 6 months and without residua
• Previous coronary artery bypass graft • Mitral valve prolapse without valvar regurgitation • Physiologic, functional, or innocent heart murmurs • Previous rheumatic fever, Kawasaki disease or con-
nective tissue disorders without valvar dysfunction • Cardiac pacemakers and implanted defibrillators
Modified from Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. Circulation 1997;96:358–66.
66 Periodontal Medicine
thorough understanding of the patient’s condition and its possible ramifications.32,33
Systemic lupus erythematosus (SLE) may place affected individuals at risk for valvar disease and subsequent IE. Lupus erythematosus may affect virtually any body organ. Recent evidence suggests that the cardiovascular system is frequent- ly involved. Mitral valve insufficiency may occur because SLE occasionally induces nonbacterial vegetations or thickening of the valves, sometimes leading to regurgitation; however, IE is relatively rare. Liebman Sacks verrucae associated with SLE may induce mitral valve prolapse if the valve leaflets or the chordae tendineae cordis are affect- ed. The antiphospholipid syndrome occasionally associated with SLE or other collagen-vascular dis- orders may lead to myxomatous mitral valve tissue changes and prolapse, with regurgitation in approximately one-third of patients with myxoma- tous disease.23 Patients with SLE often receive immunosuppressant drugs on a long-term basis which may increase susceptibility to IE.11,22,29
Echocardiographic examination will usually detect the presence of SLE-induced heart lesions.22,23 Medical consultation is indicated in patients with SLE to determine any need for pro- phylactic antibiotic coverage during periodontal therapy. Patients with SLE that have not been medically evaluated for cardiac changes should receive only emergency dental therapy with pro- phylactic antibiotic coverage until medical clear- ance is obtained.11,29
Mitral regurgitation may be managed by sur- gical correction or by prosthetic replacement of the involved valves. Whenever possible, repair of native valves is the treatment of choice. It is most likely to be successful in the presence of myxoma-
tous disease and least successful in rheumatic heart disease or endocarditis.22,23
Native valves may be surgically treated with commissurotomy or percutaneous balloon valvulo- plasty. These therapies are often only palliative, and mitral valve prosthetic replacement may ultimately be necessary, especially if the valves are heavily scarred or calcified to such a degree that severe valve regurgitation is present. Prosthetic replacement, however, has a higher mortality and morbidity.22
Valvar prostheses may be either mechanical or biologic, with each type presenting certain advan- tages and disadvantages. Currently, more than 40 types of mechanical valve prostheses are available (Figure 5–1). They are often indicated for young or middle-aged individuals because they are generally quite durable. The greatest structural risk is fracture of the strut that holds the ball or disk in place. This, however, rarely occurs. The disadvantage of the mechanical prosthesis is that it predisposes the recip- ient patient to thromboembolism, necessitating the long-term use of anticoagulant medications.22
Bioprosthetic valves may be xenographic (usu- ally porcine) or allographic (Figure 5–2). On occa- sion, an autographic valve is transplanted from one site to another following placement of a prosthesis in the donor site. Bioprostheses are more likely to deteriorate over time but durability increases in patients over age 60 years and continues to improve with the increasing age of the recipient. Xenographs offer the advantage of a lower risk for thromboembolism, and long-term anticoagulant therapy is usually not necessary.22
Failure of mechanical valves is rare but can have catastrophic effects (Figure 5–3). In contrast, failure of bioprosthetic valves is an expected conse- quence, and young recipients of these devices
Figure 5–1. Diagram of a mechanical valvar prosthesis.
Cardiovascular Diseases and Oral Infections 67
should anticipate future prophylactic replacement. Fortunately, the degenerative process is slow and may take many years to manifest significant hemo- dynamic symptoms.22
DENTAL CONSIDERATIONS
The patient with valvar heart disease faces the risk of congestive heart failure, hemodynamically sig- nificant arrhythmias, and IE. Although dentists may provide dental care for patients with any of these disorders, most often they are called upon to manage patients at risk of IE.35 Dental procedures that involve manipulation of soft tissue and result in bleeding can produce transient bacteremias. For example, 43% of patients with periodontitis expe- rienced transient bacteremia following routine periodontal probing.41 Administration of local intraligamental analgesia may be more likely to induce odontogenic bacteremia than tooth extrac- tion.42 However, available evidence clearly indi- cates that transient odontogenic bacteremias may be associated with routine body functions such as chewing food and brushing teeth and many authorities have challenged the benefits of prophy- lactic antibiotic coverage for dental treatment pro- cedures.14–17,25 Not all bacteremias are significant in that they may be extremely transient (2 to 3 minutes) and may not involve microorganisms likely to lodge in damaged heart tissue.43 The inci- dence and severity of odontogenic bacteremias increase markedly in the presence of periodontitis
or focal oral infections, with or without manipula- tion of oral tissues.14,15,25,34,44 It is generally not possible to predict which patient will develop IE or which particular procedure will be responsible.14,45
Recently, Lamas demonstrated an absence of bac- teremias among patients receiving oral mucosal biopsies except when periodontal tissues were included in the specimen.43
Transient bacteremias may be induced by some surgical or nonsurgical periodontal treatment procedures. However, these bacteremias rarely per- sist longer than 15 minutes and the majority dissi- pate within 3 to 5 minutes.14,15,43 The risk of IE derived from transient bacteremias associated with manipulation of dental tissues must be weighed against the cost and risk of complications associat- ed with administration of systemic antibiotics. Use
Figure 5–3. Failed mechanical valve prosthesis.
Figure 5–2. Porcine bioprosthesis: A, Closed. B, Open
A B
68 Periodontal Medicine
of prophylactic antibiotics may well induce a higher morbidity and mortality rate than do transient bacteremias, and several authorities have recom- mended more conservative use of antibiotic pro- phylaxis during dental treatment.7,14,15,17,43
In 1997, the American Heart Association (AHA) updated its recommendations for dental management of patients at risk for IE induced by odontogenic bacteremias.14 These guidelines are applicable for prevention of endocarditis induced by oral S. viridans (alpha hemolytic Streptococcus). Dental procedures likely to induce significant bac- teremia are listed in Table 5–3, and procedures at low risk of bacteremias are identified in Table 5–4.
There is some evidence that oral irrigation or use of air-abrasive polishing devices may induce bacteremia when used inappropriately or in patients with poor periodontal health, and these devices are not recommended.14,46–49 Rinsing with antimicrobial agents containing chlorhexidine glu- conate or povidone iodine prior to manipulation of dental tissues may reduce the overall bacterial bioload. This may be especially important in high- risk patients and in those with poor oral hygiene. There is, however, no conclusive evidence to con- firm that prerinsing reduces the risk of oral bac- teremias or IE.50–53 Frequent home use of antisep- tic rinses is not recommended due to the potential for developing resistant microorganisms.14
Certain cardiac conditions are more often associated with endocarditis than are others (see Tables 5–1 and 5–2). In patients at risk, antibiot- ic prophylaxis is recommended for all dental pro- cedures likely to induce significant bleeding of hard or soft oral tissues to include surgical or non- surgical periodontal therapy. If a series of dental
procedures is required, it may be prudent to observe an interval of 9 to14 days between proce- dures to minimize the risk of the emergence of resistant strains of organisms.14,54–57 In the event unanticipated bleeding occurs during low-risk dental procedures, the administration of antibi- otics within 2 hours may be effective in prevent- ing IE. There is no prophylactic benefit, however, if antibiotics are administered more than 4 hours after the incident.14
The AHA recommendations for specific pro- phylactic antibiotic regimens for dental procedures are widely published and will not be repeated in this text. For most adults, oral administration of 2 g of amoxicillin 1 hour before the dental procedure is recommended. Clindamycin (600 mg 1 hour before the dental procedure), cephalexin/cefadroxil or azithromycin/clarithromycin are recommended as alternatives in patients that are allergic to penicillin. Intramuscular or intravascular antibiotic regimens are prescribed for patients that cannot take oral medications. The recommendations are considered adequate for patients that are at high risk from IE, including those with cardiac valve prostheses.14
Individuals that take penicillin for secondary prevention of rheumatic fever or for other purpos- es may harbor oral microorganisms that are rela- tively resistant to penicillin, amoxicillin, or ampi- cillin. In such cases, the dentist should select clin- damycin or another of the alternative regimens for endocarditis prophylaxis. Cephalosporins should not be used due to the potential for microbial cross-resistance between cephalosporin and peni- cillin derivatives.
TABLE 5–3. Dental Procedures Creating Bacteremia Risk
• Dental extractions • Implant placement and tooth reimplantation • Surgical and nonsurgical periodontal procedures • Endodontic instrumentation beyond the root apex
or endodontic surgery • Initial placement of orthodontic bands • Intraligamentary injection • Prophylaxis when bleeding is expected • Subgingival placement of antibiotic fibers or strips
Modified from Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. Circulation 1997;96:358–66.
TABLE 5–4. Dental Procedures with Low Bacteremia Risk
• Restorative procedures with or without retraction cord
• Local anesthetic injections • Placement of rubber dams • Suture removal • Placement or adjustment of orthodontic or removable
prosthodontic appliances • Oral impressions • Fluoride treatments • Oral radiographs • Shedding of primary teeth
Modified from Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. Circulation 1997;96:358–66.
Cardiovascular Diseases and Oral Infections 69
Professional judgment may have to be used for patients that do not fit established guidelines set forth by the AHA. Tetracyclines are not recom- mended for prophylactic cardiovascular antibiotic coverage.14 It has been suggested, however, that patients with periodontal diseases associated with tetracycline-sensitive organisms may be best treated by administration of tetracyclines for 2 to 3 weeks prior to periodontal treatment followed by a 1-week delay and then performance of periodontal therapy using AHA-recommended prophylactic regimens.58
When possible, multiple dental procedures should be performed on the day of prophylactic antibiotic coverage and further treatment delayed for 9 to 14 days before the same antibiotic is used. Medical con- sultation should be obtained as indicated for patients that require multiple, prolonged, or unusual regimens of prophylactic antibiotic cover- age. The relationship between IE and periodontal treatment procedures incorporating local delivery of antibiotics or antimicrobials into gingival pock- ets is not known at present although the AHA rec- ommends systemic prophylaxis when antibiotic fibers or strips are inserted, presumably because of the potential for traumatic injury and bleeding during these procedures.14 Antibiotic prophylaxis minimizes the risk of infective endocarditis but does not preclude its occurrence, and the clinician must remain alert for persistent fever or other symptoms associated with the condition.14,59–61
PROSTHETIC VALVE ENDOCARDITIS
Individuals with prosthetic heart valves have high morbidity and mortality in the event IE occurs. Therefore, these individuals may require especially diligent dental care before and after open heart surgery. Potential oral foci of infection should be eliminated before the surgery.11,16,27 Questionable teeth should not be retained, and the patient’s motivation and ability to maintain effective oral hygiene procedures should be assessed (Figure 5–4). Prior to cardiac surgery, dental procedures associated with a high risk of significant bac- teremia should be accompanied by appropriate prophylactic antibiotic support. When possible, dental extractions should be accomplished at least 2 weeks prior to the heart surgery to allow ade- quate wound healing (Figure 5–5).
Following placement of a prosthetic heart valve, close medical-dental cooperation is essential. Peri- odontal therapy is usually not appropriate within 6 months of valve placement, and periodontal health
must be sustained, if possible, for the patient’s life- time (Figures 5–6 and 5–7). For obvious reasons, antibiotic prophylaxis is indicated for all high-risk dental treatment procedures. Some periodontal treatment procedures may be contraindicated. For example, surgical procedures that create an open wound surface (gingivectomy, free gingival grafts) should probably be avoided due to the prolonged wound healing time. These procedures also may be contraindicated in patients receiving concomitant
Figure 5–4. A 47-year-old Caucasian female with a history of rheumatic heart disease. The patient is scheduled for valve replacement open heart surgery in 1 month. A, Facial view. B, Mandibular anterior lingual view. C, Panoramic radiograph.
A
B
C
70 Periodontal Medicine
anticoagulant therapy to minimize the potential for postoperative hemorrhage.27
ANTICOAGULATED PATIENTS
Patients with prosthetic valves, thromboembolic phenomena, or other blood flow disturbances often receive anticoagulant medication immediately fol- lowing heart surgery or for their lifetime. Coumarin is usually used for outpatient anticoagu- lation. It exerts its effect through the competitive inhibition of vitamin K, with subsequent depletion of coagulation factors dependent on that substance for their synthesis (II, VII, IX, and X). Coumarin has a delayed onset and a prolonged effect. Its effec- tiveness is monitored via the corrected prothrom- bin time known as the international normalized ratio (INR). In the past, prothrombin times (PT) varied between laboratories, potentially leading to
misleading information regarding the patient’s state of coagulability. To standardize PT measurements, the World Health Organization developed an inter- national reference thromboplastin, using human brain thromboplastin as the universal standard for comparison purposes. Each laboratory performing prothrombin tests must now compare their pro- thrombin against the standard. This results in a cor- rected normal prothrombin time for all medical laboratories.15,34,36 Under most circumstances, the INR for patients with a normal PT is approximate- ly 1.0. Patients requiring anticoagulant therapy are usually maintained at an INR ranging from 1.2 to 4.5. So far as is known today, patients within this range can receive all types of periodontal therapy, provided local hemostatic measures are taken. These include atraumatic surgery, adequate wound closure using sutures, application of postsurgical pressure, and the use of topical clotting agents such as thrombin, foamed gelatin, oxidized regenerated cellulose, or synthetic collagen. Oral rinses contain- ing tranexamic acid have markedly reduced the risk of excessive hemorrhage without alteration of the INR level.15,34,62 Tetracyclines are contraindicated in patients on anticoagulant drugs since they inter- fere with prothrombin formation.54
When contemplating procedures likely to cause bleeding, it is appropriate to communicate with the patient’s physician.63 On occasion, pharmacologic manipulation becomes necessary for the anticoagu- lated patient. If the patient can tolerate a wait of sev- eral hours or more, vitamin K administration will reverse the effect of coumarin. More urgent situa- tions may require blood transfusion or infusion of fresh-frozen plasma or packed platelets.1,15,23
Aspirin is often used as an antithrombotic agent because of its inhibition of platelet aggregation.
Figure 5–5. Same patient as Figure 5–4 one day before heart surgery. A, Maxillary anterior palatal view. Dental and peri- odontal infections have been eliminated. B, Mandibular anterior lingual view.
A B
Figure 5–6. Same patient as Figure 5–4 6 months after successful placement of valvar prosthesis. A, Anterior view. B, Maxillary anterior palatal view.
Cardiovascular Diseases and Oral Infections 71
Most cardiologists prescribe very small daily dosages (80 to 325 mg). At these dose levels, the medication will not significantly alter bleeding time.15,62 On occasion, however, patients on higher aspirin levels are at a slight risk for prolonged postoperative hem- orrhage following periodontal therapy. For these individuals, the medication should be discontinued for 4 to 7 days prior to the scheduled procedure with the concurrence of the cardiologist.4,34
Summary
The patient with valvar heart disease is frequently encountered in dental practice. Safe and effective management of such patients requires close med- ical and dental cooperation. Periodontal health and absence of oral foci of infection are essential, and on some occasions, prophylactic antiobiotic coverage is required for dental treatment proce- dures. The dental practitioner must remain knowl- edgeable regarding current concepts in the man- agement of such patients.
ORAL INFECTIONS AS A RISK FACTOR FOR ATHEROSCLEROSIS, CORONARY ARTERY DISEASE,AND ISCHEMIC STROKE
The role of infections in atherosclerosis has been discussed for many years. Recently, evidence has accumulated that certain common oral infections play a significant in role in atherosclerosis. Athero- sclerosis lesions can occur in large- and medium- sized elastic and muscular arteries. They can lead to ischemic lesions of the brain, heart, or extremities and can result in thrombosis and infarction of affected vessels, leading to death. Cardiovascular disease, mostly associated with atherosclerosis,
remains one of the primary causes of death in the United States, Europe, and much of Asia.64,65
The process, supported by a considerable body of evidence, is that atherosclerosis is an inflamma- tory disease.66 This concept, also termed the Ross response-to-injury hypothesis of atherosclerosis, proposes that the initial lesion results from injury to the endothelium and leads to a chronic inflam- matory process in the artery. This results in the migration of monocytes through the endothelium into the underlying tissue and the proliferation of smooth muscle cells. Activation of the monocytes (macrophages) in the blood vessel leads to the release of hydrolytic enzymes, cytokines, chemokines, and growth factors, which induces fur- ther damage, leading to focal necrosis. Accumula- tion of lipids is a key feature of this process, and in later stages, the atheromatous plaque can be covered with a fibrous cap over the focal necrotic area. At some point, the fibrous cap may become eroded and rupture, which leads to thrombus formation and occlusion of the artery, resulting in an infarction.
The initial event in the development of an atheroma appears to be endothelial injury that results in the activation of the endothelial cells. This results in the upregulation of surface adhesin mole- cules and chemokines, both of which result in monocyte recruitment from the bloodstream (Fig- ure 5–8). The monocytes then pass through the endothelium into the blood vessel and become macrophages. The macrophages in the atheroma are activated and produce growth factors, which induce smooth muscle proliferation as well as production of cytokines and other mediators that further activate the endothelium. Macrophages also accumulate lipids, especially low-density lipoproteins (LDL) in the oxidized or modified form. Modified LDL can be a major cause of injury of both the endothelium and the underlying smooth muscle. When the LDL
Figure 5–7. The patient from Figure 5–4 has maintained oral health for 7 years after heart surgery.
A B
72 Periodontal Medicine
particles are trapped in the artery, they can undergo progressive oxidation and be internalized by macrophages, with formation of lipid peroxidases and accumulation of cholesterol esters. This results in the production of foam cells. Modified LDL is chemotactic for other monocytes and can induce the production of factors from macrophages that expand the inflammatory response.
Antioxidants can increase the resistance of LDL to oxidation, and this may explain why antioxidants, such as vitamin E, can reduce the size of fatty streaks and atherosclerotic lesions and pos-
sibly protect against atheroma formation. Dia- betes, through hyperglycemia and glycation of LDL and other proteins, as well as the dyslipi- demia associated with diabetes, cigarette smoking, through toxic factors in smoke, and hypertension and hyperhomocystinemia are also factors that can lead to endothelial injury and the subsequent cas- cade of events leading to atherosclerotic lesions.
Other stages in the formation of atherosclerot- ic plaque are depicted in Figure 5–9. A fatty streak can become a fibrous plaque, which becomes com- plex with a lipid core, calcification, and deposition of extracellular matrix protein. Activated T cells may stimulate metalloproteinase production by macrophages, which remodel the fibrotic plaque. Eventually, a uniformly dense fibrous cap can cover the atheroma resulting from deposition and remodeling of the extracellular matrix in the plaque. Through remodeling of the extracellular matrix, the fibrous cap may become thin and rup- ture, leading to activation of the clotting system with thrombosis. It is thought that thrombosis and subsequent occlusion of the artery may be respon- sible for as many as one-half of the cases of acute myocardial infarction.67
Figure 5–10 depicts the intersecting protease cascade that connects the blood clotting system with extracellular matrix deposition and degrada- tion. The extracellular matrix is produced by smooth muscle cells and endothelium and remod- eled through degradation with endopeptidases, the matrix metalloproteinases. From Figure 5–10 it can be seen that plasminogen is converted to plas- min in the presence of tissue plasmin activator (TPA). Plasmin then activates the latent matrix metalloproteinases, which results in matrix degra- dation. Tissue inhibitors of matrix metallopro- teinases (TIMPs) can inhibit matrix degradation whereas alpha-1-antitrypsin can inhibit plasmin- mediated degradation of the extracellular matrix. Plasmin can also result in the production of fibrin from fibrinogen, which then undergoes fibrinoly- sis. It is likely that inflammatory mediators, such as cytokines and proteases produced by macrophages, and other cells in the atheromatous plaque, as well as bacterial proteases, contribute to extracellular matrix remodeling of fibrofatty atheromatous plaques through activation at various stages in the protease cascade depicted in Figure 5–10.
Role of Infections in Endothelial Injury
There is accumulating evidence of an association between some common infections of man and ath-
Macrophage accumulation
Endothelial activation
CytokinesLDL oxidation
Chemokines Adhesion molecule
expression
Monocyte recruitment
Endothelial injury
Growth factors
Smooth muscle proliferation
Endothelial activation
Fibrous plaque Complex plaque with lipid core and calcification
Fatty streak
Thrombosis
Plaque rupture
Figure 5–8. Illustration of mechanisms of atherosclerosis resulting from endothelial injury.
Figure 5–9. Stages in the formation of atherosclerotic plaque.
Cardiovascular Diseases and Oral Infections 73
erosclerosis. One possible mechanism is through endothelial injury by infectious agents, triggering, in part, the inflammatory response seen in athero- sclerosis. The role of infections has been recently reviewed by Danesh and colleagues,68 and there is mounting evidence that infection with Chlamydia pneumoniae, Helicobacter pylori, periodontal bacte- ria, and cytomegalovirus are associated with heart disease (Table 5–5).
Studies Relating Oral Infections to Coronary Artery Disease
Several studies relate oral infections, including periodontal disease, to coronary artery disease. In Table 5–6, case-control and cross-sectional studies of the association between periodontal disease as well as other oral conditions and coronary artery disease are presented. In the study by Mattila and colleagues,69 102 controls were compared with 100 patients that had a myocardial infarction (MI). They measured oral status, using the total dental index (TDI), which is a measure of caries, peri- odontitis, periapical lesions, and pericoronitis, and the pantomographic index, which is a measure of periapical lesions, vertical bony defects, and furca- tion lesions. They found that dental health was worse in MI patients than in controls, after adjust- ment for age, social class, smoking, serum lipids, and diabetes. In a large cross-sectional study of 1,384 men, 45 to 64 years of age, Paunio and col- leagues70 found that a history of missing teeth was related to ischemic heart disease, after adjusting for age, hypertension, geographic area, education, and
smoking. Mattila and colleagues71 studied 100 patients with angiographic measurements of the degree of coronary artery occlusion and previous MI. They used the dental pantomography index, which assessed periapical lesions, vertical bony defects, and furcations lesions in bone, and found that dental infections were associated with coro- nary atheromatosis (p = .003). These results were statistically significant after adjusting for age, serum lipids, body mass index, social class, and hypertension. Arbes and colleagues studied the association between the extent of periodontal attachment loss and self-reported history of heart attack from the National Health and Nutrition Examination Survey (NHANES) III data.72 They found that when the percent of periodontal sites per person with attachment loss of ³ 3 mm were categorized as 0%, > 0 to 33%, > 33 to 67%, and > 67%, the adjusted odds ratio with each higher category of attachment loss as relative to the 0% category was 1.4 (0.8 to 2.5), 2.3 (1.2 to 4.4), and 3.8 (1.5 to 9.7), respectively. Adjustments were made for age, sex, race, socioeconomic status, smoking, diabetes, high blood pressure, body mass
Fibrin
Matrix Degradation
Fibrinolysis
Latent MMPs
Active MMPs
Plasminogen
Plasmin
(–) a1 AT
(–) TIMPs
TPA
Fibrinogen
Figure 5–10. Proteases in the atheromatous plaque. TPA = tissue plasmin activator; MMP = matrix metalloproteinases; TIMPs = tissue inhibitors of matrix metalloproteinases; a1AT = a1 antitrypsin.
TABLE 5–5. Infections and Atherosclerosis Injury
• Chlamydia pneumoniae • Helicobacter pylori • Periodontal bacteria (Porphyromonas gingivalis,
Bacteroides forsythus, and Campylobacter rectus) • Cytomegalovirus
74 Periodontal Medicine
index, and serum cholesterol. This study supports findings from previous cross-sectional studies of an association between periodontal disease and coro- nary artery disease (CAD). These cross-sectional and case-control studies support the hypothesis that oral infections, including periodontal disease, are associated with CAD.
Perhaps more convincing evidence for the asso- ciation of periodontal disease and CAD comes from a series of longitudinal and prospective studies, which are tabulated in Table 5–7. One of the first longitudinal studies to address the association between periodontal disease and coronary artery dis- ease was published by DeStefano and colleagues in 1993.73 They looked at 9,760 individuals in the NHANES I, who were evaluated between 1971 and 1974. These individuals were assessed at baseline for periodontal disease using the Russell periodontal index, and for decayed and missing teeth, and these individuals were followed up for 14 years for devel- opment of CAD. Subjects with periodontitis at baseline had a 25% increased risk of having CAD in the follow-up period. In males under 50 years of age, the relative risk was 1.72 after adjusting for age, blood pressure, and diabetes. Unfortunately, base- line data on smoking was available for only about one-quarter of the subjects, hence these data are only partially adjusted for smoking. Therefore, lifestyle issues, such as smoking and oral hygiene,
remain unresolved by this study. Mattila and col- leagues74 conducted a 7-year follow-up study of 214 subjects (182 men, 32 females) that had fatal and nonfatal CAD and measured the TDI as the oral condition. They found that the TDI was a statisti- cally significant predictor of coronary artery disease after adjustment for smoking, diabetes, hyperten- sion, socioeconomic status, previous MI, body mass index, and serum lipids.
In 1996, Beck and colleagues75 published a study of 1,147 males enrolled in a normative aging study. Fatal and nonfatal coronary heart disease and stroke were assessed over 18 years. Baseline radiographic measurements of alveolar crestal heights were made, and the mean alveolar bone loss was dichotomized into high or low. Those individuals with high levels of mean whole mouth alveolar bone loss at baseline had a greater relative risk of total coronary heart disease (1.5; 95% CI 1.04 to 2.14) than those with low bone loss at baseline. These results remained statistically signif- icant, after adjusting for age, body mass index, sys- tolic blood pressure, and cholesterol. High and low alveolar bone loss at baseline was also found to be associated with fatal coronary heart disease, that is, those with high levels of alveolar bone loss had a greater chance of developing fatal heart disease with a relative risk of 1.9 (95% CI 1.10 to 3.43), after adjusting for age, smoking, systolic blood
TABLE 5–6. Summary of Case-Control and Cross-sectional Studies of the Association between Periodontal Disease and Other Oral Conditions and Coronary Artery Disease
Study Design/ Systemic Study Subjects Outcome Oral Condition Findings
Mattila et al, 100 myocardial MI Total dental index Dental health worse in MI patients, 198969 infarction (MI); score and a after adjustments for age, social
102 controls “pantomographic” class, smoking, serum lipids, index of periapical and diabetes lesions, vertical bony defects, and furcation lesions
Paunio et al, 1,384 men, 45 to History of Missing teeth Number of missing teeth 199370 64 years of age angina or statistically associated (p = .0374)
previous MI with ischemic heart disease, along with age, hypertension, geographic area, education, and smoking
Mattila et al, 100 angiography Degree of Dental Dental infections associated with 199371 patients coronary pantomographic coronary atheromatosis (p = .003),
artery index after adjusting for age, serum lipids, occlusion, body mass index, socio economic previous MI status class, and hypertension
Cardiovascular Diseases and Oral Infections 75
pressure, and diabetes. From these studies assessing total coronary heart disease and fatal heart disease, it appears that the analyses were adjusted for many of the important risk factors that are relevant to both periodontal disease and heart disease. It is of considerable interest that Beck and colleagues75
also found that the cumulative incidence of coro- nary heart disease increases with greater levels of age-adjusted alveolar bone at baseline, suggesting a dose response, that is, the more periodontal disease at baseline, the greater is the cumulative incidence of coronary heart disease over time.
TABLE 5–7. Summary of Longitudinal Studies of the Association between Periodontal Disease and Other Oral Conditions and Coronary Artery Disease
Study Design/ Systemic Study Subjects Outcome Oral Condition Findings
DeStefano 9,760 in the Coronary Russell periodontal Subjects with periodontitis had 25% et al, National Health artery index, number increased risk of CAD. In males under 199373 and Nutrition disease of decayed and 50 years of age, the relative risk was
Examination (CAD) missing teeth 1.72. Results were adjusted for age, Survey I blood pressure, diabetes, and partially
adjusted for smoking
Mattila et al, 214 subjects Fatal and Total dental The total dental index was a statistically 199574 (182 males, nonfatal index significant predictor of CAD. Adjust-
32 females) at CAD ments made for smoking, diabetes, 7-year follow-up hypertension, socioeconomic status,
previous MI, body mass index (BMI), and serum lipids
Beck et al, 1,147 males Coronary Radiographic Dichotomized mean whole mouth bone 199675 heart disease interproximal loss hi-lo at baseline associated with
(CHD) alveolar crestal total CHD with relative risk of 1.5 and stroke heights (1.04, 2.14), after adjusting for age,
BMI, systolic blood pressure, and cholesterol. Hi-lo alveolar bone loss at baseline associated with fatal CHD with relative risk of 1.9 (1.10, 3.43), after adjusting for age, smoking, systolic blood pressure, and diabetes. Cumulative incidence of CHD increased with greater levels of age- adjusted alveolar bone loss at baseline
Joshipura 44,119 male health Coronary Self-reported Those who reported periodontal disease et al, professionals artery periodontal and less than 10 teeth at baseline had 199676 followed up over disease disease and a relative risk of CAD of 1.67. Adjust-
6 years self-reported ment was made for smoking, physical number of activity, hypertension, cholesterol, teeth family history of CAD, dietary and
alcohol intake
Genco et al, 1,372 Native Electrocardio- Alveolar bone Baseline periodontal disease showed that 199777 Americans followed graphic level and tooth for those ² 60 years of age, periodontal
up for 10 years; evidence of loss disease was a predictor for subsequent population has a cardiovascular CVD, with a relative risk of 2.68 low level of smoking disease (CVD) (1.30, 5.5) after adjusting for diabetes,
age, gender, cholesterol, BMI, smoking, and hypertension
76 Periodontal Medicine
Joshipura and colleagues76 studied 44,119 male health professionals for a period of 6 years. Seven- hundred and fifty cases of CAD, including fatal and nonfatal MI, were documented. Periodontal status and number of teeth were self-reported. It was found that among those men that reported peri- odontal disease and fewer than 10 teeth at baseline, there was an increased risk of cardiovascular disease as compared with men that had 25 or more teeth at baseline (1.67 relative risk). In those that reported no previous periodontal disease, no relationship to coronary heart disease was found (1.11 relative risk). This study mainly shows an association between tooth loss (in those that reported peri- odontal disease) and coronary heart disease. It is likely that the reported tooth loss was associated with periodontal disease. Self-reported periodontal disease is fraught with inaccuracies and misclassifi- cations; however, the authors point out that when combined with assessment of tooth loss, which may be more accurately self-reported, this study does point to a possible association between heart disease and periodontal disease. The relative risk of 1.67 remained after adjustment for smoking, physical activity, hypertension, cholesterol, family history of CAD, and dietary and alcohol intake.
Genco and colleagues77 reported a longitudi- nal study of 1,372 Native Americans, who were assessed for periodontal disease at baseline, and fol- lowed up for 10 years for electrocardiographic evi- dence of cardiovascular disease, using the Pooling criteria. Periodontal status was measured by alveo- lar bone levels. It was found that baseline peri- odontal disease for those under age 60 years was a predictor of subsequent cardiovascular disease, with a relative risk of 2.68 (95% CI 1.30 to 5.50). These results were significant, after adjusting for diabetes, age, gender, cholesterol, body mass index, smoking, and hypertension. It should be noted that in this population, the level of smoking is very low, and, in fact, smoking per se was not a risk fac- tor for either cardiovascular disease or periodontal disease. Hence, this study was carried out in a pop- ulation which minimized or eliminated smoking as a co–risk factor, which may confound the relation- ship between periodontal disease and heart disease in other studies.
All these data support the association of increased CAD, especially in men under age 60 to 65 years. The relationship, however, is weaker for men over age 60 to 65 years in most of these stud- ies. The reason for the weak association in older individuals is not yet clear but the stronger relation- ship in men under the age of 60 to 65 years remains
confirmed in all the studies reported to date. In con- clusion, there is considerable cross-sectional, case- control, and longitudinal/epidemiologic evidence of an association between periodontal infection and CAD. Other oral infections also may contribute, but the evidence suggests that caries, per se, is not related to CAD. Good evidence is not yet available to determine if there is an association of periapical lesions, pericoronal lesions, or other oral infections with heart disease. Also, little evidence is available for women, Hispanic, Black, or Asian populations with respect to the relationship between periodontal infections and heart disease.
Studies Relating Oral Infections to Stroke
There are several studies which provide suggestive evidence for an association between atherosclerosis- related ischemic stroke and oral infections (Table 5–8). One of the first studies to report this associa- tion was conducted by Syrjänen and colleagues.78
In a case-control study, they compared 40 patients with ischemic cerebral infarction with 40 randomly selected community-based controls that were matched for age and gender. The systemic outcome was ischemic cerebral infarction, and oral condi- tions were assessed by the TDI. These investigators found a statistically significant poorer level of oral health in patients with ischemic cerebral infarction as compared to controls. However, this is a small case-control study that did not control for other co–risk or confounding factors, such as smoking, hypertriglyceridemia, hypertension, and febrile infections, which were also found to be at statisti- cally significantly higher prevalence in the patient group. Therefore, the extent to which these other confounding variables were related to the associa- tion between dental health and ischemic cerebral infarction is not clear. However, this study suggests that infections, per se, are related to ischemic cere- bral infarction, and it is not unreasonable that oral infections would also contribute.
Grau and colleagues79 also presented a case- control study of 66 cases and 66 controls. The patients suffered from acute cerebral ischemia evi- denced by computed tomography (CT) or magnet- ic resonance imaging (MRI), or from transient cere- bral ischemia. These investigators also used the TDI, with orthopantomography as part of the index. They found that poor dental status with a TDI of > 6 was associated with cerebral ischemia (2.51, 95% CI 1.20 to 5.20). Grau and colleagues79
also analyzed the components of the TDI and found that there was no association with the dental
Cardiovascular Diseases and Oral Infections 77
caries component. These results were obtained after adjusting for current smoking, diabetes, socioeco- nomic status, and pre-existing vascular disease.
Beck and colleagues75 provided the first longi- tudinal data relating stroke to oral infections. They followed up 1,147 men over 18 years of age and identified 40 stroke cases, including 29 that also had coronary heart disease. Periodontal status was measured using the mean alveolar bone height, and dichotomized into high and low groups. They found that high mean alveolar bone loss was pre- dictive of subsequent stroke with a relative risk of
2.8 (95% CI 1.45 to 5.48). These results were obtained after adjusting for age, smoking, diabetes, diastolic blood pressure, family history, and educa- tional level.
The largest study relating stroke to periodon- tal disease comes from Wu and colleagues.80 They studied the NHANES I database on 9,962 adults followed up for 18 years. The systemic outcome was cerebrovascular disease, including nonhemor- rhagic and hemorrhagic strokes and transient cere- bral ischemia. Subjects were classified as suffering from periodontitis, gingivitis, or as exhibiting a
TABLE 5–8. Summary of Studies of the Association between Periodontal Disease and Other Oral Conditions and Stroke
Study Design/ Systemic Study Subjects Outcome Oral Condition Findings
Syrjänen Case-control; 40 Ischemic Total dental index (TDI) A statistically significantly poorer et al, patients with cerebral (caries, periodontitis, level of oral health was found 198978 ischemic cerebral infarction periapical lesions, and among patients as compared
infarction, and pericoronitis included) with controls. However, 40 randomly smoking, hypertriglyceridemia, selected community hypertension, and febrile controls matched infections also greater for age and gender in patients than in controls
Grau et al, Case-control; Acute cerebral TDI with Poor dental health (TDI >6) 199779 66 cases, ischemia orthopantomography was associated with cerebral
66 controls evidenced by ischemia with an odds ratio of CT or MRI; 2.51 (1.20, 5.2) after adjusting or transient for current smoking, diabetes, cerebral socioeconomic status, and ischemia pre-existing vascular disease
Beck et al. Longitudinal 40 stroke cases, Mean alveolar bone High alveolar bone loss was 199675 follow-up of including 29 height, hi-lo predictive of subsequent
1,147 men with coronary dichotomous stroke with a relative risk of heart disease 2.8 (1.45, 5.48) after adjusting
for age, smoking, diabetes, diastolic blood pressure, family history, and education
Wu et al, Longitudinal, Cerebrovascular Subjects classified as Periodontitis was associated with 199980 NHANES I; disease, suffering from nonhemorrhagic stroke with a
9,962 adults nonhemorrhagic periodontitis, relative risk of 2.11 (1.30, 3.42). followed up and hemorrhagic gingivitis, no Increased risk for nonhemor- for 18 years stroke, and periodontal disease, rhagic stroke seen in men,
transient cerebral and edentulous women, African Americans ischemia based on Russell and Caucasian Americans. The
index population-attributable risk for nonhemorrhagic stroke was 19% based on baseline periodontal disease.
78 Periodontal Medicine
healthy periodontium on the basis of the Russell periodontal index. They found that periodontitis at baseline was associated with nonhemorrhagic (ischemic) stroke, with a relative risk of 2.1 (95% CI 1.3 to 3.4). Of considerable importance was the finding that in this same population, there was no association of periodontitis with hemorrhagic stroke. Hence the association of periodontal disease with ischemic stroke, which is largely due to atheroscle- rotic lesions, and not with hemorrhagic stroke, which is associated with bleeding vessels, provides further evidence for the role of infections in athero- sclerotic processes. The increased risk for nonhem- orrhagic stroke was seen in men, women, African Americans, and Caucasians. Baseline periodontal disease accounted for 19% of the population-attrib- utable risk for nonhemorrhagic stroke in this study, suggesting that periodontal disease is of significant public health importance in relation to stroke. This study is of interest because there was an internal control, that is, there was no relationship between periodontal disease in the same population and hemorrhagic stroke, which is not associated with atherosclerosis but rather with bleeding.
In general, the relationship of oral infections, especially periodontal disease, to fatal and nonfatal CAD as well as to nonhemorrhagic stroke, much of which is ischemic atherosclerotic stroke, strong- ly points to a relationship between periodontal infection and atherosclerosis and related sequelae such as coronary artery and cerebral artery disease.
MECHANISMS BY WHICH INFECTIONS MAY CONTRIBUTE TO ATHEROSCLEROSIS
Several possible mechanisms may operate indepen- dently or in concert to explain the association between infections in general and periodontal infections specifically and atherosclerosis, myocar- dial infarction, and stroke. For purposes of discus- sion, we will consider four main mechanisms: (1) direct effects of infectious agents in atheroma for- mation; (2) indirect or host-mediated effects trig- gered by infection; (3) common genetic predispo- sition for periodontal disease and atherosclerosis; and (4) common risk factors, such as lifestyle.
Direct Effects of Infectious Agents in Atheroma Formation
There are three lines of evidence suggesting that periodontal bacteria may have direct effects on
atheroma formation. The first comes from studies finding Porphyromonas gingivalis in carotid and coronary atheromas.81,82 The second comes from the findings of Deshpande and colleagues83 showing in vitro that P. gingivalis can invade and may prolif- erate in the endothelial cells. The third line of evi- dence comes from studies by Herzberg and Meyer84
showing that P. gingivalis is able to induce aggrega- tion of platelets, which is thought to be associated with thrombus formation. Other possible mecha- nisms include protease production by P. gingivalis and other periodontal pathogens, which may con- tribute to remodeling of the extracellular matrix in atheromatous plaques. Evidence for any of these mechanisms is, at this point, in vitro or preliminary. However, it is not unreasonable to expect that organisms that infect atheromatous plaques may contribute to their formation or to the thrombotic events associated with myocardial infarction.
Indirect or Host-Mediated Effects Triggered by Infection
One possible mechanism that has garnered con- siderable support is that periodontitis induces an inflammatory response that is manifested, in part, by the production of acute-phase proteins, such as C-reactive protein and fibrinogen, by the liver. C-reactive protein and fibrinogen are indepen- dent risk factors for coronary artery disease, hence if they are induced, in part at least, by peri- odontal infection, this may help explain the link between periodontal disease and heart disease. A recent study by Wu and colleagues85 using the NHANES III database, found that C-reactive protein and plasma fibrinogen were related to poor periodontal health, which provides support for this hypothesis.
Another indirect effect of periodontal infec- tion that may explain the association between peri- odontal disease and heart disease is that periodon- tal organisms contain proteins which cross-react with the heart. In fact, the heat-shock protein-60, which is produced by Bacteroides forsythus and P. gingivalis, has about 60% homology with the mammalian heat-shock protein. It is known that antibodies to the heat-shock protein are found in patients with periodontal disease. It is conceivable then that these antibodies to heat-shock proteins of periodontal bacteria are cross-reactive with the heat-shock protein that is exposed in an injured endothelium or atheromatous plaque. This could set in motion autoimmune phenomena and con- tribute to atheroma formation.
Cardiovascular Diseases and Oral Infections 79
Common Genetic Predisposition for Periodontal Disease and Atherosclerosis
There may be common genetic mechanisms which provide the link between periodontal disease and cardiovascular disease. Beck and colleagues75 have provided a model proposing that there is a geneti- cally determined hyperinflammatory macrophage phenotype in periodontal disease, which con- tributes to the susceptibility for atherosclerosis.
Common Risk Factors Affecting Both Periodontal Disease and Heart Disease
DeStefano and colleagues73 found that periodon- tal disease and poor oral hygiene are stronger indicators of risk of total mortality and of coro- nary heart disease. They suggest that oral hygiene may be an indicator or a surrogate for lifestyle affecting personal hygiene and health care and might explain the relationship between peri- odontal disease and heart disease. Multiple stud- ies showing the relationship between periodontal disease and heart disease, after adjusting for many factors associated with lifestyle, such as smoking and weight, suggest that the relation- ship is not simply explained by lifestyle (see Tables 5–6, 5–7, and 5–8). Also, the finding that the graded exposure of periodontal disease leads to an increased cumulative index of coronary heart disease argues against lifestyle as a simple explanation for this association.75
The association between periodontal disease and cardiovascular disease or stroke could be due to residual confounders or incomplete control of confounders. As with most studies that adjust for possible confounders, the adjustments may not be complete, so associations of this magnitude may be due to residual confounders. Perhaps new stud- ies with more detailed adjustments for con- founders will clarify this issue. In fact, there are two studies in progress, supported by the Nation- al Institutes of Health (NIH), which may help resolve this issue.
Further research will be needed to determine which, and to what extent, factors act singly or in concert to contribute to the formation of athero- matous plaques. It is important to know the mech- anisms, however, since they add evidence to sup- port the association between periodontal infection and atherosclerosis. In addition, knowing the mechanisms may well lead to simple, cost-effective interventions that would moderate, in part, the contribution of infection to atherosclerosis.
Management of Periodontal Disease in Patients at High Risk for Atherosclerosis
Since there is mounting evidence relating peri- odontal infections to atherosclerosis, it is reason- able that patients with periodontal disease that are at risk for atherosclerotic disease should be man- aged in the following manner:
1. Patients at high risk for atherosclerotic disease should be subjected to a complete periodontal examination.
2. Patients that have periodontal disease should have a thorough medical history evaluating systemic conditions, medications, and risk fac- tors for atherosclerosis and related conditions such as heart disease and stroke.
3. Treatment of patients with periodontal disease and pre-existing atherosclerotic disease, such as stroke, nonfatal myocardial infarction, and atherosclerosis in general, should be coordinat- ed among health professionals to ensure that patients are adequately managed taking into account medical as well as dental considera- tions and complications.
4. Aggressive prevention of periodontal disease should be undertaken in patients at high risk for atherosclerotic disease. If periodontal dis- ease exists in these high-risk patients, compre- hensive treatment should be instituted to erad- icate, as much as possible, the periodontal infection and prevent its recurrence.
5. Patients should be made completely aware of the possible relationship between heart disease, stroke, and periodontal disease, without undu- ly alarming them, so that they may participate in the modification of risk factors for both artherosclerosis and periodontal disease, such as smoking.
REFERENCES
1. Redding S, Montgomery M. Dentistry in systemic disease: In: Diagnostic and therapeutic approach to patient management. Portland: JBK Publish- ing, Inc; 1990. P. 169–213.
2. Rose LF, Kaye D. Cardiovascular disorders. In: Internal medicine for dentistry. 2nd ed. Mosby Publishing Co; 1990. p. 505–14.
3. University of Washington. Medically compromised patient with cardiovascular disorders: a self- instructional series in rehabilitation dentistry. Seattle, WA; Module IV, Unit A.; 1986.
80 Periodontal Medicine
4. Mealey BL. Influence of periodontal infections on systemic health. Periodontol 2000 1999. [In press]
5. Mulligan R. Preventive care for the geriatric dental patient. Cal Dent Assoc J 1984;12:21–32.
6. Aragon SB, Buckley SB, Tilson HB. Oral surgery management of the geriatric patient. Spec Care Dent 1984;4:124–9.
7. Little JW, Falace, DA. Therapeutic considerations in special patients. Dent Clin North Am 1984; 28:455–69.
8. Little JW, Falace DA. Dental management of the medically compromised patient. 3rd ed. St. Louis: Mosby Publishing Co.; 1988. p. 83–195.
9. Matsuura H. Systemic complications and their management during dental treatment. Int Dent J 1989;39:113–21.
10. McCarthy FM, Pallasch TJ, Gates, R. Document- ing safe treatment of the medical-risk patient. J Am Dent Assoc 1989;119:383–9.
11. Mulligan R. Pretreatment for the cardiovascularly compromised geriatric dental patient. Spec Care Dent 1985;5:116–23.
12. Thornton JB, Wright JT. Special and medically compromised patients in dentistry. St. Louis: Mosby Year-Book Publishers; 1989. p. 149–68.
13. Cash J, Raab RW, Coke JM. Understanding your patient with cardiac disease. J Colorado Dent Assoc 1990;68:16–9.
14. Dajani AS, Taubert KA, Wilson W, et al. Preven- tion of bacterial endocarditis. Recommenda- tions by the American Heart Association. JAMA 1997;277:1794–801. Circulation 1997;96: 358–66.
15. Mealey BL. Periodontal implications: medically compromised patients. Ann Periodontol 1996; 1:256–321.
16. Rees TD. Adjunctive therapy. Discussion section X. In: Nevins M, Becker W, Kornman K, edi- tors. Proceedings of the world workshop in clin- ical periodontics. Chicago, IL: The American Academy of Periodontology; 1989.
17. Strom BL, Abrutyn E, Berlin JA, et al. Dental and cardiac risk factors for infective endocarditis. A population-based, case-control study. Ann Intern Med 1998;129:761–9.
18. Younessi OJ, Walker DM, Ellis P, Dwyer DF. Fatal Staphylococcus aureus infective endocarditis: den- tal implications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:168–72.
19. Burne RA. Concise review. Oral streptococci, prod- ucts of their environment. J Dent Res 1998; 77:445–52.
20. Slots J. Causal or casual relationship between peri-
odontal infection and non-oral disease [guest editorial]. J Dent Res 1998;77:1764–5.
21. Atkinson BA, Abu-Al-Jaibat A, LeBlanc DJ. Antibiotic resistance among enterococci isolated from clinical specimens between 1953 and 1954. Antimicrobial Agents Chemother 1997; 41:1598–600.
22. Griffin BP. Valvular heart disease. In: Dale DC, Federman DD, editors. Scientific American Medicine. New York, NY: Scientific American Inc.; 1998.
23. Karchmer AW. Infective endocarditis. In: Dale DC, Federman DD, editors. Scientific American Medicine. New York, NY: Scientific American, Inc.; 1999.
24. Sanabria TJ, Alpert JS, Goldberg R, et al. Increas- ing frequency of staphylococcal infective endo- carditis. Experience at a university hospital, 1981 through 1988. Arch Intern Med 1990; 150:1305–9.
25. Cowper TR. Pharmacologic management of the patient with disorders of the cardiovascular sys- tem. Infective endocarditis. Dent Clin North Am 1996;40:611–47.
26. Kupferwasser HD, Muller AM, Morh-Kahaly S, et al. Clinical and morphological characteristics in Streptococcus bovis endocarditis: a comparison with other causative microorganisms in 177 cases. Heart 1998;80:276–80.
27. Rees TD. Dental management of the medically compromised patient. In: McDonald RE, Hurt WC, Gilmore HW, Middleton, RA, editors. Current therapy in dentistry. 7th ed. St. Louis: C.V. Mosby Co.; 1980. p. 1–30.
28. McKinsey DS, Ratts TE, Bisno AL. Underlying cardiac lesions in adults with infective endo- carditis. Am J Med 1987;82:681–8.
29. Zysset MK, Montgomery MT, Redding SW, Dell’ Italia LJ. Systemic lupus erythematosus: a con- sideration for antimicrobial prophylaxis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987;64:30–4.
30. Friedlander AH, Yoshikaua TT. Pathogenesis, man- agement, and prevention of infective endocardi- tis in the elderly dental patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1990; 69:177–81.
31. Friedlander AH. Risk assessment of the older den- tal patient: a review of the pathophysiology of the cardiovascular system. Spec Care Dent 1987; 7:41–2.
32. Bayer AS, Lam K, Ginzton L, et al. Staphylococcus aureus bacteremia. Arch Intern Med 1987;147: 457–62.
Cardiovascular Diseases and Oral Infections 81
33. Devereux RB, Kramer-Fox R, Kligfield P. Mitral valve prolapse: causes, clinical manifestations, and management. Ann Intern Med 1989;111: 305–17.
34. Rees TD. Periodontal considerations in patients with bone marrow or solid organ transplants. 1999. In: Periodontal Medicine etc.
35. Rees, TD, Rose LF. Periodontal management of patients with cardiovascular diseases [position paper, American Academy of Periodontology]. J Periodontol 1996;67:627–35.
36. Taylor MH, Peterson DS. Kawasaki’s disease. J Am Dent Assoc 1982;104:44–7.
37. Barnett ML, Friedman D, Kastner, T. The preva- lence of mitral valve prolapse in patients with Down’s syndrome: implications for dental man- agement. Oral Surg Oral Med Oral Pathol 1988;66:445–7.
38. Clemens JD, Ransohoff DF. A quantitative assess- ment of pre-dental antibiotic prophylaxis for patients with mitral-valve prolapse. J Chron Dis 1984;37:531–41.
39. Friedlander AH, Gorelick DA. Panic disorder: its association with mitral valve prolapse and appropriate dental management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987; 63:309–12.
40. Meyers DG, Starke H, Pearson PH, Wilken MK. Mitral valve prolapse in anorexia nervosa. Ann Intern Med 1986;105:384–6.
41. Daly C, Mitchell D, Grossberg D, et al. Bacter- aemia caused by periodontal probing. Aust Dent J 1997;42:77–80.
42. Roberts GJ, Simmons NB, Longhurst P. Odonto- genic bacteraemia and intraligamental analgesia. Br Dent J 1992;173:195.
43. Lamas WP. A study of transient bacteremia follow- ing an intraoral soft tissue biopsy [thesis]. Dallas, TX: Baylor College of Dentistry-TAMUS; 1998.
44. Francis JL. Significance of bacteremias of dental origin. J Am Dent Assoc 1986;112:306–8.
45. Pallasch TJ. Antibiotic prophylaxis: theory and reality. Calif. Dent Assoc J 1989;17:27–39.
46. Berger SA, Weitzman S, Edberg SC, Coreg JI. Bac- teremia after the use of an oral irrigating device. Ann Intern Med 1974;80:510–1.
47. Felix JE, Rosen S, App GR. Detection of bac- teremia after the use of an oral irrigation device on subjects with periodontitis. J Periodontol 1971;42:785–7.
48. Hunter KM, Holborow DW, Kardos TB, et al. Bacteremia and tissue damage resulting from air polishing. Br Dent J 1989;167:275–7.
49. Romans AR, App GR. Bacteremia, a result from oral irrigation in subjects with gingivitis. J Peri- odontol 1971;42:757–60.
50. Barco CT. Prevention of infective endocarditis: a review of the medical and dental literature. J Periodontol 1991;62:510–23.
51. Bender IB, Naidorf IJ, Garvey GJ. Bacterial endo- carditis: a consideration for physician and den- tist. J Am Dent Assoc 1984;109:415–20.
52. MacFarlane TW, Ferguson MM, Mulgrew CJ. Post-extraction bacteremia: role of antiseptics and antibiotics. Br Dent J 1984;156:179–81.
53. Tzukert AA, Leviner E, Sela M. Prevention of infec- tive endocarditis: not by antibiotics alone. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1986;62:385–8.
54. Fay JT, O’Neal RB. Dental responsibility for the medically compromised patient IV. J Oral Med 1984;39:218–25.
55. Kilmartin C, Munroe C. The dental management of the cardiac patient requiring antibiotic pro- phylaxis. J Can Dent Assoc 1986;52:77–82.
56. Kilmartin C, Munroe CO. Cardiovascular diseases and the dental patient. J Can Dent Assoc 1986; 52:513–8.
57. Leviner E, Tzukert AA, Berioliol R, et al. Develop- ment of resistant oral viridans streptococci after administration of prophylactic antibiotics: time management in the dental treatment of patients susceptible to infective endocarditis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987;64:417–20.
58. Slots J, Rosling BG, Genco RJ. Suppression of penicillin-resistant oral Actinobacillus actino- mycetemcomitans with tetracycline: considerations in endocarditis prophylaxis. J Periodontol 1983; 54:193–6.
59. American Dental Association. Patients with cardio- vascular disease. Oral Health Care Guidelines 1989; September:1–13.
60. Baltch AL, Pressman HL, Schaffer C, et al. Bac- teremia in patients undergoing oral procedures. Arch Intern Med 1988;148:1084–8.
61. Steinberg BJ, Brown S. Dental treatment of the health compromised. Medical and psychological considerations. Alpha Omegan 1986;79:34–41.
62. Glasser S. The problems of patients with cardiovas- cular disease undergoing dental treatment. J Am Dent Assoc 1977;94:1158–62.
63. Mulligan R, Weitzel KG. Pretreatment manage- ment of the patient receiving anticoagulant drugs J Am Dent Assoc 1988;117:479–83.
64. Breslow JL. Cardiovascular disease burden increases, NIH funding decreases. Nat Med 1997;3:600–1.
82 Periodontal Medicine
65. Braunwald E. Shattuck Lecture—cardiovascular medicine at the turn of the millennium: tri- umphs, concerns, and opportunities. N Engl J Med 1997;337:1360–9.
66. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115–26.
67. Falk E, Shah PK, Fuster V. Pathogenesis of plaque disruption. In: Fuster V, Ross R, Topol EJ, edi- tors. Atherosclerosis and coronary artery disease. Vol 2. Philadelphia: Lippincott-Raven; 1996. p. 492–510.
68. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet 1997;350:430–6.
69. Mattila K, Nieminen M, Valtonen V, et al. Associ- ation between dental health and acute myocar- dial infarction. BMJ 1989;298:779–82.
70. Paunio K, Impivaara O, Tiekso J, Maki J. Missing teeth and ischaemic heart disease in men aged 45-64 years. Eur Heart J 1993;14Suppl:54–6.
71. Mattila KJ, Valle M, Nieminen MS, et al. Dental infections and coronary atherosclerosis. Athero- sclerosis 1993;103:205–11.
72. Arbes S, Slade GD, Beck JD. Association between extent of periodontal attachment loss and self- reported history of heart attack: an analysis of NHANES III data. J Dent Res 1999. [In press]
73. DeStefano F, Anda RF, Kahn HS, et al. Dental dis- ease and risk of coronary heart disease. BMJ 1993;306:688–91.
74. Mattila KJ, Valtonen VV, Nieminen M, Huttunen JK. Dental infection and the risk of new coro- nary events: prospective study of patients with documented coronary artery disease. Clin Infect Dis 1995;20:588–92.
75. Beck J, Garcia J, Heiss G, et al. Periodontal disease and cardiovascular disease. J Periodontol 1996; 67:1123–37.
76. Joshipura KJ, Rimm EB, Douglass CW, et al. Poor
oral health and coronary heart disease. J Dent Res 1996;75:1631–6.
77. Genco RJ, Chadda S, Grossi S, et al. Periodontal disease is a predictor of cardiovascular disease in a Native American population [abstract]. J Dent Res 1997;76(Special Issue):3158.
78. Syrjänen J, Peltola J, Valtonen V, et al. Dental infections in association with cerebral infarction in young and middle-aged men. J Intern Med 1989;255:179–84.
79. Grau AJ, Buggle F, Ziegler C, et al. Association between acute cerebrovascular ischemia and chronic and recurrent infection. Stroke 1997; 28:1724–9.
80. Wu T, Trevisan M, Genco RJ, et al. Periodontal disease and risk of cerebrovascular disease: the first National Health and Nutrition Examina- tion Survey and its follow-up study. JAMA 1999. [In press]
81. Haraszthy VI, Zambon JJ, Trevisan M, et al. Iden- tification of pathogens in atheromatous plaques [abstract]. J Dent Res 1998;77(Special Issue): 273.
82. Chiu B, Viira E, Evans RT, Genco RJ. Detection of an odontopathogen: Porphyromonas gingivalis in atherosclerotic plaques: an immunohistochemical and in situ hybridization study. Appl Immuno- histochem Molec Morphol 1999. [In press]
83. Deshpande RG, Kahn MB, Genco CA. Invasion of aortic and heart endothelial cells by Porphyromonas gingivalis. Infect Immun 1998;66:5337–43.
84. Herzberg MC, Meyer MW. Effects of oral flora on platelets: possible consequences in cardiovascu- lar disease. J Periodontol 1996;67:1138–42.
85. Wu T, Trevisan M, Genco RJ, et al. An examination of the relation between periodontal health status and cardiovascular risk factors: serum total and HDL cholesterol, C-reactive protein, and plasma fibrinogen. Am J Epidemiol 1999. [In press]
CHAPTER 6
RELATIONSHIPS BETWEEN PERIODONTAL AND RESPIRATORY DISEASES Frank A. Scannapieco, DMD, PhD
Respiratory diseases are responsible for a significant number of deaths and considerable suffering in humans. These diseases are widely prevalent. For example, lower respiratory infections were the third commonest cause of mortality worldwide in 1990 (causing 4.3 million deaths), and chronic obstructive pulmonary disease (COPD) was the sixth leading cause of mortality (2.2 million deaths);1 it was the fourth leading cause of death in the United States in 1996,2 claiming 100,000 lives while pneumonia and influenza together caused almost 84,000 deaths.
Accumulating evidence suggests that oral dis- orders, particularly periodontal disease, may influ- ence the course of respiratory infection. This chap- ter will describe the major respiratory diseases caused or influenced by bacteria, the epidemiolog- ic evidence that supports a role for oral bacteria in the process of respiratory infection, and possible mechanisms that may explain the role of oral bac- teria in the process of respiratory infection.
RESPIRATORY DISEASES
Bacterial Pneumonia
Pneumonia is a group of related diseases caused by a wide variety of infectious agents, including bacte- ria, mycoplasma, fungi, parasites, and viruses, resulting in infection of the pulmonary parenchy- ma (Figure 6–1). Pneumonia can be a life-threaten- ing infection, especially in the elderly and immuno- compromised patient,3,4 and it is a significant cause of morbidity and mortality in patients of all ages. Bacterial pneumonia, a common form of the dis- ease, can arise de novo or as a superinfection of an
underlying viral pneumonia. Up until the early part of this century, bacterial pneumonia was a com- mon, severe, and often fatal infection.5 With the advent of the widespread use of antibiotics, many of these infections became treatable. However, the continuing emergence of antibiotic-resistant bacte- ria (eg, penicillin-resistant pneumococci) suggests that the number of cases of bacterial pneumonia caused by resistant organisms will increase in the years to come.6 Thus, knowledge of the pathogene- sis of and the risk factors for bacterial pneumonia is critical to the development of strategies for the treatment and prevention of these infections.
Pneumonia can be classified as community acquired or hospital acquired (nosocomial). These types of pneumonia differ with respect to their causative agents (Table 6–1). Community- acquired bacterial pneumonia is usually associated with Streptococcus pneumoniae and Haemophilus influenzae, with other species such as Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, and a variety of anaerobic species also involved.7,8 The spectrum of organisms responsible for nosocomial pneumonia is quite different, with gram-negative bacilli (including enterics such as Escherichia coli, Klebsiella pneumoniae, Serratia spp., and Enterobacter spp. as well as Pseudomonas aeruginosa) and Staphylococcus aureus being the most prevalent.4,8–10 The spectrum of organisms prevalent in nursing homes is even broader, with pathogens common to both community- and hospital-acquired pneumonias involved.4
Infections are of particular concern in the hospital environment. Greater than 5% of all hos- pitalized patients develop an infection following their admission to the hospital, and pneumonia
84 Periodontal Medicine
typically accounts for 10 to 20% of these.10–13
Hospital-acquired pneumonia often prolongs hos- pital stay, increases patient care costs, and causes significant morbidity and mortality.14 There are more than 300,000 nosocomial respiratory infec- tions each year,11 leading to about 20,000 deaths,13 and such infection adds 7 to 9 days to the average length of stay in the hospital.13 The annual direct cost of diagnosing and treating nosocomial pneumonia may exceed $2 billion.15
While also contributing to a significant number of deaths by acting as a complicating or secondary factor, pneumonia is of special significance in the elderly population, accounting for the majority of admissions to hospitals from nursing homes.4,16
Chronic Obstructive Pulmonary Disease
Another severe respiratory disease affecting a sig- nificant segment of the population is COPD. This
condition is characterized by chronic obstruction to airflow, with excess production of sputum resulting from chronic bronchitis (CB) and/or emphysema.17 Chronic bronchitis is the result of irritation to the bronchial airway, which causes an expansion of the proportion of mucus-secreting cells within the airway epithelium (Figure 6–2). These cells secrete excessive tracheobronchial mucus sufficient to cause cough with expectora- tion for at least 3 months of the year over two con- secutive years.18 Emphysema is defined as the dis- tention of the air spaces distal to the terminal bronchiole with destruction of the alveolar septa.
Chronic bronchitis is quite prevalent, with 20 to 30% of all adults over 45 years reporting a histo- ry of asthma or chronic bronchitis.19 Chronic bron- chitis is more prevalent in men than in woman, with about 20% of all adult males displaying some evidence of it.17 The prevalence of the disease in women is on the rise since more women are smok-
Figure 6–1. Histopathology of bronchopneumonia. A, Low power of a bronchiole showing the presence of an inflammato- ry exudate in its lumen. A patchy inflammatory cell infiltrate is observed in the subephithelial region. (Hematoxylin-eosin stain, original magnification ´ 20) B, Higher power view illus- trates the simple columnar ciliated epithelium that lines the bronchiole. The lamina propria and lumen of the bronchiole contain numerous inflammatory cells. (Hematoxylin-eosin stain, original magnification ´ 400) C, High power view of pulmonary alveoli shows early red hepatization characterized by capillary congestion in the septae. In addition, an extensive neutrophilic exudation in the alveoli is also observed. (Hema- toxylin-eosin stain, original magnification ´ 400)
A B
C
Relationships between Periodontal and Respiratory Diseases 85
ing than ever before. The incidence of emphysema is less well known since the main tool for noninva- sive diagnosis (computed tomographic [CT] scan- ning) cannot be applied to population studies. It is interesting that it is rare to find lungs completely free of emphysema post mortem. However, the vast majority of individuals, while showing well-defined histologic evidence of emphysema, will not have clinical symptoms of the disease.
The major risk factor for COPD is a history of prolonged cigarette smoking, with chronic exposure to toxic atmospheric pollutants (eg, second-hand smoke) also being a contributory factor. Genetic conditions, such as the presence of a defective alpha1-antitrypsin gene, variant alpha1-antichy- motrypsin, alpha2-macroglobulin, vitamin D–bind- ing protein, and blood group antigen genes, may also predispose subjects to this disease.20
One of the major complications of COPD is the occurrence of “exacerbations,” or episodes in which there are objective signs that the disease has worsened such as increased sputum production showing a change in color and/or consistency, cough, dyspnea, chest tightness, and fatigue. The factors responsible for the initiation of exacerba- tion are not completely known although they are thought to be provoked, in part, by bacterial infec- tion.21,22 The organisms most closely associated with exacerbations are nontypeable H. influenzae, S. pneumoniae, and Moraxella catarrhalis. It should be pointed out that the frequency of exacerbations in COPD patients varies from individual to indi- vidual. The frequency of exacerbations is not relat- ed to the severity of lung disease. Although viral infections, fluid overload, and allergy have been suggested to enhance the risk for exacerbation, no studies have yet proven the role of these factors in the disease process.17
Pathogenesis and Risk Factors for Lung Infection
The lung is composed of numerous units formed by the progressive branching of the airways. The airway of each terminal respiratory unit (bronchiole, alveo- lar duct, alveolar sac, and alveoli) is lined by epithe- lial cells in close proximity on their basal aspect to the capillaries, which permits the efficient exchange of gases. In normal healthy individuals, the lower airways are normally sterile, in spite of the fact that the secretions of the upper airways are heavily cont- aminated with microorganisms seeded from the oral and nasal surfaces.23,24 Sterility of the lower airway is maintained by intact cough reflexes, the action of the tracheobronchial secretions, mucociliary trans-
TABLE 6–1. Etiology of Bacterial Pneumonia
Community-Acquired Pneumonia Nosocomial Pneumonia
• Streptococcus pneumoniae • Gram-negative bacilli (including enterics such as Escherichia coli, • Haemophilus influenzae Klebsiella pneumoniae, Serratia spp, Enterobacter spp, Pseudomonas • Mycoplasma pneumoniae aeruginosa) • Chlamydia pneumoniae • Staphylococcus aureus • Legionella pneumophila • Staphylococcus aureus • Candida albicans • Anaerobic species
Figure 6–2. Histopathology of panacinar emphysema. Low power view shows distended alveoli, destruction of the alve- olar walls, and fibrosis. (Hematoxylin-eosin stain, original magnification ´ 20)
86 Periodontal Medicine
port of inhaled microorganisms and particulate material from the lower respiratory tract to the oropharynx, and immune and nonimmune defense factors (cell-mediated immunity, humoral immuni- ty, and polymorphonuclear leukocytes).5,25 Other defense factors contained within the secretions that coat the pulmonary epithelium include surfactant, other proteins such as fibronectin, complement, and immunoglobulins. The lung also contains a rich sys- tem of phagocytic cells, which remove microorgan- isms and particulate debris.
Microorganisms can contaminate the lower air- ways by four possible routes: aspiration of oropha- ryngeal contents,26 inhalation of infectious aerosols,11
spread of infection from contiguous sites,27 and hematogenous spread from extrapulmonary sites of infection (eg, translocation from the gastrointesti- nal tract).27 Aspiration of the oropharyngeal con- tents is the commonest route of infection. While claims have been made supporting the stomach as a primary source of nosocomial respiratory pathogens,28 especially in patients treated with H2- blockers and other antiulcer medications, it is more likely that most pathogens first colonize the sur- faces of the oral cavity or pharyngeal mucosa before aspiration.29 These pathogens can colonize from an exogenous source or can emerge following over- growth of the normal oral flora after antibiotic treatment. Common respiratory pathogens such as S. pneumoniae, Streptococcus pyogenes, M. pneumo- nia, and H. influenzae can colonize the oropharynx and be aspirated into the lower airways. As will be discussed below, other species thought to comprise the normal oral flora, including Actinobacillus actin- omycetemcomitans, and anaerobes such as Porphy- romonas gingivalis and Fusobacterium spp., can also be aspirated into the lower airways to cause pneu- monia. Indeed, studies using careful sampling and strict anaerobic culture conditions have found that a considerable proportion of community-acquired and nosocomial pneumonia may involve anaerobic agents.26,30 Pneumonia can be the result of a mixed infection, with anaerobes combining with faculta- tive agents such as oral viridans streptococci or enteric rods.31,32
Aspiration of oropharyngeal secretions is not uncommon, even in healthy subjects. Studies have demonstrated that 50% of normal adults aspirate oropharyngeal contents during sleep. However, aspiration occurs more frequently in individuals with impaired consciousness, such as alcoholics, drug abusers, and epileptics, and those with chron- ic swallowing disorders or mechanical interven- tions such as nasogastric or endotracheal tubes.26,33
All these patient groups tend to have a greater inci- dence of bacterial pneumonia than the population as a whole.34
Generally accepted risk factors that predispose to nosocomial pneumonia include the presence of underlying diseases such as chronic lung disease, congestive heart failure, or diabetes mellitus, age > 70 years; mechanical ventilation or intubation, a history of smoking, previous antibiotic treatment, immunosuppression, a long preoperative stay, and/or prolonged surgical procedures.10–12,28 Other commonly accepted risk factors in mechanically ventilated patients include placement of intracranial pressure monitors, anti–stress ulcer therapy, hospi- talization in the fall or winter seasons, and changes of ventilatory circuits every 24 hours.12,28 In nursing home residents, risk factors for pneumonia include difficulty with oropharyngeal secretions, deteriorat- ing health status, and occurrence of unusual events (confusion, agitation, falls, or wandering).35
It is possible that oral disorders such as perio- dontal disease may also predispose subjects to nosocomial pneumonia. For example, hospitalized patients, especially those admitted to an intensive care unit, are likely to pay less attention to person- al hygiene than less ill patients. One important dimension of this personal neglect may be dimin- ished attention to oral hygiene. A lapse in oral hygiene may optimize conditions that contribute to the initiation of pneumonia.
DENTAL CONSIDERATIONS
Oral Bacteria as Etiologic Agents of Respiratory Infection
It is possible that the teeth can serve as a reservoir for respiratory infection. Indeed, the notion that the oral cavity may influence the bacterial flora of the lower bronchi is not new. For example, Potter and colleagues noted in 1968 that infected teeth were present in 25% of 80 patients with potential respiratory pathogens in the bronchi, as against only 7.5% of 80 patients free of pathogens in the bronchi.36 Oral bacteria can be released from the dental plaque into the salivary secretions, which are then aspirated into the lower respiratory tract to cause pneumonia (Figure 6–3). It has long been known that severe anaerobic lung infections can occur following aspiration of salivary secretions, especially in patients with periodontal dis- ease.5,25,34,37 Estimates have been made that 30 to 40% of all cases of aspiration pneumonia, necro- tizing pneumonia, or lung abscess involve anaero-
Relationships between Periodontal and Respiratory Diseases 87
bic bacteria.38 A variety of oral anaerobes and fac- ultative species have been cultured from infected lung fluids, including P. gingivalis, Bacteroides gracilus, Bacteroides oralis, Bacteroides buccae, Eikenella corrodens, Fusobacterium nucleatum, Fusobacterium necrophorum, A. actinomycetemcomi- tans, Peptostreptococcus, Clostridium, and Actino- myces.38–47 Most, if not all, of these organisms have been implicated as etiologic agents in the patho- genesis of periodontal disease.48,49 It is also possible that viridans streptococci, thought to be exclusive- ly benign members of the oral flora, may partici- pate in the initiation and/or progression of pneu- monia.32,43,50–52
Oral bacteria may also have a role in the exac- erbations of COPD. For example, oral bacteria can be cultured from a significant proportion of the lung fluids obtained from transtracheal aspiration, a technique that avoids contamination with oropharyngeal secretions. Thus, anaerobic bacteria (presumably from the oral cavity) were cultured from 17% of transtracheal aspirates from patients with COPD.53 The distal airway of COPD sub- jects frequently shows bacterial colonization by presumably nonpathogenic oral bacteria, including oral streptococci (Table 6–2).24 Indeed, Streptococ- cus viridans was found to be the cause of pneumo- nia in 4% of COPD patients.54
Laboratory studies suggest that oral anaerobes such as P. gingivalis can cause marked inflamma- tion when instilled into the lungs of laboratory animals.55 A relationship between the systemic humoral response to Prevotella species (bacteria associated with periodontal disease) and ventilator- associated pneumonia in hospitalized patients has also been described. Thus, colonization of patients by Prevotella species may be associated with an infectious process leading to ventilator-associated pneumonia and a systemic humoral response.56
Dental Plaque as a Reservoir of Respiratory Pathogens
Ill persons probably do not pay close attention to oral hygiene. Several studies have documented that hospitalized individuals tend to have poorer oral hygiene than matched ambulatory, community- dwelling controls.57–62 Lack of attention to oral hygiene results in an increase in the mass and com- plexity of dental plaque, which may foster bacterial interactions between indigenous plaque bacteria and acknowledged respiratory pathogens such as P. aeruginosa and enteric bacilli.63 These interactions may result in colonization of the dental plaque by
respiratory pathogens. Dental plaque may therefore provide a reservoir for colonization of respiratory pathogens that can be shed into saliva. Contamina- tion of the distal portions of the respiratory tree by saliva containing such organisms may result in pul- monary infections. It should also be pointed out that respiratory pathogens that establish in dental plaque may be difficult to eradicate. It is well known that bacteria in biofilms are much more resistant to antibiotics than planktonic bacteria.64
Previous studies have documented that patients admitted to medical intensive care units (ICU) have poorer oral hygiene than nonhospital- ized patients and have a higher prevalence of respi- ratory pathogen colonization on the teeth and oral mucosa than do age- and gender-matched outpa-
Figure 6–3. Oral bacteria, oral infection, and pneumonia. Bacteria that colonize the supra- or subgingival dental plaque are shed into the saliva. These pathogenic bacteria can be either those associated with periodontal disease (P. gingivalis, Fusobacterium nucleatum) or respiratory pathogens (P. aerug- inosa, Klebsiella pneumonia). The saliva is aspirated into the lower respiratory tract (bronchus), where an infection can ensue. Cytokines from diseased periodontal tissues can enter the saliva from the gingival crevice fluid and also be aspirated to stimulate local inflammatory processes that contribute to the initiation and/or progression of infection in the lung. With permission from Scannapieco FA. Role of oral bacteria in respiratory infection. J Periodontol 1998;70:793–802.
P. gingivalis
H. influenzae
88 Periodontal Medicine
tients (Table 6–3).59,65 In some cases, respiratory pathogens comprise up to 100% of the cultivable aerobic flora. In general, heavily colonized patients tend to be on antibiotic therapy. Respiratory pathogens are also more likely to colonize the oral cavities of patients with teeth or dentures than edentulous patients not wearing dentures. This finding suggests that respiratory pathogen colo- nization is favored by the presence of nonshedding surfaces and/or the conditioning of mucosal sur- faces by dental plaque.
More recently, a prospective study of 57 con- secutive patients admitted to medical ICU during a
3-month period assessed the colonization of dental plaque by respiratory pathogens.61 The amount of dental plaque on the teeth of inpatients increased over time, as did the proportion of respiratory pathogens in their dental plaque. A high concor- dance was found between respiratory colonization of dental plaque by pathogens and the presence of the same pathogens in tracheal aspirate cultures and between salivary and dental plaque cultures. Clini- cally, 21 patients developed a nosocomial infection in the ICU. Dental plaque colonization on days 0 and 5 was significantly associated with the occur- rence of nosocomial pneumonia and bacteremia. In
TABLE 6–3. Comparison of Patient Characteristics between the Preventive Dentistry Clinic (PDC) and the Medical ICUs at BGH and VAMC
PDC BGH VAMC
Mean age (years) 62.4 63.6 63.8 Gender (male/total numer patients studied) 23/25 12/19 32/34 Mean APACHE II score* Not done 14.8 17.1 Oral hygiene (mean plaque score)† 1.4 1.7 1.9 % positive oral cultures‡ 16 (4/25) 58 (11/19)§ 65 (22/34)§
BGH = Buffalo General Hospital; VAMC = Veterans Administration Medical Center; ICU = intensive care unit; APACHE = Acute Physiology, Age, Chronic Health Evaluation; PDC = Preventive Dental Clinic *APACHE II score was used to semiquantitate the physiologic status of each patient at the time of admission to the medical ICU.65a This system evaluates a variety of parameters, including physiologic information (temperature, mean arterial pressure, heart rate, respiratory rate, oxygenation, arterial pH, serum levels of Na, K, and creatinine, hematocrit, white blood count), the patient’s age, chronic health status, and cardiovascular, renal, respiratory, and immune status. The higher the score, the more severely ill is the patient. †Plaque score performed as described by Silness and Löe.65a ‡% of patients having colonization of buccal mucosa and/or dental plaque with a target respiratory pathogen (enteric rod, P. aeruginosa, S. aureus). §The differences observed were found to be significantly different from PDC patients by contingency table analysis.59,65b
TABLE 6–2. Bacterial Colonization of the Lower Airway Determined by Bronchoscopic Protected Specimen Brush
Number of Percent Subjects Patients Colonized Flora
Healthy 15 12 Viridans streptococci, group D streptococci, S. aureus Bronchogenic 33 39 Viridans streptococci, Neisseria, Staphylococcus, H. influenzae,
carcinoma S. pneumoniae COPD 18 83 Viridans streptococci, Neisseria, Staphylococcus, Corynebacterium,
Candida, Haemophilus, S. pneumoniae, S. aureus Bronchiectasis 17 82 Viridans streptococci, group D streptococci, Staphylococcus Long-term 32 38 Viridans streptococci, Corynebacterium, M. catarrhalis, S. aureus
tracheostomy
COPD= chronic obstructive pulmonary disease. With permission from Cabello H, Torres A, Celis R, et al. Bacterial colonization of distal airways in healthy subjects and chronic lung disease: a bronchoscopic study. Eur Resp J 1997;10:1137–44.
Relationships between Periodontal and Respiratory Diseases 89
six cases of nosocomial infection, the pathogen was first isolated from the dental plaque.
Taken together, these results strongly suggest that patients admitted to medical ICUs have a sig- nificant risk for oral colonization by respiratory pathogens. Thus, the oral cavity may serve as important nidus of infection for respiratory disease in high-risk subjects, such as hospitalized or COPD patients.
It has been suggested that high-risk patients in nursing home settings are also at risk for lower res- piratory tract infection. The possibility therefore exists that, like the hospital intensive care environ- ment, poor oral health may predispose nursing home residents to oral colonization by respiratory pathogens.66,67 Recently, the prevalence and distrib- ution patterns of suspected respiratory pathogens in the dental plaque of older individuals living in a long-term care facility were studied.62 Findings from this group were compared with those from a similar number of age-, race-, and gender-matched community-dwelling subjects. Briefly, no differ- ences were noted in the prevalence of colonization by respiratory pathogens between the long-term care facility subjects and dental outpatient subjects; 25% (7 of 28) of long-term care facility subjects were colonized with respiratory pathogens versus 27% (8 of 30) of dental clinic outpatients. Howev- er, when only those subjects that were positively colonized were considered (with the respiratory pathogen comprising ³ 0.1% of the total cultivable flora), there was a statistically significant difference between the prevalence of subjects that were colo- nized in each group (14% [4 of 28] of the long- term care facility subjects versus 0% [0 of 30] of the dental clinic outpatients). Nursing home subjects harbored more dental plaque than did the dental
outpatients (Figure 6–4). Colonized long-term care facility subjects tended to be colonized to a much greater degree than did those dental clinic outpa- tient subjects (42.88 ± 53.4 versus 0.02 ± 0.04).
In summary, these results suggest that nursing home subjects (who are at greater risk for lower res- piratory infection) have a greater tendency for their dental plaque to be colonized by respiratory pathogens. This finding is substantiated by the report of Mojon and colleagues,68 who found that poor oral hygiene may be a major risk factor for respiratory tract infection in elderly institutional- ized individuals.
Oral Status and Chronic Obstructive Pulmonary Disease
To evaluate the relationship between COPD and oral health status, a study was performed and data from the National Health and Nutrition Examina- tion Survey I (HANES I) was analyzed.69 Of 23,808 individuals, 386 reported a suspected res- piratory condition that was further assessed by a physician. These subjects were categorized as hav- ing a confirmed chronic respiratory disease (chronic bronchitis or emphysema), acute respiratory dis- ease (influenza, pneumonia, acute bronchitis), or not to have a respiratory disease.
Significant differences were noted between subjects having no disease and those having a chronic respiratory disease confirmed by a physi- cian. Individuals with a confirmed chronic respira- tory disease had a significantly greater oral hygiene index (OHI) than had subjects without a respirato- ry disease. Logistic regression analysis was per- formed to simultaneously control for multiple vari- ables including gender, age, race, OHI, and smok-
Figure 6–4. Comparison of dental plaque status of community-dwelling and nursing home residents. A, Facial aspect of mandibular anterior teeth of a typical community-dwelling elder. B, Facial aspect of mandibular anterior teeth of a typical nursing home resident elder (Courtesy of Dr. Stephanie Russell, New York University School of Dentistry).
A B
90 Periodontal Medicine
ing status. The final model included OHI and smoking status alone. The results of this analysis suggest that for patients having the highest OHI values, the odds ratio for chronic respiratory disease was 4.5. These data are supported by the recent study of Hayes and colleagues,70 who found that periodontal disease, measured as alveolar bone loss from periapical radiographs, was an independent risk factor for COPD in adult males enrolled in the Veterans Administration Normative Aging study.
Potential Mechanisms of Action of Oral Bacteria in the Pathogenesis of Respiratory Infection
Several mechanisms can be envisioned to help explain how oral bacteria can participate in the pathogenesis of respiratory infection: (1) oral pathogens (such as P. gingivalis, A. actinomycetemco- mitans) may be aspirated into the lung to cause infection; (2) periodontal disease–associated enzymes in saliva may modify mucosal surfaces to promote adhesion and colonization by respiratory pathogens; (3) periodontal disease–associated enzymes may destroy salivary pellicles on patho- genic bacteria; and (4) cytokines originating from periodontal tissues may alter respiratory epitheli- um to promote infection by respiratory pathogens.
Periodontal Disease–Associated Enzymes in Saliva Modifying Mucosal Surfaces Previous studies have shown that respiratory pathogens such as P. aeruginosa may adhere better to oral epithelial cells obtained from patients colonized by respiratory pathogens than to cells harvested from noncolonized patients.71,72 Trypsin treatment of epithelial cells from noncolonized patients in vitro resulted in increased adhesion by respiratory pathogens. These data suggest that a mucosal alter- ation promoted enhanced bacterial adhesion by these bacteria, perhaps the loss of fibronectin from the epithelial cell surface.73 Buccal epithelial cells from critically ill patients, all colonized by P. aerugi- nosa, interacted with greater numbers of bacterial cells in vitro and possessed lesser amounts of surface fibronectin as determined by immunofluorescence. The removal of fibronectin (by exposure to proteas- es) may unmask mucosal surface receptors for respi- ratory pathogen adhesins. Other investigators have also pointed out an inverse relationship between the amount of mucosal epithelial cell fibronectin and gram-negative bacilli binding to these cells.74
Saliva contains many hydrolytic enzymes, and the amount of enzyme activity in saliva is related to
the periodontal and oral hygiene status of the sub- jects tested.75–77 For example, a direct relationship has been found between the ability of saliva to degrade fibronectin and oral hygiene status.77 Sub- jects practicing meticulous oral hygiene (dental hygiene students) have very low levels of salivary fibronectin degrading enzymes. In contrast, saliva samples collected from laboratory workers having less than ideal oral hygiene had higher amounts of enzyme activity, and saliva collected on awakening in the latter group had even higher levels. The source of these enzymes has been attributed to bac- teria75,76,78–80 or polymorphonuclear leukocytes, which enter the saliva from the gingival sulcus.81 It is conceivable that in subjects with periodontal dis- ease that harbor dental plaque with elevated levels of bacteria such as P. gingivalis and spirochetes (bacte- ria known to be prolific producers of proteases), protease activity may alter the mucosal epithelium in such a way as to increase the adhesion and colo- nization by respiratory pathogens (Figure 6–5A). Such bacteria may also produce other enzymes such as mannosidase, fucosidase, hexosaminidase, and sialidase, known to be elevated in the saliva of such patients.82,83 Exposure of the epithelium and glyco- proteins to such enzymes may increase the adhesion of gram-negative bacteria to the mucosal surface by exposing the “buried” adhesin receptors on the mucosal epithelium,84 which may foster increased adhesion and colonization by respiratory pathogens.
Destruction of Protective Salivary Pellicles by Oral Bacteria Recent evidence suggests that the respiratory pathogen H. influenzae binds to mucins contained within the mucosal secretions.85–87 This binding may involve sialic acid residues.85,88 In the context of COPD, it is possible that subjects with poor oral hygiene may have elevated levels of hydrolytic enzymes (eg, sialidase) in their saliva. These enzymes may process mucins to reduce their ability to bind to and clear pathogens such as H. influenzae (Figure 6–5B). Conversely, the enzymes may process the respiratory epithelium to modulate the adhesion of such pathogens to the mucosal surface (Figure 6–5C). Indeed, several studies have suggested that certain oral bacteria can break down a variety of sali- vary components.89,90 Thus, poor oral hygiene results in increased dental plaque load and salivary hydrolytic enzyme levels. These enzymes may then destroy the protective domains of the host secretory components (eg, mucins), thus diminishing non- specific host defense against respiratory pathogens in high-risk subjects.
Relationships between Periodontal and Respiratory Diseases 91
Cytokines That May Alter Respiratory Epithelium Periodontal disease (periodontitis) is a localized chronic inflammatory disease caused by bacterial infection of the periodontal tissues by bacteria in dental plaque, resulting in the destruction of the supporting bone and connective tissues. In untreated periodontal disease, oral pathogens con- tinuously stimulate the cells of the periodontium (epithelial cells, endothelial cells, fibroblasts, macrophages, white cells) to release a wide variety of cytokines and other biologically active mole- cules.91,92 Cytokines produced by epithelial and connective tissue cells in response to these bacteria including interleukin (IL)-1a, IL-1b, IL-6, IL-8, and TNF-a.92 Oral bacteria can also stimulate the peripheral mononuclear cells to release cytokines (IL-1a and TNF-a). In fact, oral streptococci (for example, Streptococcus sanguis), which are abun- dant in dental plaque, stimulate the release of high levels of these cytokines from such cells.93 Epithe- lial cells are also known to alter the expression of the adhesion molecules on the surface of various cells in response to cytokine stimulation. Variation
in the expression of such adhesion molecules may alter the interaction of the bacterial pathogens with the mucosal surface.94
One mechanism proposed for the gross airway epithelial damage observed in COPD involves release of proinflammatory cytokines (ie, IL-8) from the respiratory epithelium, resulting in the recruit- ment and infiltration of neutrophils and the subse- quent release of proteolytic enzymes and toxic oxy- gen radicals from the neutrophils.95,96. The mecha- nism of release of cytokines from the respiratory epithelium may be the result of the binding of res- piratory pathogens (eg, H. influenzae) or their prod- ucts to the respiratory epithelial cells, followed by stimulation of the respiratory epithelial cells to pro- duce a variety of cytokines. This mechanism has been demonstrated for medical pathogens such as S. pneumoniae and H. influenzae, which are also known to attach to mucosal receptors and to stimu- late cytokine production by the underlying cells.97 It is also conceivable that the oral bacteria in secretions come in contact with the respiratory epithelial sur- faces and may adhere to the mucosal surface. Oral bacteria are routinely cultivated, for example, from
Figure 6–5. A, Dental pathogens such as P. gingivalis produce enzymes (such as proteases) that alter mucosal surface adhesion receptors for respiratory pathogens such as H. influenzae, which adhere, colonize, and can subsequently be aspirated into the lung to cause infection. B, Oral bacteria such as P. gingivalis produce enzymes that degrade the salivary molecules that nor- mally form a pellicle on the pathogens, which prevents the pathogens from adhering to mucosal surfaces. C, Oral bacteria pro- duce enzymes that degrade the salivary pellicle on the mucosal surface, thereby exposing adhesion receptors for respiratory pathogens. D, Cytokines from the saliva, from inflamed periodontal tissues, upregulate the expression of adhesion receptors on the mucosal surfaces to promote respiratory pathogen colonization. With permission from Scannapieco FA. Role of oral bacteria in respiratory infection. J Periodontol 1998;70:793–802.
P. gingivalis
H. influenzae protease
a P. gingivalis
H. influenzae
Salivary pellicle b
A B
P. gingivalis
H. influenzae
Mucous layer
cC
H. influenzae
salivary cytokines dD
92 Periodontal Medicine
tonsillar epithelium.98 These bound oral bacteria may stimulate cytokine production by mucosal epithelium. It is also possible that cytokines origi- nating from the oral tissues (for example, from the gingival crevicular fluids99–101), which exit the gingi- val sulcus to be mixed with whole saliva, may cont- aminate the distal respiratory epithelium to stimu- late the respiratory epithelial cells. These stimulated respiratory cells may then release other cytokines that recruit inflammatory cells (eg, neutrophils) to the site. These inflammatory cells may release hydrolytic enzymes and other modifying molecules, resulting in damaged epithelium that may be more susceptible to colonization by respiratory pathogens.
Oral bacteria may influence the expression and effects of cytokines in more novel ways. Darveau and colleagues102 have shown that IL-8 is secreted by gin- gival epithelial cells in response to components of the normal oral flora. In contrast, P. gingivalis strongly inhibits IL-8 accumulation from the gingival epithelial cells. Inhibition was shown to be associ- ated with a decrease in mRNA for IL-8. Antago- nism of IL-8 accumulation did not occur in KB cells, an epithelial cell line that does not support high levels of intracellular invasion by P. gingivalis. Furthermore, a noninvasive mutant of P. gingivalis was unable to antagonize IL-8 accumulation. They concluded that invasion-dependent destruction of the gingival IL-8 chemokine gradient at sites of P. gingivalis colonization may impair mucosal defense. It is not yet known if P. gingivalis would have a similar effect on the respiratory epithelium. Such an effect might result in perturbation of local cytokine networks and thus promote a destructive inflammatory lesion within the lung.
Prevention of Oral Colonization by Potential Respiratory Pathogens
Few studies have evaluated the role of poor oral hygiene and/or periodontal disease in the develop- ment of pneumonia in high-risk patients (for example, those that are mechanically ventilated). Several reports have documented a strong associa- tion between periodontal disease and an increased frequency of oral infections in nursing home resi- dents.57,103 However, there are no studies that have identified an association between poor oral hygiene and the increased incidence of pneumonia in such subjects. A possible link between poor oral hygiene and the increased incidence of pneumonia in nursing home residents has been suggested but no supporting evidence was provided.65 Recently, Terpenning and colleagues, in a preliminary report
of a longitudinal study of medical and dental con- ditions in nursing home residents, observed an association between the development of aspiration pneumonia and dental status.104 Among 26 den- tate nursing home residents followed up for 1 year, 5 (19.8%) developed pneumonia compared with 2 (7.6%) of 26 edentulous nursing home residents.
Because of the key role that oropharyngeal bacterial colonization plays in the pathogenesis of bacterial pneumonia, several methods have been proposed to reduce or eliminate colonization in susceptible patients, such as those on mechanical ventilation. We hypothesize that improved oral hygiene in the hospital setting may decrease the occurrence of oropharyngeal colonization by respi- ratory pathogens and thus decrease the risk of nosocomial pneumonia. Current oral hygiene measures recommended by nursing educators are probably inadequate to prevent dental plaque for- mation.105 One method, called selective digestive decontamination (SDD), uses antibiotics topically applied to the surfaces of the gastrointestinal tract (including the oral cavity) to reduce the carriage of pathogenic bacteria and thus to prevent respirato- ry infection.106–108 For example, the use of lozenges containing polymyxin B, tobramycin, and ampho- tericin B have been shown to diminish oral colo- nization by gram-negative bacilli.109 The study by Pugin and colleagues110 has particular relevance because it focused on the elimination of oropha- ryngeal colonization by pathogens and the subse- quent development of pneumonia. These investi- gators used topical oropharyngeal antibiotics (ver- sus topical placebo) in mechanically ventilated patients. Oropharyngeal colonization by aerobic gram-negative bacilli and S. aureus and also pneu- monia rates were significantly reduced in the treat- ed population versus the placebo group (16% ver- sus 78%; p < .0001). These findings suggest that focusing specifically on factors promoting oropha- ryngeal bacterial colonization may be useful in developing other strategies to prevent colonization and thereby prevent bacterial pneumonia in sus- ceptible populations. However, while diminishing the colonization rate of pathogenic bacteria in the hospital setting, SDD does not appear to have an effect on the mortality rate111 and seems to foster the selection of antibiotic-resistant bacteria and cross-infection.112,113 These findings have raised doubts about the widespread use of SDD. Other approaches to reduce colonization of these pathogens certainly deserve more study.
Maintenance of good oral hygiene may, by itself, reduce oropharyngeal colonization by respi-
Relationships between Periodontal and Respiratory Diseases 93
ratory pathogens. Methods of maintaining good oral hygiene in mechanically ventilated patients, if as effective as SDD in reducing pneumonia occur- rence, may be much less expensive than SDD reg- imens, may lessen the risk of emergence of antibi- otic resistance among bacteria indigenous to the intensive care unit, and may lessen antibiotic use. The overall effect may be a reduction in the cost of intensive care. Similarly, if providing and main- taining good oral hygiene in nursing home resi- dents is effective in reducing pneumonia rates, sig- nificant benefits to this high-risk population would include reduced morbidity and mortality related to pneumonia occurrence, reduced medical care costs because hospital admissions will be reduced, and an enhanced sense of well being.58
Although antiseptics with demonstrable abili- ty to disinfect the oral environment are avail- able,114,115 little research has been done concerning the efficacy of these agents to inhibit oral respira- tory pathogen colonization in institutionalized patients. Chlorhexidine appears to be a reasonable choice for this as it has been shown to reduce plaque and salivary levels of bacteria by up to 85%.116 Interestingly, chlorhexidine gluconate has been shown to reduce transfer of group B strepto- cocci from mother to infant during parturition.117
An analogous method used in the mouth may inhibit oral colonization by respiratory pathogens, with minimal risk. Chlorhexidine has had wide- spread use in dentistry to inhibit dental plaque for- mation,114 gingivitis,118 and oral mucosal ulcera- tions.119 This agent also appears to inhibit the pro- duction of proteases by subgingival bacteria.120 By inhibiting protease activity, chlorhexidine may diminish the potential of these enzymes to process oral surfaces to expose “cryptitopes” that may act as receptors for bacterial adhesins.84
An interesting report by DeRiso and col- leagues121 suggests that a 0.12% chlorhexidine glu- conate oral rinse reduced the overall nosocomial infection rate by 65% in 353 patients admitted to a cardiovascular ICU, and the incidence of total respiratory tract infections by 69%. These investi- gators also noted a 43% reduction in the use of nonprophylactic antibiotics in chlorhexidine-treat- ed patients. Finally, overall mortality was reduced to 1.16% in the chlorhexidine-treated group versus 5.56% in the placebo group.
A variety of recommendations have been made to reduce the incidence of nosocomial pneumo- nia.12 Fastidious infection control remains the cor- nerstone of prevention. Surveillance of potential pathogens, identification of high-risk patients,
staff education, hand washing, and the proper use of gloves and gowns, all have a positive impact on reducing nosocomial pneumonia. Additional attention paid to oral hygiene may even further reduce the risk of nosocomial pneumonia. Unfor- tunately, little information is available concerning the effect of improved oral hygiene on infection rates in the hospital or nursing home setting. It would, therefore, seem reasonable to perform appropriate studies to evaluate the effect of improved oral hygiene on respiratory pathogen colonization in high-risk subjects.
REFERENCES
1. Harvard School of Public Health B, Massachusetts, US. Mortality by cause for eight regions of the world: global burden of disease study. Lancet 1997;349:1269–76.
2. Petty TL, Weinmann GG. Building a national strat- egy for the prevention and management of and research in chronic obstructive pulmonary dis- ease. JAMA 1997;277:246–53.
3. Garibaldi RA, Brodine S, Matsumiya S. Infections among patients in nursing homes: policies, prevalence and problems. N Engl J Med 1981; 305:731–5.
4. Bentley DW. Bacterial pneumonia in the elderly: clinical features, diagnosis, etiology, and treat- ment. Gerontologist 1984;30:297–307.
5. Donowitz GR, Mandell GL. Acute pneumonia. In: Mandell GL, Douglas RG, Bennett JE, editors. Principles and practice of infectious diseases. New York: Churchill Liningstone; 1990.
6. Levy SB. The challenge of antibiotic resistance. Sci Am 1998;278:46–53.
7. Østergaard L, Andersen PL. Etiology of community- acquired pneumonia. Evaluation by transtra- cheal aspiration, blood culture, or serology. Chest 1993;104:1400–7.
8. Rosenthal S, Tager IB. Prevalence of gram-negative rods in the normal pharyngeal flora. Ann Intern Med 1975;83:355–7.
9. Bartlett JG, O’Keefe P, Tally FP, et al. Bacteriology of hospital-acquired pneumonia. Arch Intern Med 1986;146:868–71.
10. Cunha BA. Hospital-acquired pneumonias, clinical diagnosis and treatment. Hosp Phys 1986;22: 12–7.
11. Toews GB. Nosocomial pneumonia. Am J Med Sci 1986;291:355–67.
12. Craven DE, Steger KE, Barber TW. Preventing noso- comial pneumonia: state of the art and perspec- tives for the 1990s. Am J Med 1991;91:44S–53S.
94 Periodontal Medicine
13. Wenzel RP. Epidemiology of hospital-acquired infection. In: Balows A, Hausler WJ, Herrmann KI, et al, editors. Manual of clinical microbiol- ogy. Washington, D.C.: American Society for Microbiology; 1991. p. 147–50.
14. Boyce JM, Potter-Bynoe G, Dziobek L, Solomon SL. Nosocomial pneumonia in Medicare patients. Hospital costs and reimbursement pat- terns under the prospective payment system. Arch Intern Med 1991;151:1109–14.
15. Wenzel RP. Hospital-acquired pneumonia: overview of the current state of the art preven- tion and control. Eur J Clin Microbiol Infect Dis 1989;8:56–60.
16. McDonald AM, Dietsche L, Litsche M, et al. A ret- rospective study of nosocomial pneumonia at a long-term care facility. Am J Infect Cont 1992; 20:234–8.
17. Ingram RH. Chronic bronchitis, emphysema, and airways obstruction. In: Isselbacher KJ, Braun- wald E, Wilson JD, et al, editors. Harrison’s Principles of internal medicine. New York: McGraw-Hill; 1994. p. 1197–206.
18. Society AT. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152: S77–121.
19. Renwick DS, Connolly MJ. Prevalence and treat- ment of chronic airways obstruction in adults over the age of 45. Thorax 1996;51:164–8.
20. Sandford AJ, Weir TD, Pare PD. Genetic risk fac- tors for chronic obstructive pulmonary disease. Eur Resp J 1997;10:1380–91.
21. Murphy TF, Sethi S. Bacterial infection in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992;146:1067–83.
22. Fagon JY, Chastre J. Severe exacerbations of COPD patients: the role of pulmonary infec- tions. Semin Respir Infect 1996;11:109–18.
23. Laurenzi GA, Potter RT, Hass EH. Bacteriologic flora of the lower respiratory tract. N Engl J Med 1961;265:1273–8.
24. Cabello H, Torres A, Celis R, et al. Bacterial colo- nization of distal airways in healthy subjects and chronic lung disease: a bronchoscopic study. Eur Respir J 1997;10:1137–44.
25. Levison ME. Pneumonia, including necrotizing pulmonary infections (lung abscess). In: Issel- bacher KJ, Braunwald E, Wilson JD, et al, edi- tors. Harrison’s Principles of internal medicine. New York: McGraw-Hill; 1994. p. 1184–91.
26. Megran DW, Chow AW. Bacterial aspiration and anaerobic pleuropulmonary infections. In: Sande MA, Hudson LD, Root RK, editors. Res-
piratory infections. New York: Churchill Liv- ingstone; 1986. p. 269–92.
27. Fiddian-Green R, Baker S. Nosocomial pneumonia in the critical ill: product of aspiration or translocation? Crit Care Med 1991;19:793–9.
28. Sinclair DG, Evans TW. Nosocomial pneumonia in the intensive care unit. Br J Hosp Med 1994; 51:177–80.
29. Bonten MJM, Gaillard CA, Tiel FHV, et al. The stomach is not a source for colonization of the upper respiratory tract and pneumonia in ICU patients. Chest 1994;105:878–84.
30. Bartlett JG, Finegold SM. Anaerobic infections of the lung and pleural space. Am Rev Respir Dis 1974;110:56–77.
31. Bartlett JG. Anaerobic bacterial infections of the lung. Chest 1987;91:901–9.
32. Shinzato T, Saito A. A mechanism of pathogenicity of “Streptococcus milleri group” in pulmonary infection: synergy with an anaerobe. J Med Microbiol 1994;40:118–23.
33. Elpern EH, Scott MG, Petro L, Ries MH. Pul- monary aspiration in mechanically ventilated patients with tracheostomies. Chest 1994;105: 563–6.
34. Finegold SM. Aspiration pneumonia. Rev Infect Dis 1991;13:S737–42.
35. Harkness GA, Bentley DW, Roghman KJ. Risk fac- tors for nosocomial pneumonia in the elderly. Am J Med 1990;89:457–63.
36. Potter RT, Rotman F, Fernandez F, et al. The bac- teriology of the lower respiratory tract. Bron- choscopic study of 100 clinical cases. Am Rev Respir Dis 1968;97:1051–61.
37. Schreiner A. Anaerobic pulmonary infections. Scand J Infect Dis 1979;19 Suppl:77–9.
38. Brook I, Frazier EH. Aerobic and anaerobic micro- biology of empyema. A retrospective review in two military hospitals. Chest 1993;103:1502–7.
39. Goldstein EJ, Kirby BD, Finegold SM. Isolation of Eikenella corrodens from pulmonary infections. Am Rev Respir Dis 1979;119:55–8.
40. Suwanagool S, Rothkopf MM, Smith SM, et al. Pathogenicity of Eikenella corrodens in humans. Arch Intern Med 1983;143:2265–68.
41. Joshi N, O’Bryan T, Appelbaum PC. Pleuropul- monary infections caused by Eikenella corrodens. Rev Infect Dis 1991;13:1207–12.
42. Zijlstra EE, Swart GR, Godfroy FJM, Degener JE. Pericarditis, pneumonia and brain abscess due to a combined Actinomyces-Actinobacillus actino- mycetemcomitans infection. J Infect 1992;25: 83–7.
43. Mahomed AG, Feldman C, Smith C, et al. Does
Relationships between Periodontal and Respiratory Diseases 95
primary Streptococcus viridans pneumonia exist? S Afr Med J 1992;82:432–4.
44. Lorenz KA, Weiss PJ. Capnocytophageal pneumo- nia in a healthy man. West J Med 1994;160: 79–80.
45. Morris JF, Sewell DL. Necrotizing pneumonia caused by mixed infection with Actinobacillus actinomycetemcomitans and Actinomyces israelii: Case report and review. Clin Infect Dis 1994;18:450–2.
46. Yuan A, Luh KT, Yang PC. Actinobacillus actino- mycetemcomitans pneumonia with possible sep- tic embolization [letter]. Chest 1994;105:646.
47. Chen AC, Liu CC, Yao WJ, et al. Actinobacillus actinomycetemcomitans pneumonia with chest wall and subphrenic abscess. Scand J Infect Dis 1995;27:289–90.
48. Moore WEC, Moore LVH. The bacteria of perio- dontal disease. Periodontol 2000 1994;5: 66–77.
49. Slots J, Rams TE. Microbiology of periodontal dis- ease. In: Slots J, Taubman MA, editors. Con- temporary oral microbiology and immunology. St. Louis, MO: Mosby-Year Book Inc.; 1992. p. 425–43.
50. Appelbaum PC, Cameron EW, Hutton WS, et al. The bacteriology of chronic destructive pneu- monia. S Afr Med J 1978;53:541–2.
51. Pratter MR, Irwin RS. Viridans streptococcal pul- monary parenchymal infections. JAMA 1980; 243:2515–7.
52. Marrie TJ. Bacteremic community-acquired pneu- monia due to viridans group streptococci. Clin Invest Med 1993;16:38–44.
53. Haas H, Morris JF, Samson S, et al. Bacterial flora of the respiratory tract in chronic bronchitis: comparison of transtracheal, fiberbronchoscop- ic, and oropharyngeal sampling methods. Am Rev Respir Dis 1977;116:41–7.
54. Torres A, Dorca J, Zalacain R, et al. Community- acquired pneumonia in chronic obstructive pul- monary disease: a Spanish multicenter study. Am J Respir Crit Care Med 1996;154:1456–61.
55. Nelson S, Laughon BE, Summer WR, et al. Char- acterization of the pulmonary inflammatory response to an anaerobic bacterial challenge. Am Rev Respir Dis 1986;133:212–7.
56. Grollier G, Dore P, Robert R, et al. Antibody response to Prevotella spp. in patients with ven- tilator-associated pneumonia. Clin Diag Lab Immunol 1996;3:61–5.
57. Bagramian RA, Heller RP. Dental health assess- ment of a population of nursing home residents. J Gerontol 1977;32:168–74.
58. Karuza J, Miller WA, Lieberman D, et al. Oral sta- tus and resident well-being in a skilled nursing facility population. Gerontologist 1992;32: 104–12.
59. Scannapieco FA, Stewart EM, Mylotte JM. Colo- nization of dental plaque by respiratory pathogens in medical intensive care patients. Crit Care Med 1992;20:740–5.
60. Kiyak HA, Grayston MN, Crinean CL. Oral health problems and needs of nursing home res- idents. Comm Dent Oral Epidemiol 1993;21: 49–52.
61. Fourrier F, Duvivier B, Boutigny H, et al. Colo- nization of dental plaque: a source of nosocomi- al infections in intensive care unit patients. Crit Care Med 1998;26:301–8.
62. Russell SL, Boylan RJ, Kaslick R, et al. Respiratory pathogen colonization of the dental plaque of institutionalized elders. Spec Care Dent 1999; 19:1–7.
63. Komiyama K, Tynan JJ, Habbick BF, et al. Pseudomonas aeruginosa in the oral cavity and sputum of patients with cystic fibrosis. Oral Surg Oral Med Oral Pathol 1985;59:590–4.
64. Costerton JW, Lewandowski Z, Caldwell DE, et al. Microbial biofilms. Ann Rev Microbiol 1995; 49:711–45.
65. Scannapieco FA, Mylotte JM. Relationships between periodontal disease and bacterial pneu- monia. J Periodontol 1996;67:1114–22.
65a. Silness J, Löe H. Periodontal disease in pregnancy. II. Correlation between oral hygiene and perio- dontal condition. Acta Odontol Scand 1964; 24:747–59.
65b.Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classifica- tion system. Crit Care Med 1985;13:818–29.
66. Limeback H. The relationship between oral health and systemic infections among elderly residents of chronic care facilities: a review. Gerodontolo- gist 1988;7:131–7.
67. Limeback H. Implications of oral infections on sys- temic diseases in the institutionalized elderly with a special focus on pneumonia. Ann Perio- dontol 1998;3:262–75.
68. Mojon P, Budtz-Jørgensen E, Michel JP, Limeback H. Oral health and history of respiratory tract infection in frail institutionalised elders. Gerodontologist 1997;14:9–16.
69. Scannapieco FA, Papandonatos GD, Dunford RG. Associations between oral conditions and respi- ratory disease in a national sample survey popu- lation. Ann Periodontol 1998;3:251–6.
70. Hayes C, Sparrow D, Cohen M, et al. Periodontal
96 Periodontal Medicine
disease and pulmonary function: the VA longi- tudinal study. Ann Periodontol 1998; 257–61.
71. Johanson WG, Pierce AK, Sanford AK, Thomas JP. Nosocomial respiratory infections with gram- negative bacilli: the significance of colonization of the respiratory tract. Ann Intern Med 1972; 77:701–6.
72. Johanson WG, Higuchi JH, Chaudhuri TR, Woods DE. Bacterial adherence to epithelial cells in bacillary colonization of the respiratory tract. Am Rev Respir Dis 1980;121:55–63.
73. Woods DE, Straus DC, Johanson WG, Bass JA. Role of fibronectin in the prevention of adher- ence of Pseudomonas aeruginosa to buccal cells. J Infect Dis 1981;143:784–90.
74. Abraham SN, Beachey EH, Simpson WA. Adher- ence of Streptococcus pyogenes, Escherichia coli and Pseudomonas aeruginosa to fibronectin-coat- ed and uncoated epithelial cells. Infect Immun 1983;41:1261–8.
75. Nakamura M, Slots J. Salivary enzymes. Origin and relationship to periodontal disease. J Perio- dontal Res 1983;18:559–69.
76. Zambon JJ, Nakamura M, Slots J. Effect of perio- dontal therapy on salivary enzyme activity. J Periodontal Res 1985;20:652–9.
77. Gibbons RJ, Etherden I. Fibronectin-degrading enzymes in saliva and their relation to oral cleanliness. J Periodontal Res 1986;21:386–95.
78. Loesche WJ, Syed SA, Stoll J. Trypsin-like activity in subgingival plaque. A diagnostic marker for spirochetes and periodontal disease. J Periodon- tol 1987;58:266–73.
79. Wikstrom M, Linde A. Ability of oral bacteria to degrade fibronectin. Infect Immun 1986;51: 707–11.
80. Frandsen EG, Reinholdt J, Kilian M. Enzymatic and antigenic characterization of immunoglob- ulin A1 proteases from Bacteroides and Capnocy- tophaga spp. Infect Immun 1987;55:631–8.
81. Cimasoni G, Ishikawa I, Jacccard F. Enzyme activ- ity in the gingival crevice. In: Lehner T, editor. Borderland between caries and periodontal dis- ease. London: Academic Press; 1977. p. 13–41.
82. Quinn MO, Miller VE, Dal Nogare AR. Increased salivary exoglycosidase activity during critical illness. Am J Respir Crit Care Med 1994;150: 179–83.
83. Weinmeister KD, Dal Nogare AR. Buccal cell car- bohydrates are altered during critical illness. Am J Respir Crit Care Med 1994;150:131–4.
84. Gibbons RJ, Hay DI, Childs WC, Davis G. Role of cryptic receptors (cryptitopes) in bacterial adhe- sion to oral surfaces. Arch Oral Biol 1990;35: 107S–114S.
85. Reddy MS, Murphy TF, Faden HS, Bernstein JM. Middle ear mucin glycoprotein: purification and interaction with nontypable Haemophilus influenzae and Moraxella catarrhalis. Otolaryn- gol Head Neck Surg 1997;116:175–80.
86. Davies J, Carlstedt I, Nilsson AK, et al. Binding of Haemophilus influenzae to purified mucins from the human respiratory tract. Infect Immun 1995;63:2485–92.
87. Barsum W, Wilson R, Read RC, et al. Interaction of fimbriated and nonfimbriated strains of unencapsulated Haemophilus influenzae with human respiratory tract mucus in vitro. Eur Respir J 1995;8:709–14.
88. Fakih MG, Murphy TF, Pattoli MA, Berenson CS. Specific binding of Haemophilus influenzae to minor gangliosides of human respiratory epithe- lial cells. Infect Immun 1997;65:1695–700.
89. van der Hoeven JS, van den Kieboom CW, Camp PJM. Utilization of mucin by oral Streptococcus species. Antonie van Leeuwenhoek 1990;57: 165–72.
90. Scannapieco FA. Saliva-bacterium interactions in oral microbial ecology. Crit Rev Oral Biol Med 1994;5:203–48.
91. Reddi K, Wilson M, Nair S, et al. Comparison of the pro-inflammatory cytokine-stimulating activity of the surface-associated proteins of periodontopathic bacteria. J Periodontal Res 1996;31:120–30.
92. Wilson M, Reddi K, Henderson B. Cytokine- inducing components of periodontopathogenic bacteria. J Periodontal Res 1996; 31:393–407.
93. Kjeldsen M, Holmstrup P, Lindemann RA, Bendtzen K. Bacterial-stimulated cytokine pro- duction of peripheral mononuclear cells from patients of various periodontitis categories. J Periodontol 1995;66:139–44.
94. Svanborg C, Hedlund M, Connell H, et al. Bacte- rial adherence and mucosal cytokine responses. Receptors and transmembrane signaling. Ann N Y Acad Sci 1996;797:177–90.
95. Khair OA, Davies RJ, Devalia JL. Bacterial- induced release of inflammatory mediators by bronchial epithelial cells. Eur Respir J 1996;9: 1913–22.
96. Durum SK, Oppenheim J. Proinflammatory cytokines and immunity. In: Paul WE, editor. Fundamental immunology. New York, NY: Raven Press Ltd.; 1993.
97. Håkansson A, Carlstedt I, Davies J, et al. Aspects on the interactions of Streptococcus pneumoniae and Haemophilus influenzae with human respi- ratory tract mucosa. Am J Respir Crit Care Med 1996;154:S187–91.
Relationships between Periodontal and Respiratory Diseases 97
98. Brook I, Yocum P, Foote PAJ. Changes in the core tonsillar bacteriology of recurrent tonsillitis: 1977–1993. Clin Infect Dis 1995;21:171–6.
99. Rossomando EF, White L. A novel method for the detection of TNF-alpha in gingival crevicular fluid. J Periodontol 1993;64:445–9.
100. Tatakis DN. Interleukin-1 and bone metabolism: a review. J Periodontol 1993;64:416–31.
101. Birkedal-Hansen H. Role of cytokines and inflam- matory mediators in tissue destruction. J Perio- dontal Res 1993;28:500–10.
102. Darveau RP, Belton CM, Reife RA, Lamont RJ. Local chemokine paralysis, a novel pathogenic mechanism for Porphyromonas gingivalis. Infect Immun 1998;66:1660–5.
103. Viglid M. Oral hygiene and periodontal condi- tions among 201 dentate institutionalized elder- ly. Gerodontologist. 1988;4:140–5.
104. Terpenning M, Bretz W, Lopatin D, et al. Bacteri- al colonization of saliva and plaque in the elder- ly. Clin Infect Dis 1993;16 Suppl:314–6.
105. Luckman J, Sorensen KC. Medical-surgical nurs- ing. Philadelphia, PA: W.B. Saunders Co.; 1987.
106. Kerver AJH, Rommes JH, Mevissen-Verhage EAE, et al. Prevention of colonization and infection in critically ill patients: a prospective randomized study. Crit Care Med 1988;16:1087–93.
107. Nord CE, Heindahl A. Impact of orally adminis- tered antimicrobial agents on human oropha- ryngeal and colonic microflora. J Antimicrob Ther 1986;18 Suppl C:159–64.
108. Stoutenbeek CP, Hendrik HKF, Miranda DR, et al. The effect of oropharyngeal decontamination using topical nonabsorbable antibiotics on the incidence of nosocomial respiratory tract infec- tions in multiple trauma patients. J Trauma 1987;27:357–64.
109. Spijkervet FKL, Saene HKFV, Saene JJMV, et al. Effect of selective elimination of the oral flora on mucositis in irradiated head and neck cancer patients. J Surg Oncol 1991;46:167–73.
110. Pugin J, Auckenthaler R, Lew DP, Suter PM. Oropharyngeal decontamination decreases inci- dence of ventilator-associated pneumonia. A randomized, placebo-controlled, double-blind clinical trial. JAMA 1991;265:2704–10.
111. Gastinne H, Wolff M, Delatour F, et al. A con-
trolled trial in intensive care units of selective decontamination of the digestive tract with nonabsorbable antibiotics. N Engl J Med 1992;326:594–9.
112. Johanson WG, Seidenfeld JJ, de los Santos R, et al. Prevention of nosocomial pneumonia using topical and parenteral antimicrobial agents. Am Rev Respir Dis 1988;137:265–72.
113. Hurley JC. Prophylaxis with enteral antibiotics in ventilated patients: selective decontamination or selective cross-infection? Antimicrob Agents Chemother 1995;39:941–7.
114. Tonelli PM, Hume WR, Kenney EB. Chlorhexi- dine: a review of the literature. J West Soc Perio- dontol 1983;31:5–30.
115. Exner M, Gregori G, Pau HW, Vogel F. In vivo studies on the microbicidal activity of antisep- tics on the flora of the oropharyngeal cavity. J Hosp Infect 1985;6 Suppl:185–8.
116. Balbuena L, Stambaugh KI, Ramirez SG, Yeager C. Effects of topical oral antiseptic rinses on bacter- ial counts of saliva in healthy human subjects. Otolaryngol Head Neck Surg 1998;118:625–9.
117. Nilsson G, Larsson L, Christensen K, et al. Chlorhexidine for prevention of neonatal colo- nization with group B streptococci. V. Chlor- hexidine concentrations in blood following vaginal washing during delivery. Eur J Obstet Gynec Reprod Biol 1989;31:221–6.
118. Lang NP, Brecx MC. Chlorhexidine gluconate— an agent for chemical plaque control and pre- vention of gingival inflammation. J Periodontal Res 1986;21 Suppl 16:74–89.
119. Ferretti GA, Ash RC, Brown AT, et al. Control of oral mucositis and candidiasis in marrow trans- plantation: a prospective double blind trial of chlorhexidine. Bone Marrow Transplant 1988;3: 483–94.
120. Radford JR, Homer KA, Naylor MN, Beighton D. Inhibition of human subgingival plaque pro- tease activity by chlorhexidine. Arch Oral Biol 1992;37:245–8.
121. DeRiso AJN, Ladowski JS, Dillon TA, et al. Chlorhexidine gluconate 0.12% oral rinse reduces the incidence of total nosocomial respi- ratory infection and nonprophylactic systemic antibiotic use in patients undergoing heart surgery. Chest 1996;109:1556–61.
CHAPTER 7
TOBACCO USE AND INTERVENTION Robert E. Mecklenburg, DDS, MPH Sara G. Grossi, DDS, MS
The good news is that three-quarters of the adult population in the United States do not use tobac- co. Smoking decreased in the general population from 42% in 1965 to 25% by 1995.1 Among adults aged 18 to 24 years, tobacco use was approx- imately half as high in 1991 (23%) as in 1965 (46%).2 Among high school seniors, the prevalence of daily smoking decreased from 29% in 1976 to 17% in 1992.3 Public awareness of the risks associ- ated with tobacco use is increasing, and some pub- lic policy ground has been gained, such as the enactment of several community, state, and federal clean-air laws.
The bad news is that trends in tobacco use reversed during the 1990s.3 Large, protracted tobacco industry advertising and promotion cam- paigns influenced the susceptible adolescent popu- lation. Youth use of tobacco increased year by year after 1991 to 43% of U.S. high school students using cigarettes, smokeless tobacco, or cigars in 1997, which is a 32% increase. By 1997, this trend led to a new increase in tobacco use among adults aged 18 to 24 years.3a Some cigarette smokers switched to or started using smokeless/spit tobacco and/or cigars, and some never-smokers began using smokeless/spit tobacco and/or cigars only. A common mistaken belief is that a reduced risk is equivalent to a negligible risk.3b,3c Also, few youths appreciate the addictive properties of nicotine inherent in the use of any tobacco product, non adults perceive the extent of their tobacco-related health risks.3
Cigarette smoking is the single most impor- tant and modifiable factor responsible for cases of lung cancer, hypertension, and cardiovascular dis- eases in the western world. Malignant and prema- lignant oral lesions alike have been associated with cigarette smoking.4,5 Generally speaking, soft tis- sue conditions, dental caries, and delayed wound
healing are exceedingly more prevalent in smokers compared with nonsmokers. Periodontal disease has been added to the ever-increasing list of health consequences (oral and systemic) of tobacco smok- ing.6-12 Chronic exposure to many substances in tobacco and tobacco byproducts significantly affects the prevalence and progression of periodon- tal diseases.8,9,12,13 So profound is the negative effect of cigarette smoking on the periodontium that exposure to second-hand smoke accounts for 30% of periodontal disease in nonsmokers.14 In addition, tobacco use complicates periodontal therapy and substantially reduces the possibility of favorable treatment outcomes.15–17 Integrating tobacco intervention services within clinical prac- tice is a prudent clinical step and professional obligation. From a broader perspective, providing such services is a civic duty. All scientifically sound clinical intervention services available to the health professional should be applied to help dental patients overcome this life-endangering behavior.
COST OF USING TOBACCO
Most adults and adolescents are aware that tobac- co use jeopardizes their health but may not realize how great the risk is compared with other behav- iors that are considered risky.1 Cigarette smoking is the most important preventable cause of morbidi- ty and mortality in the United States. It is respon- sible for more than 400,000 deaths each year (1998 estimate, 430,700).18 Indeed, nearly one of every five American deaths can be attributed to cigarette smoking. Each year, more than 140,000 women die as a result of smoking-related diseases. Among women, cardiovascular disease is the most common cause of smoking-related death.19 Lung cancer, the second most common cause, has been
100 Periodontal Medicine
rising rapidly since the early 1960s and, in 1989, exceeded breast cancer as the most common form of cancer death among women.20 The lung cancer mortality rate among men has stabilized but remains the leading cause of cancer in all male age groups ages 15 and older.21–23
Tobacco use produces massive economic costs to society. The direct annual cost of treating smok- ing related illness is greater than the gross sales of tobacco products.24,25 When the indirect costs of smoking during pregnancy, lost workdays, lost out- put from early death or retirement and the external costs, such as fires caused by smoking, are added to medical costs, the burden to the U.S. economy in 1998 approaches $130 billion per year, more than two and a half times the gross sales of tobacco prod- ucts.25,26 Intangible costs add to the burden, such as tobacco-related suffering, disability, and worsening in the quality of life. Cigar and pipe smoking and the use of smokeless/spit tobacco significantly ele- vate health risks and are not safe alternatives to cig- arette smoking.3c,27,28 Their relatively low propor- tion of use and recent increase in popularity do not provide as solid an evidence base for adverse eco- nomic consequences as does the overwhelming evi- dence attributed to cigarette smoking.
On a global perspective tobacco use is responsi- ble for about 4 million deaths each year. That figure represents more deaths than are caused by HIV, tuberculosis, maternal mortality, motor vehicle acci- dents, suicides, and homicides combined. By 2030, the World Health Organization projects that tobacco will be the leading cause of death and disability, killing more than 10 million people annually. 28a,28b
These statistics are even more alarming when one considers that all smoking-related deaths are essen- tially preventable. The decline in cigarette smoking in the United States over the last 25 years has not been equal across all populations. The number of adults currently remains high, and adult prevalence has changed little from 1993 to 1997.1 Increased trends in tobacco use by youths in the United States por- tends a worsening state of tobacco-related diseases.
Cost to the Periodontium: Risk Factors
Cigarette smoking accounts for approximately half the cases of periodontitis diagnosed in young adults (< 35 years ).29 A meta-analysis from six cross-sec- tional and case-control studies reported an odds ratio of 2.82 (95% CI 2.36 to 3.39) for “severe” periodontal disease (Figure 7–1).30 Smokers are, therefore, almost three times more likely to show severe periodontal disease compared with non-
smokers. Since smokers with slight or moderate periodontitis were either excluded from this analy- sis or included as controls, this figure may represent an underestimation of the real magnitude of the association. Current smokers were also 3.3 times more likely to attend a periodontal practice office compared with nonsmokers.31 The effect of smok- ing on periodontal tissues is cumulative and dose dependent (Figures 7–2 and 7–3). Evidence for this biologic gradient is demonstrated in the Erie County Study, where 80% of individuals smoking at least 20 pack-years exhibited moderate to severe periodontal disease, measured by either clinical attachment loss (see Figure 7–2)8 or alveolar bone loss (see Figure 7–3).9 Clinically, smoking-associated periodontal disease presents with thick inflamed marginal gingiva and generalized recession. The buccal marginal gingiva of both upper and lower anterior teeth often present with the characteristic stain of smoker melanosis (Figure 7–4). The degree of alveolar bone destruction far exceeds the peri- odontal destruction evident clinically (Figures 7–5 and 7–6). If these figures do not speak for them- selves, 30% of the incidence of periodontal disease in nonsmokers is accounted for by exposure to environmental (household) second-hand smoke.14
Thus, cigarette smoking is the single, modifiable environmental factor responsible for the excess prevalence of periodontal disease in the population. Cases of periodontal disease attributed solely to smoking are by far greater than the ones owed to other important factors such as diabetes mellitus.7
Accordingly, cigarette smoking has been demon- strated to fit all of the nine “Bradford Hill criteria” for causation and, as such, is proposed as a causal factor in severe periodontal disease.32
Mechanisms of Tobacco Toxicity to the Periodontium
There is an established biologic rationale for the negative effect of cigarette smoking on periodontal tissues. First and foremost, smoking has an immunosuppressive effect on the host, adversely affecting host-parasite interactions. Peripheral blood polymorphonuclear leukocyte motility, chemotaxis, and phagocytosis are significantly impaired,33-36
thus, compromising this very important first line of defense against subgingival bacteria. In addition, smokers have decreased antibody production, espe- cially IgG2,37 the subclass most important in the opsonization of periodontal bacteria, and decreased immunoregulatory T-cell subset ratios.38 The net result is that periodontal organisms in current ciga-
Tobacco Use and Intervention 101
rette smokers escape specific and nonspecific immune clearance mechanisms allowing them to establish as subgingival inhabitants. Alteration in the physical subgingival environment, such as decreased oxygen tension, would allow the over- growth of an essentially anaerobic flora.39,40 In addi- ton, cigarette smoking also increases bacterial adhe- sion to epithelial cells.41 Indeed, current smokers are significantly more likely to be infected with Bac- teroides forsythus and Porphyromonas gingivalis com- pared with nonsmokers.42
Several studies have demonstrated the absorp- tion of nicotine in periodontal tissues. Nicotine has been detected on root surfaces in smokers with peri- odontal disease.43 Cotinine, the major metabolite of nicotine, is found in the serum, saliva, and gingival crevicular fluid of smokers.44 Fibroblasts exposed to nicotine have shown reduced proliferation,45 migra- tion, and attachment to root surfaces.46 In addition, fibroblasts have been shown to nonspecifically bind and internalize nicotine,47 which could, in turn, result in an alteration of the cell metabolism, includ- ing collagen synthesis and protein secretion. In sum- mary, cigarette smoking appears to trigger a cycle of impaired immune response, anaerobic subgingival infection, and connective tissue cytotoxicity, leading to greater severity of periodontal disease and impaired wound healing.
Tobacco Use and Response to Periodontal Therapy
Nonsurgical Therapy Scientific evidence shows that smoking impairs wound healing throughout the body, including the
oral cavity. Periodontal intervention studies consis- tently demonstrate that smokers do not heal as well as nonsmokers after periodontal therapy. The clin- ical outcomes of periodontal therapy, that is reduc- tion in pocket depth and gain in probing attach- ment level, are significantly reduced in current smokers compared with former and nonsmokers (Figure 7–7)15,17,48,49 The reduced clinical response to mechanical therapy seen in current smokers is paralleled by a persistence of subgingival B. forsythus and P. gingivalis compared with nonsmok- ers or former smokers (Figure 7–8).16 This reduced clinical response is directly related to active smok- ing. Former smokers, on the other hand, respond to periodontal therapy in a manner similar to never-smokers.16 Although no studies have specifi- cally addressed the effect of smoking cessation on periodontal therapy, indirect data from interven- tion studies that have included former smokers indicate that smoking cessation restores the host’s
Figure 7–1. Meta-analysis of smoking as a risk factor for periodontal diseases. Bars indicate the 95% confidence lim- its for the depicted odds ratios. Adapted from Papapanou, PN. Periodontal diseases: epidemiology. Ann Periodontol 1996;1:1–36.
Figure 7–2. Dose-dependent effect of cigarette smoking and severity of attachment loss. For every 10 pack-years incre- ment, there is 1 mm increase in mean attachment loss. Adapted from Grossi et al. J Periodontol 1994;65:260–7.
Figure 7–3. Severity of alveolar bone loss is directly propor- tional to the overall lifetime exposure to tobacco smoke, measured as pack-years. Adapted from Grossi et al. J Perio- dontol 1995;66:23–9.
102 Periodontal Medicine
healing capacity to levels comparable with those who never smoked.
Surgical, Regenerative, and Implant Therapy Current cigarette smoking impairs wound healing following surgical periodontal therapy to a greater extent than following nonsurgical therapy. Smok- ers that underwent periodontal surgery with either modified Widman flap or mucoperiosteal flap had significantly less reduction in pocket depth and gain in probing attachment levels compared with nonsmokers.50 Cigarette smoking has also been associated with a reduced healing response after guided tissue-regeneration therapy in the deep intrabony defects51,52 and with an 80% failure rate in the treatment of furcation defects.53 Current smoking also decreases the percentage of root cov- erage that takes place after tissue grafting.54 Eighty percent of current smokers undergoing intraoral bone grafting and simultaneous implant placement showed impaired wound healing, defined as loss of bone or implant, compared with only 10% of non-
smokers.55 In a 15-year prospective study of mandibular implant prostheses, current smoking was more closely associated with marginal bone loss around implants than was poor oral hygiene.56
In summary, current smoking is by far the most significant factor responsible for impaired peri- odontal wound healing and poor clinical outcome following flap and regenerative surgery and implant failure.51,52,54–57
Supportive Periodontal Therapy and Need for Re-treatment Two independent studies on the long-term effects of supportive periodontal therapy (SPT) consistently agreed that smokers have a less favorable response to SPT compared with nonsmokers.17,50 This reduced response is dose dependent in that heavy smokers, that is, > 20 cigarettes per day, respond less favorably than light smokers (< 19 cigarettes/day) to long- term SPT.17 Both studies report the encouraging finding that former smokers respond to STP in a manner similar to those that never smoked. A sim- ilar benefit of smoking cessation has been reported for dental implant survival.58 Ninety percent of patients diagnosed with refractory periodontitis are current smokers.36 Thus, not only does smoking result in reduced response to all modalities of peri- odontal treatment and less favorable outcome, sus- ceptibility to recurrence and need for re-treatment are increased as well.
Cost to Patient and Provider to Treat Tobacco-Related Periodontal Conditions
When one considers the simple fact that severe peri- odontal disease will result in more clinic visits, longer clinic appointments, and more complex treatment procedures than will less severe forms of disease, the
Figure 7–4. Female heavy smoker (more than 20 pack- years). Attached gingiva is thick, chronically inflamed, and fibrotic. Smoker melanosis is evident as well.
Figure 7–5. Male heavy smoker (more than 20 pack-years) with severe periodontal disease. Gingival tissue is thick, fibrotic, and with receded margins.
Figure 7–6. Radiographic evaluation of same patient as in Fig- ure 7–5. Generalized severe alveolar bone loss is evident, involving 50% of the root length or more. Furcation involve- ment (class III) in all molars is evident. Degree of alveolar bone destruction in this patient exceeds the clinical involvement.
Tobacco Use and Intervention 103
increased cost of treating smoking-related periodon- tal disease to both patient and provider becomes evi- dent. If one then considers that 80% of moderate to severe periodontal disease is associated with heavy smoking, the figures are rather staggering. If the costs of periodontal treatment are calculated, smoking is second only to number of remaining teeth and age. Following the same trend seen for disease severity and response to periodontal therapy, smoking, mea- sured as number of cigarettes per day, has a signifi- cant effect both on the treatment cost per patient and per individual tooth.59 Thus, in addition to causing and exacerbating oral diseases and condi- tions, tobacco use adversely affects oral health care. Occasionally, patients that exhibit tobacco-related diseases may require special planning, premedica- tion, consultation, or unanticipated medical care during their oral health care. Conversely, tobacco intervention services for the prevention and treat- ment of oral diseases also benefit the general health and well-being of the patient and reduce collateral risks to clinical practice and society.60
UNDERLYING DISEASE
Understanding of the nature of nicotine depen- dency is essential to applying substantive, efficient means to treat this debilitating condition. Provid- ing periodontal therapy or several other clinical services to tobacco users without treating their tobacco dependency is analogous to painting a rusty surface—a major underlying cause and/or major contributor to the problem is not addressed, thus predisposing to recurrence.
Nicotine dependency is a progressive, chronic, relapsing disease; it is a brain disease imbedded in a social context. That is, nicotine governs tobacco- using behavior, but many psychologic and social cues reinforce the process. Nicotine is considered as addictive as other commonly used substances of abuse; however, more tobacco experimenters become dependent and, once dependent, have greater difficulty while quitting and lower success rates.61 This is partly because of the low cost and easy availability of tobacco and partly because use is socially acceptable in some environments.62
At the molecular-cellular level, nicotine is a tertiary amine that is highly psychoactive. In the brain, chronic exposure to nicotine stimulates release of dopamine and other neurotransmitter monoamines into the CNS neuronal cleft and other sites. In the presence of repeated exposure, nicotinic acetylcholine receptors proliferate on the
postsynaptic neurons. Intraneuronal changes occur that alter gene expression. With repeated exposure, central nervous system (CNS) stimulation by nico- tine gradually wanes, and more nicotine becomes necessary to ward off withdrawal symptoms. Brain metabolism initially increases and then stabilizes in the presence of nicotine. Thus, continued periodic dosing with nicotine becomes a necessity for indi- viduals to function normally as they would had
Figure 7–8. Percent of patients that became negative for A. actinomycetemcomitans, B. forsythus, and P. gingivalis at 3 months following mechanical periodontal therapy. Half as many smokers continued to become negative for any of these periodontal organisms after treatment compared with non- smokers, suggesting that the reduced clinical response to periodontal treatment seen in smokers is due to persistence of periodontal infection of these patients.
Figure 7–7. Clinical response to mechanical periodontal therapy in smokers and nonsmokers at 3 months after ther- apy, in deep sites (pocket depth ³ 5 mm). Current smokers had significantly less (p < .001) reduction in pocket depth and gain in clinical attachment (p < .05) in deep pockets compared with former and nonsmokers. The clinical response to mechanical therapy in former smokers was com- parable with that in nonsmokers, suggesting the benefit of smoking cessation in response to periodontal therapy. PD = pocket depth; CAL = clinical attachment loss.
104 Periodontal Medicine
they never been exposed. A pack-a-day smoker, drawing ten puffs, self-administers about 200 “hits” each day. This frequently repeated behavior becomes part of the dependency.
The presence of low levels of nicotine in the body over time produces many other effects. For example, in the cardiovascular system, nicotine increases circulating catecholamines, modulates heart A-V node conduction, contracts collateral arteries, promotes platelet aggregation, increases low density lipoproteins, decreases high density lipoproteins, and promotes formation of athero- sclerotic plaques. In the respiratory tract, it decreases cilia motility, increases airway resistance, and decreases lung tissue elasticity.
Physical dependency on nicotine is recognized by a cluster of specific patterns of behavior. Dependent individuals typically construct their daily activities around the self-administration of nicotine.
The American Psychiatric Association diag- nostic criteria for substance dependency, which includes nicotine addiction are given below:
DMS-IV Diagnostic Criteria for Substance Dependence A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as man- ifested by three or more of the following, occurring at any time in the same 12-month period:
Tolerance, as defined by • a need for markedly increased amounts of the
substance to achieve the desired effect, or • markedly diminished effect with continued use
of the same amount of the substance.
Withdrawal, as manifested by • the characteristic withdrawal syndrome for the
substance; • the substance is taken to relieve or avoid with-
drawal symptoms; or • the substance is often taken in larger amounts or
over longer periods than was intended.
There is persistent desire or unsuccessful effort to cut down substance use • A great deal of time is spent in activities neces-
sary to abstain from the substance, use the sub- stance, or recover from its effects.
• Important social, occupational, or recreational activities are given up or reduced because of sub- stance use. The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that
is likely to have been caused or exacerbated by the substance.
A nicotine-dependent individual uses the drug for avoidance of withdrawal symptoms as much as or more than for perceived benefits such as calm- ing, stimulation, or suppression of hunger. A major component of the “pleasure” of smoking or chew- ing is relief from the building withdrawal symp- toms produced by nicotine depletion.
With permission from Henningfield JE, Cohen C, Pickworth WB. Psychopharmacology of nicotine. In: Orleans CT, Slade J, editors. Nicotine addiction: prin- ciples and management. New York, NY: Oxford Uni- versity Press; 1993.
DMS-IV Criteria for Nicotine Withdrawal A. Daily use of nicotine for at least several weeks.
B. Abrupt cessation of nicotine use, or reduction in the amount of nicotine used, followed within 24 hours by four (or more) of the following signs: 1. dysphoric or depressed mood 2. insomnia 3. irritability, frustration or, anger 4. anxiety 5. difficulty concentrating 6. restlessness 7. decreased heart rate 8. increased appetite or weight gain
C. The symptoms in criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of func- tioning.
D. The symptoms are not due to a general med- ical condition and are not better accounted for by another mental disorder.
With permission from Hughes JR. Nicotine withdraw- al, dependence, and abuse. In: Widiger TA, Frances AJ, Pincus HA, editors. DMS-IV sourcebook. Washington, D.C.: American Psychiatric Association; 1994. p.109– 16.63
EPIDEMIOLOGY OF TOBACCO USE
Physical dependency upon nicotine is not, of course, a factor when an individual is first exposed. Initially, a very small level of exposure can produce symptoms of nicotine intoxication such as dizzi- ness, nausea, and confusion. Establishing patterns of tobacco use occur gradually over months to years
Tobacco Use and Intervention 105
and occur for a variety of psychologic and social reasons.64–66 Desire for tobacco products in adoles- cents is cultivated by tobacco industry advertising and promotions. A wide variety of communication channels are used. Also, the tobacco industry actively attempts to circumvent and abolish barriers to youth access, recognizing that adolescents, although comprising less than 10% of the market, are vital to the industry’s long-term profitability.
Nearly 90% of users begin as children and adolescents, long before they become old enough to legally purchase tobacco products. It is estimat- ed that of the more than 5,000 young people each day that try smoking for the first time, more than 3,000 become regular smokers, many for decades and some for life.67 Few adolescents smoke daily. However, long before a daily pattern is established, nicotine dependency has begun. An individual that has smoked as few as 100 cigarettes is at high risk of becoming a long-term, dependent smoker. Smokeless tobacco users quickly develop high nicotine tolerance and dependency due to the steady transfer of nicotine across the oral mucosa and throughout the body.
With continued exposure, the effects of nico- tine on the central nervous system gradually increase, building up to a physical dependency that dominates the pattern of use.68 Once dependency is established, the desire for nicotine becomes the principal reason that individuals continue to use tobacco products. Indeed, nicotine is one of the most addictive substances known, and the vast majority of people that quit smoking relapse with- in days.69,70 Thus, each year, only 2 to 3% of smokers become nonsmokers without help.71
About 70% of adults that smoke would like to stop, and about 34% attempt to quit each year.72
More women than men would like to stop, but women have greater difficulty in doing so. Adoles- cent patterns are similar, with 50 to 74% of 12- to 18-year-olds wanting to stop and 40 to 49% per- cent making an attempt to quit. One survey showed that among adolescents that smoked at some time within the past month but are not smok- ing daily, over 30% found they could not quit.73
NICOTINE DEPENDENCY RISK FACTORS
Smoking prevalence has consistently been in inverse relation to education and income. In 1993, the prevalence of current smoking among adults was 37% for persons that had completed 9 to 11 years of
education, 29% among high school graduates, and less than 2% for individuals that had at least 4 years of college education.72 As defined by the Social Secu- rity Administration, 22% of individuals above the poverty level smoked and 28% of those below the poverty level. In addition to poverty, other sociode- mographic factors associated with higher prevalence of smoking are being a blue collar worker, separat- ed or divorced, and in active military service.72
The prevalence of cigarette smoking is highest among American Indians and Alaska Natives (39%), intermediate in African Americans (26%) and Euro- pean Americans (25%), and lowest in Hispanics (20%) and Asian Americans and Pacific Islanders (18%).74 Smokeless tobacco use is also highest among American Indians and Alaska Natives of both genders, followed by European Americans (12%), Hispanics (5%), and African Americans (2%). Cul- tural and socioeconomic factors may influence ini- tiation, but genetic factors may contribute to some races being more susceptible than others once exposed to nicotine.75,76 Within any race, genetic factors in some individuals predispose them to nicotine dependency when exposed.77
No single factor determines patterns of tobac- co use among racial/ethnic minority groups. These patterns are the result of complex interactions of multiple factors, such as socioeconomic status, cul- tural characteristics, acculturation, stress, biologic elements, targeted advertising, price of tobacco products, and varying capacities of communities to mount effective tobacco control initiatives.78
Certain effects of nicotine, such as its ability to suppress appetite, may selectively increase the risk of nicotine dependency in women. Evidence indi- cates that people with depression are especially vul- nerable to nicotine dependency, and since the prevalence of depression is twice as high in women as in men, this relationship may be particularly important for women.79
It is alarming that by 1997, tobacco use in high school students was 43%. This exceedingly high smoking prevalence in adolescents suggests a commensurate rise in the number of adults that will want to quit, as well as an increase in the inci- dence of tobacco-related morbidity and mortality.
WHO QUITS?
In recent years, tobacco use among men has declined more rapidly than among women so that rates are similar (27 versus 24%), and differences may become smaller in the future. Men are some-
106 Periodontal Medicine
what less interested than women in quitting (67 versus 73%), but a greater number of men than women have quit (51 versus 47%).72
Surveys of gender differences in the ratios of cigarette smoking cessation suggest that men have an easier time of it (49 versus 40%). When the ratios are adjusted for the use of other tobacco products (cigars, pipes, smokeless tobacco), how- ever, the ratios are quite similar (42 versus 40%). More men than women merely switch from ciga- rettes to other forms of tobacco to sustain their nicotine dependency rather than truly quit. Long- term abstinence rates for those that quit show vir- tually no difference by gender.80 Thus, men and women may have different reasons for initiation, continuing to use, wanting to quit, quitting, and staying abstinent, but the net behavior outcome is not very significant. Nevertheless, helping patients during the quitting process requires an apprecia- tion of gender differences; physiologic factors, such as differential sensitivity and tolerance to nicotine, more intense withdrawal symptoms by women, timing of quit attempts in relation to the menstru- al cycle; and behavioral and psychologic factors, such as women’s fear of weight gain, greater need for social support, and their lower confidence in their ability to quit.81
DENTAL PROFESSION’S ROLE IN TREATING NICOTINE ADDICTION
In recent years, dentists have been acquiring clini- cal tobacco intervention skills. A quarter of den- tists (24%) routinely identify their patients’ status of tobacco-use and accordingly advise them to quit.82 More than half the dentists that do not pro- vide such services state that they desire training that would enable them to do so.83,84 The reasons for providing clinical tobacco intervention services are compelling.
Of course, helping patients quit and stay absti- nent is an ethical obligation. Overwhelming evi- dence indicates that tobacco is harmful to oral health and that smoking status is an important fac- tor in the prognoses of several dental therapies, including periodontal therapy, oral surgery, implant dentistry, and cosmetic dentistry. Second, clinical tobacco intervention services have a moral basis as well. It is a regular act of citizenship to attempt to preserve life and prevent injury and death. Smoking kills half the regular users, and half of these will die prematurely, losing, on average, two decades of life.28b Third, clinical tobacco intervention services
are cost effective. Long-term tobacco users develop chronic conditions that often become time-con- suming patient management problems. Smokers are ill more often than are nonsmokers, which fre- quently leads to problems with appointments, medical considerations, and emergencies during treatment. Many patients are prematurely lost to practice when tobacco-related disabilities severely restrict their mobility and resources.
Many professional organizations have devel- oped support systems that help clinicians integrate cessation services into their practices. For example, several dental organizations have adopted tobacco- related clinical policies. The American Dental Asso- ciation (ADA) now has published and distributed a guide to therapeutics titled “Tobacco counseling for the control and prevention of oral disease,” established a service code (01320) and included tobacco use status and interest in quitting questions in the ADA Health History Form. Educational guidelines have been developed for educational institutions. Such infrastructure developments help ease the integration of clinical tobacco intervention services into practice.85
TREATING NICOTINE DEPENDENCY
Nicotine dependency is not merely a “risk factor” for other disease, but it is a disease requiring treat- ment in its own right.86 There are numerous meth- ods for helping nicotine-dependent patients. Unfortunately, most are not supported by scientific evidence, even though some seem attractive or are popular. Until recently, empirical approaches, pri- marily combinations of methods, have been used. Any method will yield its success stories. When studied, using scientifically sound methods, and critically analyzed, success rates for most methods do not compare favorably with not using the method. Often individual successes can be explained by other factors.
Systematic studies of smoking cessation began in earnest during the early 1980s.87 Randomized controlled trials demonstrated that physicians, using minimum clinical intervention methods, could be effective in increasing patient cessation rates.88–92 Dentists and other clinicians subsequent- ly were also shown to be as effective.93–96 Currently, there is overwhelming evidence that medical and dental practices are an essential part of helping the public avoid and discontinue tobacco use.97
Within the scientific community, “success” is considered long-term abstinence, with “long-term”
Tobacco Use and Intervention 107
defined as being tobacco-free for 6 months or longer. Studies that do not include follow-up for at least 5 months are generally not seriously consid- ered when assessing effectiveness. “Abstinence” is defined as being tobacco free, not nicotine free. Food and Drug Administration (FDA)-approved nicotine replacement products are routinely used to help individuals quit using tobacco. Some prod- ucts are available without prescription.
In 1981, a 2-mg nicotine gum was approved by the FDA to supplement behavioral interven- tions. During the 1990s, a variety of nicotine replacement products and one non-nicotine tablet were approved. Other pharmaceutical agents are under investigation. Research on nicotine addic- tion and CNS function promises to provide more effective treatments in the future. There is no “sil- ver bullet” method or pharmaceutical agent. Although a selected combination of clinical meth- ods combined with an FDA-approved pharmaceu- tical agent can significantly increase cessation rates, none sustain long-term abstinence for as many as half the number of the individuals that make a ces- sation attempt.97a
Since 1996, Clinical Practice Guideline Num- ber 18: Smoking Cessation of the Agency for Health Care Policy and Research (AHCPR) has become the international gold standard for clinical tobacco intervention services.98 This guideline and its subsequent revisions (one scheduled for early 2000) can help focus valuable clinician time on services that are evidence based and return the highest success rates for the time invested. The fol- lowing statements and recommendations are based on or taken from the guideline, except where sup- plemental references are shown.
Although the long-duration, intensive treat- ments are more effective than the brief treatments, such interventions can be reserved for smoking ces- sation specialists and other specialists in the man- agement of patients who experience multiple relaps- es, have multiple drug dependencies, are mentally challenged, or have severe psychiatric disorders. Guidelines are available for such clinicians.99,100
However, most patients can be approached by and benefit from brief, practical interventions by even the busiest clinician of any health discipline.
RECOMMENDED MINIMUM CLINICAL INTERVENTION METHODS
A practical routine should be integrated into every clinical practice. Basic steps are known as the “4 A’s,”
Ask, Advise, Assist, and Arrange (Table 7–1).101,102
First proposed by Marc Manley and Thomas Glynn of the National Cancer Institute, the steps have remained the core of successful clinical programs, even when other names are applied. The basic steps are as follows:
Ask
Identify the tobacco use status of every patient. “Do you use tobacco?” This information should be considered a vital sign.103,104 Inquiry can be inte- grated within existing patient questionnaire sys- tems. It is essential that each patient record show the current tobacco use status so that all clinic staff are aware of it.105 As nicotine dependency is chron- ic and relapsing, it is important to ask this question at every encounter. Of course, since most patients do not use tobacco, the answer under most cir- cumstances is a brief “no.” Tobacco users must be asked about the duration and intensity of their use, past experience with quitting, and especially about their desire to stop. “How interested are you in quitting now?”
Advise
This step focuses on building the patient’s motiva- tion to be tobacco free. Although brief and simple, building motivation is one of three basic clinical intervention services. Commend never-users and former users on the wisdom of their behavior. This is an especially important message to children and adolescents to help prevent and postpone initiation and to former users, who are vulnerable to relapse.
1. Advise all tobacco users in clear language that you think they should quit. Patients place great weight on such advice by clinicians.
TABLE 7–1. Basic Steps of Successful Smoking Cessation Program
“4 A’s” • Ask Identify the tobacco use status of every
patient • Advise Increase the tobacco user’s interest in
quitting • Assist Help those who are ready with their
problem solving skills and with pharmacotherapy
• Arrange Arrange follow-up support throughout the quitting process
108 Periodontal Medicine
2. Associate use with existing patient health con- ditions. When possible, show the patient his or her own tobacco-related conditions. Patients also should understand other health risks and tobacco risks to planned health ser- vices and prognoses, but not only that.
3. Ask each patient for his or her own reasons for wanting to quit. Most will have a reason, per- haps several. Expressing those reasons helps strengthen them, even though many have little to do with health. The patient’s reasons provide clues to which the clinician can add motivating ideas and perspectives that help dispel unwar- ranted hesitancy. The clinician should be as upbeat as possible. Emphasize the benefits of quitting in terms that are specific to each patient’s interests, circumstances, and culture.
Many patients will not be interested in quit- ting at the moment, but the “Advice” step strengthens the decision-making process that indi- viduals must progress through to initiate a behav- ior change. The discussion clarifies in the patient’s mind the opinion of a respected individual. It introduces to contented users ideas that will begin to offset their reasons for continuing. Discussion helps individuals that are generally interested in quitting to begin thinking more seriously about what they are doing to themselves and about their prospects for living tobacco free. Discussion iden- tifies highly motivated patients, that is, those that previously attempted to quit or have an intention to quit in the foreseeable future. A clinician’s advice to quit can trigger the decision to act.
The patient’s desire for clinical therapy to be successful and enduring can influence his or her desire to quit. Other personal benefits become bonus advantages in this situation. The ever-pre- sent goal of doing everything possible to save each patient’s life may remain a silent imperative in the clinician’s mind.
Patients that are not interested in quitting at the moment should be offered assistance in the future, “When (not if ) you are ready, I’ll be glad to help.” In addition, patients should be given moti- vational literature that is appropriate to their inter- ests, circumstances, and, if possible, culture.
Assist
While “Ask” and “Advise” are routine steps for all patients, the “Assist” step is used with a subset of patients that are ready to quit. This step focuses on helping patients cope with the quitting process.
The clinician acts as a caring, skilled facilitator because, of course, the primary responsibility remains with the individual that must quit. Three specific components are essential: establishing a plan for (1) preparing to quit, (2) coping with psy- chologic and social cues during the quitting process, and (3) managing the physical challenges of nicotine withdrawal.
Preparing to Quit Ask the patient to choose a quit date. The date ide- ally should be within 2 weeks, but not so soon that there is no time for mental preparation. Give the patient a reminder of the date, perhaps on a pre- scription form, that can be posted at home.
Suggest that the patient inform family, friends, and co-workers and solicit their support. One’s spouse can be an especially important ally. The patient should arrange to have others that use tobacco not use it in their presence during the quitting process.
The final use of tobacco should be during the day before the selected quit date. Advise the patient to remove all tobacco products and the materials that they use from home, car, work place, and any other readily accessible site.
Advise that other forms of tobacco also con- tain nicotine and their use will work against the goal of quitting for good.
Coping with Psychologic and Social Cues Ask the patient what is most likely to lead to a relapse and how he or she would plan to manage that. Encourage the patient to solve the problem. Then offer specific suggestions and answer patient concerns.
Advise that even a single puff is dangerous and often leads to relapse.
Caution that alcohol and other drug use impairs judgment and can lead to relapse.
Stress and weight gain are two common con- cerns. The quit date selected should be at a time of least possible stress; however, the management of stress should be discussed, and the patient should be advised that the transition period is often accompanied by a period of anxiety, restlessness, insomnia, and reduced ability to concentrate while the brain adjusts to the absence of nicotine. Help the patient with stress management strategies that are alternatives to using tobacco.
Although dieting should be postponed dur- ing the first few weeks, alternatives to adding calories and approaches to burning calories should be addressed. Advise the patient that
Tobacco Use and Intervention 109
weight gain is a minor risk compared with con- tinuing to use tobacco. Tell the patient to tackle one problem at a time; first be confident that they have quit using tobacco for good before working on weight gain. The use of nicotine gum may delay weight gain.
If the patient has previously attempted to quit and relapsed, address how to deal with that specif- ic situation. Determine if the precipitating event was due to nicotine withdrawal, psychologic,or a social situation.
Provide literature on the quitting process. This saves clinician time and can be referred to as often as wanted. The AHCPR’s booklet “You can quit,” available in eight languages, the National Cancer Institute’s “Clearing the air,” and other organiza- tion pamphlets provide reinforcement to motiva- tion and offer suggestions for preparing to quit and managing the effects of quitting, such as nicotine withdrawal and weight gain. Such booklets describe coping strategies not commonly shown in the flyers aimed at motivating various segments of the public.
As with other substances of abuse, individuals that successfully quit must appreciate that perma- nent CNS neuron changes have occurred. They must be alert to the possibility that even a single exposure can rapidly lead to complete relapse, even years after quitting.
Certain psychologic states, such as acute stress, depression, or encountering a previously learned social cue, can trigger a relapse.
Managing the Physical Dynamics of Nicotine Withdrawal 1. Prescribe or recommend an FDA-approved
nicotine replacement for use, beginning on the quit date. The intent is to reduce the intensity and duration of nicotine withdrawal symp- toms while the patient is learning to cope with the psychologic challenges and social cues that had become part of the addiction. It extends the use of the one drug that drives tobacco use behavior, but places its administration under supervision and in amounts that do not pro- duce the “hits” or peaks of nicotine in the brain. Also, the patient learns how to live without possessing tobacco products and going through the rituals of using tobacco- associated paraphernalia.
Nicotine transdermal patches approximate- ly double long-term abstinence compared with abstinence using behavioral intervention alone.106 Patches are often the preferred route for clinical use because there are few compli-
ance problems, and little clinician time and effort are required to train patients in their effective use. A patch is applied to a different skin area each day to minimize irritation. Three brands of patch are available in three strengths, according to patch size, and are used either for 16 or 24 hours each (Table 7–2). The largest patch is used for the initial 4 weeks and the next smaller sizes for two 2-week, stepped withdrawal periods. The midsize patch should be used initially by patients that are light smokers (less than 10 cigarettes daily) or are of small stature (weight less than 100 pounds). One patch is used for 16 hours only and patches are used for 6 weeks, after which use is discontinued entirely. If the particular patch is not effective for a patient, another brand may help.
TABLE 7–2. Recommended Agents to Manage Nicotine Withdrawal
Nicotine Replacement Agents Patch • Habitrol® (Novartis)
Nicotine 21 mg 14 mg 7 mg
• Prostep® (Lederle Labs) 22 mg/24 h 11 mg/24 h
• Nicotrol® (McNeil Consumer) 15 mg/16 h
• Nicoderm® CQ® (SmithKline Beecham Consumer) – Step I 21 mg/24 h – Step II 14 mg/24 h – Step III 7 mg/24 h
Gum • Nicorette® (SmithKline Beecham Consumer)
2 mg or 4 mg Nasal spray • Nicotrol® NS (McNeil Consumer)
Nicotine 0.5 mg
Inhaler • Nicotrol® Inhaler (McNeil Consumer)
2 mg 4 mg
Non-nicotine agents Bupropion HCL • Zyban® (Glaxo Wellcome)
150 mg
110 Periodontal Medicine
The 4-mg nicotine gum (nicotine polacri- lex) is usually preferred when a skin disease or adhesive allergy rules out use of a patch, when a patient has not been successful with using a patch, as a supplement to a patch, or when gum is preferred by the patient for any rea- son.107 One piece should be used every 1 to 2 hours for 6 weeks, then every 2 to 4 hours for 3 weeks, and 4 to 8 hours for 3 weeks. Patients must be instructed to chew each piece until a peppery taste is noticeable, and then to park the gum as nicotine absorption occurs. The “chew and park” routine is followed for about 30 minutes per piece. The patient must be instructed to stop using acidic liquids such as coffee, soft drinks, and fruit juices, at least 15 minutes before using the gum since the nico- tine is not absorbed in an acidic environment. Light smokers may use a 2-mg gum. Long- term quit rates are about 40 to 60% higher in using nicotine gum than in using behavioral intervention alone.
The nicotine nasal spray is an option that simulates the rapid delivery effect of cigarette smoking.108,109 The recommended dosage is one spray into each nostril 8 to 16 times daily. Long-term quit rates reported are from 18 to 27%. The nicotine oral inhaler is another option.110,111 Its ritual and sensory aspects resemble smoking. The recommended dosage is up to 16 cartridges per day. Long-term quit rates are reported to range from 13 to 28%. Use of any of the products are recommended for an 8- to 10-week period.112
Contraindications for all nicotine replace- ments are similar. They are not recommended for patients in an immediate postmyocardial infarction period, those that have severe arrhy- thmias, or those that have a severe or worsening angina pectoris. Specific contraindications include skin disorders for patches, asthma or chronic nasal disorders for nasal spray and inhalation systems, and temporomandibular joint disorders or dentures for nicotine gum.
Because of the serious risks of smoking to both mother and fetus, pregnant smokers should be offered intensive counseling. Nico- tine replacement should be used during preg- nancy only if the increased likelihood of smok- ing cessation, with its potential benefits, out- weigh the risk of nicotine replacement and potential concomitant smoking.
Nicotine replacement should be consid- ered for adolescents, only when there is clear
evidence of nicotine dependency and a clear desire to quit using tobacco.
Many individuals that are not successful in becoming nicotine free are able to become tobacco free by using a nicotine replacement for several months or indefinitely.113,114 Although continued use of a nicotine replacement beyond a 10- to 12-week period is not recommended, it is infinitely better than returning to tobacco use. Nicotine is harmful, but not as much as many other tobacco constituents. Of the at least 2,550 known compounds in tobacco and over 4,000 compounds in tobacco smoke, primary tobacco biohazards include at least 43 carcinogens, such as the nicotine nitrosamines, and alpha-emitting radionuclides, such as Polonium 210. Tobacco smoke contains carbon monoxide, thiocyanate, herbicide, fungicide, and pesticide residues, tars, and many other substances that promote disease and impair body functions. Tobacco is a highly polluting nicotine delivery system.
2. Bupropion HCl (Zyban) is a nicotine replace- ment alternative. Bupropion is used in tobac- co use cessation treatment as a centrally acting non-nicotine agent. The long-term abstinence rate through its use is equivalent to that through using a nicotine patch.115 Patients that are strongly dependent upon nicotine may use bupropion in combination with a nicotine replacement.
The patient’s medical history, current medical status, and patterns of behavior must be carefully evaluated before recommending bupropion. It interacts with many drugs, including alcohol, antipsychotic agents, hepatic enzyme inducers and inhibitors, levodopa, and monoamine (MAO) inhibitors. This is of con- cern because many of these potentiate the risk of seizures. The use of bupropion is con- traindicated in patients being treated with Wellbutrin (which is also bupropion HCl), antipsychotics, antidepressants, theophylline, or systemic steroids and in patients that abruptly discontinue use of a benzodiazepine or another agent that lowers seizure threshold. Bupropion is contraindicated in patients with anorexia nervosa or bulimia, bipolar disorders, CNS tumor, a history of head trauma or drug abuse, hepatic or renal impairment, recent his- tory of myocardial infarct, unstable heart dis- ease, psychosis, or seizure disorders.116
The use of bupropion differs from nicotine replacement in that bupropion treatment should begin 7 to 10 days before the patient-selected
Tobacco Use and Intervention 111
quit date, whereas the pharmaceutical nicotine substitution should begin on the quit date.
A recent review of randomized clinical tri- als and of meta-analyses of smoking interven- tion studies concludes that pharmacotherapy for smoking cessation should be made avail- able to all smokers.117 All currently available therapies appear equally efficacious, approxi- mately doubling the quit rate compared with placebo. In addition, combined therapies are more successful in obtaining long-term suc- cess. Thus, combining patch with gum or patch with bupropion may increase the quit rate compared with any single treatment.117
3. Consult package inserts, the Physician’s Desk Reference, the ADA Guide to Accepted Dental Therapeutics, and comparable resources for dosage and management information on spe- cific FDA-approved pharmaceutical agents for tobacco use cessation.
4. Other pharmaceutical agents have been stud- ied. There is little scientific evidence for the use of clonidine, either as a primary or as an adjunctive pharmacologic treatment for tobac- co use cessation. There is no scientific evidence demonstrating the effectiveness of any antide- pressant other than bupropion. The use of anxiolytics, benzodiazepines, lobeline, silver acetate, cotinine, beta blockers, glucose, sodi- um bicarbonate, and stimulants have not been shown to be effective. The use of mecamy- lamine, buspirone, phenylpropanolamine, and various other drugs, independently and in combination with approved agents, are under investigation but not recommended for use outside the research protocols.
Other behavioral intervention methods and nonpharmacologic agents have been assessed. Of the self-help methods, hotline/helpline support is effective, but providing video and audiotapes, lists of community programs, and pamphlets and booklets is not. Group coun- seling is beneficial for selected individuals but is no more effective than the basic clinical interventions described above. Evidence does not support methods based on motivation, weight/diet/nutrition counseling, exercise/fit- ness, contingency contracting, relaxation/ breathing, or nicotine fading. Aversive smok- ing increases cessation rates and may be used, with caution, with smokers that desire such treatment or have been unsuccessful using other interventions. There is insufficient evi- dence to assess the effectiveness of hypnosis or
acupuncture. There is no evidence supporting the use of herbal products and foods for tobac- co intervention.
It is recommended that those few practical (brief ) methods that are supported by substan- tial scientific evidence be mastered and routine- ly used. They can become the basis for develop- ing one’s art and practice, as the science of clin- ical tobacco intervention services evolves. Clin- ical interventions against an addictive behavior must be considered incremental. Indeed, most patients relapse, but this should not be a deter- rent. Other adverse health conditions also have recurrences. As with other chronic diseases and conditions, cures for smoking cessation are unusual, but the absence of a high success rate from single intervention attempts are never a reason to withhold treatment, especially when continued tobacco use is clearly a high risk to a multitude of diseases and life itself.
Arrange
Establish a schedule for follow-up contacts, either in person or by telephone. Although some increase in patient quit rates can be anticipated from a sin- gle encounter, long-term abstinence is dramatically improved, three to four-fold, when there is timely follow-up.
Schedule a first contact by clinic staff for a day or two before the patient-selected quit date. This serves as a quit date reminder, as an expression of support and encouragement, and as an opportuni- ty to solicit questions and concerns related to preparations.
The recommended post–quit-date follow-up contact schedule is four to seven contacts over a 3- month period. The first follow-up contact should be within 2 weeks of the quit date, preferably with- in the first week. The second, third, and fourth contacts should be near the end of the first, second, and third months. Studies suggest that fewer than four and more than seven contacts yield lower results than this follow-up interval and frequency.
During each follow-up contact, the clinician should applaud success. If a lapse occurred, the patient should be asked for a recommitment to total abstinence. Remind the patient that a lapse can be used as a learning experience, and review the circumstances that caused it. Ask the patient how he or she could better manage that situation next time. Suggest alternative behaviors.
Even if the patient remains abstinent, identify problems encountered and anticipate challenges in
112 Periodontal Medicine
the immediate future. Review the benefits, includ- ing potential health benefits, to be derived from cessation. Discuss specific problems such as weight gain, negative mood/depression, prolonged nico- tine withdrawal, and lack of support for cessation from others. Discussion helps the patient to clarify and cope with such problems.
All treatment strategies apply to individuals that are of any age, gender, or ethnic origin, gener- ally healthy or ill, or inpatient or outpatient. All treatment strategies apply to adolescents who want to quit using tobacco. Clinicians should be firm but nonjudgmental and should personalize the encounter to the individual situation.
One primary finding has been that all types of clinicians are about equally effective, that is, regardless of discipline. Providing a brief interven- tion can yield about a 50% increase in patient quit rates compared with not helping. It is significant that interventions by multiple providers reinforce and nearly quadruple patient quit rates. Success may be partially due to previous efforts by col- leagues; lack of immediate success with a patient actually serves as an important preparation for a subsequent clinician contact that becomes persua- sive. Thus, each clinician is part of a broad, not necessarily known-by-name, professional tobacco intervention network.
As little as 3 minutes’ cessation helps produce a significant increase in long-term abstinence from tobacco. However, even less than 3 minutes’ cessa- tion yields a measurable benefit over self-help methods. If 3 or more minutes are not available, even the briefest help should be employed, given the ever increasing life-threatening risk when the individual continues to use tobacco and the impor- tance of reinforcement by multiple providers, to achieve a commitment to quitting and long-term abstinence. More intense interventions, that is more time-per-patient contact, increase long-term abstinence rates.
In general, actual cessation rates vary widely by demographic factors, such as income and educa- tional level. The practical clinical intervention methods recommended above compare the relative increase in long-term abstinence compared to withholding clinician intervention and are not absolute values. Also, any quit attempt is useful as preparation for long-term abstinence. It is estimat- ed that unsuccessful cigarette smokers, on average, make three to four attempts before achieving long- term abstinence.118
Tobacco users with psychiatric comorbidity should be offered the same treatments recom-
mended to other individuals. Although it is not necessary to assess psychiatric comorbidity prior to initiating an intervention, such an assessment may be helpful in that it allows the clinician to prepare for an increased likelihood of relapse or for exacer- bation of the comorbid condition as a result of nicotine withdrawal. Individuals that experience depressive and anxiety symptoms are at higher risk for smoking initiation.119 Individuals experiencing psychiatric disorders are at high risk of initiation and may smoke as a form of self-treatment.120
Individuals with a history of clinical depression are more likely to experience a recurrence during the quitting process.121
TREATMENT ENVIRONMENT
Providing clinical intervention services requires a team approach. Clinic personnel, the office envi- ronment, and the management system need a few simple adjustments for services to be provided effi- ciently, effectively, and pleasantly. First, one indi- vidual, usually not the primary-care provider, needs to be responsible for the service operation. All members of the clinic team need to understand the objectives and methods employed. The “ASK” step is usually managed by the reception/receiving staff, as well as the recording of the patient’s tobacco use status. This is verified when other vital signs are taken and initial work-up begun. Diagnosis and treatment planning must include the “Advice” step. “Assist” is often begun by the primary clinician or other provider. Other staff may provide more detailed help for the patient that commits to a quit date and ensure that the “Arrange” step is done so that follow-up will occur.
Clinic staff that use tobacco present a special consideration. Patients should not be able to deter- mine that staff do so, for mixed messages are sent about the clinic being a responsible health unit. Offers to help patients quit may lack credibility if smelly hands, hair, or clothes are detected. Every effort must be made to encourage tobacco-using staff to quit. Intense help may be needed. Employ- ee unions, personnel offices, and facility directors may need to be involved.
The clinic’s physical environment should con- vey a positive tobacco-free message. A “Thank you for not Smoking” sign establishes the authority of the office in a manner that invites cooperation. The absence of ash trays and presence of posters and a display of motivational literature enhances the message. Magazines available for patients
Tobacco Use and Intervention 113
should not carry tobacco advertizing. The back covers are especially important since they may be seen by several patients at once.
Patient records should have an identifying mark so that all clinic staff can easily recognize the tobacco use status of each patient. Records of patients who are tobacco-free also need an identify- ing mark so that patients whose tobacco use status has not been determined will be easily recognized. Basic information required is patient status and interest in quitting. More complete information includes details about duration, intensity, and type of tobacco used, the level of patient dependency on nicotine, factors that would enhance or hinder a quit attempt, and the history of previous quit attempts. Such information, when completed by patients saves clinic staff time. The record should include progress notes on cessation attempts. Also, the recall system should be able to trigger a contact with patients who are making a quit attempt. The contacts should be scheduled for a day or two before the quit date, during the first few days post quit date, and at least once a month through the quitting period.
The clinic system should trigger an inquiry about all patients of any age. Of course, prenatal vis- its focus on the importance of both mother and fetus being tobacco free until term. The caregivers of infants and children less than age 5 years need the “4 As.” Ask about tobacco use in the home and other tobacco smoke exposure. Advise that steps be taken to protect the infants and children from exposure. In addition to discussion with caregivers, children aged 5 to 11 years should be asked directly, com- mended for not using tobacco, and be given other reinforcing messages to help counter the allure already being transmitted by the tobacco industry and to prevent initiation. Adolescents need to be encouraged to quit as well as given proved messages to avoid tobacco and exposure to tobacco smoke.
Beyond individual patient contact, clinicians have unlimited opportunity to prevent adolescent interest in tobacco, prevent initiation, prevent nicotine addiction, and promote cessation. Health professionals are respected opinion leaders in pro- fessional affairs, religious and other community organizations, hobby and other personal interests, and with patients that are involved in the develop- ment of public policy, worksite policies, adminis- trative affairs, and public education. Educated views about tobacco, born of one’s experience with patients and organized initiatives, carry weight. It is from such discussions that community norms evolve. Each health professional has a continuing
stream of unique opportunities to counter the influence of the tobacco industry by helping pre- vent nicotine addiction among youths and increas- ing the determination of adult tobacco users who are trying to break free.
Studies supported by the National Cancer Institute during the 1980s and statewide demon- stration projects in the 1990s demonstrated that tobacco use among adults can decline at twice the rate of secular trends when media, community, business, policy, and professional tobacco educa- tion and public health promotion efforts are made concurrently. Messages via these channels reinforce each other, helping the public conclude that avoid- ing tobacco use is in their own best interests and those of their loved ones and communities.
During the 1990s, concurrent with media cov- erage of the struggle between public health and the tobacco industry, the FDA approved several phar- macologic agents to aid smoking cessation. Adver- tising and promotion by pharmaceutical compa- nies contributed to public awareness that smoking cessation is possible and desirable and that certain drugs could help. Nicotine replacement products were determined to be sufficiently safe, delivering substantially lower peak doses than self-adminis- tered tobacco products. Two brands of nicotine patch and two strengths of nicotine gum were approved for over-the-counter sales.
The public is better informed about risks in tobacco use, including nicotine dependency, than ever before. There is a willingness, indeed an expectation, that health professionals are informed and interested in helping patients quit. National Center for Health Statistics surveys consistently show that each year about 70% of smokers want to quit and about a third make a quit attempt. Yet, only slightly over 60% of U.S. physicians report that they identify patient smoking status, and slightly over a fifth report counseling their patients that are smokers. It is even less encouraging when it is noted that most counseling is selective, pri- marily restricted to patients already exhibiting clin- ical symptoms of smoking-related diseases. Few smoking patients that do not exhibit a smoking- related disease are counseled.122
Primary barriers to counseling have been a belief that intervention is not effective, not know- ing which methods are effective, lack of compensa- tion for the service, and perceived time available to provide help. The AHCPR Clinical Practice Guide- line responds to such concerns. Many methods are examined, and those most effective are recom- mended. Recommendations are targeted at clini-
114 Periodontal Medicine
cians that have little time, specialists, researchers, educators, administrators, and health policy mak- ers. Studies show that the health-care system must support tobacco cessation services. Managed-care programs are taking note that tobacco cessation has been found to be more cost effective than any other preventive medical service.123 Standards for facility accreditation are being upgraded to include clinical tobacco intervention services. Having the Clinical Practice Guideline as an evidence-based model, sev- eral health professions are integrating tobacco top- ics appropriately into educational curricula and continuing education programs. As the 1990s draw to a close, the health professions are developing the necessary infrastructure.
SUMMARY AND CONCLUSION
The late 1980s and 1990s have brought an over- whelming body of evidence to substantiate unequivocally that tobacco use has a profound negative effect on periodontal disease severity, prevalence, incidence, and progression. Tobacco use has also a profound negative effect on the health and well being of users, society, and clinical practice. The public is increasingly aware of this fact. Tobacco use is preventable. Most nicotine dependent individuals want to quit and can quit, when guided by proper support.
Advances in the art and science of addiction medicine, and especially nicotine addiction medi- cine, are being increasingly published in the pro- fessional literature and presented in scientific forums. Some convergence is occurring in the understanding and treatment of all substances of abuse, binding stronger relations between the behavioral and bench sciences. In recent years, sev- eral pharmacologic agents for smoking cessation have been approved by the FDA. Additional phar- macologic agents and refined behavioral interven- tion methods should be expected.
Adoption of scientifically sound clinical tobacco cessation services is a professional obliga- tion, a moral imperative, and a practical matter. Three to five minutes of cessation assistance inte- grated into other clinical services is a life-saving service that benefits patients, community, and practice. Periodontal health and prognoses for periodontal therapy substantially improve when patients quit smoking.
The AHCPR’s Clinical Practice Guideline Number 18: Smoking Cessation provides the infor- mation needed to develop the art and skill neces-
sary to make cessation services a routine practice. The experience of a few successful cases provides satisfaction and ensures commitment to bringing hope of successful cessation to people whose tobac- co use places them at high risk of developing major life-threatening illnesses.
Clinicians also have expanding opportunities to help patients in a collective manner. Profession- al opinion and guidance are important to the pub- lic’s development of self-directed health behaviors.
AREAS OF FUTURE RESEARCH
Tobacco-related research questions abound. Major conferences, government agencies, and public advocacy organizations frequently update informa- tion on tobacco and behavior, tobacco as a risk fac- tor, tobacco dependency, tobacco and adolescents, tobacco cessation, tobacco economics, and tobacco intervention policy research agenda. On the one hand, fruits of such areas of research benefit indi- viduals engaged in the tobacco-related aspects of oral health care, research, education, program management, and policy making. On the other, experts in oral health affairs provide insights into related general health and human behavior research questions, professional education system content, health-care policies and practices, and monitoring and assessment systems.
Some areas of research need leadership by oral health investigators. Their focus is on how each of the many forms of tobacco and tobacco use prac- tices impact on oral health and oral health care. Research is needed on the public response to the dental profession as a resource for tobacco cessa- tion assistance and how the profession regards its ability to help the public through its clinical and extraclinical endeavors. More research is needed on how to provide effective intervention when avail- able smoking cessation therapies are ineffective; the impact of tobacco use on the oral and cranio- facial development of the growing fetus, infants, children, adolescents; and the direct and con- tributing influence of tobacco on oral diseases and conditions and on prognoses, recovery, and recur- rence. Tobacco-related oral health research is need- ed within subpopulations, on the basis of race/ ethnicity, gender, age, lifestyle, codependencies, and environmental factors.
Assessment of the expanding scientific base for tobacco intervention services is a professional imperative for researchers, educators, and clini- cians. Such monitoring ensures that professional
Tobacco Use and Intervention 115
education and practice are evidence-based, that health service resources expended are in the best interests of both patient and public, and that the dental profession is a viable member of a broad community of professional, public, and private sec- tors committed to creating a tobacco-free society.
REFERENCES
1. U.S. Department of Health and Human Services. Cigarette smoking among adults—United States, 1995. MMWR 1997;46:1217–20.
2. U.S. Department of Health and Human Services. Surveillance for selected tobacco-use behaviors —United States, 1900–1994. MMWR 1994;43 (SS-3):34.
3. U.S. Department of Health and Human Services. Tobacco use among high school students— United States, 1997. MMWR 1998;47:229–33.
3a. Wechester H, Riggot NA, Gledhill-Hoyt J, Lee H. Increasing levels of cigarette use among college students: a cause for national concern. JAMA 1998;280:1673–8.
3b.Krall EA, Garvey AJ, Garcia RI. Alveolar bone loss and tooth loss in male cigar and pipe smokers. J Am Dental Assoc 1999;130:57–64.
3c. Iribarren C, Tekawa IS, Sidney S, Friedman GD. Effects of cigar smoking on the risk of cardio- vascular disease, chronic obstructive pulmonary disease, and cancer in men. NEJM 1999;340: 1773–80.
3d.Ayaian JZ, Cleary PD. Perceived risks of heart dis- ease and cancer among cigarette smokers. JAMA 1999;281:1019–21.
4. Research, Science and Therapy Committee. Tobac- co use and the periodontal patient. J Periodon- tol 1996;67:51–6.
5. Mecklenburg RE, Greenspan D, Manley MW, et al. Tobacco effects in the mouth. Bethesda, MD: NIH publication No. 93–3330;1991.p 5–13.
6. Burgan SW. The role of tobacco use in periodontal diseases: a literature review. Gen Dent 1997;45: 449–60.
7. Haber J, Wattles J, Crowley M, et al. Evidence for cigarette smoking as a major risk factor for periodontitis. J Periodontol 1993;64:16–23.
8. Grossi SG, Zambon JJ, Ho AW, et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994;65:260–7.
9. Grossi SG, Genco RJ, Machtei EE, et al. Assess- ment of risk for periodontal disease. II. Risk indicators for alveolar bone loss. J Periodontol 1995;66:23–9.
10. Mandel I. Smoke signals: an alert for oral disease. J Am Dent Assoc 1994;125:872–8.
11. Genco RJ. Risk factors for periodontal diseases. J Periodontol 1996;67:1041–9.
12. Bergstrom J. Cigarette smoking as risk factor in chronic periodontal disease. Dent Oral Epi- demiol 1989;17:245–7.
13. Machtei EE, Dunford R, Hausmann E, et al. Lon- gitudinal study of prognostic factors in estab- lished periodontitis patients. J Clin Periodontol 1997;24(2):102–9.
14. Ho AW, Grossi SG, Genco RJ. Assessment of pas- sive smoking and risk for periodontal disease [abstract]. J Dent Res 1999;78:542.
15. Kinane DF, Rafvar M. The effects of smoking on mechanical and antimicrobial periodontal ther- apy. J Periodontol 1997;68:467–72.
16. Grossi SG, Zambon J, Machtei EE, et al. Effects of smoking and smoking cessation on healing after mechanical periodontal therapy. J Am Dent Assoc 1997;128:599–607.
17. Kaldahl WB, Johnson GK, Patil KD, Kalkwarf KL. Levels of cigarette consumption and response to periodontal therapy. J Periodontol 1996;67: 675–81.
18. U.S. Department of Health and Human Services. Reducing the health consequences of smoking: 25 years of progress: a report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, DHHS Publication No. (CDC) 89–8411;1989. p. 204–17.
19. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA 1993;270:2207–12.
20. U.S. Department of Health and Human Services. Mortality trends for selected smoking-related cancers and breast cancer—United States 1950– 1990. MMWR 1993;42:857,863–6.
21. U.S. Department of Health and Human Services. Cigarette smoking-attributable mortality and years of potential life lost—United States, 1990. MMWR 1993;42:645–9.
22. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. Cancer 1995;45:8–30.
23. Landis SH, Murray T, Bolden S, Wingo PA. Can- cer statistics, 1998. Cancer 1998;48:6–29.
24. U.S. Department of Agriculture. Tobacco outlook and situation report. April 1996;TBS-234: tables 1,33,34.
25. U.S. Department of Health and Human Services. Medical-care expenditures attributed to ciga- rette smoking—United States, 1993. MMWR 1994;43:469–72.
116 Periodontal Medicine
26. Summers LH. The economic case for comprehen- sive tobacco legislation. Department of the Treasury remarks at the George Washington School of Health; March 25, 1998. Table 1.
27. National Cancer Institute. Cigars: health effects and trends. Smoking and tobacco control, monograph 9. National Cancer Institute; 1998. NIH Publication No. 98–1302.
28. National Cancer Institute. Smokeless tobacco or health: an international perspective. Smoking and tobacco control, monograph 2. National Cancer Institute; 1992. NIH Publication No. 93–3461.
28a. Hurt RD. Treat tobacco dependence and “bend to treat.” Bull World Health Org 1999;77:367.
28b.Peto R, Lopez AD, Boreham J, Thun M, Health C Jr. Mortality from tobacco in developed coun- tries: indirect estimations from national vital statistics. Lancet 1992;339:1268–78.
29. Linden GJ, Mullally BH. Cigarette smoking and periodontal destruction in young adults. J Perio- dontol 1994;65:718–23.
30. Papapanou PN. Periodontal diseases: epidemiology. Ann Periodontol 1996;1:1–36.
31. Haber J, Kent RL. Cigarette smoking in a peri- odontal practice. J Periodontol 1992;63:100–6.
32. Gelskey SC. Cigarette smoking and periodontitis: methodology to assess the strength of evidence in support of a casual association. Comm Dent Oral Epidemiol 1999;27:16–24.
33. Kenney EB, Kraal JH, Saxe SR, Jones J. The effect of cigarette smoke on human oral polymorpho- nuclear leukocytes. J Periodontal Res 1977;12: 223–34.
34. Noble R, Penny B. Comparison of leukocyte count and function in smoking and nonsmoking young men. Infect Immun 1975;12:550–5.
35. Corberand J, Laharraghe P, Nguyen F, et al. In vitro effect of tobacco smoke components on the func- tion of normal human polymorphonuclear leuko- cytes. Infect Immun. 1980;30:649–55.
36. MacFarlane GD, Herzberg MC, Wolff LF, Hardie NA. Refractory periodontitis associated with abnormal polymorphonuclear leukocyte phago- cytosis and cigarette smoking. J Periodontol 1992;63:908–13.
37. Tew JG, Zhang J-B, Quinn S, et al. Antibody of the IgG2 subclass, Actinobacillus actinomy- cetemeomitans and early-onset periodontitis. J Periodontol 1996;67(Suppl):317–22.
38. Costabel U, Bross KJ, Reuter C, et al. Alterations in immunoregulatory T-cell subsets in cigarette smokers: a phenotypic analysis of brochoalveolar and blood lymphocytes. Chest 1986;90:39–44.
39. Loeshe WJ, Gusberti F, Mettraux G, et al. Relation-
ship between oxygen tension and subgingival bacterial flora in untreated human periodontal pockets. Infect Immun 1983;42:659–67.
40. Mettraux G, Gusberti F, Graf H. Oxygen tension (pO2) in untreated human periodontal pockets. J Periodontol 1984;55:516–21.
41. Venditto MA. Therapeutic considerations: lower respiratory tract infections in smokers. J Am Osteopath Assoc 1992;92:897–900.
42. Zambon JJ, Grossi SG, Machtei EE, et al. Cigarette smoking and subgingival infection. J Periodon- tol 1996;67:1050–5.
43. Cuff MJ, McQuade MJ, Scheidt MJ, et al. The pres- ence of nicotine on root surfaces of periodontally diseased teeth in smokers. J Periodontol 1989; 60(10):564–9.
44. McGuire JR, McQuade MJ, Rossman JA, et al. Cotinine in saliva and gingival crevicular fluid of smokers with periodontal disease. J Periodontol 1989;60(4):176–81.
45. Silverstein P. Smoking and wound healing. Am J Med 1992;93(1A):22s–24s.
46. Raulin LA, McPherson JC III, McQuade MJ, Hanson BS. The effect of nicotine on the attachment of human fibroblasts to glass and human root surfaces in vitro. J Periodontol 1988;59(5):318–25.
47. Hanes PJ, Schuster GS, Lubas S. Binding, uptake and release of nicotine by human gingival fibroblasts. J Periodontol 1991;62(2):142–7.
48. Preber H, Begström J. The effect of non-surgical treatment on periodontal pockets in smokers and nonsmokers. J Clin Periodontol 1986; 13(4):319–23.
49. Grossi SG, Skrepcinski FB, DeCaro T, et al. Response to periodontal therapy in diabetics and smokers. J Periodontol 1996;67:1094–102.
50. Ah MK, Johnson GK, Kaldahl WB, et al. The effect of smoking on the response to periodontal ther- apy. J Clin Periodontol 1994;21(2):91–7.
51. Tonetti MS, Pini-Prato G, Cortellini P. Effect of cigarette smoking on periodontal healing fol- lowing GTR in infrabony defects: a preliminary retrospective study. J Clin Periodontol 1995; 22(3):229–34.
52. Rosen PS, Marks MH, Reynolds MA. Influence of smoking on long-term clinical results of intra- bony defects treated with regenerative therapy. J Periodontol 1996;67:1159–63.
53. Rosenberg ES, Cutler SA. The effect of cigarette smoking on the long-term success of guided tis- sue regeneration: a preliminary study. Ann R Austral Coll Dent Surg 1994;12(4):89–93.
54. Miller PD Jr. Root coverage with the free gingival
Tobacco Use and Intervention 117
graft: factors associated with incomplete cover- age. J Periodontol 1987;58(10):674–81.
55. Jones JK, Triplett RG. The relationship of cigarete smoking to impaired intraoral wound healing: a review of evidence and implications for patient care. J Oral Maxillofac Surg 1992;50(3):237–40.
56. Lindquist LW, Carlsson GE, Jemt T. A prospective 15-year follow-up study of mandibular fixed prosthesis supported by osseointegrated implants. Clin Oral Implant Res 1996;7:329–36.
57. Bain CA, Moy PK. The association between the failure of dental implants and cigarette smoking. Int J Oral Maxillofac Implants 1993;8:609–615.
58. Bain CA. Smoking and implant failure—benefits of a smoking cessation protocol. J Oral Maxillo- fac Implants 1996;11:756–759.
59. Sintonen H, Tuominen R. Exploring the determi- nants of periodontal treatment costs: a special focus on cigarette smoking. Soc Sci Med 1989; 29:835–44.
60. U.S. Department of Health and Human Services. The health benefits of smoking cessation: a report of the Surgeon General. Rockville, MD:U.S. Department of Health and Human Services, Centers for Disease Control and Pre- vention, Center for Chronic Disease Prevention and Health Education, Office on Smoking and Health; 1990. DHHS Publication No. (CDC) 90–8416, vii-viii.
61. Henningfield JE, Cohen C, Pickworth WB. Psy- chopharmacology of nicotine. In: Orleans CT, Slade J, editors Nicotine addiction: principles and management. New York, NY: Oxford Uni- versity Press; 1993.
62. Hughes JR. Smoking as a drug dependence, a reply to Robinson and Pritchard. Psychopharmacology 1993;113:282–3.
63. Hughes JR. Nicotine withdrawal, dependence, and abuse. In Widiger TA, Frances AJ, Pincus HA, et al, editors. DMS-IV sourcebook. Washing- ton, D.C.: American Psychiatric Association; 1994. p. 109–16.
64. U.S. Department of Health and Human Services. Preventing tobacco use among young people: a report of the Surgeon General. Washington, D.C.: U.S. Department of Health and Human Services, Public Health Service, Centers for Dis- ease Control and Prevention, Center for Chron- ic Disease Prevention and Health Promotion, Office on Smoking and Health; 1994.
65. Institute of Medicine. Lynch BS, Bonnie RJ, edi- tors. Growing up tobacco free: preventing nico- tine addiction in children and youths. Washing- ton, D.C.: National Academy Press; 1994.
66. U.S. Department of Health and Human Services. Preventing tobacco use among young people: a report of the Surgeon General. Washington, D.C.: U.S. Department of Health and Human Services, Public Health Service, Centers for Dis- ease Control and Prevention, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 1994. p. 125–46.
67. Pierce JP, Fiore MC, Novotny TE, et al. Trends in cigarette smoking in the United States. JAMA 1989;261:61–5.
68. U.S. Department of Health and Human Services. The health consequences of smoking: nicotine addiction: a report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Health Promo- tion and Education, Office on Smoking and Health; 1988.
69. Henningfield JE, Cohen C, Slade JD. Is nicotine more addictive than cocaine? Br J Addict 1991; 86:565–9.
70. Hughes JR, Gulliver SB, Fenwick JW. Smoking cessation among self-quitters. Health Psychol 1992;11:331–4.
71. Fiore MC. Trends in cigarette smoking in the Unit- ed States: the epidemiology of tobacco use. Med Clin North Am 1992;76:289–303.
72. U.S. Department of Health and Human Services. Cigarette smoking among adults: United States, 1993. MMWR 1994;43:925–30.
73. U.S. Department of Health and Human Services. Preventing tobacco use among young people: a report of the Surgeon General. Washington, D.C.: U.S. Department of Health and Human Services, Centers for Disease Control and Pre- vention, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 1994.
74. Giovino GA, Henningfield JE, Tomar SL, et al. Epidemiology of tobacco use and dependence. Epidemiol Rev 1995;17:48–65.
75. Caraballo RS, Giovino GA, Pechacek TF, et al. Racial and ethnic differences in serum cotinine levels of cigarette smokers. JAMA 1998;280:135–9.
76. Perez-Stable EJ, Herrera B, Jacob P III, Benowitz NL. Nicotine metabolism and intake in black and white smokers. JAMA 1998;280:152–6.
77. Spitz MR, Shi H, Yang F, et al. Case-control study of D2 dopamine receptor gene and smoking sta- tus in lung cancer patients. J Natl Cancer Inst 1998;90:358–63.
78. U.S. Department of Health and Human Services. Tobacco use among U.S. racial/ethnic minority
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groups—African Americans, American Indians and Alaska Natives, Asian Americans and Pacif- ic Islanders, and Hispanics: a report of the Sur- geon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Dis- ease Control and Prevention, National Center for Chronic Disease Prevention and Health Pro- motion, Office on Smoking and Health; 1998.
79. Fant RV, Everson D, Dayton G, et al. Nicotine dependence in women. J Am Med Wom Assoc 1996;51:19–20,22–3.
80. U.S. Department of Health and Human Services. The health benefits of smoking cessation: a report of the Surgeon General. Washington, D.C.: U.S. Government Printing Office; 1990 DHHS Publication No. (CDC) 90–8416.
81. Gritz ER, Nielsen IR, Brooks LA. Smoking cessa- tion and gender: the influence of physiological, psychological, and behavioral factors. J Am Med Wom Assoc 1996;51:35–42.
82. Tomar SL, Husten CG, Manley MW. Do dentists and physicians advise tobacco users to quit? J Am Dent Assoc 1996;127:259–65.
83. Dolan TA, McGorray SP, Grinstead-Skigen CL, Mecklenburg RE. Tobacco control activities in U.S. dental practices. J Am Dent Assoc 1997; 128:1669–79.
84. Hayes C, Kressin N, Garcia R, et al. Tobacco con- trol practices: how do Massachusetts dentists compare with dentists nationwide? J Massachu- setts Dent Soc 1997;46:9–12,14.
85. Mecklenburg RE. Tobacco: addiction, oral health, and cessation. Quint Int 1998;29:250–2.
86. Orleans CT. In: Orleans CT, Slade J, editors: Nico- tine addiction: principles and management. New York, NY: Oxford University Press; 1993. P. ix.
87. National Cancer Institute. Smoking, tobacco, and cancer program: 1985–1989 status report. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, Nation- al Institutes of Health, National Cancer Insti- tute; 1990. NIH Publication No. 90–3107.
88. Ockene JK, Kristellar J, Goldberg R. Increasing the efficacy of physician-delivered smoking inter- ventions: a randomized clinical trial. J Gen Intern Med 1991;6:1–8.
89. Cohen SJ, Stookey GK, Katz BP, et al. Encourag- ing primary care physicians to help smokers quit: a randomized, controlled trial. Ann Intern Med 1989;110:648–52.
90. Cummings SR, Coates TJ, Richard RJ, et al. Train- ing physicians in counseling about smoking ces- sation: a randomized trial of the “Quit for Life”
program. Ann Intern Med 1989;110:640–7. 91. Wilson DMC, Taylor DW, Gilbert JR, et al. A ran-
domized trial of a family physician intervention for smoking cessation. JAMA 1988;260:1570–4.
92. Kottke TE, Brekkle MI, Solberg LI, Hughes JR. A randomized trial to increase smoking interven- tion by physicians: doctors helping smokers, round I. JAMA 1989;261:2101–6.
93. Cohen SJ, Stookey GK, Katz BP, et al. Helping smokers quit: a randomized controlled trial with private practice dentists. J Am Dent Assoc 1989;118:41–5.
94. Hollis JF, Lichtenstein E, Vogt TM, et al. Nurse- assisted counseling for smokers in primary care. Ann Intern Med 1993;118:521–5.
95. Dix SM, McGhan WF, Lauger G. Pharmacist counseling and outcomes of smoking cessation. Am Pharm 1995;NS35:20–32.
96. Wewers ME, Bowen JM, Stanislaw AE, Desimone VB. A nurse-delivered smoking cessation inter- vention among hospitalized postoperative patients—influence of a smoking-related diag- nosis: a pilot study. Heart Lung 1994;23:151–6.
97. National Cancer Institute. Tobacco and the clini- cian: interventions for medical and dental prac- titioners. U.S. Department of Health and Human Services, Public Health Service, Nation- al Institutes of Health, 1994. NIH Publication No. 94–3693.
97a. Cincirpini PM, McClure JB. Smoking cessation: recent developments in behavioral and pharma- cologic interventions. Table 2. Oncology 1998; 12:249–259.
98. Fiore MC, Bailey WC, Cohen SJ, et al. Clinic prac- tice guideline number 18: smoking cessation. U.S. Department of Health and Human Ser- vices, Public Health Service, Agency for Health Care Policy and Research, Centers for Disease Control and Prevention; 1996. AHCPR Publi- cation No. 96–0692.
99. Fiore MC, Bailey WC, Cohen SJ, et al. Smoking cessation: information for specialists. U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, Centers for Disease Con- trol and Prevention; 1996. AHCPR Publication No. 96–0694.
100.Hughes JR, Fiester S, Goldstein MG, et al. Practice guidelines for the treatment of patients with nicotine dependence. Am J Psychiatry 1996; 153:S1–31.
101.Glynn TJ, Manley MW. How to help your patients stop smoking: a National Cancer Institute man- ual for physicians. U.S. Department of Health
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and Human Services, Public Health Service, National Institutes of Health; 1989. NIH Pub- lication No. 90–3064.
102.Husten CG, Manley MW. How to help your patients stop smoking. Am Fam Phys 1990;42: 1017–26.
103.Fiore MC. The new vital sign. JAMA 1991;266: 3183–4.
104.Fiore MC, Jorenby DE, Schensky AE, et al. Smok- ing status as the new vital sign: effect on assess- ment and intervention in patients who smoke. Mayo Clin Proc 1995;70:209–13.
105.Cohen SJ, Christen AG, Katz BP, et al. Counseling medical and dental patients about cigarette smoking: the impact of nicotine gum and chart reminders. Am J Public Health 1987;77:313–6.
106.Fiore MC, Jorenby DE, Baker TB, Kenford SL. Tobacco dependence and the nicotine patch: clinical guidelines for effective use. JAMA 1992;268:2687–94.
107.Henningfield JE. Nicotine medications for smoking cessation. N Eng J Med 1995;333:1196–203.
108.Hjalmarson A, Franzon M, Westin A, Wiklund O. Effect of nicotine nasal spray on smoking cessa- tion. A randomized, placebo-controlled, double- blind study. Arch Intern Med 1994;154: 2567–72.
109.Benowitz NL, Zevin S, Jacob P III. Sources of vari- ability in nicotine and cotinine levels with use of nicotine nasal spray, transdermal nicotine, and cigarette smoking. Br J Clin Pharmacol 1997; 43:259–67.
110.Leischow SJ, Nilsson F, Franzon M, et al. Efficacy of the nicotine inhaler as an adjunct to smoking cessation. Am J Health Behav 1996;20:364– 71.
111.Schneider NG, Olmstead R, Nilsson F, et al. Effi- cacy of a nicotine inhaler in smoking cessation: a double-blind, placebo-controlled trial. Addic- tion 1996;91:1293–306.
112.Ostrowski DJ, DeNelsky GY. Pharmacologic man-
agement of patients using smoking cessation aids. Dent Clin North Am 1996;40:779–801.
113.Fagerstrom KO, Tejding R, Westin A, Lunell E. Aiding reduction of smoking with nicotine replacement medications: hope for the recalci- trant smoker? Tobacco Cont 1997;6:311–6.
114.Warner KE, Slade J, Sweanor DT. The emerging market for long-term nicotine maintenance. JAMA 1997;278:1087–92.
115.Hurt RD, Sachs DPL, Glover ED, et al. A com- parison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;337:1195–202.
116.Somerman M, Mecklenburg RE. Cessation of tobacco use. In Ciancio SG, editors. ADA guide to dental therapeutics. Chicago, IL: ADA Pub- lishing Company; 1998. p. 505–16.
117.Hughes JR, Goldstein MG, Hurt RD, Shiffman S. Recent advances in the pharmacotherapy of smoking. JAMA 1999;281:72–6.
118.Prochaska J, DeClemente C, Norcross J. In search of how people change: applications to addiction behaviors. Am Psychol 1992;47:1102–14.
119.Patton GC, Carlin JB, Coffey C, et al. Depression, anxiety, and smoking initiation: a prospective study over 3 years. Am J Public Health 1998;88: 1518–22.
120.Nisell M, Nomikos GG, Svenson TH. Nicotine dependence, midbrain dopamine systems and psychiatric disorders. J Pharmacol 1995;76: 157–62.
121.Glassman AH, Helzer JE, Covey LS, et al. Smok- ing, smoking cessation, and major depression. JAMA 1990;264:1546–9.
122.Thorndyke AN, Rigotti NA, Stafford RS, Singer DE. National patterns in the treatment of smokers by physicians. JAMA 1998;279:604–8.
123.Cromwell J, Bartosch WJ, Fiore MC, et al. Cost- effectiveness of the clinical recommendations in the AHCPR guideline for smoking cessation. JAMA 1997;278:1759–66.
CHAPTER 8
DIABETES MELLITUS Brian Mealey, DDS, MS
Diabetes mellitus is a disease of metabolic dysreg- ulation, primarily of carbohydrate metabolism, characterized by hyperglycemia (elevated blood glucose) that results from defects in insulin secre- tion, impaired insulin action, or both. Alterations in lipid and protein metabolism are also seen. Chronic elevation in blood glucose is associated with long-term dysfunction and damage to numer- ous organs, especially the eyes, kidneys, heart, nerves, and blood vessels.
Approximately 16 million Americans (6 to 7% of the population) have diabetes, but about half these individuals are unaware that they have the disease.1 More than 600,000 new cases are diag- nosed each year, and the worldwide prevalence of diabetes is projected to double between 1994 and 2010, to 240 million.2,3 The number of cases in the United States continues to rise due to increas- ing population and life expectancy, combined with an increased prevalence of obesity, which is strong- ly associated with the most common form of dia- betes. The total direct and indirect costs of diabetes constitute almost 12% of all annual health care costs in the United States, exceeding $90 billion.4
Given the high prevalence of this disease, it is like- ly that every practicing dentist will encounter patients with diabetes. In a dental practice with 2,000 patients and an average prevalence of 6 to 7%, approximately 120 to 140 patients would have diabetes. Again, only half these people would be aware of their diabetic condition.
CLASSIFICATION AND PATHOPHYSIOLOGY OF DIABETES
Over the past three decades, the diagnosis and clas- sification of diabetes has undergone numerous changes. In 1997, the American Diabetes Associa- tion provided the current classification.5 The two most common forms are type 1 diabetes, formerly
called insulin-dependent diabetes, and type 2 dia- betes, previously known as non–insulin-dependent diabetes (Table 8–1). Because insulin injection is frequently used in the treatment of both forms of diabetes, the terms “insulin-dependent” and “non–insulin-dependent” were often confusing. The new classification is based on the underlying pathophysiology of the disease types, rather than on treatment approaches.
Gestational diabetes is another form of the dis- ease that occurs during pregnancy and generally resolves after parturition. Other, less common forms of diabetes may be related to genetic defects in insulin-secreting cells in the pancreas, genetic defects in insulin action, pancreatic diseases or injuries, drug- or chemical-induced changes in metabolism, other endocrine disorders, infections, and genetic syndromes of which diabetes is one component.5
TABLE 8–1. Classification of Diabetes Mellitus
• Type 1 diabetes (formerly, insulin-dependent diabetes) • Type 2 diabetes (formerly, non–insulin-dependent
diabetes) • Gestational diabetes • Other types of diabetes
– Genetic defects in b cell function – Genetic defects in insulin action – Pancreatic diseases or injuries
Pancreatitis, neoplasia, cystic fibrosis, trauma, pancreatectomy
– Infections Cytomegalovirus, congenital rubella
– Drug-induced or chemical-induced diabetes Glucocorticoids, thyroid hormone
– Endocrinopathies Acromegaly, pheochromocytoma, glucagonoma, hyperthyroidism, Cushing’s syndrome
– Other genetic syndromes with associated diabetes
122 Periodontal Medicine
During digestion, most foods are broken down into glucose, which then enters the circulatory sys- tem and is subsequently used by tissue cells for energy and growth (Figure 8–1). Most cells, exclud- ing those in the brain and central nervous system, require the presence of insulin to allow glucose entry. Insulin binds to specific cellular receptors to exert its effects. Insulin is produced by the b cells of the pancreas, and increased insulin secretion occurs in response to increased blood glucose concentra- tions. With the secretion of insulin from the pan- creas into the circulatory system and its subsequent binding to its cellular receptors, glucose is able to exit the bloodstream and enter the tissues, resulting in its utilization by the cells and thus decreased blood glucose concentrations. Decreased insulin production or diminished insulin action will alter glucose metabolism and result in hyperglycemia. Conversely, increased insulin levels may cause hypoglycemia (low blood glucose).
The excess glucose that is not required by the body for current activity is stored in the liver in the form of glycogen. In the fasting state, or when glu- cose demand exceeds glucose available from recent food consumption, the liver breaks down glycogen and releases glucose into the bloodstream through the process of glycogenolysis. The liver also pro- duces glucose through the process of gluconeogen- esis—the production of glucose from noncarbohy- drate sources such as amino acids and fatty acids.
Insulin is the primary hormone that reduces blood glucose levels. A group of counter-regulato-
ry hormones serve to balance glycemia (Table 8–2). While these hormones have a wide variety of functions, they all result in elevation of blood glu- cose. If insulin function is normal, as in the non- diabetic patient, elevated blood glucose levels resulting from secretion of counter-regulatory hor- mones are quickly normalized through compen- satory secretion of endogenous insulin. If, howev- er, insulin secretion is impaired, as in the diabetic patient, elevated blood glucose levels in response to counter-regulatory hormone release will remain elevated. For example, if an individual with type 1 diabetes is placed under significant stress, epineph- rine and cortisol are released. This causes an increase in blood glucose levels. Since the patient is unable to secrete insulin, hyperglycemia results.
Type 1 Diabetes
Type 1 diabetes is caused by cell-mediated autoim- mune destruction of the insulin-producing b cells in the pancreas. This results in absolute insulin deficiency; the individual no longer produces insulin. The rate of b-cell destruction is variable. Some individuals, especially children and adoles- cents, quickly develop signs and symptoms of type 1 diabetes following rapid destruction of b cells. Others retain some insulin-producing capacity as the b cells are slowly destroyed. Numerous markers are available for assessing risk and aiding diagnosis of type 1 diabetes, including autoantibodies to pan- creatic islet cells, insulin, glutamic acid decarboxy- lase, and tyrosine phosphatases.5 One or more of these markers can be detected in 90% of type 1 dia- betic patients at the time of initial diagnosis.
Type 1 diabetes has multiple genetic predisposi- tions but is also strongly related to various environ- mental factors. Monozygous (identical) twins have a concordance rate for type 1 diabetes of approxi- mately 30 to 50%. Thus, less than half the monozy- gous siblings of patients with type 1 diabetes will be diagnosed with the disease. This suggests that envi-
Figure 8–1. Insulin control of blood glucose. Hormonal control of blood glucose by insulin. Ingestion of food results in increased blood glucose levels. The pancreas is stimulated to increase insulin secretion. Insulin then allows glucose to enter cells, especially muscle. Insulin also stimulates storage of excess glucose by muscle and the liver in the form of glycogen. Insulin prevents the breakdown of stored glycogen into glucose by the liver. The net result is a decrease in blood glucose levels. Glycogen stores are used during periods of fasting or increased tissue glucose demand.
TABLE 8–2. Hormonal Control of Glycemia
Hormones that raise blood glucose • Glucagon • Catecholamines (epinephrine) • Growth hormone • Thyroid hormone • Glucocorticoids (cortisol)
Hormone that lowers blood glucose • Insulin
Diabetes Mellitus 123
ronmental influences are superimposed on the genetic components. Susceptibility to type 1 dia- betes is linked to the presence of certain genetically determined antigens found on the cell surface of lymphocytes (human leukocyte antigens [HLA]). These HLA associations are linked primarily to DQ and DR genes. Some HLA loci, such as DR3 and DR4, are associated with increased risk for develop- ing type 1 diabetes while other loci may be protec- tive. Alterations in these major histocompatibility complex (MHC) antigens on cell surfaces may explain why individuals become intolerant of self- antigens, resulting in T-cell-mediated destruction of pancreatic b cells. The complex genetic susceptibili- ty of type 1 diabetes is not clearly understood.
Onset of b–cell destruction in people with a genetic susceptibility to type 1 diabetes may be ini- tiated by an environmental event. Viral infections have long been targeted as possible triggering events although evidence is not conclusive. Of par- ticular interest are coxsackie virus, cytomega- lovirus, and rubella infections. A working model of type 1 diabetes suggests that an environmental event may cause focal damage to pancreatic b cells.3
The autoantigens that are then released from the damaged b cells are taken up by antigen-presenting cells such as macrophages. The autoantigens are then processed and presented to host T helper cells, which respond via increased cytokine production. These cytokines cause influx into the pancreatic islets of both nonspecific and antigen-specific mononuclear inflammatory cells. These cells release cytokines that eventually result in the death of b cells and loss of insulin production.
The onset of type 1 diabetes occurs most often before the age of 30 years; in fact, type 1 diabetes
was once known as “juvenile” diabetes (Table 8–3). However, it may be diagnosed at any age. Onset of clinical symptoms is usually abrupt. Most people with type 1 diabetes are of normal weight or are thin in stature. The lack of endogenous insulin production makes the type 1 individual dependent on exogenous insulin injections for survival.
People with type 1 diabetes are highly suscepti- ble to ketoacidosis.2 In the absence of adequate insulin levels, glucose cannot be used by the tissue and remains in the bloodstream, leading to cellular starvation. Body fat stores are then broken down for energy through the process of lipolysis. The glycerol portion of triglyceride is converted to glu- cose, and free fatty acids are released. With pro- longed insulin deficiency, lipolysis continues and fatty acids are converted to ketones. Increased ketone levels in body fluids lead to excretion of ketones in the urine. Large amounts of water are excreted along with ketones, resulting in dehydra- tion. Diabetic ketoacidosis results from accumula- tion of ketones in body fluids, increased loss of elec- trolytes in the urine, and alterations in the bicar- bonate buffer system (Table 8–4). If not treated properly, severe acidosis can lead to coma or death.
Severe diabetic ketoacidosis usually occurs when the signs and symptoms of undiagnosed type 1 diabetes are not recognized or when the known diabetic patient’s glycemia is poorly con- trolled. For many individuals, a diagnosis of type 1 diabetes is not made until they are hospitalized for treatment of acute ketoacidosis. In the patient with previously diagnosed type 1 diabetes, keto- acidosis may be precipitated by systemic infection or stress. Elevated levels of cortisol, epinephrine, or glucagon as a result of stress promote increased
TABLE 8–3. Characteristics of Type 1 and Type 2 Diabetes
Type 1 Diabetes Type 2 Diabetes
Age at onset Generally <30 years Generally in adulthood Most common body type Thin or normal stature Obese Race most commonly affected White African American, Hispanic, American Indian,
(in the United States) Pacific Islanders Family history Common More common Rapidity of clinical onset Abrupt Slow Pathogenesis Autoimmune b cell Insulin resistance, impaired insulin secretion,
destruction increased liver glucose production Endogenous insulin None Decreased, normal, or elevated
production Susceptibility to ketoacidosis High Low Treatment may include Diet, exercise, insulin Diet, exercise, oral agents, insulin
124 Periodontal Medicine
hepatic glucose production and ketogenesis. Ketoacidosis is often seen when the type 1 diabet- ic person remains hyperglycemic for several days or longer due to inadequate amounts of exogenous insulin or excessive amounts of glucose intake. Many people with type 1 diabetes suffer multiple episodes of diabetic ketoacidosis as a result of poor daily glycemic control.
Type 2 Diabetes
Type 2 diabetes is much more common than type 1, constituting 90% of all diabetic cases. While type 1 diabetes is most common in Caucasian Americans, the prevalence of type 2 is higher in African Americans, Hispanics, American Indians, and Pacific Islanders.5 The highest prevalence and incidence of type 2 diabetes in the United States is found in the Pima Indian population of Arizona, in which almost 50% of those between 30 and 65 years of age have the disease. Type 2 diabetes com- monly leads not only to hyperglycemia but also to hypertension, dyslipidemia (elevated triglycerides and/or decreased high-density lipoprotein), central obesity (abdominal), and atherosclerosis. This group of disorders is often called “the insulin resis- tance syndrome,” or “syndrome X.”5,6
The pathophysiology of type 2 diabetes is dif- ferent from that of type 1. While the specific eti- ologies are not known, autoimmune destruction of b cells does not occur. Type 2 diabetes is character- ized by three major abnormalities: (1) peripheral resistance to insulin, particularly in muscle; (2) impaired pancreatic insulin secretion; and (3)
increased glucose production by the liver. The clin- ical effect of these disorders is the same as in type 1 diabetes, namely, hyperglycemia. Evidence strongly suggests that the initial defect in the pathogenesis of type 2 diabetes is insulin resis- tance, which is eventually followed by impaired insulin secretion.7
Even though the pancreas still produces insulin, the presence of insulin resistance prevents transport of glucose into tissue cells, causing hyperglycemia. Relative to nondiabetic individu- als, pancreatic insulin secretion may also be decreased, worsening hyperglycemia. Paradoxical- ly, in many type 2 diabetic patients, there is actu- ally an increase in insulin production. This is a direct result of insulin resistance and the subse- quent decrease in glucose utilization. The pancreas may respond to poor glucose utilization and hyper- glycemia by a compensatory increase in insulin production, resulting in hyperinsulinemia. There may also be differences in pathophysiology within the type 2 diabetic population. The majority of people with type 2 diabetes are obese, and these individuals tend to exhibit significant insulin resis- tance accompanied by hyperinsulinemia. Obesity itself can result in insulin resistance, even in the absence of diabetes.8 Conversely, thin individuals with type 2 diabetes primarily suffer from impaired insulin secretion, with insulin resistance being less severe than in obese people.5
Type 2 diabetes has a stronger genetic compo- nent than type 1, with a concordance rate of up to 90% in identical twins.9 Unfortunately, while over 250 genes have been tested for possible relation- ships with type 2 diabetes, none has shown consis- tent associations in multiple study populations.10
It is possible that no single genetic defect is respon- sible for type 2 diabetes. Besides obesity, acquired risk factors for type 2 diabetes include advancing age and a sedentary lifestyle.
Unlike the sudden onset of clinical symptoms in type 1 diabetes, type 2 diabetes may remain undiagnosed for years. Thus, it is estimated that about half of all patients with type 2 diabetes are unaware of their condition. Because they still pro- duce endogenous insulin, people with type 2 dia- betes are not generally dependent on exogenous insulin administration for survival. However, a large number of these individuals take insulin injections as a part of their treatment regimen. Type 2 diabetic patients are also resistant to ketosis since their pancreatic insulin production is usually sufficient to suppress ketone formation. Under conditions of extreme physiologic stress, type 2
TABLE 8–4. Signs, Symptoms, and Laboratory Findings in Diabetic Ketoacidosis
Nausea and vomiting Abdominal pain Dehydration
• Dry mucous membranes • Tachycardia • Hypotension • Abnormal skin turgor
Kussmaul’s respiration Altered mental state Possible coma Hyperglycemia Increased blood urea nitrogen (BUN) and serum
creatinine Decreased serum potassium and phosphorus Acidosis (arterial pH <7.3)
Diabetes Mellitus 125
patients may develop ketoacidosis. With pro- longed hyperglycemia, individuals with type 2 dia- betes may develop hyperosmolar nonketotic acido- sis. Excretion of large amounts of glucose in the urine is accompanied by significant water loss. Failure to replace lost fluids may lead to electrolyte imbalance and acidosis in the absence of ketones. Another similar entity called hyperosmolar nonaci- dotic diabetes is characterized by severe hyper- glycemia (plasma glucose >600 mg/dL), hyperos- molarity, and dehydration. This disorder is associ- ated with severe fluid depletion and renal impair- ment, with a high mortality rate.
Impaired Glucose Tolerance/Impaired Fasting Glucose
Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) imply a metabolic state between normal glycemia and diabetes. Many peo- ple with IGT have normal blood glucose levels most of the time, often manifesting hyperglycemia only after challenge with a large glucose load.4
Those with IFG have elevated fasting glucose lev- els but may be normal in a fed state. Both IGT and IFG are not considered to be clinical entities in themselves. Rather, they are primarily risk factors for future development of diabetes.11 In fact, they can be seen as intermediate stages in all types of diabetes. Both IGT and IFG are strongly associat- ed with insulin resistance and with syndrome X.6
Endogenous insulin production is normal and remains so in the majority of IGT/IFG patients. However, about 30 to 40% of patients with IGT/IFG will develop type 2 diabetes within 10 years after initial diagnosis. During the transition to type 2 diabetes, several changes occur.5 Insulin resistance increases and insulin secretion is impaired as b-cell function diminishes. Hepatic glucose production also increases. Eventually, the patient manifests overt clinical and laboratory signs of diabetes.
Patients with IGT/IFG are not at increased risk for microvascular complications such as those seen in diabetic individuals. However, they are at greater risk for cardiovascular disease than are peo- ple with normal glucose tolerance. The reasons why IGT and IFG increase the risk of cardiovascu- lar disease are not well understood. Both IGT and IFG are frequently associated with hypertension, hypertriglyceridemia, and low levels of high-densi- ty lipoproteins (HDL), all well-known risk factors for cardiovascular disease. Thus, IGT/IFG may not be directly involved in the pathogenesis of cardio-
vascular disease but may be risk factors in con- junction with other components of syndrome X.
Gestational Diabetes
Gestational diabetes usually develops during the third trimester of pregnancy but can occur earlier. About 4% of all pregnancies in the United States are complicated by gestational diabetes.12 An increased prevalence of gestational diabetes is seen in women who are overweight, older than 25 years of age, have a family history of diabetes, and are members of ethnic groups with higher prevalence rates for type 2 diabetes (African American, His- panic, American Indian).13,14 The disorder appears to have a similar pathophysiology to IGT/IFG and type 2 diabetes, ie, it is strongly associated with insulin resistance.
Gestational diabetes significantly increases perinatal morbidity and mortality as well as increasing the rate of cesarean delivery.15 Diagnosis of gestational diabetes is important because proper management significantly improves pregnancy outcomes.16 About 6 weeks or more after parturi- tion, women with gestational diabetes are reclassi- fied as having either diabetes, IGT, IFG, or nor- moglycemia. Most patients who develop gestation- al diabetes return to normal after delivery. Others will be diagnosed at some time postpartum with IGT, IFG, type 1 or type 2 diabetes. It is estimat- ed that 30 to 50% of women with a history of ges- tational diabetes will develop type 2 diabetes with- in 10 years of the initial diagnosis.
CLASSIC COMPLICATIONS OF DIABETES
In addition to dysregulation in carbohydrate, lipid and protein metabolism, type 1 and type 2 dia- betes are associated with a classic group of micro- vascular and macrovascular complications (Table 8–5). While the microvascular complications of retinopathy, nephropathy, and neuropathy are specifically associated with diabetes, macrovascular diseases occur in the nondiabetic population as well. However, the risk of macrovascular disease is greatly increased in diabetic patients.
These complications are the major cause of the high morbidity and mortality of diabetes. The dia- betic patient has a dramatically increased risk for visual impairment or blindness, kidney failure, limb amputation, stroke, and myocardial infarc- tion. Sustained hyperglycemia plays a central role
126 Periodontal Medicine
in the onset and progression of diabetic complica- tions. The duration of diabetes is an important risk factor as the prevalence of these complications increases with longer duration of disease. Hyper- tension and dyslipidemia are also risk factors for both microvascular and macrovascular complica- tions. There are also genetic influences affecting the propensity to develop these complications.
Vascular complications of diabetes result from microangiopathy and atherosclerosis.17–19 Changes in the blood vessels include endothelial prolifera- tion and thickening of the basement membrane, thickening of the walls of larger vessels, and increased lipid deposition and atheroma forma- tion. These changes occur throughout the body and are primarily responsible for the majority of diabetic complications.
Diabetic retinopathy consists of both prolifer- ative and nonproliferative changes in the retina. Development of retinopathy increases as the dura- tion of diabetes increases and is more common in type 1 diabetes.19 After 15 years’ duration of type 1 diabetes, about 95% of individuals have some degree of retinopathy, with about 50% having the more advanced form of proliferative retinopathy. The earliest retinal changes are nonproliferative and include dilation, occlusion, and increased per- meability of retinal blood vessels. The basement membrane of retinal capillaries thickens, and microaneurysms develop. Extravasation of blood from the capillaries results in soft and hard exudate formation on the retina. Microaneurysms tend to occur near the macula, the region of the retina responsible for visual acuity and central vision. Macular edema may result from hemorrhages and deposit formation, leading to loss of central vision and acuity. Capillary occlusion causes retinal
ischemia, which may then lead to proliferation of abnormal blood vessels and fibrous tissue from the surface of the retina out into the vitreous, a process known as proliferative retinopathy. These new blood vessels are fragile and may bleed into the vit- reous. As that blood is reabsorbed from the vitre- ous, scarring occurs. Over time, macular edema and proliferative retinopathy may lead to severe vision loss or blindness.2,19
Renal failure is the leading cause of death in the type 1 diabetic population. Approximately 35 to 45% of type 1 patients develop nephropathy, compared with about 20% of type 2 individuals. The mesangium, the membrane supporting the capillary loops in the renal glomeruli, expands due to increased production of mesangial matrix pro- teins.18 As the mesangium expands, the surface area for glomerular capillary filtration decreases, and the glomerular filtration rate (GFR) declines. The basement membrane in glomerular capillaries also thickens, further decreasing glomerular filtra- tion. Clinically, the earliest sign of diabetic nephropathy is the excretion of small amounts of albumin in the urine (microalbuminuria). With progressive disease and reduction in glomerular fil- tration capacity, macroalbuminuria may develop, with large amounts of protein excreted in the urine (proteinuria). Increased renal blood pressure may also occur. The expanding mesangium, thickening of capillary basement membranes, renal hyperten- sion, and declining GFR may then progress to end-stage renal disease. Patients with end-stage renal disease are treated with hemodialysis, peri- toneal dialysis, or kidney transplantation, each of which has its own host of potential complications and adverse sequelae.
Diabetic neuropathy occurs in up to 50% of diabetic patients, its prevalence increasing with the duration of diabetes.20 Neuropathy may affect the sensory, motor, and autonomic nerves. Peripheral sensorimotor neuropathy is the most common variety, frequently manifesting as numbness or tin- gling of the toes or feet. This may be accompanied by muscle weakness or cramping, alterations in gait, and burning pain. As neuropathy worsens, the paresthesia or dysesthesia may disappear and be replaced by hypoesthesia or even anesthesia. This reduction in sensory ability makes the affected areas highly prone to injury since the patient is unable to perceive painful stimuli. Diabetic foot ulcers resulting from repetitive injury to an insen- sate foot are a major cause of hospitalization and amputation. The patient is unable to perceive pain in the limb, leading to repeated trauma. When
TABLE 8–5. Classic Complications of Diabetes Mellitus
Retinopathy • Blindness
Nephropathy • Renal failure
Neuropathy • Sensory • Autonomic
Macrovascular disease (accelerated atherosclerosis) • Peripheral • Cardiovascular (coronary artery disease) • Cerebrovascular (stroke)
Altered wound healing
Diabetes Mellitus 127
combined with alterations in wound healing capacity and changes in the peripheral vasculature, this otherwise relatively minor injury may lead to gangrene and amputation of the affected area (Fig- ures 8–2).
Diabetic neuropathy may also affect the auto- nomic nervous system. Cardiovascular autonomic neuropathy can lead to dysrhythmias and alter- ations in blood pressure. Genitourinary neuropathy may cause incontinence due to hypotonia or atonia of the bladder. Sensory and autonomic genitouri- nary neuropathy often leads to impotence in dia- betic men. Diabetic gastroparesis results from gas- trointestinal neuropathy and manifests as delayed gastric emptying, sensation of fullness, nausea and vomiting. Diabetic diarrhea may present as noctur- nal diarrhea or incontinence, alternating with peri- ods of constipation. The mechanisms involved in diabetic neuropathy are not completely under- stood. Sustained hyperglycemia is certainly involved and alterations in specific glucose-linked biochemical processes may lead to progressive structural and functional nerve changes.2,20
The most common cause of death in type 2 diabetes is myocardial infarction, underlining the importance of macrovascular complications in these individuals.17 Similarly, macrovascular com- plications are very common in type 1 diabetes. Atherosclerosis affects the cardiac, cerebral, and peripheral vasculature. Atherosclerosis and coro- nary artery disease are not unique to the diabetic population, but the risk and incidence of these changes are significantly increased in diabetes. Hyperglycemia plays an important role in macrovascular disease. Increased intimal thickness and atheroma formation are related to hyper- glycemia-induced tissue alterations. Increased thickness of vessel walls leads to partial obstruction and reduced blood flow. Atheroma formation fur- ther narrows the vessels, diminishing the flow of blood. Decreased blood flow in peripheral vessels leads to alteration in tissue homeostasis and wound healing. In central vessels, reduction in blood flow places major organs such as the heart and brain at risk for altered function.17
Poorly controlled or previously undiagnosed diabetic patients have major modifications in their lipoprotein metabolism.21,22 Triglyceride levels are often dramatically elevated while HDL levels are decreased. Low-density lipoprotein (LDL) levels may be normal, but there are often changes in LDL composition. In some cases, LDL levels are also markedly elevated. Improved glycemic control generally improves lipoprotein metabolism.
Hyperglycemia increases the oxidation of LDL, and oxidized LDL is much more atherogenic than the native form. Thrombus formation is also great- ly enhanced in the diabetic patient. Increased fibrin deposition along the vessel wall and increased platelet aggregation lead to formation of intravas- cular microthrombi.22 These alterations can cause intermittent hypercoagulation. Increased formation of atheromas and microthrombi in the diabetic patient results in increased risk for thromboembol- ic events such as stroke and myocardial infarction. Peripheral thromboemboli place end-terminal organs at risk for poor oxygenation and exchange of metabolic waste products. Risk factors commonly associated with atherosclerosis, coronary artery dis- ease, and stroke in the nondiabetic population— smoking, hypertension, obesity, and dyslipi- demia—also apply to diabetes patients. The pres- ence of diabetes, however, warrants more aggressive management and alteration of these risk factors.
The underlying pathophysiology of diabetes complications is complex and diverse. Hyper- glycemia is, in large part, responsible for both the macrovascular and microvascular complications. Hyperglycemia alters cell function and produces a cascade of events leading to the structural changes seen in affected tissues. Current research has focused on alterations in lipoprotein metabolism and on nonenzymatic glycosylation of proteins as possible common links between these various complications.
Because the physical and chemical properties of membranes are determined, in part, by the fatty
Figure 8–2. Gangrenous foot (dorsal view) in patient with long- standing diabetes mellitus. Foot was amputated due to extensive tissue necrosis (Photograph courtesy of Dr. Kathyrn Cripps).
128 Periodontal Medicine
acids within the phospholipid bilayer, alterations in lipid metabolism may have wide-ranging effects on cellular function.21 Oxidization of LDL in the hyperglycemic patient may increase oxidant stress, inducing chemotaxis of monocytes/macrophages in affected tissues such as vessel walls. Once resi- dent within the affected tissue site, oxidized LDL may induce alterations in cellular adhesion as well as increased production of chemotactic factors, cytokines, and growth factors.23 This may then lead to increased vessel wall thickness and forma- tion of atheromas and microthrombi in the large vessels and alterations in endothelial cell function and vascular permeability in the microvasculature.
Another common link between the complica- tions of diabetes is the glycosylation of proteins, lipids, and nucleic acids.24,25 In many diabetic patients, the small blood vessels of the retina, glomerulus, and endoneurial region and the walls of the large blood vessels accumulate deposits of carbo- hydrate-containing plasma proteins. In addition, expansion of the extracellular matrix is seen in all these sites. Increased basement membrane thickness is noted in the retina and around the nerves, the mesangial matrix is thickened in the glomerulus, and accumulation of collagen is seen in the diabet- ic arteries. The cumulative effect is a progressive narrowing of the vessel lumen and decreased per- fusion of affected organs.
The carbohydrate-containing proteins which accumulate in patients with sustained hyper- glycemia are known as advanced glycosylation end- products (AGEs).24–26 Formation of AGEs begins with the attachment of glucose to the amino groups on proteins to form an unstable Schiff base adduct (Figure 8–3). Through a slow chemical rearrange-
ment, these are converted to a more stable but still reversible glucose-protein adduct known as an Amadori product. Normalization of glycemia at this stage results in reversal of the Amadori product. Thus, while these early glycosylation products increase when blood glucose levels are elevated, a return to normal glycemia results in their reversal, and they do not accumulate in tissues. If hyper- glycemia is sustained, the Amadori products become highly stable and form AGEs. Because AGEs are irreversible, once formed, they remain attached to proteins for the lifetime of those proteins. Thus, even if hyperglycemia is corrected, the level of AGEs in the affected tissues does not return to normal.
Formation of AGEs varies among individuals; AGEs form in everyone, not only in people with diabetes. The accumulation of AGEs also increases with age and may be the basis for many age-relat- ed physiologic changes. However, AGE accumula- tion is greatly increased in many diabetic patients.24,25 There is significant heterogeneity in AGE formation within the diabetic population. It is thought that this heterogeneity may provide a partial explanation for the variation in the inci- dence of complications seen in diabetes. While hyperglycemia is distinctly linked to the onset and progression of diabetic complications, there are many poorly controlled diabetic individuals who do not develop significant complications. Con- versely, some patients with well-controlled diabetes still develop complications. It is postulated that the differences between individuals in AGE accumula- tion may explain some of this variance in compli- cations within the diabetic population.
Advanced glycosylation end-products form on collagen, a major component of the extracellular matrix. Once formed, AGEs cause increased colla- gen cross-linking, resulting in the formation of highly stable collagen macromolecules that are resistant to normal enzymatic degradation and tis- sue turnover.24–26 This causes the accumulation of protein at the affected site. In the blood vessel wall, AGE-modified collagen accumulates, thickening the vessel wall and narrowing the lumen. In addi- tion, circulating LDL in the vessel lumen is immo- bilized in the presence of AGE-modified arterial collagen.21,24,25 The amount of LDL that covalent- ly cross-links to collagen increases as levels of AGE increase. Therefore, hyperglycemia contributes to formation of increasing levels of AGE-modified collagen in the vessel wall. Circulating LDL becomes cross-linked to this AGE-modified colla- gen and contributes to atheroma formation in the diabetic macrovasculature.
Figure 8–3. Advanced glycosylation end-product formation. Glucose attaches to the amino-terminal end of proteins to form unstable Schiff-base adduct. Over a period of weeks, this product stabilizes to form a reversible Amadori product. With sustained hyperglycemia, the Amadori product rearranges to form irreversible advanced glycosylation end-product.
Diabetes Mellitus 129
The formation of AGEs occurs in both the central and peripheral diabetic arteries and is thought to contribute greatly to macrovascular complications of diabetes. The modification of col- lagen by AGEs also occurs in the basement mem- brane of small blood vessels. Again, AGE-modified collagen accumulates and increases basement membrane thickness, altering normal homeostatic transport across the membrane.
At the cellular level, AGEs have significant effects. Accumulation of AGEs not only affects extracellular matrix components but can affect matrix-to-matrix interactions and cell-to-matrix interactions. A receptor for AGEs known as RAGE (receptor for AGE) has been identified on the sur- face of smooth muscle cells, endothelial cells, neu- rons, and monocytes/macrophages.27–29 Hyper- glycemia results in increased RAGE expression and AGE-RAGE interaction. The effect on the endothelial cells is an increase in vascular perme- ability and thrombus formation.30 The AGE- RAGE interaction on smooth muscle cells results in cellular proliferation within the arterial wall. As AGEs are chemotactic for monocytes, AGE-RAGE interaction induces increased cellular oxidant stress and activates the transcription factor Nf-kB on monocytes. This then alters the phenotype of the monocyte/macrophage and results in increased production of proinflammatory cytokines and growth factors such as interleukin-1 (IL-1), tumor necrosis factor (TNF), platelet-derived growth fac- tor (PDGF), and insulin-like growth factor (IGF).27,28,31,32 All these cytokines and growth fac- tors have been shown to contribute to the chronic inflammatory process in the formation of athero- matous lesions. Interestingly, oxidized LDL, ele- vated in many diabetic patients, also activates NF- kB, and may result in similar processes. Thus, alterations in lipid and protein metabolism induced by the sustained hyperglycemia character- istic of diabetes may play a major role and provide a common link between all the classic complica- tions of this disease.
CLINICAL PRESENTATION AND DIAGNOSIS OF DIABETES
The onset of type 1 diabetes is usually quite sud- den while type 2 diabetes may be present for years before the patient develops symptoms. The classic signs and symptoms of undiagnosed diabetes are polydipsia (excessive thirst), polyuria (excessive urination), unexplained weight loss, and polypha-
gia (excessive hunger). Patients may also suffer from weakness, malaise, irritability, blurriness or other changes in vision, nausea, and dry mouth. The type 1 patient who does not seek medical eval- uation quickly may develop diabetic ketoacidosis.
The diagnosis of diabetes is established through recognition of its signs and symptoms and by laboratory evaluation. Urinalysis was once a pri- mary diagnostic tool, but is no longer used in this manner. Hyperglycemia may lead to excretion of glucose in the urine. Urinary glucose can be detect- ed by use of a urine dip-stick test. However, many diabetic patients do not excrete large amounts of glucose, even at relatively high blood glucose levels. Conversely, finding glucose in the urine is not diagnostic for diabetes as glucose may be excreted from the kidneys in nondiabetic conditions.
The primary methods used to diagnose dia- betes mellitus and monitor blood glucose levels have been the fasting blood glucose, a combination of fasting blood glucose plus a 2-hour test after glucose loading (2-hour postprandial), and oral glucose tolerance tests. In 1997, the American Dia- betes Association provided the most current labo- ratory diagnostic parameters for diabetes33 (Table 8–6). The new diagnostic guidelines allow use of a casual (nonfasting) plasma glucose for diagnosis and restrict routine use of the oral glucose toler- ance test. These diagnostic tests clearly demon- strate the individual’s capacity to regulate plasma glucose levels.
The fasting and casual plasma glucose tests and the oral glucose tolerance test allow determi- nation of glycemia at the moment in time when the blood sample is drawn. They do not allow eval- uation of glycemic control over a more extended time period. The primary test used for this purpose is the glycosylated hemoglobin assay (also called the glycohemoglobin test). This test measures the amount of glucose bound to the hemoglobin mol- ecule on red blood cells. Glucose binds irreversibly to hemoglobin to form glycosylated hemoglobin and will remain bound for the lifespan of the red blood cell, ranging from about 30 to 90 days. This process is an example of AGE formation. The higher the blood glucose levels over time, the greater is the percentage of glycosylated hemoglo- bin. The glycosylated hemoglobin value is propor- tional to the blood glucose levels; thus, this test gives a measure of the blood glucose status over the preceding 30 to 90 days.
Two different glycosylated hemoglobin tests are available: the hemoglobin A1 (HbA1) test and the hemoglobin A1c (HbA1c) test. Each has a dif-
130 Periodontal Medicine
ferent range of normal values, with the normal HbA1 being less than about 8% and the normal HbA1c less than 6 to 6.5%.34,35 Because different laboratories use different forms of the assay, glyco- sylated hemoglobin values must be interpreted in the context of the range of normal values for the individual medical laboratory performing the ser- vice. The American Diabetes Association recom- mends that diabetic patients try to achieve a target HbA1c of <7%.36 An HbA1c >8% suggests that alteration in patient management is needed to improve glycemic control.
More recently, glycosylated albumin and fruc- tosamine tests have been developed as monitoring tools although they are not used as commonly as the glycosylated hemoglobin assay. Fructosamine levels provide assessment of glycemic control over the past 4 to 6 weeks.37 The normal range for fruc- tosamine is 2 to 2.80 mmol/L.
While the above laboratory tests are available for professional diagnosis of diabetes and determi- nation of glycemic control, the advent of self- blood glucose monitoring (SBGM) has allowed the individual diabetic patient to rapidly assess his or her own blood glucose levels almost instantaneous- ly. Almost all diabetic patients using insulin and many on oral agents have a glucometer for SBGM. A small sterile lancet is used to create a puncture on the finger. A drop of capillary blood is drawn from the puncture site (Figure 8–4) and placed on
a strip which is inserted in the glucometer (Figure 8–5). A reading of capillary whole blood glucose is given in 1 to 2 minutes. The person can then adjust their medication, food consumption, or activity level on the basis of the test results.
There are numerous glucometers on the mar- ket, each with slightly different user instructions. The frequency with which the diabetic patient uses SBGM depends on the patient’s individual treat- ment regimen. In some cases, the blood glucose may be checked once a day, or even less often. In other patients, especially those using insulin, the blood glucose may be checked many times daily. In gener- al, the more intensively a diabetes patient is man- aged, the more frequently he or she will use SBGM.
ORAL DISEASES AND DIABETES
Oral complications of diabetes may include alter- ations in salivary flow and constituents, increased incidence of infection, burning mouth, altered wound healing, and increased prevalence and severity of periodontal disease. Xerostomia and parotid gland enlargement may occur in the dia- betic individual.38,39 These complications may be related to the degree of glycemic control.40 Dia- betes patients may complain of burning mouth syndrome associated with decreased salivary flow. Dry mucosal surfaces are easily irritated and often
Table 8–6. Laboratory Diagnostic Criteria for Diabetes
Laboratory Methods* 1. Symptoms of diabetes plus casual (nonfasting) plasma glucose ³ 200 mg/dL. Casual glucose may be drawn
at any time of day without regard to time since the last meal. Classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.
2. Fasting plasma glucose ³126 mg/dL. Fasting is defined as no caloric intake for at least 8 hours. 3. Two-hour postprandial glucose ³200 mg/dL during an oral glucose tolerance test. The test should be per-
formed using a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved in water.†
Categories of fasting plasma glucose (FPG) 1. FPG <110 mg/dL = normal fasting glucose 2. FPG ³110 mg/dL and <126 mg/dL = Impaired fasting glucose (IFG) 3. FPG ³126 mg/dL = provisional diagnosis of diabetes (must be confirmed on subsequent day as described
below) Categories of 2-hour postprandial glucose (2hPG)
1. 2hPG <140 mg/dL = normal glucose tolerance 2. 2hPG ³140 mg/dL and <200 mg/dL = impaired glucose tolerance (IGT) 3. 2hPG ³200 mg/dL = provisional diagnosis of diabetes (must be confirmed on subsequent day as described
below)
*Whatever method is used, it must be confirmed on a subsequent day by using any one of the three methods. †The third method is not recommended for routine clinical use.
Diabetes Mellitus 131
provide a favorable substrate for the growth of fun- gal organisms. The incidence of candidiasis may be increased in patients with diabetes41 although not all studies support this relationship.42
Dental caries rates may also be altered in dia- betes. While some studies have shown an increased caries incidence in diabetes,43 others have demonstrated similar or lower rates than in nondiabetic individuals.44,45 An increased caries rate may be associated with decreased salivation or with increased glucose concentrations in the saliva and gingival crevicular fluid (GCF). Conversely, most diabetic patients restrict fermentable carbo- hydrate intake as part of their disease management diet. This less cariogenic diet may be associated with decreased caries rates. In addition to medica-
tions used to manage blood glucose levels, many diabetic patients also take other drugs for treat- ment of related complications or unrelated disor- ders. These drugs can have xerostomic effects. Therefore, xerostomia may result not from the diabetic condition itself but from medications taken by the patient. Autonomic neuropathy may also cause disturbances in the regulation of saliva secretion.46 Salivary flow is controlled by sympa- thetic and parasympathetic pathways. Diabetic neuropathy may disturb these pathways, leading to decreased salivation.
In recent studies of type 2 diabetic subjects and nondiabetic controls, no significant differ- ences in salivary flow rates were seen.46 There were also no differences between groups in the organic constituents of saliva. However, the effect of xeros- tomic medications on salivary flow rates was greater in diabetic individuals than in control patients. No differences were seen in the preva- lence of coronal caries or root caries.47 The salivary counts of acidogenic bacteria (Streptococcus mutans and lactobacilli) were similar between the diabetic
TABLE 8–7. Oral Agents for Treatment of Diabetes
Sulfonylureas • First generation
– Chlorpropamide – Tolazamide – Tolbutamide
• Second generation – Glyburide – Glipizide – Glimepiride
Nonsulfonylurea insulin secretogogues • Repaglinide
Biguanides • Metformin
Thiazolidinediones • Troglitazone
a-glucosidase inhibitors • Acarbose
Figure 8–4. Obtaining drop of blood for glucometer test- ing. Finger lancet used to “prick” finger and drop of blood “milked” from puncture site.
Figure 8–5. Test strip in glucometer with glucose reading. Blood is placed on a specific area of the glucometer strip. After an appropriate period of time, blood glucose reading is given by the glucometer.
132 Periodontal Medicine
and nondiabetic subjects. Likewise, carriage of sali- vary yeasts was similar between groups.
Diabetes and Periodontal Disease
The influence of diabetes on the periodontium has been thoroughly studied. It is difficult to make definitive conclusions from many of these studies owing to the heterogeneity of study designs, differ- ences in the populations studied, changes in the classification of periodontal diseases and diabetes over the years, changes in the methods for diag- nosing diabetes and evaluating glycemic control, inadequacy of study controls, and differences in periodontal parameters or outcome variables mea- sured. Some research with relatively small numbers of subjects suggests that diabetes has little influ- ence on the prevalence and severity of periodontal diseases. However, modern epidemiologic methods used in large populations have clearly established that diabetes is a risk factor for periodontal disease.
Diabetes is often associated with increased gin- gival inflammation in response to bacterial plaque.48–50 This response may be related to the level of glycemic control, with subjects with well-con- trolled diabetes having a similar degree of gingivitis as nondiabetic individuals and poorly controlled diabetic subjects having significantly increased inflammation.51,52 Increased gingival inflammation may be seen in diabetic subjects even though plaque levels are similar to nondiabetic controls.
The prevalence of periodontitis in diabetic adolescents and young adults is significantly greater than similar-aged nondiabetic individuals.49 While some young diabetic people develop periodontitis, especially those with poor metabolic control, peri- odontal disease is much more common in adults. In a thorough analysis of the literature, Papapanou demonstrated that the majority of studies show a more severe periodontal condition in adult patients with diabetes than in nondiabetic adults.53
In large populations, type 2 diabetes has been shown to be a significant risk factor for periodonti- tis. The Pima Indian population of Arizona, with the highest prevalence of type 2 diabetes in the world, has been extensively studied.54,55 The preva- lence of attachment loss and bone loss was greater among diabetic subjects than among nondiabetic control subjects in all age groups. The differences in disease prevalence were most pronounced in the younger age groups. In addition, periodontal destruction was more severe in diabetic patients, with greater mean bone loss and attachment loss. Again, the differences in disease severity were great-
est in the younger age groups. For example, diabet- ic subjects from 15 to 34 years of age had mean attachment loss and bone loss scores approximately twice as high as similar-aged nondiabetic subjects. In a multivariate risk analysis, it was determined that diabetic subjects had a risk of periodontitis 2.8 to 3.4 times higher than nondiabetic subjects after adjusting for the effects of confounding variables such as age, sex, and oral hygiene measures.
A recent meta-analysis of data from several studies of type 2 diabetes and periodontal disease was performed.53 These studies included a total of 3,524 adults over 18 years of age and clearly demonstrated a significant association between periodontitis and diabetes mellitus. Diabetes may influence not only the prevalence and severity of periodontitis but also the progression of disease. Taylor and colleagues demonstrated that type 2 diabetes significantly increased the rate of alveolar bone loss progression over a 2-year period when compared to nondiabetic subjects.56 The risk for progressive bone loss was 4.2 times greater in dia- betic subjects, with the greatest increase in risk occurring in patients under the age of 34 years.
The relationship between metabolic control of diabetes and periodontal disease is not clear.57 Some diabetic patients with poor glycemic control devel- op extensive periodontal destruction while others do not. Conversely, many patients with well-controlled diabetes have excellent periodontal health, but others develop periodontitis. In this way, periodontal dis- ease is similar to the classic complications of dia- betes. Poor glycemic control is clearly associated with increased risk for complications, but not all patients with poorly controlled diabetes develop these complications. While there is no unequivocal dose-response relationship between glycemia and periodontitis, many studies support the clinical observation that patients with poorly controlled dia- betes of long duration tend to develop more advanced periodontal destruction than diabetic patients with good metabolic control. Over 2 to 3 years, Seppala and colleagues demonstrated that subjects with poorly controlled diabetes had signifi- cantly greater longitudinal attachment loss and bone loss than did subjects with well controlled dia- betes.58 Tervonen and Oliver showed that subjects with poor metabolic control over the preceding 2 to 5 years had a significantly greater prevalence of deep probing depths and advanced attachment loss than did subjects with good glycemic control.59 Longitu- dinally, Taylor and colleagues found that poor glycemic control was associated with significantly increased risk of progressive bone loss compared
Diabetes Mellitus 133
with better metabolic control.56 Thus, metabolic control of diabetes may be an important variable in the onset and progression of periodontal disease. Patients with well-controlled diabetes may be simi- lar to nondiabetic individuals. It is important to remember that periodontal disease prevalence and severity varies greatly within the nondiabetic popu- lation. Presence of periodontal disease in a diabetic individual may therefore have more to do with other risk factors for periodontitis such as poor oral hygiene and smoking than it does with the mere presence of a diabetic state.
An important question for the dental practi- tioner is, Will diabetic patients with periodontal disease respond favorably to periodontal treatment In a study of patients with predominantly well-con- trolled diabetes and moderate to advanced peri- odontal disease, Christgau and colleagues found similar responses to nonsurgical scaling and root planing when compared with nondiabetic subjects 4 months after treatment.60 Conversely, patients with poorly controlled diabetes often have a less favorable response to treatment than those with well-controlled diabetes.61 Westfelt and colleagues performed a longitudinal assessment of diabetic subjects and nondiabetic controls with moderate to advanced periodontitis.62 Patients received scaling and root planing, modified Widman flap surgery and supportive periodontal therapy every 3 months. Five years after the study began, there was a similar percentage of sites gaining or losing attachment, and a similar percentage of sites with stable attachment levels when comparing diabetic and nondiabetic subject groups. Most of the dia- betic patients in this study had well-controlled or moderately well-controlled glycemia.
Diabetic patients must be examined individual- ly to assess their potential response to periodontal therapy. The mere presence of diabetes does not con- demn the person to a less favorable periodontal out- come. A diabetic patient with good glycemic control can be expected to respond in a fashion similar to the nondiabetic subject. The presence of poor glycemic control may place the patient at risk of a less favor- able response. In addition, other factors such as smoking or poor plaque control may adversely affect the response to periodontal therapy in diabetic indi- viduals, just as they may in a nondiabetic person.
Mechanisms of Diabetic Influence on Periodontium
A number of possible mechanisms have been pro- posed by which diabetes may affect the periodon-
tium. These are primarily related to changes in the subgingival microbiota, GCF glucose levels, peri- odontal vasculature, host response, and collagen metabolism.57 While early studies showed possible differences in subgingival bacterial colonization between diabetic and nondiabetic patients with periodontitis, more recent research has demon- strated few differences. Periodontally diseased sites in diabetic patients harbor similar species as com- parable sites in nondiabetic individuals.60,63,64 This lack of significant differences between diabetic and nondiabetic individuals in the primary bacterial etiologic agents of periodontal disease suggests that the increased prevalence and severity of periodon- titis in diabetes may be due to differences in host response factors.
Increased blood glucose levels in diabetes are reflected in increased levels of GCF glucose.65,66 In vitro studies show decreased chemotaxis of peri- odontal ligament fibroblasts to PDGF when placed in a hyperglycemic environment compared with normoglycemic conditions.67 Thus, elevated GCF glucose levels in diabetes may adversely affect periodontal wound healing events and the local host response to microbial challenge.
Changes affecting the renal, retinal, and per- ineural vasculature in diabetes also occur in the periodontium. Increased thickness of gingival cap- illary endothelial cell basement membranes and the walls of small blood vessels may be seen in dia- betic individuals.68–70 This thickening may impair oxygen diffusion and nutrient provision across basement membranes. Increased thickness of small vessel walls results in narrowing of the lumen, altering normal periodontal tissue homeostasis.
The formation of AGEs occurs in the peri- odontium as it does in other tissue sites. Schmidt and colleagues have demonstrated a two fold increase in AGE accumulation in diabetic gingiva compared with gingiva from nondiabetic subjects. Increased oxidant stress was also noted in diabetic tissues.71 Enhanced oxidant stress has been target- ed as the underlying mechanism responsible for the widespread vascular injury associated with dia- betes. The formation of AGEs stimulates arterial smooth muscle cell proliferation, increasing thick- ness of vessel walls. In the capillaries, enhanced cross-linking of AGE-modified collagen in the basement membrane inhibits the normal degrada- tion of these proteins, increasing the thickness of the basement membrane. Elevated LDL levels, especially common in type 2 diabetes, may cause changes in the gingival vasculature.21 The AGE- modified arterial collagen in gingival blood vessel
134 Periodontal Medicine
walls can bind circulating LDL, resulting in atheroma formation and further narrowing of the vessel lumen. All these events may play a role in altering the tissue response to periodontopathic bacteria, resulting in increased severity and pro- gression of periodontitis.
Altered host defenses have long been consid- ered important in the pathogenesis of periodontitis associated with diabetes. Defects in polymor- phonuclear leukocyte (PMN) adherence, chemo- taxis, and phagocytosis have been observed in some individuals with diabetes.57,72,73 Many of these PMN abnormalities can be corrected with improved glycemic control. Defects affecting this first line of defense against subgingival microbial agents may result in significantly increased tissue destruction. In many diabetic patients, PMN func- tion is normal. Oliver and colleagues have even sug- gested hyper-responsiveness or increased numbers of PMNs within the gingival crevice of poorly con- trolled diabetic patients as indicated by elevated lev- els of the PMN-derived enzyme b-glucuronidase.74
The monocyte/macrophage cell line is critical to cell-mediated host defense in periodontal dis- eases. Studies suggest that many diabetic patients possess a hyper-responsive monocyte/macrophage phenotype in which stimulation by bacterial anti- gens such as lipopolysaccharide (LPS) results in dramatically increased proinflammatory cytokine production.75 Salvi and colleagues have demon- strated significantly increased production of proin- flammatory cytokines by monocytes derived from patients with diabetes compared with nondiabetic subjects.76 In response to LPS from the periodon- tal pathogen P. gingivalis, diabetic monocytes pro- duced 24 to 32 times the level of TNFa compared with nondiabetic monocytes. Also, there was a four fold increase LPS-stimulated monocyte production of PGE2 and IL-1b in diabetic subjects than in nondiabetic subjects.77 The gingival crevicular fluid levels of PGE2 and IL-1b were significantly higher in diabetic patients with periodontitis than in nondiabetic subjects with a similar degree of periodontal destruction.
It is likely that there is a genetic component to the development of a hyper-responsive mono- cyte/macrophage phenotype in some diabetic patients. Not all individuals with diabetes have this phenotype. The formation of AGEs also plays an important role in the upregulation of the mono- cyte/macrophage cell line. Accumulation of AGEs in the periodontium stimulates influx of mono- cytes. Once in the tissue, AGEs interact with the receptor RAGE on monocyte cell surfaces. This
halts the migration of the monocytes, fixing them at the local site. The AGE-RAGE interaction then induces a change in monocyte phenotype, upregu- lating the cell and significantly increasing proin- flammatory cytokine production. This provides another explanation for increased GCF production of TNFa, PGE2 and IL-1b noted in diabetic patients with periodontitis.28,32
As previously discussed, there is a great deal of heterogeneity in AGE formation within the diabet- ic population. Thus, these AGE-associated changes may be present in some patients but absent in oth- ers. Those individuals at greatest risk for increased AGE accumulation and its adverse effects are those with poor glycemic control, who may accumulate large deposits of AGEs within target tissues. Simi- larly, the patient with poorly controlled diabetes is most likely to suffer more rapid and advanced peri- odontal destruction. However, just as some individ- uals with poorly controlled diabetes do not develop classic vascular complications of the disease, some such patients have little, if any, significant peri- odontal disease. The variability in AGE formation may provide some explanation for the variance in risk of periodontal complications of diabetes.
Collagen is the primary constituent of gingival connective tissue and the organic matrix of alveo- lar bone. Changes in collagen metabolism con- tribute to alterations in wound healing and to peri- odontal disease initiation and progression. Pro- teinases are enzymes involved in matrix degrada- tion. In the periodontium, these matrix metallo- proteinases (MMPs) include collagenases, gelati- nases, and elastases.78,79 There are at least 12 dis- tinct members of the MMP family, and these enzymes are responsible for the breakdown of bone and connective tissue during periodontal disease. Matrix metalloproteinases are produced by all of the major cell types in the periodontium when activated by various cytokines and growth factors, including PMNs, fibroblasts, macrophages, endothelial cells, osteoblasts, and osteoclasts.78
Increased collagen breakdown through stimu- lation of collagenase activity has been observed in the periodontium of diabetic patients.80 Collage- nases primarily degrade more newly formed and, therefore, more soluble collagen macromolecules. Sustained hyperglycemia results in AGE modifica- tion of existing collagen, with increased cross-link- ing. The net effect of these alterations in collagen metabolism is a rapid degradation of recently syn- thesized collagen by host collagenase and a pre- dominance of older, highly cross-linked, AGE- modified collagen. Since collagen production and
Diabetes Mellitus 135
degradation exist as a highly balanced homeostatic mechanism, changes in collagen metabolism result in altered wound healing in response to physical or microbial wounding of the periodontium. Impair- ed wound healing is a well-recognized complica- tion of diabetes and may affect any tissue site, including the periodontium.
Reduction in host collagenase production can be achieved by tetracycline therapy.78,81,82 This is accomplished via mechanisms which are indepen- dent of the antimicrobial properties of these agents. Low-dose tetracyclines and chemically modified tetracyclines (CMTs), which have no antimicrobial effect, have been shown to signifi- cantly decrease collagenase production and colla- gen degradation.83–85 Although CMTs are not yet available for routine use, tetracyclines such as doxycycline, minocycline, and tetracycline HCl have been used for many years. Low-dose doxycy- cline is now available as well86 although its use in diabetic patients has not yet been reported. Due to their anticollagenolytic effect, tetracyclines and CMTs have potential benefits in inhibiting the onset and progression of periodontitis, arthritis, and osteoporosis, among other conditions.85 In a disease such as diabetes, where collagenase produc- tion is significantly increased, these agents may have even greater beneficial effects by normalizing collagen metabolism and wound healing events.
EFFECTS OF PERIODONTAL INFECTION ON GLYCEMIC CONTROL OF DIABETES
While diabetes significantly impacts the periodon- tium, evidence also suggests the potential for peri- odontal infection to adversely influence glycemic control in diabetes. Taylor and colleagues exam- ined subjects with type 2 diabetes to determine whether severe periodontitis increased the risk for poor glycemic control.87 The subjects, some of whom had severe periodontitis and others who did not, all had relatively well-controlled glycemia at baseline, as indicated by glycosylated hemoglobin (HbA1) levels of less than 9%. At re-examination 2 years later, a greater proportion of subjects with severe periodontitis had poor glycemic control (HbA1 >9%) than did subjects without severe periodontitis. Severe periodontitis at baseline was associated with a six fold increased risk of poor glycemic control at follow-up.
In a case-control study of diabetic adults hav- ing gingivitis or mild periodontitis compared with
patients with severe periodontitis, those with severe periodontal disease had a significantly greater prevalence of cardiovascular and kidney complications during the 1- to 11-year follow-up period than did patients with minimal periodontal disease.88 This was true despite the fact that HbA1c levels were similar in both groups, indicat- ing a similar level of long-term glycemic control. Thus, the classic complications of diabetes may be closely associated with periodontal disease in these individuals, lending further credence to the con- cept that periodontal disease may be the “sixth complication of diabetes.”89
If periodontal infection adversely affects glycemic control in diabetes, then the question arises, Can periodontal treatment directed at elim- ination of pathogenic organisms and reduction of inflammation have a positive impact on glycemic control? In case studies of patients with poorly controlled diabetes and periodontitis, improve- ment in metabolic control has been noted coinci- dent with improvement in periodontal health fol- lowing treatment. In 1960, Williams and Mahan performed extractions and periodontal surgery in combination with systemic antibiotic therapy on 9 diabetic patients with severe periodontitis to elim- inate periodontal infection.90 The metabolic para- meters, including daily insulin dose and periodic blood glucose readings, were crude by today’s stan- dard but were routinely used at the time. With improved periodontal health, 7 of the 9 patients had decreased daily insulin requirements, some by over 50%. Miller and colleagues evaluated the effect of scaling and root planing combined with 14 days of systemic doxycycline on glycemia in 9 poorly controlled type 1 diabetic patients with periodontitis.91 At post-treatment examinations 4 and 8 weeks after therapy, 5 of 9 patients had sig- nificant improvement in bleeding on probing. These same 5 subjects also had improvement in metabolic control, indicated by significant reduc- tions in HbA1c values. The 4 patients who had no improvement in bleeding on probing also had no improvement in glycemic control. This noncon- trolled case study suggests that improved peri- odontal health may be accompanied by a parallel improvement in metabolic control of diabetes, and indicates the potential systemic benefits of peri- odontal treatment in patients with poorly con- trolled diabetes and periodontitis.
In the first long-term placebo-controlled study of its kind, Grossi and colleagues examined a large group of poorly controlled type 2 diabetic patients with severe periodontitis following non-surgical
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débridement combined with either systemic doxy- cycline (100 mg/day) or placebo for 14 days.92,93
All patient groups had significant reductions in gin- gival bleeding and probing depths, with gains in clinical attachment. Doxycycline-treated patients had a greater reduction in prevalence of P. gingivalis at 3 and 6 months. The doxycycline-treated patients also demonstrated significant reductions in HbA1c at 3 months, which gradually reverted to baseline levels by 6 months. Placebo-treated sub- jects had no significant change in HbA1c levels at any time point. Consequently, the combination of subgingival débridement and systemic doxycycline resulted in significant short-term improvement in the parameters of metabolic control.
Conversely, subjects with well-controlled or moderately controlled diabetes and periodontitis who receive scaling and root planing without adjunctive systemic antibiotic therapy may demonstrate no significant changes in glycemic control despite improvement in their periodontal parameters.60,94 The mechanisms by which adjunc- tive antibiotics may induce positive changes in glycemic control when combined with thorough mechanical débridement are unknown at this time. It is possible that improved glycemia is asso- ciated with the more complete elimination of pathogenic organisms in antibiotic-treated patients. Tetracyclines and CMTs are also known to sup- press glycosylation of proteins, AGE formation, and MMP activity.78
Acute bacterial and viral infections have been shown to increase insulin resistance and aggravate glycemic control.95,96 This occurs in both diabetic and nondiabetic individuals. Insulin resistance per- sists for an extended period of time after clinical recovery from infection, often for weeks or months. In the type 2 diabetes patient, who already has significant insulin resistance, further resistance induced by infection may considerably exacerbate poor glycemic control. In type 1 patients, prescribed doses of injected insulin may be insufficient to maintain good glycemic control in the presence of infection-induced tissue resis- tance. It is possible that chronic gram-negative periodontal infections may also result in increased insulin resistance and poor glycemic control.97
Periodontal treatment designed to decrease the bacterial challenge and reduce inflammation might restore insulin sensitivity over time, resulting in improved metabolic control. The improved glycemic control seen in studies of combined mechanical and antibiotic periodontal therapy would support such a hypothesis.
DIABETES AND DENTAL IMPLANT THERAPY
There is little scientific evidence regarding the suc- cess or failure of dental implant therapy in diabet- ic individuals. Diabetes is often considered a rela- tive contraindication to implant placement, but in well-controlled diabetes there is no reason to avoid implant therapy. Patients with poorly controlled diabetes may not respond well to any surgical treat- ment, including implant placement, due to impaired wound healing. In animal models, dia- betes has been associated with decreased bone-to- implant contact and decreased bone density in the peri-implant region.98,99 It is not known if this occurs in humans. The effect of diabetes on long- term clinical implant stability is also unknown at this time.
MEDICAL MANAGEMENT OF DIABETES
Treatment of diabetes aims to achieve blood glu- cose levels as close to normal as possible and to pre- vent diabetic complications. The American Dia- betes Association has standards of care to guide treatment, with a goal of achieving HbA1c levels <7%.37 This goal is difficult to attain for most dia- betic patients, and the majority of these individu- als have less than ideal metabolic control.2,5,100 Spe- cific goals of therapy include maintaining normal growth and development, attaining normal body weight, avoiding sustained hyperglycemia or symp- tomatic hypoglycemia, preventing diabetic ketoacidosis and nonketotic acidosis, and immedi- ately detecting and treating long-term diabetic complications. Treatment options for type 2 dia- betes may include diet, exercise, weight control, oral medications, and insulin injections. Generally, a combination of these therapeutic approaches is used. While treatment for type 1 diabetes also involves diet, exercise, and weight control, insulin injection is essential to sustain life.
Diet, exercise, and weight control are the mainstay of therapy. Proper diet allows intake of carbohydrate, protein and fat in proportions com- mensurate with the target weight and nutritional needs. Obesity is common in type 2 diabetes and contributes substantially to insulin resistance. Exercise and weight reduction significantly improve tissue sensitivity to insulin and utilization of glucose by target tissues. Even small reductions in body weight can have dramatic effects on
Diabetes Mellitus 137
insulin sensitivity. Many patients with type 2 dia- betes take oral medications which either increase pancreatic insulin production, decrease production of glucose by the liver, improve tissue sensitivity to insulin, or alter absorption of carbohydrate from the gut. All type 1 diabetic patients and many type 2 patients inject exogenous insulin to allow glucose utilization by the tissues. Self-blood glucose moni- toring through use of a glucometer is recommend- ed for all type 1 and most type 2 diabetic individ- uals as it provides vital feedback to the patient regarding blood glucose levels and allows tailoring and adjustment of individual treatment regimens on the basis of knowledge of glucose levels at dif- ferent times of the day.
In the course of a typical day, blood glucose levels rise after meals, resulting in increased pan- creatic insulin secretion (see Figure 8–1). Insulin allows glucose to be removed from the blood- stream for tissue utilization and storage; thus, blood glucose levels fall. A feedback mechanism then results in decreased insulin secretion until the next meal when the cycle is repeated (Figure 8–6). In healthy subjects, blood glucose fluctuations are held within a relatively tight range throughout the day, rarely falling below 60 mg/dL or rising above 150 mg/dL. In diabetes mellitus, wide ranges in glycemic fluctuation are common even with treat- ment. Deficiencies in plasma insulin levels result in hyperglycemia while excess levels of insulin cause hypoglycemia. The ideal treatment of the diabetic individual would establish glycemic patterns simi- lar to those of nondiabetic persons.
In 1985, a prospective, randomized, con- trolled, multicenter clinical trial known as the Dia- betes Control and Complications Trial (DCCT) was begun to determine the relationship between glycemic control and diabetic complications.100
This landmark study compared the effects of intensive insulin therapy directed at near normal- ization of glycemia with the effects of convention- al insulin therapy on the initiation and progression of microvascular complications in type 1 diabetes.
In the DCCT, 1,441 type 1 diabetic subjects were followed for 3 to 9 years after being random- ly assigned to one of two groups. The first was a conventional insulin therapy group, who took 1 or 2 insulin injections each day. The second was an intensive insulin therapy group, who took 3 or 4 daily injections or used an external subcutaneous insulin infusion pump. The study was designed to determine whether intensive insulin therapy, used to maintain blood glucose values within the nor- mal range over a long period of time, could prevent
the initial development of retinopathy, nephropa- thy, and neuropathy in subjects who entered the study free of these complications. The study also determined the effect of intensive insulin therapy on the progression of these complications in patients who began the study with pre-existing early complications.
The results of the DCCT provided strong evi- dence that improved glycemic control, achieved through intensified insulin regimens, inhibited the onset and delayed the progression of diabetic com- plications.101,102 The risk of developing retinopathy was reduced by 76% in intensively treated patients compared with those on conventional insulin regi- mens. The progression of existing retinopathy decreased by 54% in the intensively treated group. Albuminuria, a sign of nephropathy, and clinical neuropathy were reduced by 54% and 60%, respec- tively. Thus, change from conventional insulin reg- imens, which rarely achieve normoglycemia, to intensive regimens resulted in improved glycemic control and dramatic reductions in the risk of microvascular complications. Improvement in glycemic control was also associated with a reduc- tion in macrovascular complications.103 The potential reduction in morbidity and mortality related to diabetic complications seen in the DCCT led the American Diabetes Association to issue a position statement declaring that a primary goal in treating type 1 diabetes is to attain blood glucose control “at least equal to that achieved in the intensively treated cohort” of the DCCT.104
Physicians have begun to intensify insulin regi-
Figure 8–6. Glucose-insulin relationship. Rise in blood glu- cose following each meal or snack stimulates increased insulin secretion, which then allows glucose utilization and storage. Blood glucose levels decrease until the next meal, when the cycle is repeated. In healthy subjects, glycemic fluctuations are held within a tight range between approxi- mately 60 and 150 mg/dL.
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mens in response to these results, and diabetic patients who know about the DCCT are motivat- ed to improve their glycemic control.105,106
Several studies have substantiated the conclu- sions of the DCCT for individuals with type 2 dia- betes as well.107,108 In one study with a similar design, the patient group that maintained near-nor- mal blood glucose values over a 6-year study period had a 69% reduction in the risk of retinopathy compared with the group with poorly controlled diabetes.107 The risk of neuropathy and nephropa- thy decreased by 57% and 70%, respectively. The risk of cardiac, cerebral, and peripheral macrovas- cular complications was reduced by 54%. Thus, it is likely that dental professionals will encounter increasing numbers of type 1 and type 2 diabetic patients using intensified treatment regimens.
Oral Agents Used in Diabetes
A number of oral agents are used to treat type 2 diabetes5,34,109 (Table 8–7). Sulfonylureas stimulate the b cells of the pancreas to increase insulin secre- tion. First-generation sulfonylureas are used infre- quently today. Second-generation agents (glipizide, glyburide, and glimepiride) are more potent, pro- duce less significant side effects, and have fewer drug interactions than first-generation sulfony- lureas. However, the major complication of sul- fonylurea therapy is hypoglycemia, which may be more frequent with second-generation agents. As pancreatic insulin secretion increases in response to sulfonylureas, food intake must be adequate to avoid low blood glucose levels.
Repaglinide is a new antidiabetic agent, which, like sulfonylureas, stimulates pancreatic insulin secretion.110 It does so via a different mech- anism, and its pharmacodynamic properties are unique. Unlike sulfonylureas which have a dura- tion of action of 12 to 24 hours, repaglinide is rapidly absorbed, reaching peak plasma levels in 30 to 60 minutes. It is then rapidly metabolized into inactive metabolites, with a plasma half-life of only about 1 hour. The drug is taken with meals, and it decreases postprandial blood glucose peaks, com- mon in type 2 diabetes, to a significantly greater degree than sulfonylureas.
Metformin lowers blood glucose primarily by preventing glycogenolysis in the liver. It also increases tissue uptake and utilization of glucose, counteracting the insulin resistance characteristic of type 2 diabetes. Unlike sulfonylureas, met- formin rarely causes hypoglycemia. Troglitazone, a relatively new thiazolidinedione agent, increases
tissue sensitivity to insulin, thereby stimulating glucose utilization in muscle. It also reduces blood glucose levels by suppressing gluconeogenesis in the liver. Like metformin, troglitazone generally does not cause hypoglycemia.
The a-glucosidase inhibitor acarbose works in a manner different from other oral agents. Taken with meals, acarbose slows the digestion and uptake of carbohydrates from the gut, thus lower- ing postprandial peaks in blood glucose. Since acarbose is not absorbed, few systemic effects are seen although gastrointestinal side effects are not uncommon. Acarbose may be used by both type 1 and type 2 diabetic patients. While acarbose itself does not cause hypoglycemia, when taken by a patient who also uses insulin or sulfonylureas, the delay in glucose absorption from the gut into the bloodstream can lead to relative insulin excess and hypoglycemia.
Insulin Therapy
Insulin is used by all patients with type 1 diabetes and many patients with type 2 diabetes. Insulin is administered by subcutaneous injection, usually with a syringe. Insulin pumps provide an insulin infusion through a subcutaneous catheter. The amount of insulin taken each day and the exact reg- imen for insulin delivery vary with each patient.111
Insulins vary in their onset, peak, and duration of activity and are classified as rapid-, short-, inter- mediate-, or long-acting (Table 8–8). While human insulin is currently the most used, beef and pork insulins are also still encountered. An ideal insulin profile obtained by insulin injection would closely mimic daily insulin fluctuations in nondia- betic individuals (see Figure 8–6), a very difficult goal to achieve. Lispro and regular insulin are gen- erally taken close to meal time in an attempt to match the peak absorption of glucose from the gut into the bloodstream with the peak activity of the injected insulin. Ultralente insulin is taken to sim- ulate the basal metabolic rate of insulin secreted from a normally functioning pancreas. Ultralente is often called “peakless” insulin due to its very slow onset, minimal peak activity and long dura- tion of action. Intermediate-acting insulins such as NPH and lente have a slower onset and peak activ- ity than rapid- or short-acting insulins. Thus, NPH or Lente insulin injected at 7:00 AM will usu- ally reach its peak activity sometime around noon or shortly thereafter.
While many regimens exist, some convention- al daily insulin injection regimens include (1) a
Diabetes Mellitus 139
single morning injection of intermediate-acting insulin; (2) a single morning injection of interme- diate-acting insulin mixed with regular or lispro insulin; (3) twice-daily injections of intermediate- acting insulin; or (4) twice-daily injections of intermediate-acting insulin mixed with regular or lispro insulin (Figures 8–7, 8–8, 8–9). While the insulin injection regimen in Figure 8–9 appears to closely mimic the normal pancreatic insulin secre- tion profile seen in Figure 8–6, even this regimen often results in relatively poor glycemic control with wide fluctuations in blood glucose levels throughout the day. This was clear in the DCCT, where glycemic control with all conventional regi- mens was poor compared with intensive regimens. The variability in the activity of injected insulin makes it very difficult to match peak plasma insulin levels with peak blood glucose levels fol- lowing ingestion of food.
Intensive insulin regimens such as those used in the DCCT generally dictate injection of regular or lispro insulin before each meal since these insulins
have less variability in absorption and activity than either intermediate- or long-acting insulins. Insulin injection is timed so that peak plasma insulin levels coincide with peak postprandial glucose levels. Intensive regimens may also include intermediate- or long-acting insulin to provide a basal metabolic level of plasma insulin (Figure 8–10, 8–11).
Insulin pumps use either regular or lispro insulin only. A continuous basal metabolic infu- sion rate is programmed into the pump to mimic normal pancreatic basal secretion. Then the patient programs a bolus of insulin prior to each meal. The pump is battery operated and delivers insulin from a storage syringe within the pump through tubing into a subcutaneous catheter. The catheter and infusion set are changed every 2 to 3 days. Since the results of the DCCT were published, the num- ber of patients using intensive insulin regimens has increased significantly.112 However, even the most intensive insulin regimens used in highly motivat- ed patients are relatively poor substitutes for a nor- mally functioning pancreas.
TABLE 8–8. Types of Insulin
Insulin Type Insulin Classification Onset of Activity Peak Activity Duration of Activity
Lispro Rapid-acting 15 min 30 to 90 min <5 h Regular Short-acting 30 to 60 min 2 to 3 h 4 to 12 h NPH Intermediate-acting 2 to 4 h 4 to 10 h 14 to 18 h Lente Intermediate-acting 3 to 4 h 4 to 12 h 16 to 20 h Ultralente Long-acting 6 to 10 h 12 to 16 h 20 to 30 h
Figure 8–7. Conventional insulin injection regimen: one injection of NPH/Lente. Example of conventional insulin regimen using single injection of intermediate-acting insulin (NPH or Lente) each day. Arrow indicates time of injection. The only meal that is covered by injected insulin is lunch. Glucose absorbed from breakfast, dinner, and evening snack remains in the bloodstream due to insufficient insulin levels, resulting in hyperglycemia.
Figure 8–8. Conventional insulin injection regimen: one injection of NPH/Lente mixed with Regular/Lispro. Exam- ple of conventional insulin regimen using single injection of intermediate-acting insulin (NPH or Lente) mixed with short-acting (Regular) or rapid-acting (Lispro) insulin. Arrow indicates time of injection. Glucose absorption from breakfast and lunch is covered by injected insulin but that from dinner and evening snack is not.
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Hypoglycemia is the most common complica- tion of insulin therapy. Hypoglycemia can and does occur in patients using oral sulfonylurea agents; however, its incidence is higher in those taking insulin injections. While intensified treatment regi- mens decrease the risk of long-term diabetic com- plications, they increase the risk of hypoglycemia. In the DCCT, the incidence of severe hypoglycemia was three times higher in the intensive insulin group compared with the conventional therapy group.113,114 Severe hypoglycemia was defined as hypoglycemia in which the neurologic impairment was so severe that the patient required the assistance of another person. One-third of all severe hypo- glycemic episodes in the DCCT led to seizures or loss of consciousness. Perhaps even more significant,
36% of severe hypoglycemic reactions occurred without warning symptoms for the patient. In another 51% of cases, warning symptoms occurred but were not recognized as such by the patient. This suggests the seriousness with which dental practi- tioners should manage hypoglycemia, especially in insulin-using diabetic patients.
DENTAL MANAGEMENT OF THE DIABETIC PATIENT
Patients who present to the dental office with intra- oral findings suggestive of a previously undiagnosed diabetic condition should be questioned closely. Questions should be targeted toward eliciting a clear history of polydipsia, polyuria, polyphagia, or recent unexplained weight loss. Patients should also be asked about family history of diabetes.
The patient in Figure 8–12, a 50-year-old Mexican-American male, presented with general- ized moderate adult periodontitis. Heavy accumu- lations of plaque and calculus were noted. The patient was healthy, although obese, and was tak- ing no medications. Following scaling and root planing, he failed to return for re-evaluation. Five years later, he presented again to the periodontist. This time, severe bone loss was noted in the incisor and molar regions (Figure 8–12B). Oral hygiene was poor, but the rapidity of bone loss was incon- sistent with adult periodontitis. Upon questioning, the patient stated that it was common for him to urinate three to five times a night. The positive his-
Figure 8–9. Conventional insulin injection regimen: two injections of mixed Regular/Lispro and NPH/Lente. Exam- ple of conventional insulin regimen using both morning and evening injections of intermediate-acting insulin (NPH or Lente) mixed with short-acting (Regular) or rapid-acting (Lispro) insulin. Arrows indicate time of injection. Theoret- ically, glucose absorption from all meals is covered.
Figure 8–10. Intensive insulin regimen: three daily injections of Regular/Lispro plus one injection of Ultralente. Example of intensive insulin regimen using injections of Regular or Lispro insulin before breakfast, lunch, and dinner. A single injection of long-acting (Ultralente) insulin in the morning provides basal metabolic insulin levels during the day.
Figure 8–11. Intensive insulin regimen: three daily injec- tions of Regular/Lispro plus one injection of NPH/Lente. Example of intensive insulin regimen using injections of Regular or Lispro insulin before breakfast, lunch, and din- ner. A single injection of intermediate-acting (NPH or Lente) insulin is taken at bedtime to cover an evening snack and the increased glucose production that normally occurs before awakening in the morning.
Diabetes Mellitus 141
tory of polyuria led to appropriate laboratory eval- uation and diagnosis of type 2 diabetes.
Rapid attachment loss and bone loss that are inconsistent with local factors may indicate an underlying systemic component to the patient’s periodontal condition. When supported by a thor- ough review of the medical history, clinical exami- nation and laboratory evaluation, a previously undiagnosed diabetic state may be revealed. Other periodontal manifestations of undiagnosed dia- betes include enlarged, hemorrhagic gingival tis- sues and multiple periodontal abscesses (Figure 8–13). If the clinician suspects undiagnosed dia- betes, laboratory evaluation and physician referral are indicated (see Table 8–6).
Previously diagnosed but poorly controlled diabetic patients may present with oral manifesta- tions similar to the undiagnosed diabetic individ- ual. The patient in Figures 8–13 and 8–14 had type 2 diabetes. Her glycemic control had wors- ened considerably over the previous 12 months as indicated by a rise in HbA1c values from 7.7 to 13.9% in 1 year. She acknowledged poor compli- ance with her oral antidiabetic medication regi- men. In patients with suspected poorly controlled diabetes, dental treatment should be limited ini- tially to provision of emergency care.34 Referral to the patient’s physician should include a description of intraoral findings and a brief outline of the patient’s dental treatment needs. The dental prac- titioner should request evaluation of the patient’s glycemic control and appropriate medical manage- ment prior to elective dental treatment.
In known diabetic patients, it is important to establish the level of glycemic control early in the examination process. This can be done through physician referral or review of medical records. Most patients who do SBGM record their glucose readings for future review by their diabetes man- agement team. Having the patient bring this log to the dental office may provide the practitioner with information regarding the patient’s overall glycemic control and normal blood glucose fluctu- ations during the day. It is helpful to determine the patient’s most recent glycosylated hemoglobin val- ues, since this test provides a measure of glycemic control over the preceding 2 to 3 months (Table 8–9). Comparison with past values provides infor- mation on the stability of glycemic control over time. Addressing the issue of glycemic control at the beginning of treatment often results in improved periodontal status, affording a more accurate assessment of actual treatment needs. Periodontal therapy, if needed, involves numerous patient visits and regularly scheduled maintenance following active treatment. Thus, the dentist and dental hygienist are in a perfect position to encour- age patient compliance and control.
The patient with well-controlled diabetes with no significant complications can generally be man- aged in a fashion similar to the nondiabetic dental patient, with the notable exception of the need to monitor for signs and symptoms of hypoglycemia during treatment. Key considerations related to dental treatment of the diabetic patient include stress reduction, diet modification, inpatient versus
Figure 8–12. A, Six-radiograph set of anterior teeth (minimal bone loss). Fifty-year-old patient prior to diagnosis of diabetes. Heavy local factors with mild to moderate adult periodontitis. B, Six-radiograph set of anterior teeth (severe bone loss). Five years after initial presentation, patient in Figure 8–12 has severe bone loss. Patient had undiagnosed type 2 diabetes.
BA
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outpatient care, antibiotic use, changes in medica- tion regimens, and appointment timing.115,116
Stress reduction and adequate pain control are important in treating the diabetic patient. Epi- nephrine and cortisol secretion often increases in stressful situations. Both these hormones elevate blood glucose levels and interfere with glycemic control. Efforts to allay patient apprehension and minimize discomfort are important and may include preoperative sedation and analgesia.116,117
Local anesthetics used in conjunction with most dental procedures may contain varying concentra- tions of vasoconstrictors (eg, 1/100,000 epineph- rine). Use of these agents has minimal effect on blood glucose levels, probably due to their relative- ly slow absorption from the local site and the low concentrations and small volumes used. Profound anesthesia with such agents minimizes endogenous epinephrine release.34
Periodontal therapy often requires surgical procedures that may result in mild to moderate postoperative discomfort. Modification of the dia- betic patient’s diet may be needed as a result of compromised chewing and swallowing that can accompany extensive dental procedures.34,115
While many diabetic individuals are very knowl- edgeable about diet and medication modifications, others are not. It may be necessary to consult the patient’s diabetes management team prior to the appointment for suggested liquid or semi-solid dietary alternatives.
Most diabetic patients can be easily managed in the dental office on an outpatient basis.115,116
However, for those with very poor glycemic con- trol, severe medical complications, and extensive treatment needs that will alter dietary and medica- tion regimens for extended periods of time, hospi- talization may be considered. Diabetic patients with severe head and neck infections should be treated in a controlled medical environment to avert possible life-threatening complications.
Antibiotics are not necessary for routine dental treatment in most diabetic patients but may be con- sidered in the presence of overt infection.34 Antibi- otic coverage prior to surgical treatment should be considered in patients with poorly controlled dia- betes.115 Since elective procedures are generally deferred until adequate glycemic control is achieved, this most often applies to emergency situations such as periodontal and periapical abscesses or other acute odontogenic infections. Adjunctive antibiotic therapy may also be considered in the management of periodontal disease. As previously discussed, the
Figure 8–13. Mandibular anterior teeth from lingual view. Sixty-year-old African American female with poorly con- trolled type 2 diabetes. Enlarged, hemorrhagic gingival tissue at multiple sites.
Figure 8–14. Radiograph of mandibular anterior teeth (severe incisor bone loss) from patient in Figure 8–14.
TABLE 8–9. Laboratory Evaluation of Diabetes Control
Glycated Hemoglobin Assay (HbA1c): 4 to 6% Normal <7% Good diabetes control 7 to 8% Moderate diabetes control >8% Action suggested to improve
diabetes control
Diabetes Mellitus 143
use of systemic tetracycline antibiotics in conjunc- tion with mechanical root débridement may have beneficial effects not only on the periodontium but on glycemic control as well.
At one time, a general recommendation was made for diabetic patients to have their dental appointments in the morning. This recommenda- tion was also made for many other medically com- promised patients. While morning appointments may be preferable for some diabetic patients, oth- ers may be better treated in the afternoon. Appointment timing often depends on the partic- ular medication regimen used by each individual patient. When possible, it is best to plan dental treatment either before or after periods of peak insulin activity because hypoglycemic reactions are more likely to occur when insulin levels are high.34,116 Type 2 diabetic patients taking sulfony- lureas are at risk for hypoglycemia. In their case, it is prudent, when possible, to plan dental treatment to avoid periods of peak drug activity. Metformin and troglitazone rarely cause hypoglycemia.
If the patient takes insulin, the dentist should determine the exact type being used. Its onset of activity and time of peak activity relative to the planned dental therapy should be determined (see Table 8–8). The greatest risk of hypoglycemia is usu- ally during the time of peak insulin activity: 30 to 90 minutes after injection of lispro insulin; 2 to 4 hours after injection of regular insulin, or approxi- mately 6 to 8 hours after injection of NPH or Lente insulin (see Figures 8–7 to 8–11). The primary fac- tor to consider is the peak action of the insulin taken and the amount of glucose being absorbed from the gut following the last meal. A key question to con- sider is, Will the amount and type of food eaten ‘match’ the level of insulin activity? To determine the answer, other questions must be asked. Did the patient follow his or her usual routine, eat the same amount and type of food, and take the same amount of insulin as always? Or did they skip a meal or reduce the amount of food eaten before their dental appointment? These are important questions to ask since any reduction in normal food con- sumption, if not accompanied by a reduction in insulin dose, may place the patient at higher risk of hypoglycemia during the dental treatment. For example, the patient who takes intermediate-acting insulin in the morning (see Figures 8–7 to 8–9) but then skips lunch before the afternoon dental appointment faces a significant risk of hypo- glycemia. The NPH or Lente insulin will peak in the early afternoon, and blood glucose levels may fall precipitously since the patient has not had any food.
It may be impossible to plan dental appoint- ments to avoid peak insulin activity. In these instances, the dentist simply needs to be aware that the patient is at risk for hypoglycemia, assess the patient’s pretreatment blood glucose level with their glucometer, and have a carbohydrate source readily available. Just as patients with asth- ma are encouraged to bring their inhaler to the dental appointment, or patients with angina to bring their nitroglycerine, dental practitioners should recommend that diabetic patients who do SBGM bring their glucometer to the dental office for each visit. Patients can check their blood glu- cose levels at the beginning of the appointment. If glucose levels are at or near the lower end of normal, the patient may consume some carbohy- drates before starting treatment to avoid hypo- glycemia during the appointment. For example, if a long dental procedure is planned and the patient’s pretreatment blood glucose is below 70 to 80mg/dL, having the patient drink 120 mL (4 oz) of fruit juice may prevent hypoglycemia dur- ing treatment. On the other hand, a markedly elevated pretreatment blood glucose (eg, greater than 300mg/dL) may suggest postponement of the procedure until metabolic control is assessed and improved.
In addition to determining pretreatment glu- cose levels, the dentist should determine the type of insulin the patient takes, when it was last taken, and the amount taken. Next, it is important to find out when the patient last ate, what they ate, and how the last food consumption relates to the normal intake at that time of day.34,115,116 For example, if the patient took their usual dose of regular insulin in the morning before breakfast but then either failed to eat or ate a lighter break- fast than usual, the patient is at increased risk for hypoglycemia if the dental appointment is sched- uled in the morning. Carbohydrate intake must be adequate to “match” plasma insulin levels or hypo- glycemia will result. If dental treatment requires alteration in diet either before or after the appointment, the patient’s medication regimen may need to be changed. Patients who are on NPO (nothing by mouth) orders before dental treatment may need to have their insulin regimen altered. Sulfonylurea doses may also need adjust- ment. In these cases, physician consultation may be indicated. Physicians frequently recommend reduction in the insulin dose that immediately precedes lengthy or extensive procedures. Longer- term adjustments are often made when diet mod- ifications will occur.
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Management of Diabetic Emergencies
Medical emergencies related to diabetic complica- tions may occur in the dental office. For example, macrovascular disease can lead to myocardial infarction or a cerebrovascular accident, and nephropathy may cause renal failure. However, the most common medical emergency in diabetic patients is hypoglycemia. As seen in the DCCT, hypoglycemia is a potentially grave complica- tion.113,114 Frequent causes of hypoglycemia are (1) injection of excess insulin; (2) delaying or skipping meals or snacks while taking the usual dose of insulin or oral sulfonylurea; (3) increasing exercise without adjusting food intake or the dose of insulin or sulfonylurea; (4) consuming alcohol and confusing signs of hypoglycemia with those of alcohol intoxication; and, (5) stress.34,115,116
Symptoms of hypoglycemia include confu- sion, shakiness or tremors, agitation, sweating, and tachycardia (Table 8–10). If unrecognized and untreated, hypoglycemia may lead to seizures, coma, and death. If a patient has symptoms of hypoglycemia and brought a glucometer to the dental appointment, they should immediately check the blood glucose level. Symptoms of hypo- glycemia are likely to occur if the blood glucose drops below 60 mg/dL but may occur in some patients at higher or lower threshold levels.
To treat hypoglycemia in a conscious patient, the dentist should give approximately 15 g of oral carbohydrate in a form that will be rapidly absorbed (Table 8–11). About 120 to 180 mL (4 to 6 oz) of fruit juice or soda is usually adequate to relieve symptoms. Alternatively, 3 or 4 tea- spoons of table sugar or an appropriate amount of hard candy may be given. Tubes of cake icing are easy to store and provide a rapid source of readily absorbed carbohydrate. Oral carbohydrate in
these forms will generally elevate blood glucose within 10 to 20 minutes, with relief of symptoms. Changes in blood glucose can be confirmed by glucometer. If symptoms have not resolved in a short period of time or the glucometer readings show persistent low blood glucose, another 15 g of carbohydrate should be given. If this does not ele- vate blood glucose, the parenteral route of treat- ment should be considered.116
In these cases, or when the patient is sedated or unable to take food or drink by mouth, 25 to 30 mL of 50% dextrose or 1 mg of glucagon can be given intravenously. In the absence of intravenous access, 1 mg of glucagon can be injected subcuta- neously or intramuscularly at practically any loca- tion of the body. Glucagon injection results in glycogenolysis in the liver, releasing glucose from glycogen stores and rapidly increasing blood sugar levels. The patient should recover within 5 to 15 minutes following treatment. If not, a call for emergency medical assistance is warranted. When a patient experiences symptomatic hypoglycemia requiring emergency treatment in the dental office, they should be monitored for approximately 1 hour to ensure complete recovery. Evaluation of the blood glucose level by glucometer can confirm normoglycemia.
In some cases, hyperglycemia may present with symptoms similar to hypoglycemia. If a glu- cometer is not available to accurately determine blood glucose levels and the patient has symptoms
TABLE 8–11. Emergency Treatment of Hypoglycemia
Establish blood glucose level with glucometer, if possible. In awake patient, give 15 g of carbohydrate orally; in
the form of • 120 to 180 mL (4 to 6 oz) fruit juice or sugared
soda; • 3 to 4 tsp table sugar; • hard candy; or • cake frosting in tube.
If patient unable to use oral route and IV is in place, administer
• 25 to 30 mL 50% dextrose (D50) IV; or • 1 mg glucagon IV.
If patient unable to use oral route and IV is not in place, administer
• 1 mg glucagon subcutaneously or intramuscularly. Monitor patient for 1 hour after recovery. Seek emergency medical assistance if patient does not
respond.
TABLE 8–10. Signs and Symptoms of Hypoglycemia
Confusion Shakiness, tremors Agitation Anxiety Sweating Dizziness Tachycardia Feeling of “impending doom” Seizures Loss of consciousness
Diabetes Mellitus 145
suggestive of hypoglycemia, immediate carbohy- drate intake or administration of glucose-elevating medication is indicated. When in doubt, the patient who is known to have diabetes and experi- ences shakiness, sweating, tachycardia, or agitation should be treated presumptively for hypoglycemia. If the symptoms turn out to have been caused by hyperglycemia rather than hypoglycemia, the small amount of additional carbohydrate given will gen- erally not have a significant negative effect. Con- versely, if carbohydrate or medication to elevate blood glucose levels is withheld from a patient who is actually experiencing hypoglycemia, in the mis- taken belief that the symptoms are being caused by hyperglycemia, severe sequelae are possible. The best means of rapidly determining the true nature of the emergency is measurement of capillary blood glucose with a glucometer.
Hyperglycemic crisis is a far less common emer- gency in the dental office than is hypoglycemia. Pro- longed hyperglycemia may result in diabetic ketoacidosis in people with type 1 diabetes while in type 2 diabetes it may cause hyperosmolar nonke- totic acidosis or hyperosmolar nonacidotic dia- betes.116 Onset of hyperglycemic emergencies occurs more slowly than does hypoglycemia, generally after protracted elevation of blood glucose. Hyper- glycemic emergencies require immediate medical evaluation and treatment. Basic life support proce- dures should be performed, including opening the airway, administering oxygen, evaluating circula- tion, and monitoring vital signs. The emergency medical system should be activated and the patient transported to a hospital as soon as possible.
The classic signs and symptoms of hypo- glycemia may not be present immediately prior to a severe hypoglycemic reaction. The patient receiv- ing conscious sedation in conjunction with dental therapy may have even more difficulty recognizing the warning symptoms. Constant verbal and visu- al contact and assessment of the patient’s subjective symptoms is necessary. The danger of hypo- glycemia may be reduced by periodic glucose mon- itoring during longer dental appointments.
As part of the initial medical history, diabetic patients should be questioned about their past his- tory of hypoglycemic episodes. In the DCCT, patients with a history of previous severe hypo- glycemia had a 112% higher risk of having anoth- er severe hypoglycemic reaction compared with those with no prior history.113 The strongest pre- dictor of severe hypoglycemia was the number of previous hypoglycemic episodes.114 The patient’s glycemic control may also relate to the risk for
hypoglycemia. In what seems at first glance to be a paradox, the risk for hypoglycemic emergencies increases as glycemic control improves and glyco- sylated hemoglobin values decrease.113 Determin- ing the patient’s past glycosylated hemoglobin val- ues prior to treatment not only provides an excel- lent assessment of the patient’s degree of metabol- ic control but may also suggest their relative risk for severe hypoglycemia. For example, the patient with a recent HbA1c of 7.5% may pose a greater risk of hypoglycemia than a patient with a recent HbA1c of 11%.
With time, some diabetic patients lose their ability to recognize impending hypoglycemia, a phenomenon known as hypoglycemia unaware- ness.118 Hypoglycemia unawareness may occur not only in intensively treated patients but in those on conventional insulin regimens or oral agents as well. While signs and symptoms of hypoglycemia are common when blood glucose levels fall below 60 mg/dL, patients with hypoglycemia unaware- ness may feel completely normal at levels of 40 mg/dL or lower. This places the patient at risk of developing severe hypoglycemia and impairs their ability to take appropriate corrective measures. Onset of emergencies in patients with hypo- glycemia unawareness may be immediate and without warning. Dental practitioners should question their diabetic patients as to the frequency of hypoglycemic episodes and the most common symptoms experienced by them.
THE DIABETIC PATIENT AND THE ROAD TO ORAL HEALTH
Ensuring oral health in patients with diabetes requires an expanded scope of medical and dental knowledge. There is undoubtedly a close relation- ship between diabetes and periodontal disease, a relationship requiring further study and explo- ration. Diabetes increases the risk of periodontal destruction, especially in patients whose glycemic control is poor. These same patients are most like- ly to report to the dental office with significant periodontal treatment needs. All diabetic patients should have routine dental evaluation and preven- tive therapy. The practitioner who understands the role of diabetes in the etiology of oral diseases, the potential for oral infections to influence glycemic control, the current medical therapeutic approach- es to diabetes, and the implications of diabetes on dental care provides the patient with the best chances of successful treatment outcomes.
146 Periodontal Medicine
REFERENCES
1. National Diabetes Data Group: Diabetes in Amer- ica, 2 ed. Bethesda, MD: National Institutes of Health. NIH Publication No 95-1468; 1995.
2. De Sanctis RW, Dec GW. Cardiomyopathies. In: Dale DC, Federman DD, editors. Scientific American Medicine. New York: Scientific American Inc.; 1995.
3. Mandrup-Poulsen T. Recent advances—Diabetes. Br Med J 1998;316:1221–5.
4. Edelman SV. Type II diabetes mellitus. Adv Inter- nal Med 1998; 43:449–500.
5. American Diabetes Association. Report of the Expert Committee on the Diagnosis and Classi- fication of Diabetes Mellitus. Diabetes Care 1997;20:1183–97.
6. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37:1595–607.
7. Eriksson J, Franssila-Kallunki A, Ekstrand A, et al. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes melli- tus. N Engl J Med 1989; 321:337–43.
8. Bogardus C, Lillioja S, Mott DM, et al. Relationship between degree of obesity and in vivo insulin action in man. Am J Physiol 1985;248:E286–91.
9. Newman B, Selby JV, Slemenda C, et al. Concor- dance for type 2 (non-insulin-dependent) dia- betes mellitus in male twins. Diabetologia 1987;30:763–8.
10. Ghosh S, Schork NJ. Genetic analysis of NIDDM. Diabetes 1996;45:1–14.
11. Charles MA, Fontboune A, Thibult N, et al. Risk factors for NIDDM in white populations: Paris Prospective Study. Diabetes 1991;40:796–9.
12. Engelgau MM, Herman WH, Smith PJ, et al. The epidemiology of diabetes and pregnancy in the U.S., 1988. Diabetes Care 1995;18:1029–33.
13. Dietrich ML, Dolnicek TF, Rayburn WR. Gesta- tional diabetes screening in a private midwest- ern American population. Am J Obstet Gynecol 1987;156:1403–8.
14. Marquette GP, Klein VR, Niebyl JR. Efficacy of screening for gestational diabetes. Am J Perina- tol 1985;2:7–14.
15. Magee MS, Walden CE, Benedetti TJ. Influence of diagnostic criteria on the incidence of gestation- al diabetes and perinatal morbidity. JAMA 1993;269:609–15.
16. Langer O, Rodriguez DA, Xenakis EMJ, et al. Intensified versus conventional management of gestational diabetes. Am J Obstet Gynecol 1994;170:1036–47.
17. Steinberg D. Diabetes and atherosclerosis. In: Porte
D, Sherwin RS, editors. Diabetes mellitus. 5th ed. Stamford, CT: Appleton & Lange; 1997.
18. Steffes MW. Pathophysiology of renal complica- tions. In: Porte D, Sherwin RS, editors. Diabetes mellitus. 5th ed. Stamford, CT: Appleton & Lange; 1997.
19. Klein R. Retinopathy and other ocular complica- tions in diabetes. In: Porte D, Sherwin RS, edi- tors. Diabetes mellitus. 5th ed. Stamford, CT: Appleton & Lange; 1997.
20. Greene DA, Feldman EL, Stevens MJ, et al. Dia- betic neuropathy. In: Porte D, Sherwin RS, edi- tors. Diabetes mellitus. 5th ed. Stamford, CT: Appleton & Lange; 1997.
21. Iacopino AM. Diabetic periodontitis: possible lipid-induced defect in tissue repair through alteration of macrophage phenotype and func- tion. Oral Diseases 1995;1:214–29.
22. Colwell JA, Jokl R. Vascular thrombosis in diabetes. In: Porte D, Sherwin RS, editors. Diabetes mel- litus. 5th ed. Stamford, CT: Appleton & Lange; 1997.
23. Brunzell JD, Chait A. Diabetic dyslipidemia: pathology and treatment. In: Porte D, Sherwin RS, editors. Diabetes mellitus. 5th ed. Stamford, CT: Appleton & Lange; 1997.
24. Vlassara H. Recent progress on the biologic and clinical significance of advanced glycosylation end products. J Lab Clin Med 1994;124:19–30.
25. Brownlee M. Glycosylation and diabetic complica- tions. Diabetes 1994;43:836–41.
26. Monnier VM, Glomb M, Elgawish A, Sell DR. The mechanism of collagen cross-linking in dia- betes. A puzzle nearing resolution. Diabetes 1996:45(Suppl 3):S67–72.
27. Schmidt AM, Hori O, Brett J, et al. Cellular recep- tors for advanced glycosylation end products. Implications for induction of oxidant stress and cel- lular dysfunction in the pathogenesis of vascular lesions. Atheroscler Thromb 1994;14: 1521–8.
28. Schmidt AM, Hori O, Cao R, et al. RAGE. A novel cellular receptor for advanced glycosylation end products. Diabetes 1996;45(Suppl 3):S77–80.
29. Vlassara H, Bucala R. Recent progress in advanced glycosylation and diabetic vascular disease: role of advanced glycosylation end product recep- tors. Diabetes 1996;45(Suppl 3):S65–6.
30. Esposito C, Gerlach H, Brett J, et al. Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties. J Exp Med 1992;170: 1387–407.
31. Kirstein M, Aston C, Hintz R, Vlassara H. Recep- tor-specific induction of insulin-like growth fac-
Diabetes Mellitus 147
tor I in human monocytes by advanced glycosy- lation end product-modified proteins. J Clin Invest 1992;90:439–46.
32. Vlassara H, Brownlee M, Monogue K, et al. Cachetin/TNF and IL-1 induced by glucose- modified proteins: role in normal tissue remod- eling. Science 1988;240:1546–8.
33. American Diabetes Association Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Committee Report. Diabetes Care 1997;20:1183–97.
34. Mealey BL. Impact of advances in diabetes care on dental treatment of the diabetic patient. Com- pend Contin Educ Dent 1998;19:41–58.
35. Tsuji I, Nakamoto K, Hasegawa T, et al. Receiver operating characteristic analysis of fasting plasma glucose, HbA1c, and fructosamine on diabetes screening. Diabetes Care 1991;14:1075–7.
36. American Diabetes Association. Standards of med- ical care for patients with diabetes mellitus. Dia- betes Care 1998;21(Suppl 1):S23–31.
37. American Diabetes Association. Self-monitoring of blood glucose (consensus statement). Diabetes Care 1993;16:60–5.
38. Thorstensson H, Flak H, Hugoson A, Olsson J. Some salivary factors in insulin-dependent dia- betics. Acta Odontol Scand 1989;47:175–83.
39. Sreebny LM, Yu A, Green A, Valdini A. Xerostomia in diabetes mellitus. Diabetes Care 1992;15: 900–4.
40. Harrison R, Bowden WH. Flow rate and organic constituents of whole saliva in insulin-depen- dent diabetic children and adolescents. Pediatr Dent 1987;9:287–90.
41. Fisher BM, Lamey PJ, Samaranayake LP, et al. Car- riage of Candida species in the oral cavity in diabetic patients: relationship to glycaemic con- trol. J Oral Pathol 1987;16:282–4.
42. Phelan JA, Levin SM. A prevalence study of den- ture stomatitis in subjects with diabetes mellitus or elevated plasma glucose levels. Oral Surg Oral Med Oral Pathol 1986;62:303–5.
43. Jones RB, McCallum RM, Kay EJ, et al. Oral health and oral health behavior in a population of diabetic clinic attenders. Community Dent Oral Epidemiol 1992;20:204–7.
44. Tenovuo J, Alanen P, Larjava H, et al. Oral health of patients with insulin dependent diabetes mel- litus. Scand J Dent Res 1986;94:338–46.
45. Tavares M, DePaola P, Soparkar P, Joshipura K. Prevalence of root caries in a diabetic popula- tion. J Dent Res 1991;70:979–83.
46. Meurman JH, Collin HL, Niskanen L, et al. Saliva in non-insulin-dependent diabetic patients and
control subjects. The role of the autonomic ner- vous system. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:69–76.
47. Collin HL, Uusitupa M, Niskanen L, et al. Caries in patients with non-insulin-dependent diabetes mellitus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:680–5.
48. Gusberti FA, Syed SA, Bacon G, et al. Puberty gin- givitis in insulin-dependent diabetic children. J Periodontol 1983;54:714–20.
49. Cianciola LJ, Park BH, Bruck E, et al. Prevalence of periodontal disease in insulin-dependent dia- betes mellitus (juvenile diabetes). J Am Dent Assoc 1982;104:653–60.
50. De Pommereau V, Dargent-Pare C, Robert JJ, Brion M. Periodontal status in insulin-depen- dent diabetic adolescents. J Clin Periodontol 1992;19:628–32.
51. Ervasti T, Knuuttila M, Pohjamo L, Haukipuro K. Relation between control of diabetes and gingi- val bleeding. J Periodontol 1985;56:154–7.
52. Karjalainen KM, Knuuttila MLE. The onset of dia- betes and poor metabolic control increases gin- gival bleeding in children and adolescents with insulin-dependent diabetes mellitus. J Clin Peri- odontol 1996;23:1060–7.
53. Papapanou PN. 1996 World Workshop in Clinical Periodontics. Periodontal diseases: epidemiolo- gy. Ann Periodontol 1996;1:1–36.
54. Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in non-insulin-dependent diabetes mel- litus. J Periodontol 1991;62:123–30.
55. Shlossman M, Knowler WC, Pettitt DJ, Genco RJ. Type 2 diabetes mellitus and periodontal dis- ease. J Am Dent Assoc 1990;121:532–6.
56. Taylor GW, Burt BA, Becker MP, et al. Non- insulin dependent diabetes mellitus and alveolar bone loss progression over 2 years. J Periodontol 1998;69:76–83.
57. Oliver RC, Tervonen T. Diabetes—a risk factor for periodontitis in adults? J Periodontol 1994;65: 530–8.
58. Seppala B, Seppala M, Ainamo J. A longitudinal study on insulin-dependent diabetes mellitus and periodontal disease. J Clin Periodontol 1993;20:161–5.
59. Tervonen T, Oliver RC. Long-term control of dia- betes mellitus and periodontitis. J Clin Perio- dontol 1993;20:431–5.
60. Christgau M, Palitzsch KD, Schmalz G, et al. Healing response to non-surgical periodontal therapy in patients with diabetes mellitus: clini- cal, microbiological, and immunological results. J Clin Periodontol 1998;25:112–24.
148 Periodontal Medicine
61. Tervonen T, Karjalainen K. Periodontal disease related to diabetic status. A pilot study of the response to periodontal therapy in type 1 dia- betes. J Clin Periodontol 1997;24:505–10.
62. Westfelt E, Rylander H, Blohme G, et al. The effect of periodontal therapy in diabetics. Results after 5 years. J Clin Periodontol 1996;23:92–100.
63. Zambon JJ, Reynolds H, Fisher JG, et al. Microbi- ological and immunological studies of adult periodontitis in patients with non-insulin dependent diabetes mellitus. J Periodontol 1988;59:23–31.
64. Sastrowijoto SH, Hillemans P, van Steenbergen TJ, et al. Periodontal condition and microbiology of healthy and diseased periodontal pockets in type 1 diabetes mellitus patients. J Clin Periodontol 1989;16:316–22
65. Kjellman O. The presence of glucose in gingival exudate and resting saliva of subjects with insulin-treated diabetes mellitus. Swed Dent J 1970;63:11–9.
66. Ficara AJ, Levin MP, Grower MF, Kramer GD. A comparison of the glucose and protein content of gingival crevicular fluid from diabetics and nondiabetics. J Periodontal Res 1975;10:171–5.
67. Nishimura F, Takahashi K, Kurihara M, et al. Peri- odontal disease as a complication of diabetes mellitus. Ann Periodontol 1998;3:20–9.
68. Frantzis TG, Reeve CM, Brown AL. The ultra- structure of capillary basement membranes in the attached gingiva of diabetic and non-diabet- ic patients with periodontal disease. J Periodon- tol 1971;42:406–11.
69. Listgarten MA, Ricker FH, Laster L, et al. Vascular basement membrane lamina thickness in the normal and inflamed gingiva of diabetics and nondiabetics. J Periodontol 1974;45:676–84.
70. Seppala B, Sorsa T, Ainamo J. Morphometric analysis of cellular and vascular changes in gin- gival connective tissue in long-term insulin- dependent diabetes. J Periodontol 1997;68: 1237–45.
71. Schmidt AM, Weidman E, Lalla E, et al. Advanced glycosylation endproducts (AGEs) induce oxi- dant stress in the gingiva: a potential mecha- nism underlying accelerated periodontal disease associated with diabetes. J Periodontal Res 1996; 31:508–15.
72. Manoucher-Pour M, Spagnuolo PJ, Rodman HM, Bissada NF. Comparison of neutrophil chemo- tactic response in diabetic patients with mild and severe periodontal disease. J Periodontol 1981;52:410–5.
73. McMullen JA, van Dyke TE, Horoszewicz HU, Genco RJ. Neutrophil chemotaxis in individu-
als with advanced periodontal disease and a genetic predisposition to diabetes mellitus. J Periodontol 1981;52:167–73.
74. Oliver RC, Tervonen T, Flynn DG, Keenan KM. Enzyme activity in crevicular fluid in relation to metabolic control of diabetes and other peri- odontal risk factors. J Periodontol 1993;64: 358–62.
75. Offenbacher S. 1996 World Workshop in Clinical Periodontics. Periodontal diseases: pathogenesis. Ann Periodontol 1996;1:821–78.
76. Salvi GE, Collins JG, Yalda B, et al. Monocytic TNF-a secretion patterns in IDDM patients with periodontal diseases. J Clin Periodontol 1997;24:8–16.
77. Salvi GE, Yalda B, Collins JG, et al. Inflammatory mediator response as a potential risk marker for periodontal diseases in insulin-dependent dia- betes mellitus patients. J Periodontol 1997;68: 127–35.
78. Ryan ME, Ramamurthy NS, Golub LM. Matrix metalloproteinases and their inhibition in peri- odontal treatment. Curr Opin Periodont 1996; 3:85–96.
79. Birkedal-Hansen H. Role of matrix metallopro- teinases in human periodontal disease. J Peri- odontol 1993;64:474–84.
80. Ramamurthy NS, Golub LM. Diabetes increases collagenase activity in extracts of rat gingiva and skin. J Periodontal Res 1983;18:23–30.
81. Golub LM, Lee HM, Lehrer G, et al. Minocycline reduces gingival collagenolytic activity during diabetes: preliminary observations and a pro- posed new mechanism. J Periodontal Res 1983; 18:516–26.
82. McCulloch CAG, Birek P, Overall C, et al. Ran- domized controlled clinical trial of doxycycline in prevention of recurrent periodontitis in high risk patients: antimicrobial activity and collage- nase inhibition. J Clin Periodontol 1990;17: 616–22.
83. Golub LM, Lee HM, Greenwald RA, et al. A matrix metalloproteinase inhibitor reduces bone-type collagen degradation fragments and specific collagenases in gingival crevicular fluid during adult periodontitis. Inflamm Res 1997; 46:310–9.
84. Bain S, Ramamurthy NS, Impeduglia T, et al. Tetracycline prevents cancellous bone loss and maintains near-normal rates of bone formation in streptozotocin diabetic rats. Bone 1997;21: 147–53.
85. Greenwald RA, Golub LM, Ramamurthy NS, et al. In vitro sensitivity of the three mammalian col-
Diabetes Mellitus 149
lagenases to tetracycline inhibition: relationship to bone and cartilage degradation. Bone 1998; 22:33–8.
86. Caton J, Ciancio S, Crout R, et al. Adjunctive use of subantimicrobial doxycycline therapy for peri- odontitis (Abstract). J Dent Res 1998;77:1001.
87. Taylor GW, Burt BA, Becker MP, et al. Severe peri- odontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontol 1996;67:1085–93.
88. Thorstensson H, Kuylensteirna J, Hugoson A. Med- ical status and complications in relation to peri- odontal disease experience in insulin-dependent diabetics. J Clin Periodontol 1996;23:194–202.
89. Loe H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 1993;16 (Suppl 1):329–34.
90. Williams RC, Mahan CJ. Periodontal disease and diabetes in young adults. JAMA 1960;172: 776–8.
91. Miller LS, Manwell MA, Newbold D, et al. The relationship between reduction in periodontal inflammation and diabetes control: a report of 9 cases. J Periodontol 1992;63:843–8.
92. Grossi SG, Skrepcinski FB, DeCaro T, et al. Response to periodontal therapy in diabetics and smokers. J Periodontol 1996;67:1094–102.
93. Grossi SG, Skrepcinski FB, DeCaro T, et al. Treat- ment of periodontal disease in diabetics reduces glycosylated hemoglobin. J Periodontol 1997; 68:713–9.
94. Aldridge JP, Lester V, Watts TLP, et al. Single-blind studies of the effects of improved periodontal health on metabolic control in type 1 diabetes mellitus. J Clin Periodontol 1995;22:271–5.
95. Sammalkorpi K. Glucose intolerance in acute infections. J Intern Med 1989;225:15–9.
96. Yki-Jarvinen H, Sammalkorpi K, Koivisto VA, Nikkila EA. Severity, duration and mechanism of insulin resistance during acute infections. J Clin Endocrinol Metab 1989;69:317–23.
97. Grossi SG, Genco RJ. Periodontal disease and dia- betes mellitus: a two-way relationship. Ann Periodontol 1998;3:51–61.
98. Nevins ML, Karimbux NY, Weber HP, et al. Wound healing around endosseous implants in experimental diabetes. Int J Oral Maxillofac Implants 1998;13:620–9.
99. Takeshita F, Murai K, Iyama S, et al. Uncontrolled diabetes hinders bone formation around titani- um implants in rat tibiae. A light and fluores- cence microscopy, and image processing study. J Periodontol 1998; 69:314–20.
100. Diabetes Control and Complications Trial
Research Group. The Diabetes Control and Complications Trial (DCCT): design and methodologic considerations for the feasibility phase. Diabetes 1986;35:530–45.
101. Diabetes Control and Complications Trial Research Group. The effect of intensive treat- ment of diabetes on the development and pro- gression of long-term complications in insulin- dependent diabetes mellitus. N Engl J Med 1993;329:977–86.
102. Diabetes Control and Complications Trial Research Group. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Ophthalmology 1995;102:647–61.
103. Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes management on macrovascular and microvascu- lar events and risk factors in the Diabetes Con- trol and Complications Trial. Am J Cardiol 1995;75:894–903.
104. American Diabetes Association Position Statement. Implications of the Diabetes Control and Compli- cations Trial. Diabetes Spectrum 1993;6:225–7.
105. Diabetes Control and Complications Trial Research Group. Lifetime benefits and costs of intensive therapy as practiced in the Diabetes Control and Complications Trial. JAMA 1996;276:1409–15.
106. Thompson CJ, Cummings JF, Chalmers J, et al. How have patients reacted to the implications of the DCCT? Diabetes Care 1996;19:876–9.
107. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of dia- betic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103–17.
108. Andersson DKG, Svardsudd K. Long-term glycemic control relates to mortality in type II diabetes. Diabetes Care 1995;18:1534–43.
109. Scheen AJ, Lefebvre PJ. Oral antidiabetic agents. A guide to selection. Drugs 1998;55:225–36.
110. Wolffenbuttel BHR, Nijst L, Sels JPJE, et al. Effects of a new oral hypoglycaemic agent, repaglinide, on metabolic control in sulfony- lurea-treated patients with NIDDM. Eur J Clin Pharmacol 1993;45:113–6.
111. Lebovitz HE: Oral antidiabetic agents. In: Kahn CR, Weir GC, editors. Joslin’s diabetes mellitus, 13th ed. Malvern (PA): Lea & Febiger; 1994.
112. Peterson KA, Smith CK. The DCCT findings and standards of care for diabetes. Am Fam Physi- cian 1995;2:1092–8.
150 Periodontal Medicine
113. Diabetes Control and Complications Trial Research Group. Epidemiology of severe hypo- glycemia in the Diabetes Control and Compli- cations Trial. Am J Med 1991;90:450–9.
114. Diabetes Control and Complications Trial Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 1997;46:271–86.
115. Rees TD. The diabetic dental patient. Dent Clin North Am 1994;38:447–63.
116. Mealey BL. 1996 World Workshop in Clinical
Periodontics. Periodontal implications: medical- ly compromised patients. Ann Periodontol 1996;1:256–321.
117. Galili D, Findler M, Garfunkel AA. Oral and den- tal complications associated with diabetes and their treatment. Compend Contin Educ Dent 1994;15:496–509.
118. Heller SR, Herbert M, MacDonald IA, Tattersall RB. Influence of sympathetic nervous system on hypoglycemic warning symptoms. Lancet 1987;2:359–63.
CHAPTER 9
PERIODONTAL MEDICINE AND THE FEMALE PATIENT Joan Otomo-Corgel, DDS, MPH Barbara J. Steinberg, DDS
Women’s life cycle changes present unique chal- lenges to the oral health care profession. Hormon- al influences associated with the reproductive process alter periodontal and oral-tissue responses to local factors creating diagnostic and therapeutic dilemmas. It is imperative, therefore, that the clin- ician recognize, customize, and vary periodontal therapy according to the individual female and the stage of her life cycle.
This chapter will deal with phases of the female life cycle during the reproductive years: puberty, menses, and pregnancy. Oral contracep- tives, periodontal manifestations, systemic effects, and clinical management will also be discussed.
PUBERTY
Periodontal Manifestations
During puberty, the female experiences an increase in the production of sex hormones (estrogen and progesterone) that remains relatively constant fol- lowing puberty throughout the normal female life- time reproductive phase. There is also an increase in the prevalence of gingivitis without an increase in the amount of plaque.1
Gram-negative anaerobes, especially Prevotella intermedia, have been implicated in association with puberty gingivitis. Kornman and Loesche postulated that this anaerobic organism may use ovarian hormone as a substitute for vitamin K growth factor.1 Delaney and Kornman suggest that levels of black-pigmented bacteroides, especially Bacteroides intermedius, increase with increased lev- els of gonadotrophic hormones in puberty. Capno- cytophaga species also increase in incidence as well as in proportion. These organisms have been implicated in the increased bleeding tendency
observed during puberty.2 Recent studies associat- ed with puberty gingivitis indicate proportionately elevated motile rods, spirochetes, and Prevotella intermedia.3 Statistically significant increases in gingival inflammation and in the proportion of Prevotella intermedia and Prevotella nigrescens were seen in puberty gingivitis.4
Clinically, during puberty, there may be a nodular hyperplastic reaction of the gingiva in areas where food debris, materia alba, plaque, and calcu- lus are deposited. The inflamed tissues are erythe- matous and may be lobulated and retractable (Fig- ure 9–1). Bleeding may occur with brushing or mastication. Histologically, the appearance is con- sistent with inflammatory hyperplasia.
Management
Preventive care, including a vigorous program of oral hygiene, is vital. Milder gingivitis cases respond well to scaling and root planing with fre- quent oral hygiene instructions.5 Severe cases of gingivitis may require microbial culturing, antimi- crobial mouthwashes and local site delivery, or
Figure 9–1. Puberty gingivitis.
152 Periodontal Medicine
antibiotic therapy. Supportive periodontal therapy visits may need increased frequency. Whenever possible, involvement of a parent or caregiver with home care procedures is recommended.
Eating Disorders
This age group also is susceptible to eating disor- ders, bulimia nervosa, and anorexia nervosa. The clinician should recognize the intraoral effects of chronic regurgitation of gastric contents on intrao- ral tissues. Perimylolysis, or smooth erosion of the enamel and dentin, typically on the lingual surfaces of maxillary anterior teeth, varies with the duration and frequency of the behavior.6 Also, parotid gland enlargement (occasionally, sublingual glands) has been estimated at between 10 to 50 percent in the patient who binges and purges.7 Therefore, there may also be a diminished salivary flow rate, which will increase oral mucous membrane sensitivity and gingival erythema. One should also rule out other etiologies that alter salivary flow, that is, systemic conditions or medications.
MENSES
Periodontal Manifestations
During the reproductive years, there are ongoing changes in the concentration of the gonadotrophins and ovarian hormones during the monthly men- strual cycle (Figure 9–2). Estrogen and proges- terone are steroid hormones produced by the ovaries during the menstrual cycle. The gonado- trophins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) influence estrogen and
progesterone to prepare the uterus for implanta- tion of the egg. There are two phases of the month- ly reproductive cycle. During the follicular phase I, estrogen causes cellular proliferation of the stroma cells, blood vessels, and glands of the endometri- um. Phase II is called the luteal phase. Note that estrogen peaks to 0.2 ng/mL and progesterone to 10.0 ng/mL to complete the rebuilding of the endometrium for fertilized egg implantation. The corpus luteum involutes, ovarian hormone levels drop, and menstruation ensues.
The concept that ovarian hormones may increase inflammation in gingival tissues and exag- gerate the response to local irritants has been pos- tulated by several studies. Gingival inflammation seems to be aggravated by an imbalance and/or increase in sex hormones.8–11
Progesterone has been associated with increased permeability of the microvasculature, altering the rate and pattern of collagen production in the gin- giva;8 increasing folate metabolism,9,10 and altering the immune response. During menses, proges- terone increases from the second week, peaks at approximately 10 days, and dramatically drops prior to menstruation. (Note that this is based on a 28-day cycle and individual cycles are variable.) Progesterone plays a role in stimulating the produc- tion of prostaglandins that mediate the body’s response to inflammation. Prostaglandin E2 (PGE2) is one of the major secretory products of monocytes and is higher in inflamed gingiva.10 Miyagi and col- leagues found that the chemotaxis of polymor- phonuclear leukocytes (PMNs) was enhanced by progesterone, whereas it was reduced by estradiol.11
Testosterone did not have a measurable effect on PMN chemotaxis. They suggested that the altered PMN chemotaxis associated with gingival inflam- mation may be due to the effects of sex hormones.
Gingival tissues have been reported to be more edematous and erythematous preceding the onset of menses in some individuals. In addition, an increase of gingival exudate has been observed dur- ing the menstrual period and is sometimes associ- ated with a minor increase in tooth mobility.12
Intraoral recurrent aphthous ulcers,13 herpes labialis lesions, and Candidae infections occur in some women as a cyclic pattern associated with the luteal phase of their cycle when progesterone is the highest. Because the esophageal sphincter is relaxed by progesterone, women may be more susceptible to gastroesophageal reflux disease (GERD) during this time of the cycle as well. Symptoms of GERD include heartburn, regurgitation, and chest pain; when reflux is severe, some people will develop
Figure 9–2. Female reproductive cycle. Note peak of progres- terone and estrogen to follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
Periodontal Medicine and the Female Patient 153
unexplained coughing, hoarseness, sore throat, gingivitis, or asthma.
During the peak level of progesterone (about 7 to 10 days prior to menstruation), premenstrual syndrome (PMS) also occurs. There appears to be no significant differences in estrogen and proges- terone levels between women who suffer from PMS and women who do not. Yet, women with PMS seem to have lower levels of certain neuro- transmitters such as enkephalins, endorphins, g- aminobutyric acid (GABA) and serotonin. Depression, irritability, mood swings, and diffi- culty with memory and concentration may be symptoms of neurotransmitter reduction.
Management
For the women who have increased gingival bleed- ing and tenderness associated with the menstrual cycle, adherence to 3 to 4-month supportive peri- odontal therapy appointments is recommended. Antimicrobial mouthrinses prior to cyclic inflam- mation may be indicated. Particular emphasis should be placed on oral hygiene.
During PMS, physical symptoms may include fatigue, sweet and salty food cravings, abdominal bloating, swollen hands or feet, headaches, breast tenderness, and nausea or gastrointestinal upset.14
Gastroesophageal reflux disease may make it more uncomfortable for the patient to lay fully supine, especially within the hours immediately after con- sumption of a meal. Care should be taken during dental treatment to prevent stimulating the more sensitive gag reflex. The clinician should be aware that nonsteroidal anti-inflammatory medication, infection, and acidic foods exacerbate GERD. Patients taking over-the-counter antacids, H2 receptor antagonists (cimetidine, famotidine, niza- tidine, and ranitidine), prokinetic agents (cisapride and metclopramide), and proton pump inhibitors (lansoprazole and omeprazole) may be GERD can- didates.15 The aforementioned medications have interactions with some antibiotics and antifungal medications, therefore, review of the pharmacolo- gy is necessary if they are used in periodontal ther- apy. Fluoride rinses and/or trays, frequent peri- odontal débridement, and avoidance of mouth- washes with high alcohol content may reduce the associated gingival and caries sequelae.
It is common for physicians to treat PMS by increasing the levels of deficient neurotransmitters. Alprazolam mimics GABA. Fluoxetine increases the amount of serotonin in the circulation and has a reported 70 percent response rate. It is one of the
10 most-prescribed medications in the United States in the late 1990s. The clinician should be aware that patients on fluoxetine will have increased side effects with highly protein-bound drugs (eg, aspirin) and the half-life of diazepam and other central nervous system (CNS) depressants will be increased. Other common selective serotonin reup- take inhibitors are sertraline and peroxetine.
The PMS patient may be difficult to treat due to emotional and physiologic sensitivity. Treat the gingival and oral mucosal tissues gently. Moisten gauzes or cotton rolls with a lubricant, chlorhexi- dine rinse, or water before placing them in the aphthous prone patient. Careful retraction of the oral mucosa, cheeks, and lips will be necessary in both the aphthous and herpetic prone patient. Since the hypoglycemic threshold is elevated, advise the patient to have a light snack prior to her appointment. Note that 70 percent of menstruat- ing women have PMS symptoms, but only 5 per- cent meet the strict diagnostic criteria.
PREGNANCY
Pregnancy provides unique diagnostic and treat- ment challenges to the periodontal clinician. It is an opportunity to individualize care at a time when the patient may experience the most pro- found physiologic and psychologic changes in her life. Awareness exists regarding pregnancy and its effect on periodontal disease; however, recent evi- dence indicates an inverse relationship to systemic disease. Current research implies that periodontal disease may alter the systemic health of the patient as well as adversely effect the well-being of the fetus by elevating the risk of low-birth-weight, preterm infants.
Periodontal Manifestations
Periodontal Diseases In 1877, Pinard recorded the first case of “preg- nancy gingivitis.”16 Only recently has periodontal research began to focus on causative mechanisms. Pregnancy gingivitis is extremely common, occur- ring in approximately 30 to 75 percent of all preg- nant women.17–19 It is characterized by erythema, edema, hyperplasia, and increased bleeding. Histo- logically, the description is the same as gingivitis. The etiologic factors, however, are different despite clinical and histologic similarities. Cases range from mild inflammation (Figure 9–3) to severe hyperplasia, pain, and bleeding (Figure 9–4).
154 Periodontal Medicine
Alterations in immunocompetency during preg- nancy may create an exaggerated response in peri- odontal supporting structures (Figure 9–5). Peri- odontal status prior to pregnancy may influence the progression or severity as the circulating hor- mones fluctuate. The anterior region of the mouth is more commonly affected, and interproximal sites tend to be most involved.20 Increased tissue edema may lead to increased pocket depths and relate to a transient tooth mobility.21 Anterior site inflammation may be exacerbated by increased mouthbreathing, primarily in the third trimester from “pregnancy rhinitis.”
Pyogenic granulomas occur during pregnancy at a prevalence of 0.2 to 9.6 percent. The “preg- nancy tumor” or “pregnancy epulis” are clinically and histologically indistinguishable from pyogenic granulomas occurring in women who are not preg- nant or in men. They appear most commonly dur- ing the second or third month of pregnancy. The gingiva is the most common site involved (approx- imately 70% of all cases), followed by tongue and lips, buccal mucosa, and palate.22
Clinically, pregnancy tumors appear to be tumorlike growths that generally appear on the interdental papillae of maxillary anterior teeth.
Figure 9–3. Mild to moderate pregnancy gingivitis.
Figure 9–4. Severe pregnancy gingivitis with hyperplasia in a patient with non-insulin-dependent diabetes mellitus in poor control.
Periodontal Medicine and the Female Patient 155
They usually grow rapidly, bleed easily, and become hyperplastic and nodular. They may be sessile or pedunculated and may be ulcerated. Color ranges from purplish red to deep blue, depending on the vascularity of the lesion and the degree of venous stasis. The lesion classically occurs in an area of gingivitis and is associated with poor oral hygiene. Often calculus is present. Osseous destruction is not usually associated with pyogenic granulomas of pregnancy.
Etiologic Factors Despite the clinical/histologic diagnoses of gin- givitis or pyogenic granuloma, a variety of other etiologic factors contribute to these periodontal conditions during pregnancy (Table 9–1). Alter- ations in the composition of subgingival plaque, maternal immunoresponsiveness, and sex hormone concentrations create a myriad of responses in the periodontium.
Subgingival Plaque Composition. There is an alteration in the composition of subgingival plaque during pregnancy. Kornman and Loesche found that during the second trimester there was an increase in gingivitis and gingival bleeding without an increase in plaque levels.23 Bacterial anaerobic-to-aerobic ratios increased, as well as Bacteroides melaninogeni- cus, and Prevotella intermedia proportions (2.2 to 10.1%). There was also an increase in Porphyromonas gingivalis. These authors suggested that estradiol or progesterone can substitute for menadione (vitamin K) as an essential growth factor for P. intermedia but not P. gingivalis or Bacteroides coherences.
Maternal Immunoresponse. Recent studies support alteration of immunocomponents during pregnancy. These changes in maternal immunore- sponsiveness suggest increased susceptibility to gingival inflammation. In one study, gingival index was higher, but percentages of T3, T4, and B cells appear to decrease in peripheral blood and gingival tissues during pregnancy as compared to a control group.24 Other studies report decreased neutrophil chemotaxis, depression of cell-mediat- ed immunity and phagocytosis as well as a decreased T-cell response with elevated levels of ovarian hormone, especially progesterone.25 A decrease in in vitro responses of peripheral blood lymphocytes to several bacterial antigens has been reported26–28 and there is evidence for a decrease in the absolute numbers of CD4-positive cells in peripheral blood during pregnancy as compared to the number of these cells post partum.29,30 Lapp and colleagues suggest that high levels of proges- terone during pregnancy affect the development
of localized inflammation by down-regulation of IL-6 production, rendering the gingiva less effi- cient at resisting the inflammatory challenges pro- duced by the bacteria.31
Also, ovarian hormone stimulates the produc- tion of prostaglandins, mediators of the inflammato- ry response. With the prostaglandin acting as an immunosuppressant, gingival inflammation may increase when the mediator level is high.32,33 Kinnby and colleagues found that high progesterone during pregnancy influenced plasminogen activator inhibitor type 2 (PAI-2) and disturbed the balance of the fibrinolytic system.34 Because PAI-2 serves as an
Figure 9–5. Pregnant (51/2 months) patient with severe hyperplasia and acute monocytic leukemia.
156 Periodontal Medicine
important inhibitor of tissue proteolysis, the research by Kinnby and colleagues implies that components of the fibrinolytic system may be involved in the development of pregnancy gingivitis.
Sex Hormone Concentration. During preg- nancy, progesterone reaches levels of 100 ng/mL, 10 times the peak luteal phase of menses. Estradiol in the plasma may be 30 times higher than that during the reproductive cycle. Estrogens and progesterones have different roles. Estrogen may regulate cellular proliferation, differentiation, and keratinization, while progesterone influences the permeability of the microvasculature,35,36 alters the rate and pattern of collagen production, and increases the metabolic breakdown of folate (necessary for tissue mainte- nance).37 A high concentration of sex hormones in gingival tissues, saliva, serum, and crevicular fluid may exaggerate the response as well. Vittek and col- leagues have demonstrated specific estrogen and progesterone receptors in gingival tissues.38 This is direct biochemical evidence that this tissue may function as a target organ for sex hormones. Mura- matsu and Takaesu found increasing concentration of sex hormones in saliva from the first month of gestation, peaking in the ninth month along with increasing percentages of Prevotella intermedia. With increasing depth, the number of gingival sites with bleeding and redness increased until 1 month post partum.39 There is also evidence of sex hormone concentration in crevicular fluid, providing a growth media for periodontal pathogens.
Periodontal Disease and Preterm Low-Birth- weight Births. Due to the pioneering research of Offenbacher and co-workers, evidence exists that untreated periodontal disease in pregnant women may be a significant risk factor for preterm (< 37 weeks) low-birth-weight (< 2,500 g) babies.40 The relationship with genito-urinary tract infection and preterm low birth weight (PLBW) is well doc- umented in human and animal studies. Periodon- tal researchers suspecting periodontal disease as another source of infection found that mothers of low-birth-weight infants, otherwise having low risk, had significantly more periodontal attachment loss than control mothers having normal-weight infants at birth. The current opinion is that PLBW occurs as a result of infection and is mediated indi- rectly, principally by the translocation of bacterial products such as endotoxin (lipopolysaccharide [LPS]) and by the action of maternally produced inflammatory mediators.41 Biologically active mol- ecules such as prostaglandin E2 (PGE2) and tumor necrosis factor (TNF), which are involved in nor- mal parturition, are raised to artificially high levels by the infection process, which may foster prema- ture labor.42 Gram-negative bacteria in periodontal diseases, therefore, may permit selective over- growth or invasion of gram-negative bacteria with-
TABLE 9–1. Etiology of Gingival Responses to Elevated Estrogen and Progesterone during Pregnancy
Subgingival Plaque Composition Anaerobic-to-aerobic ratio increases Higher concentrations of Prevotella intermedia
(substitutes sex hormone for vitamin K growth factor)
Higher concentrations of Bacteroides melaninogenicus Higher concentrations of Porphyromonas gingivalis
Maternal Immunoresponse Depression of cell-mediated immunity Decreased neutrophil chemotaxis Depression of antibody and T cell responses Decrease in the ratio of peripheral T helper cells
to T suppressor-cytotoxic cells (CD4/CD8 ratio) Cytotoxicity directed against macrophages and b cells
may result in diminished immunoresponsiveness Decrease in absolute numbers of CD3-, CD4- and
CD19-positive cells in peripheral blood during pregnancy versus post partum
Stimulation of prostaglandin production Sex Hormone Concentration
Estrogen Increases cellular proliferation in blood vessels
(known in the endometrium) Decreases keratinization while increasing
epithelial glycogen Specific receptors are found in gingival tissues
Progesterone Increases vascular dilation and thus increases
permeability (results in edema and accumula- tion of inflammatory cells)
Increases proliferation of newly formed capillaries in gingival tissues (increased bleeding tendency)
Alters rate and pattern of collagen production Increases metabolic breakdown of folate
(a deficiency can inhibit tissue repair) Specific receptors are found in gingival tissues Decreases plasminogen activator inhibitor factor
type 2 and thus increases tissue proteolysis Estrogen and Progesterone
Affect ground substance of connective tissue by increasing fluidity
Concentrations increase in saliva and fluid with increased concentrations in serum
Periodontal Medicine and the Female Patient 157
in the genito-urinary tract. Recently, gingival crevicular fluid levels of PGE2 were positively asso- ciated with intra-amniotic PGE2 levels, suggesting that gram-negative periodontal infection may pre- sent a systemic challenge sufficient to initiate the onset of premature labor as a source of LPS and/or through stimulation of secondary inflammatory mediators such as PGE2 and interleukin-1 beta (IL-1b).43 There is ongoing research supporting the association of periodontal disease and PLBW.44,45
Offenbacher has recently published data suggesting a dose-response relationship for increasing gingival crevicular fluid PGE2 as a marker of current perio- dontal disease activity and decreasing birth weight. Four organisms associated with mature plaque and progressing periodontitis (Bacteroides forsythus, Por- phyromonas gingivalis, Actinobacillus actinomycetem- comitans, and Treponema denticola) were detected at higher levels in PLBW mothers, as compared to normal birth weight controls.46 Further longitudi- nal studies and intervention trials are needed to clarify the relationship between periodontal infec- tion and PLBW.
Other Oral Manifestations of Pregnancy Perimylolysis or acid erosion of teeth may occur if “morning sickness” or esophageal reflux is severe and involves repeated vomiting of gastric contents. Severe reflux may cause scarring of the esophageal sphincter, and the patient may become a more like- ly candidate for GERD later in life.
Xerostomia is a frequent complaint among pregnant women. One study found this persistent dryness in 44 percent of pregnant participants.47
A rare finding in pregnancy is ptyalism, or sial- orrhea. This excessive secretion of saliva usually begins at 2 to 3 weeks of gestation and may abate at the end of the first trimester. While its etiology has not been identified, ptyalism may result from the inability of nauseated gravid women to swallow normal amounts of saliva rather than from a true increase in the production of saliva.48
Because pregnancy places the woman in an immunocompromised state, the clinician must be aware of the total health of the patient (see Figure 9–4). Gestational diabetes, leukemia, and other medical conditions may appear during pregnancy.
Management
The periodontal evaluation of the pregnant patient begins with a thorough medical history. This histo- ry should note any complications the patient has encountered in the pregnancy and record any previ-
ous miscarriages, recent cramping, spotting, or per- nicious vomiting. If possible, the next step is to con- tact the obstetrician to discuss the patient’s medical status, dental needs, and proposed treatment plan.
The most important objectives in planning dental treatment for the pregnant patient are to establish a healthy oral environment and to obtain optimum oral hygiene levels. These are achieved by means of a good preventive dental program, consist- ing of nutritional counseling and rigorous plaque control measures in the dental office and at home.
Preventive program Nutrition. The quality of the diet affects caries formation and pregnancy gingivitis. Diet is also important for the developing dentition in the fetus. Pregnant patients normally receive nutrition- al guidance from their obstetricians, which may be re-inforced by the dental team. It is imperative that the mother’s diet supplies sufficient levels of need- ed nutrients, including vitamins A, C, and D, pro- tein, calcium, and phosphorus (Table 9–2 ).
Patients should select nutritious snacks, but because so many foods contain sugars and starches that can contribute to caries development, it is advisable to limit the number of times they snack between meals.
Plaque Control. The pregnant patient should be provided with a comprehensive plaque control program to minimize the exaggerated inflammato- ry response of the gingival tissues. The heightened tendency for gingival inflammation may be clearly explained to the patient so that acceptable oral hygiene techniques may be taught, re-inforced, and monitored throughout pregnancy. Scaling, polish- ing, and root planing may be performed whenever necessary throughout the pregnancy. Some practi- tioners avoid the use of high-alcohol-content antimicrobial mouthrinses in pregnant women and prefer to use non-alcohol-based mouthrinses.
Figure 9–6. Pregnancy tumor.
158 Periodontal Medicine
Prenatal Fluoride. The prescribing of prenatal fluoride supplements has been an area of controver- sy for quite some time. Although two studies have claimed beneficial results,49,50 others suggest that the clinical efficacy of prenatal fluoride supplements is uncertain and that the mechanism by which prena- tal fluorides might impart cariostasis is unclear.51
The American Dental Association (ADA) does not recommend the use of prenatal fluoride, because its efficacy has not been demonstrated. The Amer- ican Academy of Pediatric Dentistry supports this
position as well. The American Academy of Pedi- atrics has no stated position on prescribing prena- tal fluorides.
Baby-Bottle Tooth Decay. When discussing preventive oral health with the patient, it is advisable to mention the condition known as baby-bottle tooth decay (BBTD) for the benefit of the mother and other caregivers. Baby-bottle tooth decay is an easily preventable condition affecting primary teeth. It is caused by frequent and prolonged exposure of the primary teeth to fluids containing sugars, such as milk, formula, fruit juice, and other sweetened liquids provided in baby bottles.
Treatment
Elective Dental Treatment It is prudent to avoid elective dental care other than good plaque control during the first trimester and the last half of the third trimester if possible. The first trimester is the period of organogenesis, when the fetus is highly susceptible to environ- mental influences. In the last half of the third trimester, there is a hazard of premature delivery because the uterus is very sensitive to external stim- uli. Prolonged chair time may need to be avoided because the woman is most uncomfortable at this time. Further, there is a possibility that supine hypotensive syndrome may occur. In a semi-reclin- ing or supine position, the great vessels, particular- ly the inferior vena cava, are compressed by the gravid uterus. By interfering with venous return, this compression will cause maternal hypotension, decreased cardiac output, and eventual loss of con- sciousness. Supine hypotensive syndrome can usu- ally be reversed by turning the patient on her left side, thereby removing pressure on the vena cava and allowing blood to return from the lower extremities and pelvic area.
The second trimester is the safest period for providing routine dental care. The emphasis at this time is on controlling active disease and eliminating potential problems that could arise in late pregnan- cy. Extensive reconstruction procedures and major oral or periodontal surgery should be postponed until after delivery. Pregnancy tumors that are painful, interfere with mastication, or continue to bleed or suppurate after mechanical débridement may require excision and biopsy prior to delivery.
Emergency Dental Treatment Dental emergencies should be dealt with as they arise throughout the entire pregnancy to manage pain and treat infection that otherwise could result
TABLE 9–2. Guidelines for Daily Food Choices for Pregnant Women
Breads, cereals, and other whole-grain and enriched products • 1 slice bread • 1/2 hamburger bun or English muffin • 3–4 small or 2 large crackers • 1/2 cup cooked cereal, pasta, or rice • 1 oz ready-to-eat cereal
Fruits 2–4 servings (include at least one citrus fruit or juice) • 3/4 cup juice • 1 medium apple, banana, or other fruit • 1/2 cup fresh, cooked, or canned fruit
Vegetables 3–5 servings (include at least two servings of dark green leafy, yellow, or orange vegetables) • 1/2 cup cooked or chopped raw vegetables • 1 cup leafy raw vegetables
Meat, poultry, fish, and alternates 2–3 servings • Total of 6–7 oz cooked lean meat, poultry, fish, or
other protein sources daily • 1 oz = 1 egg • 1/2 cup cooked beans • 2 tablespoons peanut butter
Milk, cheese, and yogurt 4 servings • 1 cup milk • 1 cup buttermilk • 8 oz yogurt • 1/2 oz Natural cheese • 2 oz processed cheese
Fats, sweets, and alcohol • Limited fats/sweets • Avoid alcoholic beverages
Adapted from United States Department of Agriculture Home & Garden Bulletin No.232-8
Periodontal Medicine and the Female Patient 159
in increased stress for the mother and endanger- ment of the fetus. Emergency treatment calling for general anesthesia necessitates consultation with the patient’s obstetrician, as does any uncertainty about prescribing medication or pursuing a partic- ular course of treatment.
Dental Radiographs Dental radiography is one of the more controver- sial areas in the management of a pregnant patient. It is most desirable not to have any irradiation dur- ing pregnancy, especially during the first trimester, because the developing fetus is particularly suscep- tible to radiation damage.52 However, the safety of dental radiography has been well established, pro- vided features such as high-speed film, filtration, collimation, and lead aprons are used. Of all aids, the most important for the patient is the protective lead apron. Studies have shown that when an apron is used during contemporary dental radiog- raphy, gonadal and fetal radiation is virtually unmeasurable.53
Even in light of the obvious safety of dental radiography, radiographs should be used selective- ly during pregnancy and only when necessary and appropriate to aid in diagnosis and treatment. In most instances, only bite-wing, panoramic, or selected periapical films are indicated.
Medications Another area of controversy involves drug therapy because drugs given to a pregnant woman can affect the fetus by diffusion across the placenta. A conservative approach is prudent, the dentist pre- scribing only the minimum effective dose and duration absolutely essential for the pregnant patient’s well-being and only after careful consider- ation of potential side effects. The dentist may need to be familiar with the classification system established by the Food and Drug Administration (FDA) in 1979 to rate fetal risk levels associated with many prescription drugs (Table 9–3). The prudent practitioner should consult references such as Briggs and colleagues’ Drugs in Pregnancy and Lactation54 or Drug Facts and Comparisons55
for information on the FDA pregnancy risk factor associated with prescription drugs. Ideally, no drug should be administered during pregnancy, especial- ly the first trimester.52 However, it is sometimes impossible to adhere to this rule. It is, therefore, fortunate that most of the commonly used drugs in dental practice can be given during pregnancy with relative safety although there are a few important exceptions (Tables 9–4a, 9–4b, 9–4c). The tables
of drugs presented here are considered to be gener- al guidelines.56 Obviously, drugs in categories A or B are preferable for prescribing. However, many drugs that fall into category C are sometimes administered during pregnancy. These drugs pre- sent the greatest challenge to the dentist and physi- cian in terms of therapeutics and medicolegal deci- sions. It should be recognized that physicians may advise against the use of some of the approved drugs or conversely may suggest the use of ques- tionable drugs. An example of the occasional use of a questionable drug would be a narcotic for a patient in severe pain. Consulting the patient’s physician may be advisable prior to prescribing any medications during pregnancy.
TABLE 9–3. Food and Drug Administration Classification System*
A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.
B Either animal reproduction studies have not demonstrated a fetal risk and there are no con- trolled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).
C Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal, or other) and there are not controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the poten- tial benefit justifies the potential risk to the fetus.
D There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
X Studies in animals or human beings have demon- strated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contra-indicated in women who are or may become pregnant.
*The five-category system used to classify drugs based on their potential for causing birth defects.
160 Periodontal Medicine
In periodontal therapy, the use of antimicro- bial agents is common. During pregnancy, the clinician must weigh the benefits and the risks to
both mother and fetus. Antibiotics with systemic effects cross the placenta and reach the fetus. The effect of a particular medication on the fetus
TABLE 9–4a. Local Anesthetic/Analgesic Administration during Pregnancy
Drug FDA Category (Prescription Drug) During Pregnancy
Local Anesthetics * Lidocaine B Yes Mepivacaine C Use with caution; consult physician Prilocaine B Yes Bupivacaine C Use with caution; consult physician Etidocaine B Yes Procaine C Use with caution; consult physician
Analgesics Aspirin C/D 3rd trimester Caution; avoid in 3rd trimester Acetaminophen B Yes Ibuprofen B/D 3rd trimester Caution; avoid in 3rd trimester Codeine C Use with caution; consult physician Hydrocodone B Use with caution; consult physician Oxycodone B Use with caution; consult physician Propoxyphene C Use with caution; consult physician
*Can use vasoconstrictors if necessary. Avoid prolonged use.
TABLE 9–4b. Antibiotic Administration during Pregnancy
FDA Category During Drug (Prescription Drug) Pregnancy Risks
Penicillins B Yes Diarrhea Erythromycin B Yes; avoid estolate form Intrahepatic jaundice in mother Clindamycin B Yes (with caution) Drug concentrated in fetal bone, spleen,
lung, and liver Cephalosporins B Yes Limited information Tetracycline D Avoid Depression of bone growth, enamel
hypoplasia, grey-brown tooth discoloration Ciprofloxacin C Avoid Possible developing cartilage erosion Metronidazole B Avoid (controversial) Theoretical carcinogenic data in animals Gentamicin C Caution; consult physician Limited information; ototoxicity Vanocomycin C Caution; consult physician Limited information Clarithromycin D Avoid; use only if the Limited information; adverse effects on
potential benefit justifies pregnancy, outcome, and embryofetal the risk to the fetus development in animals
TABLE 9–4c. Sedative-Hypnotic Drug Administration during Pregnancy
Drug FDA Category During Pregnancy
Benzodiazepines D Avoid Barbiturates D Avoid Nitrous oxide Not assigned Avoid in 1st trimester; otherwise
use with caution; consult physician
Periodontal Medicine and the Female Patient 161
depends on the type of antimicrobial, the dosage, the trimester, and the duration of the course of therapy.57 At this date, there is inadequate research in relation to subgingival irrigation and local site delivery in relation to the developing fetus.
Dental Drugs During Breast-Feeding Another perplexing problem for the dentist arises when a nursing mother requires a drug during den- tal treatment. There is a risk that the drug can enter the breast milk and be transferred to the nursing infant, in whom exposure could have adverse effects. Unfortunately, there is little conclusive information about drug dosage and effects via breast milk. How- ever, retrospective clinical studies and empirical observations coupled with known pharmacologic pathways allow recommendations to be made.52
The amount of drug excreted in breast milk is usu- ally not more than 1 to 2 percent of the maternal dose; therefore, it is highly unlikely that most drugs have any pharmacologic significance for the infant.58,59 Tables 9–5a and 9–5b compile recom- mendations regarding administration of common- ly used dental drugs during breast-feeding. These recommendations are general guidelines only. As with drug use in pregnancy, individual physicians may wish to modify these suggestions.
In addition to choosing drugs carefully, it is desirable for the mother to take the drug just after breast-feeding and then to avoid nursing for 4 hours or more if possible.52,58 This markedly decreases the drug concentration in breast milk.
ORAL CONTRACEPTIVES
Periodontal Manifestations
Because oral contraceptive (OC) use mimics hor- monal levels of pregnancy, clinical manifestations are similar. Gingival tissues may have an exaggerat- ed response to local irritants. Inflammation ranges from mild edema and erythema to severe inflam- mation with hemorrhagic or hyperplastic gingival tissues. It has been reported that there is more exu- date in inflamed gingival tissues of OC users than in those of pregnant women.60,61
Investigators have reported several mechanisms for the heightened response in gingival tissues. Kalkwarf reported that the response may be due to alteration of the microvasculature, increased gingi- val permeability, and increasing synthesis of prostaglandgin.62 Prostaglandin E2 appears to rise significantly with increasing sex hormone.
Prostaglandin E is a potent mediator of inflamma- tion.63 Jensen and colleagues found dramatic microbial changes in pregnant and OC user groups as compared with a nonpregnant group.64 A 16- fold increase in Bacteroides species was noted in the OC user group versus the nonpregnant group despite the lack of statistically significant clinical differences in gingival index or crevicular fluid flow. The researchers state that the increased female sex hormones substituting for the napthaquinone requirement of certain Bacteroides species were most likely responsible for this increase in Bacteroides.
There have been reports that the oral contra- ceptive-associated gingival inflammation may become chronic (as opposed to the acute inflam- mation of pregnancy) due to the extended periods of time women are exposed to elevated levels of estrogen and progesterone.65,66 Some have report- ed that the inflammation increases with prolonged use of OCs. Kalkwarf did not find that duration of use made a significant difference, however, the “brand” of OC caused different responses. Further studies need to be performed in relation to dosage, duration, and type of OC used in association with the periodontium. One should note that the con- centration of female sex hormones in OCs of the 2000s will be significantly less than in those of the 1970s, yet the OCs of the 2000s will have the same level of contraceptive efficacy.
Other intraoral effects of oral contraceptives are changes in salivary composition. A decreased concentration of protein, sialic acid, hexosamine fucose, hydrogen ions, and total electrolytes has been reported. Salivary flow rates have been report- ed to be increased in one study67 and decreased in 30 percent of subjects in another study.68 ( Note that these studies were conducted in the 1970s.)
The dental literature reports that women tak- ing oral contraceptives experience a twofold to threefold increase in the incidence of localized osteitis following extraction of mandibular third molars.69 The higher incidence of osteitis in these patients may be attributed to the effects of OCs (estrogens) on clotting factors. There are, however, a number of studies that refute these findings.70
Evidence at this date is inconclusive with regard to osteitis following third molar extractions and the use of OCs.
Also, it has been reported in the medical liter- ature that there may be a spotty melanotic pig- mentation of the skin with the use of OCs. This suggests a relationship between the use of OCs and the occurrence of gingival melanosis, especially in fair-skinned individuals.71
162 Periodontal Medicine
Management
A comprehensive medical history and an assess- ment of vital signs (particularly blood pressure) are extremely important in this group of patients. Treatment of gingival inflammation exaggerated by oral contraceptives should include establishing an oral hygiene program and eliminating local predis- posing factors. It is also imperative that the patient be informed of their heightened risks and the need for meticulous home care and compliance with supportive periodontal therapy visits. Periodontal surgery may be indicated if there is inadequate res- olution after initial therapy (scaling and root plan- ing). Antimicrobial mouthwashes may be indicat- ed as part of the home care regimen. It may be advisable to perform extraction of teeth (especially of third molars) on non-estrogenic days (days 23 to 28) of the pill cycle, to reduce the risk of a postop- erative localized osteitis.72 However, evidence of this association is inconclusive and warrants fur- ther investigation.
Although the results from animal studies have demonstrated antibiotic interference adversely affecting contraceptive sex hormone levels, several studies involving human subjects have failed to support such an interaction.73–76 This issue is con- troversial, and there may be a possibility that antibiotics could render oral contraceptives ineffi- cacious in preventing pregnancies. In 1991, an ADA Health Foundation report stated that all women of childbearing age should be informed of possible reduced efficacy of oral steroid contracep-
tives during antibiotic therapy and advised to use additional forms of contraception during short- term antibiotic therapy. During long-term antibi- otic therapy, they should consult with their physi- cian about using high-dose oral contraceptive preparations.77 Although research regarding oral manifestations attributed to oral contraceptives has been reported in the literature, presumably the same effects could occur with the use of contra- ceptive implants (eg, Norplant®). Along the same lines, the remote possibility exists of reduced effi- cacy of the contraceptive implant with concurrent antibiotic administration, and the same precau- tions can be adhered to as with oral contraceptives.
CONCLUSION
There is increasing evidence that the female patient frequently presents with unique periodon- tal and systemic manifestations that alter the course of conventional periodontal therapy. The cyclic nature of the female sex hormones is often reflected in gingival tissue changes. It is the responsibility of those who treat the oral cavity to realize that they are treating the total health of the patient (and possibly the unborn fetus), not just a localized site infection.
Thorough medical histories in the female patient should include questions regarding men- strual regularity, oral contraceptive use, hormone replacement therapy, fertility medications, preg-
TABLE 9–5b. Dental Drug Administration during Breast-Feeding
Drug During Breast-Feeding
Antibiotics* Penicillins Yes Erythromycin Yes Clindamycin Yes (with caution) Cephalosporins Yes Tetracycline Avoid Ciprofloxacin Avoid Metronidazole Avoid Gentamicin Avoid Vancomycin Avoid
Sedative-hypnotics Benzodiazepines Avoid Barbiturates Avoid Nitrous oxide Yes
*Antibiotics have the risk of diarrhea and sensitization in the mother and infant.
TABLE 9–5a. Dental Drug Administration during Breast-Feeding
Drug During Breast-Feeding
Local anesthetics Lidocaine Yes Mepivacaine Yes Priolocaine Yes Bupivacaine Yes Etidocaine Yes Procaine Yes
Analgesics Aspirin Avoid Acetaminophen Yes Ibuprofen Yes Codeine Yes Hydrocodone No data Oxycodone Yes Propoxyphene Yes
Periodontal Medicine and the Female Patient 163
nancy, breast-feeding, cyclic problems that may be associated with manifestations of the sex hor- mones, as well as any question that may enhance the quality of care for the individual patient and determine her particular needs. It is possible to control the periodontal health of the patient by educating her about the profound effects of the sex hormones, especially progesterone, and the impor- tance of consistent removal of local irritants.
In the late 1990s, there has been a resurgence of curiosity relating to female issues and med- ical/periodontal therapy. There should be light shed on the specific management and etiology of sex hormone-mediated infections in the near future. It is also imperative that we disseminate this knowledge to other health care providers and to the community.
REFERENCES
1. Kornman K, Loesche WJ. Direct interaction of estradiol and progesterone with Bacteroides melaninogenicus. J Dent Res 1979;58A:10.
2. Gusberti FA, Mombelli A, Lang NP, Minder CE. Changes in subgingival microbiota during puberty. J Clin Periodontal 1990;17:685–92.
3. Mombelli A, Rutar A, Lan NP. Correlation of the periodontal status 6 years after puberty with clinical and microbiological conditions during puberty. J Clin Periodontol 1995;22(4):300–5.
4. Nakagawa S, Fujii H., Machida Y, Okuda K. A lon- gitudinal study from prepuberty to puberty of gingivitis. Correlation between the occurrence of Prevotella intermedia and sex hormones. J Clin Periodontal 1994;21(10):658–6.
5. American Dental Association. Women’s Oral Health Issues 1995; Dec.
6. Brown S, Bonifaz DZ. An overview of anorexia and bulimia nervosa and the impact of eating disor- ders on the oral cavity. Compend Contin Educ Dent 1993;14(12):1594–1608.
7. Mandel L, Kaynar A. Bulimia and parotid swelling: a review and case report. J Oral Maxillofac Surg 1992;50:1122–5.
8. Lundgren D, Magnssen B, Lindhe J. Connective tissue alterations in gingiva of rats treated with estrogens and progesterone. Odontol 1973;24: 49–58.
9. Thomson ME, Pack ARC. Effects of extended sys- temic and topical folate supplementation on gingivitis in pregnancy. J Clin Periodontol 1982;9:275–80.
10. Pack ARC, Thomson ME. Effects of topical and
systemic folic acid supplementation on gingivi- tis in pregnancy. J Clin Periodontol 1980;7: 402–14.
11. Miyagi M, Aoyama H, Morishita M, Iwamoto Y. Effects of sex hormones on chemotaxis of poly- morphonuclear leukoctyes and monocytes. J Periodontol 1992;63:28–32.
12. Grant D, Stern J, Listgarten M. The epidemiology, etiology and public health aspects of periodon- tal disease. In: Grant D, Stern J, Listegarten M. editors. Periodontics. St. Louis (MO): Mosby 1988. p. 229,332–5.
13. Ferguson MM, Carter J, Boyle P. An epidemiolog- ical study of factors associated with recurrent apthae in women. J Oral Med 1984:39(4):212.
14. Robb-Nicholson C. PMS: it’s real. Harvard Women’s Health Watch 1994; July 1(11):2–3.
15. Robb-Nicholson C. Gastroesophageal reflux dis- ease. Harvard Women’s Health Watch;4(6):4–5.
16. Pinard A. Gingivitis in pregnancy. Dent Register 1877;31:258–9.
17. Levin RP. Pregnancy gingivitis. Maryland State Dental Association 1987;30:27.
18. Hanson L, Sobol SM, Abelson T. The otolaryngo- logic manifestations of pregnancy. J Fam Pract 1986;23:51–5.
19. DeLiefde B. The dental care of pregnant women. NZ Dent J 1984;80:41–3.
20. Löe H, Silness J. Periodontal disease in pregnancy. 1. Prevalence and severity. Acta Odontol Scand 1984;21:533–51.
21. Raber-Durlacher JE, van Steenbergen TJM, van der Velden U. Experimental gingivitis during preg- nancy and post-partum; clinical, endocrino- logical and microbiological aspects. J Clin Perio- dontol 1994;21:549–58.
22. Bhashkar SN, Jacoway JR. Pyogenic granuloma: clinical features, incidence, histology, and results of treatment. Report of 242 cases. J Oral Surg 1966;24:391–8.
23. Kornman KS, Loesche WJ. The subgingival flora during pregnancy. J Periodontol 1980;15: 111–22.
24. Aboul-Dahab OM, el-Sherbiny MM, Abdel-Rah- man R, Shoeb M. Identification of lymphocytes subsets in pregnancy. Egyptian Dental J 1994; 40(1):653–6.
25. Raber-Durlacher JE, Leene W, Palmer-Bouva CCR, et al. Experimental gingivitis during preg- nancy and post partum: immunohistochemical aspects. J Periodontol 1993;64:211–18.
26. O’Neil TCA. Maternal T-lymphocyte response and gingivitis in pregnancy. J Periodontol 1979;50: 178.
164 Periodontal Medicine
27. Brabin, BJ. Epidemiology of infection in pregnancy. Rev Infect Dis 1985;7:579.
28. Lopatin DE, Kornman KS, Loesche WJ. Modula- tion of immunoreactivity to periodontal disease- associated microorganisms during pregnancy. Infect Immun 1980;28:713–18.
29. Sridama V, Pacini F, Yang SL, et al. Decreased lev- els of helper T cells. A possible cause of immun- odeficiency in pregnancy. N Engl J Med 1982; 307:352.
30. Raber-Durlacher JE, Zeylemaker WP, Meinesz AAP, Abraham-Lipijn L. CD4 to CD8 ratio and in vitro lymphoproliferative responses during experimental gingivitis in pregnancy and post- partum. J Periodontol 1991;62:663–7.
31. Lapp CA, Thomas ME, Lewis JB. Modulation by progesterone of interleukin-6 production by gingival fibroblasts. J Periodontol 1995;66(4): 279–84.
32. El-Attar TMA. Prostaglandins F2 in human gingiva in health and disease and its stimulation by female sex steroids. Prostaglandins 1976;1:331–41.
33. Ojanotko-Harri AO, Harri MOP, Hurrita HP. Altered tissue metabolism of progesterone in pregnancy gingivitis and granuloma. J Clin Peri- odontol 1991;8:262–6.
34. Kinnby B, Matsson L, Astedt B. Aggravation of gingival inflammatory symptoms during preg- nancy associated with the concentration of acti- vator inhibitor type 2 (PAI-2) in gingival fluid. J Periodontal Res 1996;31(4):271–7.
35. Lindhe J, Branemark P. Changes in vascular per- meability after local application of sex hor- mones. J Periodontal Res 1967b;2:259–265.
36. Lindhe J, Branemark P. Changes in microcircula- tion after local application of sex hormones. J Periodontal Res 1967a;2:185–93.
37. Zachariasen RD. Ovarian hormones and oral health: pregnancy gingivitis. Compend Contin Educ Dent 1989;10(9):508–12.
38. Vittek J, Gordon G, Rappaport C, Munangi P, Southern A. Specific progesterone receptors in rabbit gingiva. J Periodontal Res 1982;17:657.
39. Muramatsu Y, Takaesu Y. Oral health status related to subgingival bacterial flora and sex hormones in saliva during pregnancy. Bull Tokyo Dent College 1994;35(3):139–51.
40. Offenbacher S, Katz V, Fertik G, et al. Periodontal infection as a possible risk factor for preterm low birthweight. J Periodontol 1996;67(10 Suppl): 1103–13.
41. Gibbs RS, Romero R, Hillier SL, et al. A review of premature birth and subclinical infections. Am J Obstet 1992;166:1515–28.
42. American Academy of Periodontology Position Paper. Periodontal disease as a potential risk fac- tor for systemic disease. J Periodontol 1998; 69(7):841–50.
43. Damare SM, Wells S, Offenbacher S. Eicosanoids in periodontal diseases: potential for systemic involvement. Adv Exp Med Bio 1997;433:23–5.
44. Davenport ES, Williams CE, Sterne JA, et al. The East London study of maternal chronic peri- odontal disease and preterm low birth weight infants: study design and prevalence. Ann Perio- dontol 1998;3(1):213–21.
45. Dasanayake AP. Poor periodontal health of the pregnant woman as a risk. Ann Periodontol 1998;3(1):206–12.
46. Offenbacher S, Jared HL, O’Reilly PG, et al. Potential pathogenic mechanisms of periodonti- tis associated pregnancy complications. Ann Periodontol 1998;3(1):233–50.
47. El-Ashiry G. Comparative study of the influence of pregnancy and oral contraceptives on the gingi- vae. Oral Surg 1970;30:472–5.
48. Cruikshank O, Hayes PM. Maternal physiology. In: Gabbe S, Niebyl JR, Simpson JL, editors. Preg- nancy in obstetrics: normal and problem preg- nancies. Livingstone (NY): Churchill Livingstone; 1986.
49. Glenn FB. Immunity conveyed by a fluoride sup- plement during pregnancy. J Dent Child 1977; 44:391–5.
50. Glenn FB, Glenn WD III, Duncan RC. Fluoride tablet supplementation during pregnancy for caries immunity: a study of the offspring pro- duced. Am J Obstet Gynecol 1982;143:560–4.
51. Reference manual. Pediatr Dent 1994–95:16(7). 52. Little JW, Falace DA. Dental management of the
medically compromised patient. 4th edition. St. Louis (MO): Mosby;1993:383–9.
53. Bean LR Jr, Devore WD. The effects of protective aprons in dental roentgenography. 1969;28: 505–8.
54. Briggs GG, Freeman RK, Yaffe SJ. Drugs in preg- nancy and lactation. 4th ed. Baltimore (MD): Williams and Wilkins;1994.
55. Olin BR, editor. Drug facts and comparisons. St. Louis (MO): Walters Kluwer; 1994.
56. Reese RE, Betts RF. Handbook of antibiotics. 2nd ed. Boston (MA): Little, Brown, and Co.:1993.
57. Otomo-Corgel J. Systemic considerations for female patients. In: Antibiotics/antimicrobial use in dental practice. Tokyo: Quintessence Publishing Co.; 1990. p. 217–21.
58. Steinberg, BJ. Sex hormonal alterations. In: Rose LD, Kay D, editors. Internal medicine for dentistry. 2nd ed. St. Louis (MO): Mosby;1990. p. 1073–7.
Periodontal Medicine and the Female Patient 165
59. Wilson JT, Brown RD, Cherek DR, et al. Drug excretion in human breast milk: principles, pharmacokinetics and projects consequences. Clin Pharmacokinet 1980;5:1–66.
60. Zachariasen, RD. The effects of elevated ovarian hormones on periodontal health: oral contra- ceptives and pregnancy. Women Health 1993; 20(2):21–30.
61. Sooriyamoorthy M, Gower DB. Hormonal influ- ences on gingival tissues: relationship to perio- dontal disease. J Clin Periodontol 1989;16: 201–8.
62. Kalkwarf KL. Effect of oral contraceptive therapy on gingival inflammation in humans. J Perio- dontol 1978;49:560–3.
63. El-Attar TMA, Roth GD, Hugoson A. Compara- tive metabolism of 4-C progesterone in normal and chronically inflamed human gingival tissue. J Periodontol Res 1973;8:79.
64. Jensen J, Lilijmack W, Blookquist C. The effect of female sex hormones on subgingival plaque. J Periodontol 1981;52(10):599–602.
65. Knight GM, Wade AB. The effects of oral contra- ceptives on the human periodontium. J Perio- dontal Res 1974;9:18–22.
66. Pankhurst CL. The influence of oral contracep- tive therapy on the periodontium—duration of drug therapy. J Periodontol 1981;52:617– 620.
67. Magnusson T, Ericson T, Hugoson A. The effect of oral contraceptives on some salivary substance in women. Arch Oral Biol 1975;20:119.
68. El-Ashiry G, El-Kafrawy AH, Nasr MF, Younis N.
Effects of oral contraceptives on the gingiva. J Periodontol 1971; 42:273–5.
69. Sweet JB, Butler DP. Increased incidence of postop- erative localized osteitis in mandibular 3rd molar surgery associated with patients using oral con- traceptives. Am J Obstet Gynecol 1977;127:518.
70. Cohen ME, Simecek JW. Effects of gender-related factors on the incidence of localized alveolar osteitis. Oral Surg Oral Med Oral Path Oral Radiol Endod 1995;79(4):416–22.
71. Hertz RS, Beckstead PC, Brown WJ. Epithelial melanosis of the gingiva possibly resulting from the use of oral contraceptives. J Am Dent Assoc 1980;100:(5):173.
72. Fleisher AB Jr, Resnick SD. The effect of antibi- otics in the efficacy of oral contraceptives. Arch Dermatol 1980;125:1582–4.
73. Back DJ, Orme MLíE. Pharmacokinetic drug interactions with oral contraceptives. Clin Phar- macokinet 1990;18(6):472–84.
74. Fraser IS, Jansen RPS. Why do inadvertent preg- nancies occur in oral contraceptive users? Effec- tiveness of oral contraceptive regimens and inter- fering factors. Contraception 1983;27:531–51.
75. Murphy AA, Zacur HA, Charache P, et al. The effect of tetracycline on levels of oral contracep- tives. Am J Obstet Gynecol 1991;164:28–33.
76. Neely JL, Abate M, Swinker M, et al. The effect of doxycycline on serum levels on ethinyl estradiol, norethindrone, and endogenous progesterone. Obstet Gynecol 1991;77:410–16.
77. Antibiotic interference with oral contraceptives. J Am Dent Assoc 1991;122:79.
CHAPTER 10
OSTEOPENIA, OSTEOPOROSIS AND ORAL DISEASE Sara G. Grossi, DDS, MS Marjorie K. Jeffcoat, DMD Robert J. Genco, DDS, PhD
Normal bone is among the most metabolically active of human tissues. Once formed, bone is con- tinuously changing throughout life, constantly responding to various metabolic demands. In a process known as remodeling, bone shapes itself, creating an organ with maximal compressive strength, able to fulfill its role as the load-bearing structure of the body. The human skeleton consists of two different tissues: trabecular bone, concentrat- ed mostly in vertebrae, the pelvis and other flat bones, and cortical bone, which overlays trabecular bone and occupies mostly the shafts of long bones.1
Cortical bone is a more dense tissue than trabecular bone, as the cells are in closer proximity with less intercellular space and matrix. Trabecular bone is metabolically more active than cortical bone, likely because of its greater surface-to-volume ratio.
To maintain this phenomenally strong load- bearing structure, young bone is constantly renew- ing itself. That is, “old” bone is constantly removed and replaced with “new bone,” a process known as bone remodeling. In this process, bone is constant- ly resorbed on a particular bony surface, followed by a phase of bone formation. It is etimated that the entire skeleton is completely turned over every 7 to 10 years. Remodeling occurs at both trabecu- lar and cortical sites. In the normal adult skeleton, bone resorption is coupled with bone formation, so that bone balance is maintained.2 In this man- ner, the skeleton is maintained throughout the life of the individual.
BONE REMODELING
Bone remodeling is a complex and dynamic process aimed at the maintenance of a mineralized bone matrix. It involves a number of cellular func-
tions, including replication of undifferentiated cells and recruitment and cell differentiation in both cortical and trabecular bone.3 This concert of bone cells is referred to as the basic multicellular unit (BMU) or bone remodeling unit and consti- tutes the smallest functional unit of bone cells capable of undergoing the remodelling process.4
Four distinct phases are recognizable in the bone remodeling cycle: activation, resorption, reversal, and formation. A cycle is completed in approxi- mately 8 months. The process is under tight con- trol by both systemic and local factors.
Systemic factors regulating bone remodeling include: (1) the calcium-regulating hormones: parathyroid hormone (PTH), 1,25-dihydroxyvita- min D (1,25(OH)2D3), and calcitonin (CT); and (2) the systemic growth-regulating hormones: growth hormone, glucocorticoids, thyroid hor- mone, and sex hormones.5 Parathyroid hormone is a polypeptide with complex effects on bone metab- olism. The most important function of PTH is to maintain serum ionized calcium concentration, accomplished by stimulation of bone resorption, renal resorption of calcium, and increased synthesis of 1,25(OH)2D3, which, in turn, results in increased intestinal calcium absorption.6 Parathy- roid hormone has a dual effect on bone metabo- lism, stimulating both resorption and formation.5,6
The bone resorbing effect is dependent on the pres- ence of osteoblasts or osteoblast-derived factors. Vitamin D (1,25(OH)2D3), a hormone synthesized primarily by the kidney, has similar functions as PTH. It stimulates bone resorption and has effects on bone formation.7 The major function of vitamin D, however, is to maintain the supply of calcium and phosphate by stimulating intestinal absorp- tion.8 Vitamin D is important in cell differentia- tion, formation of osteoclasts, and the differentiat-
168 Periodontal Medicine
ed function of osteoblasts. Calcitonin is a potent inhibitor of bone resorption. Unlike PTH, the effect of calcitonin on bone metabolism is indepen- dent from osteoblasts. Accordingly, osteoclasts express receptors for calcitonin on their membrane and not for PTH.6
Insulin and growth hormone (GH) are polypeptide hormones with counter-regulation. While GH is the major regulator of somatic growth, it acts indirectly by stimulating the pro- duction of circulating and local insulin-like growth factor (IGF-I) by skeletal cells,9 which, in turn, mediates some of the effects of insulin on bone metabolism and skeletal growth.10 Insulin stimu- lates bone matrix formation and mineralization. This stimulatory effect on matrix synthesis is due to an effect on osteoblast differentiation rather than an increase in collagen-producing cells.11
Glucocorticoids are steroid hormones with direct and indirect effects on bone metabolism. The indirect effects include inhibition of intestinal absorption of calcium and GH secretion. The direct effects include inhibition of bone collagen synthesis, probably due to a decrease in osteoblast replication,5 and increased response to other sys- temic hormones such as PTH and IGF,6 possibly by increasing receptor binding. This could be one of the mechanisms involved in steroid-induced osteoporosis.12
Sex hormones, both estrogen and androgens, play a central role in skeletal development and bone loss. The increase in sex hormones at puberty is partly responsible for the events leading to acceler- ation of cartilage growth, increased bone turnover, and increased bone mass. Both estrogen and andro- gen receptors are present in bone cells, pointing to the direct effects of these hormones on bone metab- olism as well. Estrogen regulates bone remodeling by modulating the production of cytokines and growth factors, which, in turn, act as local regulators of the remodeling process. Cytokines under estrogen regu- lation with direct effects on bone cells include inter- leukin-1 (IL-1), tumor necrosis factor-a (TNF-a), granulocyte-macrophage colony–stimulating factor (GM-CSF) secreted by monocytes, and IL-6 and colony-stimulating factor (CSF) secreted by osteo- blasts.13 Interleukin-1 induces the synthesis of IL-6, which increases bone resorption through osteoclast recruitment. Colony-stimulating factor plays a role in the maturation of osteoclasts. Interleukin-1b and TNF-a stimulate mature osteoclasts, modulate bone cell proliferation, and induce bone resorption in vivo.14,15 In addition, IL-1, TNF-a, and GM- CSF contribute to bone resorption by promoting
osteoclast recruitment and differentiation from bone marrow precursors. Moreover, 17-B estradiol appears to stimulate the production of alkaline phosphatase and collagen IGF-1 by bone cells.16 In addition, estrogen may affect bone turnover indi- rectly by acting as an antagonist to PTH. The bone- sparing effect of estrogen may be explained by its fundamental ability to interact with bone cells and modulate the cytokine circuitry that controls bone remodeling.17
Other local factors regulating bone remodeling are synthesized by skeletal cells and include growth factors and prostaglandins. Polypeptide growth fac- tors include IGF-1 and -2,18 TGF-b,19 fibroblast growth factor (FGF),20 platelet-derived growth fac- tor (PDGF),21 and bone morphogenic proteins (BMPs).22 These factors have effects on cells of the same class (autocrine effect) or other cells within the tissue (paracrine effect). Prostaglandins are currently the only known regulators of bone remodeling that do not have a polypeptide structure.
Growth factors are also present in circulation and may act as systemic regulators of skeletal and nonskeletal metabolism but the locally produced factor has a more direct and possibly important function in cell growth. Circulating hormones may act on skeletal cells either directly or indirectly, modulating the synthesis, activation, and receptor binding of local growth factor. This, in turn, stim- ulates or inhibits bone formation or bone resorp- tion. It is likely that hormones are important in the targeting of growth factors to tissues expressing spe- cific hormonal receptors. Growth factors may play a critical role in the coupling of bone formation with bone resorption and possibly in pathophysio- logic processes.23
Peak Bone Mass
Bone mass increases during early childhood and adolescence by linear growth of the endochondrial growth plates and by radial growth due to periosteal apposition. After closure of the growth plate around age 20 years, radial growth continues for about 10 to 15 years. Peak bone mass is therefore reached sometime between the third and early part of the fourth decade of life, declining progressively there- after (Figure 10–1).1,2 Peak bone mass constitutes the summation of growth and turnover during what is known as the “calcium building years.” Sometime after age 40 years, a slow age-dependent phase of bone loss ensues. This calcium depletion phase results in similar losses of cortical and trabecular bone, with roughly similar rates in men and women.
Osteopenia, Osteoporosis, and Oral Disease 169
In addition, postmenopausal women experience yet another phase of bone loss, that is, an accelerated loss as a consequence of the estrogen deficiency asso- ciated with menopause. Trabecular bone, being more metabolically active than cortical bone, is lost at a disproportionately faster rate during this post- menopausal phase of bone loss.
Peak bone mass has strong genetic determi- nants. Morrison and colleagues24 have shown that bone mass, one of the main determinants of osteo- porotic fractures, has a genetic component linked to an allellic change in the receptor for vitamin D, one of the hormones controlling calcium metabolism. However, nutritional factors, such as level of dietary calcium during skeletal growth, and environmental factors, such as physical activity, modulate the genetic disposition and contribute to the achieve- ment of peak bone mass.25 Failure to achieve peak bone mass predisposes to fractures later in life as age- related bone loss ensues. Genetically determined dif- ferences in peak bone mass may explain, in part, the racial and gender differences in the incidence of osteoporosis. Caucasian women have the least bone mass and African American men have the most, while Caucasian men and African American women have intermediate bone mass. Thus, assuming a constant rate of bone loss with age, Caucasian women with the lowest peak bone mass are at great- est risk for osteoporosis and fractures later in life.1,2
OSTEOPOROSIS
Osteoporosis means literally “porous bone,” a con- dition where there is “too little bone” to provide mechanical support. Osteopenia, on the other hand, is a reduction in bone mineral density (BMD) below a predefined level. Osteoporosis is characterized by a reduction in BMD to a level below what is required for mechanical support.26,27
A Consensus Development Conference defined osteoporosis as “a systemic skeletal disease charac- terized by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture.”28 This defi- nition, though descriptive, provides little useful- ness for diagnosis and clinical management. Microarchitectural deterioration is not amenable to clinical measurement, whereas bone mass can be measured with accuracy and precision with dual x- ray absorptiometry (DXA). Thus, a World Health Organization panel has operationally defined osteoporosis as a BMD (T score) that is 2.5 SD below the mean peak value in young adults (Table 10–1).29 This definition too, has limitations since BMD values are applicable to Caucasian women
Figure 10–1. Changes that occur in bone mass with growth and aging in men and women. Factors involved in determin- ing peak bone mass are genetic and nongenetic (nutrition, smoking, exercise). Factors increasing rate of bone loss later in life include aging, estrogen deficiency, and lifestyle factors (smoking, alcohol). Results of Morrison and colleagues (1994) suggest that bone mass is under genetic control, linked to polymorphism in the gene for vitamin D receptor.
TABLE 10–1. World Health Organization (WHO) Diagnostic Guidelines for Interpretation of Bone Mass Measurements in Caucasian Women
Severe osteoporosis Bone mineral density (BMD) more than 2.5 standard deviations (SD) below the mean value of peak bone mass in young normal women and the presence of fractures.
Osteoporosis BMD more than 2.5 SD below the mean value of peak bone mass in young normal women.
Low bone mass (osteopenia) BMD within –1 SD and –2.5 SD of the mean value of peak bone mass in normal young women.
Normal BMD not more than 1SD below mean value of peak bone mass in young normal women.
170 Periodontal Medicine
only. Their relevance to other ethnic groups and to men is currently unknown.
Osteoporosis affects more than 25 million peo- ple in the United States (about 10% of the total pop- ulation), including 1 in 3 postmenopausal women, and a substantial number of men. It is responsible for more than 2 million fractures annually, resulting in health-care costs in excess of 20 billion U.S. dollars. The major portion of the social and economic bur- den caused by fractures is due to hip fracture. The intangible costs to society due to pain and suffering associated with morbidity, need for long-term care, and mortality as a result of osteoporotic fractures add to the financial burden. Osteoporosis is clearly a major public health problem.
Classification
Osteoporosis occurs either as a primary disorder, or it may be secondary to other diseases or conditions (Table 10–2).1 Primary osteoporosis includes idio- pathic (juvenile or adult) and involutional forms. Idiopathic forms of osteoporosis are rare and affect men and women equally. Involutional osteoporo- sis, by far the most common form, includes two patterns: type I (postmenopausal) and type II (age- related) osteoporosis.
Type I (postmenopausal) osteoporosis occurs in peri- and postmenopausal women. Bone loss in pre- menopausal women is slow and approximately equal to that of men (0.3 to 0.5% per year). With the onset of menopause in females, an accelerated rate of cortical bone loss of 2 to 3% per year ensues for about 8 to 10 years. Trabecular bone is lost at a rate of about 5% per year during the first 5 to 8 years
after menopause (see Figure 10–1). Thus, type 1 osteoporosis is characterized by a disproportionate loss of trabecular bone resulting in fractures at those skeletal sites with a high volume of trabecular bone, including the vertebrae, distal forearm (Colles’ frac- tures), and distal ankle. Clinical symptoms of the disease include bone pain (mostly from vertebral compression), loss of height and consequent defor- mation of the skeleton leading to dorsal kyphosis (“dowager’s hump”).
Type I osteoporosis is related to the estrogen deficiency associated with menopause, leading to a cascade of accelerated bone loss, decreased secre- tion of parathyroid hormone, increased secretion of calcitonin, and decreased calcium absorption, which further aggravates bone loss. In addition, patients with type I osteoporosis and high bone turnover have increased production of IL-1 by stimulated monocytes, as compared with age- matched controls, which also contributes to increased bone resorption.
Type II (age-related) osteoporosis appears to affect virtually the entire population of aging men and women, although it is twice as common in women. Bone loss starts around the third decade and continues through life and is characteized by slow bone loss due to decreased calcium absorp- tion and secondary hyperparathyroidism. Bone loss affects cortical and trabecular bone equally with a rate of about 0.3 to 0.5% per year (see Fig- ure 10–1). These two types of bone loss result in distinct fracture patterns. While postmenopausal osteoporosis manifests mostly in Colles’ and verte- bral fractures, age-related osteoporosis results in hip fractures in both men and women of older age. However, fractures of the humerus, proximal fibula, and pelvis are also common.
Secondary Osteoporosis
Osteoporosis may be associated with a number of endocrine diseases. Hypogonadism in either sex increases the incidence of osteoporosis. Hyperthy- roidism consistently increases bone turnover but in most patients, formation and resorption remain cou- pled. Osteoporosis may also be associated with gas- trointestinal diseases, and malabsorption syndromes that impair absorption of calcium and vitamin D. Multiple myeloma and other myeloproliferative dis- orders produce diffuse osteoporosis in about 10% of patients. Diffuse osteoporosis may also occur when disseminated carcinoma invades the bone marrow. An unusually severe form of osteoporosis may occur in connective tissue diseases such as osteogenesis
TABLE 10–2. Classification of Osteoporosis
Primary Idiopathic Juvenile
Adult
Involutional Type I (postmenopausal) Type II (age-related)
Secondary Endocrine disorders Diabetes mellitus Gastrointestinal and malabsorption syndromes Myeloproliferative disorders Multiple myeloma Connective tissue diseases
Marfan syndrome Ehlers-Danlos syndrome
Chronic obstructive pulmonary disease
Osteopenia, Osteoporosis, and Oral Disease 171
imperfecta. Marfan and Ehlers-Danlos syndromes may also be associated with vertebral osteopenia, but less frequently include vertebral fractures.
Other causes of osteoporosis include total immobilization, such as in traumatic quadriplegia. Significant bone loss also occurs during total bed rest among nonparalyzed individuals and in astro- nauts during gravitational weightlessness. Osteo- porosis is also associated with chronic obstructive pulmonary disease. Whether this is related to the underlying consumption of tobacco or to the pul- monary disease itself is unknown.
Pathophysiology
The pathophysiology of osteoporosis is poorly understood. Bone mass at any given time is related to peak bone mass and bone loss that has occurred since peak mass was attained. Bone is continuous- ly remodeled throughout the life of an individual, and the rate of remodeling is increased in older adults. With the increased rate of remodeling in older age, there is uncoupling of the remodeling cycle, that is, the rate of resorption exceeds the rate of formation.30,31 This results in a remodeling imbalance with net bone loss, lower bone mass, and ultimately increased risk for fractures. Such an imbalance would be even greater if the rate of ini- tiation of new bone remodeling cycles were to increase. Therefore, genetically determined bone mass and age constitute the major determinants of risk of osteoporosis and osteoporotic fractures.
ORAL BONE AND OSTEOPENIA/OSTEOPOROSIS
After having reviewed the biology of bone remod- eling and the basis of imbalance in coupling responsible for the onset of skeletal osteopenia and ultimately osteoporosis, the implicit question is, to what extent is oral bone affected by remodeling imbalance, and does it contribute to oral bone loss? In addition to the academic relevance of this ques- tion, it is fundamental to proper clinical manage- ment of dentate and edentulous patients suffering from both osteopenia and osteoporosis. A rational dental treatment plan in such patients is not com- plete if proper management of systemic bone loss is not included.
Relationship of Skeletal Osteopenia to Mandibular Bone Density
It has long been postulated that mandibular bone density may be indicative of systemic bone miner- al density. In a classic series of studies, Kribbs and colleagues (Table 10–3) addressed this relationship in both normal and osteoporotic women. In an early study,32 total body calcium as assessed by neu- tron activation analysis, was found to be associated with mandibular density as measured by quantita- tive analysis of intraoral radiographs. A later study33 in normal, nonosteoporotic women, revealed that bone mass was not affected by age but was significantly associated with skeletal bone mass
TABLE 10–3. Relationship between Systemic and Mandibular Bone Mineral Density
Authors Population Major Result Type of Study
Jeffcoat et al, 200 subjects from Women’s Correlation between basal Baseline data from [In press] Health Initiative bone mineral density and longitudinal
Postmenopausal women hip bone mineral density study Von Wowern et al, 12 women with osteoporotic Osteoporotic subjects had less Cross-sectional
1994 fracture bone mineral content and study 14 normal women more loss of attachment
compared with normals Kribbs et al, 1990 50 normal women, aged 20 Mandibular bone mass correlated Cross-sectional
to 90 years with bone mass as spine and wrist study Kribbs et al, 1990 85 osteoporotic and 27 Osteoporotic group had less Cross-sectional
normal women, aged 50 mandibular bone mass and study to 85 years density
Kribbs et al, 1989 85 osteoporotic women Total body calcium, bone mass at Cross-sectional radius, and bone density at spine study correlated with mandibular mass
Kribbs et al, 1983 30 postmenopausal women Total body calcium associated with Cross-sectional mandibular bone density study
172 Periodontal Medicine
at the spine and wrist. A comparison of 85 osteo- porotic women with 27 normal women showed less mandibular bone mass and density and a thin- ner cortex at the gonion in osteoporotic compared with nonosteoporotic women.34,35 Similarly, von Wowern and colleagues36 reported that 12 osteo- porotic subjects with a history of fractures had less mandibular bone mineral content as measured by dual photon absorptiometry than 14 normal women. It is noteworthy that all reports Kribbs and colleagues32–35 and von Wowern and col- leagues36 described are cross-sectional studies.
The Women’s Health Initiative (WHI), in the United States, is an unprecedented study of women’s health after menopause. Specific risk fac- tors for diseases including heart disease and osteo- porosis are being addressed nationwide. The Uni- versity of Alabama at Birmingham and the State University of New York at Buffalo are conducting oral studies ancillary to the WHI to determine whether image analysis of intraoral radiographs could be used to determine if basal mandibular BMD is correlated with hip BMD determined by DXA. Comprehensive medical histories and exam- inations performed as part of the parent study were linked with results of oral examinations and quan- titative digital intraoral radiography.37,38 A region of interest in the area of the basal bone of the first mandibular molar was selected for measurements of mandibular BMD. General linear models of mandibular basal BMD, hip BMD, midroot den- sity, age, race, hormone replacement therapy, and calcium supplements were created. Preliminary analyses from the University of Alabama cohort used data from the first 200 subjects in the study.39
Significant correlations were found between mandibular basal BMD and hip BMD (r = 0.74, p < .001). These findings are consistent with evi- dence that supports the concept that BMD of the mandible is indeed correlated with skeletal BMD.
Tooth Loss and Osteoporosis
Several studies have demonstrated a relationship between tooth loss and systemic osteoporosis in both dentate and edentulous individuals. Daniell and col- leagues40 suggested that systemic bone loss was a risk factor for edentulism. Women with severe osteo- porosis, defined as extreme thinning of the metacarpal cortical area, were three times more like- ly (44% versus 15%) to have no teeth compared with healthy, age-matched controls. Taguchi and col- leagues41 showed that a decrease in mandibular bone density, estimated as mandibular cortical width, cor-
related with tooth loss for women in their sixties. In a study of 329 healthy postmenopausal women, for each additional tooth present, spinal BMD increased 0.003 g per cm2.42 In a 7-year longitudinal study, rate of systemic bone loss was a predictor of tooth loss in postmenopausal women.43 For each 1% per year decrease in whole body BMD, the risk for tooth loss more than quadrupled. Decreases in BMD at the femoral neck and spine resulted in a 50% and 45% increased risk of tooth loss respectively. Collec- tively, this evidence indicates that osteoporotic women have lost significantly more teeth, and more are edentulous compared with nonosteoporotic women.40–44 Thus, women that are at risk for or suf- fer from osteoporosis are also at risk for tooth loss.
Periodontal Disease and Osteopenia/Osteoporosis
Unlike the clear relationship between osteoporosis and tooth loss, controversy still exists concerning the association between osteopenia/osteoporosis and periodontal disease. Conflicting results among dif- ferent studies account for much of the controversy. Small sample size and fundamental differences in study design, population examined (ie, women only versus men and women), age of population studied, and methodology to assess periodontal disease and skeletal osteopenia and osteoporosis prevent inter- pretation and comparability of results.
Wactawski-Wende and colleagues,45 in a study of 70 postmenopausal women, found a significant relationship between alveolar crestal bone height as a measure of periodontitis and skeletal osteopenia (femur and lumbar spine) measured by DXA. This relationship was seen after controlling for possible confounders such as dental plaque, years of meno- pause, and smoking. In addition, there was a rela- tionship between osteopenia at the hip and probing attachment loss in this same group. Similarly, von Wowern and colleagues,36 in a case-control study comparing 12 female patients with osteoporotic fractures and 14 normal women, reported signifi- cantly greater periodontal attachment loss in the osteoporotic women compared with the normal women. They found that the osteoporotic women had less mandibular bone mineral content, as mea- sured by dual photon absorptiometry, than the 14 normal women. The mandibular bone mineral content values were 2 SD below the mandibular bone content for young reference (normal) women in 92% of the osteoporotic group and in 64% of the control group, suggesting that a high propor- tion of the control group also suffered from
Osteopenia, Osteoporosis, and Oral Disease 173
mandibular osteopenia. The relationship between osteopenia and severity of periodontal disease was also examined in a sample from the Third Nation- al Health and Nutrition Examination Survey (NHANES III) of 11,247 individuals 20 to 90 years of age.46 Osteopenia of the hip was signifi- cantly associated with severity of periodontal dis- ease (mean attachment loss ³ 1.5 mm) in females and males alike (Figure 10–2), independently of the confounding effects of age, gender, smoking, or intake of dietary calcium. This association was increased even further in postmenopausal females. Hence, though limited, the evidence suggests an association between osteopenia, osteoporosis, and periodontal disease. Estrogen deficiency may explain, in part, the nature of this association.
CO–RISK FACTORS FOR OSTEOPOROSIS AND PERIODONTAL DISEASE
Osteoporosis and periodontal disease are chronic, multifactorial diseases. It is not surprising, there- fore, that both diseases share common risk factors. Risk factors common to both osteoporosis and periodontal disease are listed under the categories of genetic, dietary, environmental, and systemic factors (Table 10–4). Strong evidence indicates that genetic and lifestyle factors are important risk factors for osteoporosis.47–49 Family history of osteoporosis or fractures, thin body build, genetics, race, and advancing age constitute nonmodifiable risk factors for osteoporosis.
Skeletal bone loss can be slowed or even reversed if modifiable environmental and dietary risk factors, such as physical inactivity, cigarette smoking, low dietary calcium intake, and excessive use of caffeine and alcohol, are identified and reversed. A report from the National Osteoporosis Foundation concluded that the following factors were useful in identifying women at risk for fracture: low body weight (< 58 kg), current smoking, first- degree relative with low-trauma fracture, and per-
Figure 10–2. Results from the NHANES III including 11,247 individuals 20 to 90 years old indicate that BMD of the femoral neck, trochanter, intertrochanter, Ward’s triangle, and total hip is a significant predictor for severe periodontal disease in men and woman alike, independently of the con- founding effect of age, smoking, or intake of dietary calcium.
TABLE 10–4. Risk Factors for Osteoporosis and Periodontal Disease
Osteoporosis Periodontal Disease
Hereditary/genetics Female gender Age Caucasian or Asian race Race Family history Familial aggregation Menopause IL-1 polymorphism Petite body build Suboptimal peak bone
Dietary factors Low intake calcium Low intake calcium Low intake vitamin D Low intake vitamins C, E, A, selenium High intake caffeine, protein, salt, phosphate
Environment Smoking Smoking Alcohol Alcohol Physical inactivity Stress
Systemic factors Diabetes mellitus Diabetes mellitus Multiple myeloma Osteoporosis Connective tissue diseases Hormone changes
174 Periodontal Medicine
sonal history of low-trauma fracture (Table 10–5). These risk factors are simple and easy to ascertain and effective in identifying women at increased risk.
Recent evidence indicates that genetics may play an important role in the severity of periodontal disease as well.50 Environmental factors such as smoking and excessive alcohol consumption are important modifiable risk factors for periodontal disease.51,52 Stress and inadequate coping are also equally predictive for both periodontal disease and osteoporosis.53 Largescale population-based studies indicate that inadequate intake of specific nutrients is also associated with severe periodontal disease.54,55
Estrogen Deficiency
Estrogen deficiency is the factor most closely associ- ated with postmenopausal osteoporosis.48,49 Defi- ciency of estradiol in postmenopausal and oophorec- tomized women is associated with decreased lum-
bar spine bone mineral density and increased inci- dence of fractures of the vertebrae and hip.56–58
Estrogen regulates bone remodeling by modulating the production of cytokines and growth factors, especially IL-1b, TNF-a, GM-CSF, and M-CSF from bone cells.13 Interleukin-1b and TNF-a stim- ulate mature osteoclasts, modulate bone cell prolif- eration, and induce bone resorption in vivo.14,15 In addition, IL-1, TNF-a, and GM-CSF contribute to bone resorption by promoting osteoclast recruit- ment and differentiation from bone marrow precur- sors. Osteoblast precursors respond to the loss of estrogen by secreting IL-6, which then induces osteoclastogenesis.16 The loss of estrogen accompa- nying menopause results in an increase of cytokines in the bone remodeling circuitry. Subjects with “high turnover” osteoporosis secrete increased amounts of IL-1 that is blocked by estrogen/proges- terone therapy.59 This association, apparently, is not restricted to IL-1 but also affects other major mononuclear cell secretory products, such as TNF- a and GM-CSF. Cytokine production by peripher- al blood monocytes (PBM) from ovariectomized women that receive no estrogen therapy steadily increases. Moreover, in vitro treatment of human monocytes with estrogen has been shown to regulate both IL-1 and TNF.60 Accordingly, Horowitz61 pro- posed that the antiosteoporotic effect of estrogen is exerted through downregulation of cytokine synthe- sis and secretion by osteoblasts and other cells.
TABLE 10–5. Risk Factors to Identify Women at Risk for Fracture (Recommended by the National Osteoporosis Foundation)
Low body weight (< 58 kg) Current smoking First-degree relative with low-trauma fracture Personal history of low-trauma fracture
TABLE 10–6. Relationship between Estrogen Status and Periodontal Disease
Authors Study Design/Population Results Conclusion
Norderyd et al, Cross-sectional Gingival bleeding significantly ERT associated with 1993 234 postmenopausal women lower in ERT vs. non-ERT less gingivitis in
(57 ERT; 177 non-ERT) Lower levels of plaque and postmenopausal Capnocytophaga sp. women
Less attachment loss in ERT group vs. non-ERT
Payne et al, Longitudinal 1 year Estrogen-sufficient group showed Estrogen status may 1997 24 postmenopausal women mean net gain in alveolar bone influence alveolar
(10 estrogen sufficient; density bone density status 14 estrogen deficient) Estrogen-deficient group showed
mean net loss in alveolar bone density
Jacobs et al, Longitudinal 5 years Moderate relationship between Estrogen status 1996 69 women, 36 to 64 years old BMC of mandible and lumbar directly related to
Natural and surgical menopause spine mandibular Receive estrogen therapy Positive effect of estrogen therapy bone mass
on mandibular bone mass
ERT = estrogen replacement therapy; BMC = bone mineral content.
Osteopenia, Osteoporosis, and Oral Disease 175
Three studies have directly examined the rela- tionship of estrogen status/deficiency and peri- odontal disease (Table 10–6). Norderyd and col- leagues62 reported lower, although not statistically significant, levels of clinical attachment loss in post- menopausal women receiving estrogen supplemen- tation compared with estrogen-deficient post- menopausal women. In addition, gingival bleeding was statistically significantly reduced in the estro- gen-treated postmenopausal women compared with the estrogen-deficient group, after controlling for levels of supragingival plaque and frequency of dental treatment. A 5-year longitudinal study of 69 women with surgical or natural menopause receiv- ing hormone replacement therapy compared lum- bar spine BMD, measured by dual photon absorp- tiometry, with mandibular bone mass assessed by quantitative measures of standardized intraoral radiographs.63 A statistically significant but moder- ate correlation was observed between mandibular and lumbar spine bone mass and that estrogen replacement therapy after surgical or natural menopause had a positive effect on bone mass not only of the lumbar spine but the mandible as well.63
Payne and colleagues64 showed, in a 1-year longitu- dinal study of 24 postmenopausal women, that estrogen-deficient women displayed a mean net loss in alveolar bone density compared with estrogen- sufficient women, who displayed a mean net gain in alveolar bone density. The authors proposed
estrogen defieciency as a risk factor for alveolar bone density loss. Thus, in the estrogen deficient state, the governor controlling cytokines and bone remodelling is lost, resulting in increased bone resorption and net skeletal and alveolar bone loss.
Hence, consistent evidence supports the rela- tionship between estrogen status, periodontal dis- ease, and mandibular bone density. Results from three independent studies clearly suggest that estrogen deficiency plays an important role in mandibular bone loss and is likely an important factor modifying the severity of periodontal disease in postmenopausal women.
Smoking
A meta-analysis of 29 studies including 2,156 smok- ers and 9,750 nonsmokers examined the effect of cigarette smoking on skeletal bone mineral densi- ty.65 While bone density in premenopausal women was comparable in smokers and nonsmokers, in postmenopausal women bone loss was greater in current smokers compared with nonsmokers. The cumulative risk for hip fractures in women was 19% in smokers and 12% in nonsmokers. Among all women, one in eight hip fractures was attributable to smoking. Limited data was available for men; however, a similar proportionate effect of smoking was observed. The meta-analysis concluded that smoking may have a direct effect on bone metabo-
Figure 10–3. Analysis of the Erie County Study reveals that for the entire population of 1,426 indi- viduals 25 to 74 years old, men show more severe periodontal disease than women. However, male and female nonsmokers have the same levels of alveolar bone loss. Among current smokers, on the other hand, males have significantly (p = .03) more alveolar bone loss compared with females, sug- gesting that the difference in disease severity is explained, in part, by a reduced response to smoking in females, mediated possibly by estrogen status.
176 Periodontal Medicine
lism, since the association between smoking and BMD was not explained by smokers being thinner, younger at menopause, exercising less, or tobacco smoke having a direct effect on estrogen.
The direct effect of smoking on skeletal bone is modulated by gender and estrogen. Analysis of BMD at the hip, spine, and radius of the Framing- ham cohort showed that men smokers had 4 to 15% lower BMD compared with nonsmokers, independent of weight, alcohol, or caffeine use,66
implying other mechanisms for the effect of smok- ing on bone. Smoking did not affect skeletal BMD in women that had not taken estrogen. However, lower BMD was seen among women that had taken estrogen supplementation and were smokers compared with nonsmokers, suggesting that smok- ing negates the bone-sparing effect of estrogen. Smoking also accelerated the rate of bone loss at the femoral neck and total body in some elderly men and women, who participated in a 3-year placebo-controlled study of calcium and vitamin D supplementation.67 Less efficient absorption of calcium was proposed as a possible mechanism for the smoking-related accelerated bone loss.
Smoking is the single most important modifi- able risk factor for periodontal disease and osteo- porosis. A meta-analysis of available literature indi- cates that smokers have 2.5 times the risk for severe periodontal disease compared with nonsmokers,
independent of the effects of age, socioeconomic factors, diabetes mellitus, or dental plaque.68 Fur- thermore, the risk is cumulative and dose depen- dent in that the severity of periodontal disease is related to the duration and amount of smoking.51
When alveolar bone loss is used as the outcome measure, the risk is even greater.69 This increased negative effect on alveolar bone may be explained by the direct effect of smoking on bone metabolism and bone resorption. In a manner similar to skele- tal BMD, the effect of smoking on alveolar bone is modulated by gender and estrogen.
Analysis of the Erie County Study cohort reveals that the greater severity in periodontal disease seen in males is explained in part by smoking. That is, if only nonsmokers are examined, disease levels measured as alveolar bone loss are comparable between both gen- ders. However, when only smokers are examined, males exhibit greater alveolar bone loss compared with females (Figure 10–3). Therefore, the greater severity of periodontal disease seen in males appears to be related to a gender response to smoking. The lesser severity of periodontal disease in pre- menopausal women that smoke could be explained by the bone protective effects of estrogen. When the levels of periodontal disease in postmenopausal women are examined, nonsmoking women that receive estrogen supplementation through hormone replacement therapy (HRT) exhibit less alveolar
Figure 10–4. The effect of smoking and estrogen on alveolar bone loss is seen in women from the Erie County Study. Among nonsmokers, postmenopausal HRT women have levels of alveolar bone loss no different compared with premenopausal (PM) women. Non-HRT women, on the other hand, have bone loss levels significantly greater (p = .04) than PM and HRT counterparts, suggesting a protective effect of estrogen on alveolar bone loss. Among women who smoke, however, both HRT and non-HRT groups have levels of bone loss significantly greater than premenopausal women, suggesting that smoking reduces the protective effect of estrogen. HRT = hormone replacement therapy; PM = premenopausal.
Osteopenia, Osteoporosis, and Oral Disease 177
bone loss compared with women that do not take estrogen (non-HRT) (Figure 10–4).70 In fact, alve- olar bone loss levels in postmenopausal women taking HRT are no different from the levels in pre- menopausal women. Postmenopausal women that smoke and take HRT have levels of alveolar bone loss comparable with those women that do not take HRT. Thus, in a manner analogous to skeletal bone density, estrogen has a bone-sparing effect on alveolar bone, which is negated by current smok- ing (see Figure 10–4). Similar findings are evident when tooth loss is examined in this population of women, that is, estrogen supplementation is pro- tective in postmenopausal tooth loss, and current smoking negates this protective effect as well.71
Dietary Factors
Peak bone mass is attained at around 30 to 35 years of age as the summation of genetically determined factors modulated by dietary and environmental factors.72 Adequate dietary calcium is essential for the growth and development of a normal skele- ton.73 Insufficient calcium intake during childhood and adolescence can reduce peak bone mass and enhance postmenopausal and age-related osteo- porosis.74 Dietary calcium supplementation has been shown to increase bone mass in children and adolescents and to reduce age-associated bone loss.
Not surprisingly, osteoporosis has been defined as a “pediatric disease.” Radial BMD was correlated with current calcium intake in young women (20 to 23 years old).75 A study of young women failed to find an association between BMD and calcium intake.76 However, the mean calcium intake for the study group was 909 mg, high enough to obscure any possible difference. A study of about 18,000 Japanese men and women, 30 to 69 years old, found that even one glass of milk per day was protective against osteoporosis in calcium-deficient individu- als.77 The National Institutes of Health (NIH), 1994 Conference on Optimal Calcium recommends a dose of 1,000 mg per day for premenopausal women, and 1,500 mg per day for estrogen-deficient women (Table 10–7). These recommendations are for Caucasians. Requirements for other ethnic groups, as well as for persons with lower protein intakes and small skeletal size may differ.
The role of phosphorous, vitamin D, protein, fluoride, and caffeine on bone mass have been stud- ied as well.78 Vitamin D or its metabolites increase intestinal calcium absorption, suppress PTH levels, and increase bone density; their amount and action decrease with age. Osteoblasts have receptors for
1,25(OH)2D3, which is the final product of vitamin D metabolism. Excess protein intake is related to increased calcium excretion. Fluoride is a powerful stimulator of bone formation, resulting in a major increase in trabecular bone mass. However, cortical fractures have been associated with high fluoride levels, which may be related to the fact that fluoride decreases the elasticity of bone. Caffeine is correlat- ed with decreased bone density. In addition, studies in ovariectomized Sprague-Dawley rats fed a soy- protein diet showed a bone-sparing effect mediated by isoflavones in soy-protein.79
A series of recent studies examining the data from NHANES III demonstrate the significant effect of nutrition as a risk factor for periodontal dis- ease. Trained nutritionists conducted interviews on a 24-hour diet recall on a nationwide probability sam- ple of approximately 40,000 individuals 1 to 90+ years old. Individuals with diets deficient in calcium had statistically higher levels of periodontal disease compared with those with calcium sufficient diets.54
This association was especially strong in younger and premenopausal women. Individuals with diets defi- cient in vitamins C, A, alpha-carotenoids, selenium, and lutein also showed increased risk for periodontal disease, independently of the confounding effects of age, dental plaque, and smoking.55 Therefore, a diet complete in vitamins and minerals plays an impor- tant role, not only in ensuring achievement of peak bone mass and protection from age-related bone loss, but it also likely protects against the destruction of connective tissue and alveolar bone resulting from periodontal infection.
Genetic Factors
Osteoporosis is likely a multifactorial, polygenic con- dition involving mutiple genes regulating the attain- ment of peak bone mass and possibly the control of
TABLE 10–7. National Institutes of Health (NIH) Consensus Conference Recommendation for Optimum Calcium Intake
Premenopausal women 1,000 mg/d (25 to 50 years old)
Postmenopausal women 1,000 mg/d (estrogen therapy)
Postmenopausal women 1,500 mg/d (no estrogen therapy)
Men (25 to 65 years old) 1,000 mg/d Women and men > 65 years old 1,500 mg/d
178 Periodontal Medicine
turnover. Early studies showed that monozygotic twins exhibited less variation in bone mass than dizy- gotic twins.80 A landmark study by Morrison and colleagues24 reported that bone mass had a genetic component that could be ascribed to an allelic change in the receptor for 1,25 dihydroxy vitamin D. The vitamin D receptor (VDR) is required for normal calcium absorption from the gut. It is esti- mated that common allelic variants in the gene encoding the VDR account for up to 75% of the total genetic effect on bone density in healthy Cau- casian adults24 and predicts the density of femoral and vertebral bone in prepubertal American girls of Mexican descent.81 Other polymorphisms imparting susceptibility to osteoporosis include the binding site in collagen type I alpha 1 (COLIA 1) gene,82,83 trans- forming growth factor-beta (TGF-b) gene,84 the estrogen receptor,85 the vitamin D promoter region of the osteocalcin gene,86 as well as genes regulating cytokines involved in bone turnover.
Susceptibility to periodontal infection and the inflammatory responses to the infecting organism appear to be under genetic regulation as well.87 It is possible that periodontal disease is also a polygenic condition. Candidate genes for susceptibility to peri- odontal disease include genes defining the FcgRII receptor, genes regulating immunoglobulin synthe- sis, especially IgG2, and genes regulating cytokine synthesis. Specific genotypes of polymorphic IL-1b genes are associated with increased IL-1 production and associated with severity of periodontal disease in nonsmokers.50 This IL-1 genotype was found to accurately predict prognosis and tooth survival in individuals affected by periodontal disease.88 Current predictive models for both periodontal disease and osteoporosis do not account for all the observed vari- ability in disease expresssion. Genetically determined individual susceptibility to both conditions may in part explain some of the unaccounted variability.
COMMON TREATMENT STRATEGIES FOR OSTEOPOROSIS AND PERIODONTAL DISEASE
Avoidance of the morbidity of osteoporosis begins with prevention. Adequate calcium intake during adolescence and early adulthood is critical to form- ing peak bone mass. The 1994 NIH Conference on Optimal Calcium Intake recommended that daily calcium intake of 1,000 mg of calcium per day for premenopausal, and 1,500 mg per day for postmenopausal women (see Table 10–7) should be maintained until additional research warrants revisions to such recommendations. To maximize
the likelihood that bone mass is maintained over a lifetime, load-bearing exercise is also necessary. Like periodontal disease, smoking is a major risk factor for osteoporosis and avoidance of smoking or smoking cessation contributes to osseous health.
There is a limited amount of evidence that cal- cium supplementation may be beneficial in reduc- ing tooth loss. In a 7-year study of 189 post- menopausal women not taking HRT, subjects were assigned to receive either placebo, calcium supple- mentation, or vitamin D plus calcium supplemen- tation.89 Four times as many (12%) placebo-treat- ed women lost teeth during the study period com- pared with 3% in the calcium-supplemented group. No effect was observed with vitamin D.
Bone loss in women occurs most rapidly in the years immediately following menopause when nat- ural levels of estrogen are greatly reduced. Hormone replacement therapy is designed to replace estrogen after menopause since this immediate post- menopausal period is a time of rapid loss of bone mineral density.90–94 For women with a uterus, a combination of estrogen and progesterone is used; while in women without a uterus, estrogen replace- ment therapy (ERT) alone is employed. Many stud- ies have reported that HRT and ERT are efficacious in sparing bone mineral and reducing fractures.90–94
Few studies have directly assessed the relation- ship between periodontal disease and its sequelae in women receiving HRT. Most of these studies have involved HRT with either estrogen or estrogen plus progesterone, and assessed tooth loss, alveolar bone loss, or other measures of periodontal health. In a longitudinal, unblinded study of 69 women receiv- ing HRT, Jacobs and colleagues63 compared lumbar spine bone mineral density, measured by dual pho- ton absorptiometry, with mandibular bone mass assessed by quantitative measures of standardized intraoral radiographs. The average length of study was 5.1 years. A significant but moderate correla- tion was observed at the second examination. Estrogen replacement therapy was associated with less gingival bleeding after correcting for age,62 less alveolar bone loss,70 and less tooth loss71 than in women without estrogen supplementation.
Major cohorts of women have been examined in two longitudinal studies in an attempt to deter- mine if HRT has reduced the number of lost teeth in postmenopausal women. These include the 3- year study of 42,171 postmenopausal women in the Nurses Health Cohort95 and the 10-year study of 3,921 women living in a retirement community in the Leisure World Cohort.96 The Leisure World Cohort taking estrogen experienced a 36% reduc-
Osteopenia, Osteoporosis, and Oral Disease 179
tion in tooth loss and the Nurses Health Cohort showed an inverse relationship between HRT and loss of teeth, after correcting for smoking and age. One potential source of bias in these studies (and, in fact, addressed in the reports) is the fact that the same patients that seek to prevent osteoporosis may seek preventive dental care as well. Both these populations are large but composed of relatively well-educated, higher socioeconomic groups. In a third study, 488 women aged 72 to 95 years par- ticipating in the Framingham Heart Study were examined.97 Estrogen users had more teeth remi- ning than had nonusers, after controlling for age, smoking status, and education.
Therapy for osteoporosis is a rapidly changing field. The latest generation of bisphosphonate drugs, such as alendronate, deposit onto bone decreasing osteoclast numbers and activity, thereby decreasing bone resorption. Alendronate has been shown to inhibit loss of bone density and decrease the risk of fracture, without disturbance of bone healing observed with earlier drugs.98 In a pilot clinical trial, the efficacy of alendronate in slowing alveolar bone loss due to periodontitis was investigated.38
This 9-month, double-blind, placebo-controlled, randomized clinical trial (RCT) measured loss of bone height and density using digital subtraction radiography. Alendronate reduced the risk of pro- gressive loss of alveolar bone. The relative risk of progressive loss of bone height and density was 0.45 for the alendronate-treated patients compared with placebo-treated patients.
FUTURE RESEARCH
Although considerable research has been done in the last 10 years in understanding the functions and control mechanisms of bone cells, much work still remains to be done in the field of bone cell biology. New treatments addressing the multifac- torial nature of osteoporosis will require funda- mental advances in knowledge in the field of bone cell and molecular biology.
Further research is needed on the therapeutic control of bone resorption, including the nature of the cellular and molecular mechanisms by which osteoblast/ stromal cells influence progression from hematopoietic precursors to differentiated osteo- clasts. Either the factor(s) responsible or the cascade of events leading to this differentiation will provide important therapeutic alternatives. Substantial evi- dence supports the antiosteoporotic effect of estro- gen. However, significant research interest exists in
partial agonist/antagonists of estrogen, which could uniquely influence receptor conformation. Thus, research to elucidate the tertiary structure of estro- gen receptors will aid in developing “designer estro- gens.” Clearly, much more research into the bone formation process is needed as well, with the ulti- mate goal of identifying agents capable of promot- ing bone formation. Suitable agents at present are fluoride and PTH, each of which is a substantial promoter of bone formation.
Longitudinal studies are needed to definitively elucidate the contribution of systemic osteopenia to periodontal disease, alveolar bone loss, alveolar ridge resorption, and tooth loss. Additional research is needed to identify and test, in clinical trials, agents with effects on reducing skeletal and oral bone resorption. Evidence-based treatment approaches to manage individuals suffering from both periodontal disease and systemic osteopenia are urgently needed. Preservation of alveolar bone and alveolar ridge in combination with the prevention of fracture is essential to provide the quality of life in our older population. Biomedical research needs to ensure that the quality of life and well being of this rapidly growing segment of our population will continue well into older age.
Finally, the first genetic clue to susceptibility to osteoporosis came from work with the vitamin D receptor gene. Since then, other candidate genes and genetic polymorphisms conferring susceptibil- ity to osteoporosis have been identified, establish- ing osteoporosis as a polygenic disease. Additional research is needed to fully unravel the genetic make-up of osteopenia/osteoporosis. Additionally, interactions between genetic, nutritional, and lifestyle factors, such as smoking and alcohol intake, are important targets for future research. Genetic studies in osteoporosis and periodontal disease will lead to ways of not only identifying individuals susceptible to these two crippling dis- eases but also to understanding how the environ- ment may contribute to modulating the suscepti- bility to both diseases. Future research will provide ways of identifying susceptible individuals likely to benefit from prevention of both osteopenia/ osteoposis and periodontal disease.
REFERENCES
1. Riggs BL. Overview of osteoporosis. West J Med 1991;154:63–77.
2. Parfitt AM. Bone remodeling: relationship to the amount and structure for bone, and the patho-
180 Periodontal Medicine
genesis and prevention of fractures. In: Riggs BL, Melton LJ III, editors. Osteoporosis: etiolo- gy, diagnosis and management. New York: Raven Press; 1988. p. 45–93.
3. Vaanamen HK. Mechanisms of bone turnover. Ann Med 1995;25:353–9.
4. Parfitt AM. The physiological and clinical signifi- cance of bone histomorphometric data. Bone histomorphometry: techniques and interpreta- tion. Boca Raton, FL; 1983. p. 143–223.
5. Canalis E. The hormonal and local regulation of bone formation. Endocr Rev 1983;4:62–77.
6. Raisz LG. Local and systemic factors in the patho- genesis of osteoporosis. N Engl J Med 1988;318: 818–27.
7. DeLuca H. Vitamin D visited. Clin Endocrinol Metab 1980;9:1–26.
8. Raisz LG, Kream BE. Regulation of bone forma- tion. N Engl J Med 1983:309:29–35.
9. Raisz LG. Recent advances in bone cell biology: interactions of vitamin D with other local and systemic factors. Bone Mineral 1990;9:191–7.
10. Canalis E, Centrella M, Burch W, McCarthy T. Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. J Clin Invest 1989;83:60–5.
11. McCarthy T, Centrella M, Canalis E. Regulatory effects of insulin-like growth factor I and II on bone collagen synthesis in rat calvarial cultures. Endocrinology 1989;124:301–9.
12. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990;112:352–64.
13. Pacifici R. Estrogen, cytokines and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res 1996;11:1043–51.
14. Pacifici R. Is there a causal role for IL-1 in post- menopausal bone loss? Calcif Tissue Int 1992; 50:295–9.
15. Tatakis DN. Interleukin-1 and bone metabolism. A review. J Periodontol 1993;64:416–31.
16. Girasole G, Jilka RL, Passeri G, et al. 17b-Estradi- ol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteo- porotic effect of estrogens. J Clin Invest 1992; 89:883–91.
17. Horowitz MC. Cytokines and estrogen in bone: anti-osteoporotic effects. Science 1993;260: 626–7.
18. McCarthy T, Centrella M, Canalis E. Cortisol inhibits the synthesis of insulin-like growth fac- tor I in skeletal cells. Endocrinology 1990;126: 1569–75.
19. Centrella M, McCarthy T, Canalis E. Transforming growth factor beta is a bifunctional regulator of
replication and collagen synthesis in osteoblast- enriched cell cultures from fetal rat bone. J Biol Chem 1987;262:2869–74.
20. Canalis E, Centrella M, McCarthy T. Effects of basic fibroblast growth factor on bone forma- tion in vitro. J Clin Inv 1988;81:1572–7.
21. Canalis E, Centrella M, McCarthy T. Effects of platelet-derived growth factor on bone forma- tion in vitro. J Cell Physiol 1989;140:530–7.
22. Wozney M, Rosen V, Celeste A, et al. Novel regu- lators of bone formation; molecular clones and activities. Science 1988;242:1528–34.
23. Canalis E , McCarthy T, Centrella M. Growth fac- tors and cytokines in bone cell metabolism. Ann Rev Med 1991;42:17–24.
24. Morrison NA, Qi JC, Tokita A, et al. Prediction of bone density from vitamin D receptor alleles. Nature 1994;367:284–7.
25. Nordin BEC, Morris HA. The calcium deficiency model for osteoporosis. Nutr Rev 1989;47: 65–72.
26. Marcus R. The nature of osteoporosis. J Clin Endocrinol Metab 1995;81(1):1–5.
27. Kanis JA, et al. The diagnosis of osteoporosis. J Bone Miner Res 1994;9(8):1137–41.
28. Conference Report. Consensus Development Con- ference: diagnosis, prophylaxsis, and treatment of osteoporosis. Am J Med 1993;94:646–50.
29. World Health Organization. Assessment of fracture risk and its application to screening for post- menopusal osteoporosis. Technical Report Series. Geneva: WHO; 1994.
30. Parfitt AM. Trabecular bone architecture in the pathogenesis and prevention of fracture. Am J Med 1987;82:68–72.
31. Eriksen EF. Normal and pathological remodeling of human trabecular bone: threee dimensional reconstruction of the remodeling sequence in normal and in metabolic disease. Endocr Rev 1986;7:379–408.
32. Kribbs PJ, Smith DE, Chesnut CH. Oral findings in osteoporosis. Part II. Relationship between residual ridge and alveolar bone resorption and generalized skeletal osteopenia. J Prosthet Dent 1983;50:719–24.
33. Kribbs PJ, Chesnut CH, Ott SM, Kilcyne RF. Rela- tionships between mandibular and skeletal bone in a population of normal women. J Prosthet Dent 1990;63:86–9.
34. Kribbs PJ, Chesnut CH. Relationships between mandibular and skeletal bone in an osteoporot- ic population. J Prosthet Dent 1989;62:703–7.
35. Kribbs PJ. Comparison of mandibular bone in nor- mal and osteoporotic women. J Prosthet Dent 1990;63:218–22.
36. von Wowern N, Klausen B, Kollerup G. Osteo-
Osteopenia, Osteoporosis, and Oral Disease 181
porosis: a risk factor in periodontal disease. J Periodontol 1994;65:1134–8.
37. Jeffcoat MK, Reddy MS, Magnusson I, et al. Effi- cacy of quantitative digital subtraction radiogra- phy using radiographs exposed in a multicenter trial. J Periodontal Res 1996;31:157–60.
38. Jeffcoat MK, Reddy MS. Alveolar bone loss and osteoporosis: evidence for a common mode of therapy using the bisphonate alendronate. In: Davidovitch Z, editor. The biologic mechanism of tooth resorption and replacement by implants. Boston: Harvard Society for the Advancement of Orthodontics; 1996.
39. Jeffcoat MK, Lewis CE, Reddy MS, et al. Post- menopausal bone loss and its relationship to oral bone loss. Periodontol 2000. [In press]
40. Daniell HW. Postmenopausal tooth loss. Contribu- tions to edentulism by osteoporosis and cigarette smoking. Arch Intern Med 1983;143:1678–82.
41. Taguchi A, Tanimoto K, Suei Y et al. Tooth loss and mandibular osteopenia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79: 127–32.
42. Krall EA, Dawson-Hughes B, Papas A, et al. Tooth loss and skeletal bone density in healthy post- menopausal women. Osteoporosis Int 1994;4: 104–9.
43. Krall EA, Garcia RI, Dawson-Hughes B. Increased risk of tooth loss is related to bone loss at the whole body, hip, and spine. Calcif Tissue Int 1996;59:433–7.
44. Hirai T, Ishijima T, Hashikawa Y, et al. Osteoporo- sis and reduction of residual ridge in edentolous patients. J Prosthet Dent 1993;69:49–56.
45. Wactawski-Wende J, Grossi SG, Trevisan M, et al. The role of osteopenia in periodontal disease. J Periodontol 1996;67:1076–84.
46. Grossi SG, Nishida M, Wactawski-Wende J, et al. Skeletal osteopenia increases the risk for peri- odontal disease. J Dent Res 1998;77:Abstract #2140.
47. Kanis JA, McCloskey. Risk factors in osteoporosis. Maturitas 1998;30(3):229–33.
48. Ross PD. Risk factors for osteoporotic fracture. Endocrinol Metab Clin North Am 1998;27(2): 289–301.
49. Cumming SR. Treatable and untreatable risk fac- tors for hip fracture. Bone 1996;18(3 Suppl): 165S–167S.
50. Kornman KS, Crane A, Wang H-Y, et al. The inter- leukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997; 24:72–7.
51. Grossi SG, Zambon JJ, Ho AW, et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994;65:260–7.
52. Tezal M, Grossi SG, Ho AW, Genco RJ. The effcet
of alcohol consumption on periodontal disease. J Periodontol 1999. [In Press]
53. Genco RJ, Ho AW, Kopman J, et al. Models to evaluate the role of stress in periodontal disease. Ann Periodontol 1998;3(1):288–302.
54. Nishida M, Grossi SG, Dunford RG, et al. Nutrition and risk for periodontal disease. I. Dietary and serum calcium. J Periodontol 1999. [In Press]
55. Nishida M, Grossi SG, Dunford RG, et al. Nutri- tion and risk for periodontal disease. II .Dietary vitamin C. J Periodontol 1999. [In Press]
56. Utian WH. Biosynthesis and physiologic effects of estrogen and pathophysiologic effects of estro- gen deficiency: a review. Am J Obstet Gynecol 1989;161:1828–31.
57. Lindsay R, Aitken J, Anderson J. Long term pre- vention of postmenopausal osteoporosis by estrogen. Lancet 1976;1:1038–41.
58. Horsman A, Jones M, Francis R. The effect of estrogen dose on postmenopausal bone loss. N Engl J Med 1983;309:1404–7.
59. Pacifici R, Brown C, Puscheck E, et al. Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci U S A 1991;88: 5134–8.
60. Cohen-Solal ME, Graulet AM, Denne MA, et al. Peripheral monocyte culture supernatants of menopausal women can induce bone resorption: involvement of cytokines. J Clin Endocrinol Metab 1993;77:1648–53.
61. Horowitz MC. Cytokines and estrogen in bone: anti- osteoporotic effects. Science 1993;260:626–7.
62. Norderyd OM, Grossi SG, Machtei EE, et al. Periodontal status of women taking post- menopausal estrogen supplementation. J Perio- dontol 1993;64:957–62.
63. Jacobs R, Ghyselen J, Koninckx P, van Steenberghe D. Long term bone mass evaluation of mandible and lumbar spine in a group of women receiving hormone replacement therapy. Eur J Oral Sci 1996;104:10–6.
64. Payne JB, Zachs NR, Reinhardt RA, et al. The association between estrogen status and alveolar bone density changes in postmenopausal women with a history of periodontitis. J Perio- dontol 1997;68:24–31.
65. Law MR, Hackshaw AK. A meta-analysis of ciga- rette smoking, bone mineral density and risk of hip fracture: recognition of a major effect. BMJ 1997;315:841–6.
66. Kiel DP, Zhang Y, Hannan MT, et al. The effect of smoking at different life stages on bone mineral density in elderly men and women. Osteoporo- sis Int 1996;6:240–8.
67. Krall EA, Dawson-Hughes B. Smoking increases
182 Periodontal Medicine
bone loss and decreases intestinal calcium absorp- tion. J Bone Miner Res 1999;14(2):215–20.
68. Papapanou PN. Periodontal diseases; epidemiolo- gy. Ann Periodontol 1996;1:1–36.
69. Grossi, SG, Genco RJ, Machtei EE, et al. Assess- ment of risk for periodontal disease. II. Risk indicators for alveolar bone loss. J Periodontol 1995;66:23–9.
70. El-Ghorab N, Grossi SG, Dunford R, et al. Effect of smoking and estrogen supplementation on interproximal alveolar bone loss in women. J Dent Res 1996;75:Abstract 244.
71. Ferreira C, Grossi SG, Ho AW, et al. Tooth loss in women: relationship to estrogen supplementation and smoking. J Dent Res 1996:75:Abstract 245.
72. Eisman JA. Genetics, calcium intake and osteo- porosis. Proc Nutr Soc 1998;57(2):187–93.
73. Faine MP. Dietary factors related to preservation of oral and skeletal bone mass in women. J Pros- thet Dent 1995;73(1):65–72.
74. National Institutes of Health. Consensus Develop- ment Conference. JAMA 1984;252:799–802.
75. Fehily AM, Coles RJ, William DE, Elwood PC. Factors affecting bone density in young adults. Am J Clin Nutr 1992;56:579–86.
76. Mazess RB, Barden HS. Bone density in pre- menopausal women: effect of age, dietary intake, physical activity, smoking and birth con- trol pills. Am J Clin Nutr 1991;53:132–42.
77. Yoshida H, Nagaya T, Hayashi T, et al. Milk con- sumption decreases activity of human serum alkaline phosphatase: a cross-sectional study. Metab Clin Exp 1995;44(9):1190–3.
78. Heaney RP, Recker RR. Effects of nitrogen, phos- phorus and caffeine on calcium balance in women. J Lab Clin Med 1982;99:46–55.
79. Arjmandi BH, Birnbaum R, Goyal NV, et al. Bone sparing effect of soy protein in ovarian hor- mone-deficient rats is related to its isoflavone content. Am J Clin Nutr 1998;68(6 Suppl): 1364S–8S.
80. Pocock N, Eisman J, Mazess R. Genetic determi- nants of bone mass in adults: a twin study. J Clin Invest 1987;80:706–10.
81. Sainz J, Van Tornout JM, Loro ML, et al. Vitamin- D receptor gene polymorphisms and bone den- sity in prepubertal American girls of Mexican descent. N Engl J Med 1997;337:77–82.
82. Langdahl BL, Ralston SH, Grant SF, Erikson EF. An Sp1 binding site polymorphism in the COLIA1 gene predicts osteoporotic fractures in both men and women. J Bone Miner Res 1998; 13(9):1384–9.
83. Hampson G, et al. Bone mineral density, collagen type 1 alpha 1 genotypes and bone turnover in
premenopausal women with diabetes mellitus. Diabetologia 1998;41(11):1314–20.
84. Yamada Y, Miyauchi A, Goto J, et al. Association of polymorphism of the transforming growth factor beta 1 gene with genetic susceptibility to osteo- porosis in postmenopausal Japanese women. J Bone Miner Res 1998;13(10);1569–76.
85. Grant SFA, Ralston SH. Genes and osteoporosis. Trends Endocrinol Metab 1997;8:232–6.
86. Wood RJ, Fleet JC. The genetics of osteoporosis: vitamin D receptor. Ann Rev Nutr 1998;18: 223–58.
87. Michalowicz BS. Genetic and heritable risk factors in periodontal disease. J Periodontol 1994;65: 479–88.
88. McGuire MK, Nunn ME. Prognosis vs. actual out- come. IV. The effectiveness of clinical parame- ters and IL-1 genotype in accurately predicting prognoses and tooth survival. J Periodontol 1999;70:49–56.
89. Krall EA, Garcia RI, Dawson-Hughes B. Increased risk of tooth loss is related to bone loss at the whole body, hip and spine. Calcif Tissue Int 1996;59:433–7.
90. Christiansen C, Christensen MS, Transbol I. Bone mass in postmenopausal women after withdraw- al of oestrogen/gestagen replacement therapy. Lancet 1981;i:459–61.
91. Ettinger B, Genant HK, Cann C. Long-term estro- gen replacement therapy prevents bone loss and fractures. Ann Intern Med 1985;102:319–24.
92. Felson DT, Zhang Y, Hannan MT, et al. The effect of postmenopausal estrogen therapy on bone density in elderly women. N Engl J Med 1993; 329:1141–46.
93. Lindsay R. Estrogens, bone mass and osteoporotic fracture. Am J Med 1991;91:10S–13S.
94. Naessen T, Persson I, Adami HO, et al. Hormone replacement therapy and the risk for first hip fracture. A prospective, population-based cohort study. Ann Intern Med 1990;113:95–103.
95. Grodstein F, Colditz G, Stampfer G. Post- menopausal homone use and tooth loss: a prospective study. J Am Dent Assoc 1996;127: 370–7.
96. Paganini-Hill A. Benefits of estrogen replacement therapy on oral health: the leisure world cohort. Arch Intern Med 1995;155:2325–9.
97. Krall E, Dawson-Hughes B, Hannan M, et al. Post- menopausal estrogen replacement and tooth retention. Am J Med 1997;102:536–42.
98. Papapoulos SE. Bisphosphonates. Pharmacology and use in the treatment of osteoporosis. In Mar- cus RE, Feldman D, Kelsey J, editors. Osteo- porosis. San Diego: Academic Press; 1996.
CHAPTER 11
HIV INFECTION AND PERIODONTAL DISEASES Michael Glick, DMD Palle Holmstrup, PhD, Dr. Odont
The human immunodeficiency virus (HIV) epi- demic is not abating. By the end of 1998, an esti- mated 34 million individuals worldwide were infected. Eleven men, women, and children, half of these aged 15 to 24 years, acquire a new infec- tion every minute. Approximately four people suc- cumb to this disease every minute. Although the death rate from HIV infection has slowed down in the United States and Western Europe due to new and improved therapies, 75,000 new infections are still recorded annually.1 This changing face of the epidemic suggests an increasing number of people living with HIV disease requiring health services. As with all chronic diseases, a multidisciplinary approach to care results in improved quality of life and decreased morbidity and mortality. This chap- ter focuses on oral lesions and conditions affecting the periodontium that are found in individuals with HIV infection and also explores the possible connection between the propagation of periodon- tal infection and the propagation of HIV infection.
As periodontal manifestations have shown to be markers for immune deterioration and HIV dis- ease progression, early recognition of these lesions and an understanding of their significance in the course of HIV disease will impact on the overall systemic care for infected individuals. New insights into the pathogenesis of HIV infection have revealed much about the fate of, as well as the immune response to, the virus. Until recently, it was generally believed that HIV was constantly replicating, notwithstanding clinical asymptomatic periods. Therapeutic interventions focused on slowing down the replication rate as well as the transcription of viral proteins. However, new research has discovered the existence of latently infected CD4+ T cells.2,3 This phenomenon poses a significant problem both for an effective immune response and for drug therapy.
The body’s natural immune system cannot detect and eliminate cells latently infected with HIV, as these cells lack the expression of viral anti- gens on the cell surface. Furthermore, as the provi- ral DNA is already integrated into the cellular genome, it cannot be targeted by existing antiretro- viral medications which inhibit the RNA reverse transcriptase of HIV. Therefore, elimination of HIV can only be accomplished by activating latent- ly infected cells in combination with potent anti- retroviral therapy. This will create a situation where latently infected cells are induced into a state of productive infection and die, while the antiretrovi- ral therapy prevents infectious viruses released from these cells from infecting new cells.
Another concern for infected individuals is the state of their debilitated immune system. Thus, in concert with targeting infected cells, immune reconstitution also needs to be addressed. The hallmark of HIV disease is the infection and sub- sequent depletion of CD4+ Tcells. After successful institution of antiretroviral therapy, a sharp rise of CD4+ T cells can be noticed.4 However, this increase apparently occurs as a result of the redis- tribution of memory cells. These T cells are severe- ly limited in their ability to recognize different antigens. The appearance of naïve CD4+ T cells, with specificities that had previously been lost, may occur only after several months. Thus, the immunologic repertoire during the course of HIV disease predisposes to increased susceptibility to opportunistic infections. The level of immune deterioration or reconstitution determines the individual’s susceptibility to specific infections. The influence of periodontal infection on the pathogenesis of HIV disease has not been elucidat- ed. However, the immune system weakened by HIV may have a direct influence on the pathogen- esis of periodontal disease.
184 Periodontal Medicine
Individuals infected with HIV exhibit oral conditions and lesions often associated with immune suppression.5 These oral manifestations may reflect systemic conditions or could compli- cate systemic disease. Among HIV-infected indi- viduals, no oral lesions are found that are directly caused by HIV. Instead, lesions are mostly associ- ated with immune suppression and opportunistic pathogens and can therefore be found among other immunosuppressed individuals as well. For a lesion to be classified as “HIV-associated,” the lesion needs to be more common or exhibit a different clinical course and appearance than those in indi- viduals not infected with HIV.
A multitude of lesions that affect the perio- dontium have been described. Moreover, aggres- sive periodontal lesions may be the first clinical expression of the HIV infection.5–11 Bacterial, viral, fungal, or parasitic infections can all affect the course of HIV disease as well as take on differ- ent clinical manifestations and severity or require different treatment modalities than in non-HIV- infected individuals. Due to the impaired immune system characteristic of HIV disease, infections often present a more serious course compared with immunocompetent individuals. This is also found with infections of the periodontal tissues. Com- parative studies attempting to assess the association of periodontal disease entities with HIV infection are often limited by several factors. They include the lack of specific diagnostic criteria, the use of various HIV treatment regimens, and lack of infor- mation on the immune status of the HIV-infected individual. An additional problem is biased study populations, frequently selected on the basis of institutional affiliation. This means that usually the groups of HIV-infected subjects under investi- gation are more seriously affected by HIV disease than the entire group of HIV-infected individuals.
TERMINOLOGY
A wide spectrum of terms have been used to describe soft and hard tissue inflammatory and/or destructive conditions of the periodontium, pre- sumably associated with HIV infection.12–14 An internationally accepted classification of the oral manifestations of HIV infection and their diag- nostic criteria has been established by the EC- Clearinghouse on Oral Problems Related to HIV Infection and the WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus (EC-WHO) at a meeting in 1993.15
The classification includes three groups of lesions (Table 11–1): (1) lesions strongly associat- ed with HIV infection, (2) lesions less commonly associated with HIV infection, and (3) lesions seen in HIV infection.15 Most characteristic among the lesions listed in the latter category are the types of infection which are extremely rare in noninfected individuals. These include Histoplasma capsulatum and fungal infections other than candidiasis. Although a number of these diseases may affect the periodontal tissues, they are outside the scope of the present chapter. However, conventional forms of periodontal diseases affect HIV-infected indi- viduals but may differ in their clinical course. This aspect will be discussed below in the section “lesions seen in HIV infection.”
LESIONS STRONGLY ASSOCIATED WITH HIV INFECTION
Three periodontal disease entities can be consid- ered to be strongly associated with HIV infection. These are linear gingival erythema (LGE), necro- tizing gingivitis (NG) or necrotizing ulcerative gin- givitis (NUG), and necrotizing periodontitis (NP) or necrotizing ulcerative periodontitis (NUP).15 It is important to note that similar lesions may occur in non-HIV-infected individuals16–18 even with similar prevalence.19–23 Consequently, although the initial descriptions of these lesions referred to them as HIV-associated gingivitis and HIV-associ- ated periodontitis, the more descriptive terminolo- gy of the lesions is used today. In the list of lesions strongly associated with HIV (Table 11–1), a few supplementary disease entities that may also affect the periodontium are included. These entities are candidiasis, Kaposi’s sarcoma, and non-Hodgkin’s lymphoma.
Linear Gingival Erythema
Diagnosis and Clinical Presentation Linear gingival erythema presents as a fiery red band of the marginal gingiva, characterized by a disproportional inflammatory intensity in relation to the amount of plaque present. There are no ulcerations and no evidence of pocketing or attach- ment loss. A further characteristic of this type of lesion is its lack of response to improved oral hygiene and to scaling.15
The first description of LGE included a dis- tinctive erythema of the free gingiva, attached gin- giva, and alveolar mucosa in individuals with HIV
HIV Infection and Periodontal Diseases 185
TABLE 11–1. Revised Classification of Oral Lesions Associated with HIV Infection
Group 1: Lesions strongly associated with HIV infection Candidiasis
Erythematous Pseudomembranous
Hairy leukoplakia Kaposi’s sarcoma Non-Hodgkin’s lymphoma Periodontal disease
Linear gingival erythema Necrotizing (ulcerative) gingivitis Necrotizing (ulcerative) periodontitis
Group 2: Lesions less commonly associated with HIV infection Bacterial infections
Mycobacterium avium-intracellulare Mycobacterium tuberculosis
Melanotic hyperpigmentation Necrotizing (ulcerative) stomatitis Salivary gland disease
Dry mouth due to decreased salivary flow rate Unilateral or bilateral swelling of major salivary glands
Thrombocytopenic purpura Ulceration NOS (not otherwise specified) Viral infections
Herpes simplex virus Human papillomavirus (warty-like lesions)
Condyloma acuminatum Focal epithelial hyperplasia Verruca vulgaris
Varicella-zoster virus Herpes zoster Varicella
Group 3: Lesions seen in HIV infection Bacterial infections
Actinomyces israelii Escherichia coli Klebsiella pneumoniae
Cat-scratch disease Drug reactions (ulcerative, erythema, multiforme, lichenoid, toxic epidermolysis) Epithelioid (bacillary) angiomatosis Fungal infection other than candidiasis
Cryptococcus neoformans Geotrichum candidum Histoplasma capsulatum Mucoraceae (Mucormycosis/zygomycosis) Asperigillus flavus
Neurologic disturbances Facial palsy Trigeminal neuralgia
Recurrent aphthous stomatitis Viral infections
Cytomegalovirus Molluscum contagiosum
With permission from EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus. Classification and diagnostic criteria for oral lesions in HIV infection. J Oral Pathol Med 1993;22:289–91.
186 Periodontal Medicine
disease.24 Free gingival erythema, appearing as an intense linear band extending 2 to 3 mm apically from the free gingival margin was seen in more than 50% of cases. Punctate or diffuse erythema of the attached gingiva was another prominent fea- ture. The lesions were associated with pain in some instances and most frequently involved the entire mouth with an equal distribution to all quadrants. Sometimes they were limited to one or two teeth, and the changes were present even with little or no plaque accumulations. The extent of gingival banding measured by the number of affected sites was later suggested to depend on tobacco usage.25
While 15% of affected sites were originally report- ed to bleed on probing and 11% exhibited sponta- neous bleeding,24 a key feature of linear gingival erythema is now considered to be lack of bleeding on probing.14
Prevalence A few studies of unbiased groups of patients have indicated that gingivitis with bank-shaped or punctate marginal erythema may be relatively rare in HIV-infected patients and probably represents a clinical finding which is not more frequent than in the general population.20,21 Other studies of various groups of HIV-infected patients have revealed the prevalence of gingivitis with band- shaped patterns in 0.5 to 49%.25–29 These preva- lence values reflect some of the problems with non-standardized diagnosis and selection of study groups as mentioned above. There is no doubt that several studies comprise cohorts of patients with poor oral hygiene,26,27 and the degree to which the reported inflammatory processes respond to con- ventional therapy is currently unknown. A prepon- derance of HIV-associated red banding was not noted in a recent British study, while diffuse and punctate erythema was significantly more preva- lent in HIV-infected than in non-HIV-infected individuals.23 Red gingival banding as a clinical feature alone is, therefore, not strongly associated with HIV infection.
While several studies are available on HIV- infected adults, few reports describe HIV-related diseases among children. In two studies, however, as many as 30% and 37%, respectively, were diag- nosed with so-called HIV-gingivitis, which is syn- onymous with LGE.30,31
Etiology and Pathogenesis There are suggestions that candidal infection is the etiologic agent in some cases of gingival inflammation, including LGE.23,24,32 However,
some studies have revealed microflora comprising both Candida albicans and a number of perio- dontopathic bacteria consistent with those seen in conventional periodontitis, that is, Porphyromonas gingivalis, Prevotella intermedia, Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum, and Campylobacter rectus.33,34 Studies using DNA probes have suggested the percentage of A. actino- mycetemcomitans-positive sites in HIV-associated gingivitis and matched gingivitis sites of HIV- seronegative patients to be 23% and 7%, respec- tively. Furthermore, positive sites were 52% and 17% for P. gingivalis, 63% and 29% for P. inter- media, and 50% and 14% for C. rectus, respec- tively.33,34 C. albicans has been isolated by culture in about 50% of HIV-associated gingivitis sites, in 26% of unaffected sites of HIV-seropositive patients, and in 3% of healthy sites of HIV- seronegative patients. The frequent isolation and the pathogenic role of C. albicans may be related to the high levels of the yeast in the saliva and oral mucosa of HIV-infected patients.35
The significance of CD4+ T cell depletion in the pathogenesis of LGE is uncertain. A study of 25 patients with so-called HIV-associated gingivi- tis showed CD4/CD8 ratios within the low nor- mal range.24 In another study of the red banding of the gingiva, it was concluded that the condition was not related to immunosuppression, as equal number of cases had CD4+ T cell counts above and below 400/mm3.19 A similar result has been obtained by others.25 However, a more recent study comprising 396 HIV-seropositive individu- als classified according to their peripheral CD4+ lymphocyte counts revealed linear gingival erythe- ma in 2 patients with less than 200 CD4 cells/mm3 as opposed to none among patients with 200 CD4 cells/mm3 or more.6
An interesting histopathologic finding in biop- sy specimens from the banding zone has revealed no inflammatory infiltrate but an increased number of blood vessels, which explains the red color of the lesions.36 The incomplete inflammatory reaction of the host tissue may be the cause of the lack of response to conventional treatment.
Differential Diagnosis A number of diseases present clinical features resembling those described above and which, accordingly, do not resolve after improved oral hygiene and débridement. Oral lichen planus is frequently associated with a similar inflammatory red band of the attached gingiva,37 and mucous membrane pemphigoid may also have this appear-
HIV Infection and Periodontal Diseases 187
ance.38 Geotrichum candidum infection39 and hypersensitivity reactions manifesting as plasma cell gingivitis40 are other rare differential diagnoses. In rare instances, gingivitis-like changes may also be the result of thrombocytopenia.41
Treatment Important characteristics of the originally described entity of LGE included a temporal lack of response to plaque removal and an erythematous appear- ance disproportional to the amount of plaque. Reports of different therapeutic results may be due to the varied definition of LGE. Conventional therapy with 0.12% chlorhexidine gluconate mouth rinses twice daily has been reported to show significant improvement after 3 months.42 Howev- er, HIV-associated free gingival erythema did not respond to removal of plaque by intense scaling and root planing and improved plaque control measures, alone or supplemented with povidone- iodine irrigation 3 to 5 times daily. There was no significant improvement in clinical features or indices after 1 and 3 months of treatment. Howev- er, the povidone-iodine irrigation substantially reduced pain reported to be associated with the lesions examined.11
As mentioned above, LGE may in some cases be related to the presence of C. albicans. In accor- dance with this finding, clinical observations indi- cate that improvement is frequently dependent on successful eradication of intraoral C. albicans, which results in the disappearance of the charac- teristic features.24 Consequently, attempts to iden- tify the presence of fungal infection either by cul- ture or smear are recommended, followed by antimycotic therapy in C. albicans-positive cases.
Necrotizing (Ulcerative) Gingivitis and Periodontitis
Diagnosis and Clinical Presentation The necrotizing (ulcerative) diseases NG, NP, and necrotizing stomatis (NS) are the most severe perio- dontal disorders, presumably caused by bacteria. These entities may represent various stages of sim- ilar disease process.43 The distinction between NG and periodontitis is parallel to the distinction between gingivitis and periodontitis. Thus, NG should be limited to lesions only involving gingi- val tissue with no loss of periodontal attach- ment.29 In most patients, however, the disease process rapidly results in loss of attachment, in which case NP is the correct terminology. Previ- ously, progression of the disease process across the
mucogingival junction would have qualified for the diagnosis of NS,41 but the description of NP as proposed by EC-WHO incorporates tissue destruction extending across the mucogingival border. Consequently, the differential diagnosis between NP and NS is not always clear, as NS is sometimes described as extending from areas of NP.15 Necrotizing stomatitis is mentioned below in the section on “lesions less commonly associat- ed with HIV infection.”
There is considerable variation in the clinical manifestations ranging from initial lesions with necrosis limited to the top of the interdental papil- lae, to moderate manifestations with involvement of the entire attached gingiva with tooth mobility and sequestration of parts of the crestal bone, to severe cases with extensive bone loss and necrosis of supporting tissues. Fetor oris evolves in most cases as a characteristic feature.
The initial lesion typically presents with changes in gingival contour, such as interproximal necrosis, ulceration, and cratering. The most dis- tinguishing feature is soft tissue necrosis and the rapid destruction of periodontal attachment and bone. Severe cases can affect all teeth, but more fre- quently, several localized areas are affected inde- pendently, and all regions appear to have similar chances of being affected. The lesions are not always associated with deep pocket formation, as extensive gingival necrosis often coincides with loss of crestal alveolar bone. On the other hand, the rapid progression of the soft tissue necrosis some- times leads to the exposure of the alveolar bone, which becomes sequestrated and leaves deep inter- dental craters.23 Frequently, such defects are locat- ed in the molar/premolar region.
Severe pain has been mentioned as a distin- guishing feature of HIV-associated periodonti- tis15,23,41,44 and the chief reason for patients seeking treatment. Bleeding on probing is a prominent fea- ture, and about 50% of involved sites bleed spon- taneously.23 The number of sites affected by papil- lary destruction have been shown to be significant- ly determined by tobacco usage.25 About 85% of individuals with HIV-associated periodontitis lesions have been described to be aware of their serostatus at their initial visit.23
Prevalence Meaningful comparisons of prevalence data among the available studies remain unavailable because of the diversity in the study methods and diagnostic criteria and the variance in groups under investigation. One major problem is the
188 Periodontal Medicine
lack of a clear distinction between NG and NP in the majority of the literature. However, even tak- ing these limitations into account, studies show that NG is more common among HIV-seroposi- tive individuals than in the general population. The prevalence in these studies ranges from 5 to 11%.8,19,27,45–47 In contrast, other more recent studies have either found low prevalence (0 to 0.7%)23,29.48 or no significant difference between cohorts of HIV-seropositive and HIV-negative patients.22 The anterior gingiva is most common- ly affected,44 which agrees with NG in HIV- seronegative patients.49 Gingival ulceration may affect individual teeth or extend to several areas of the jaws.8
Necrotizing periodontitis has been described in 88% among 136 HIV-infected patients.28 However, most studies have shown considerably lower preva- lence values of NP among HIV-infected individuals, such as 6.3% of 700 HIV-seropositive patients50
and in 1% of 200 HIV-seropositive patients.29 Yet, other studies have suggested that HIV-associated periodontitis with ulceration and tissue necrosis may be relatively rare and that the prevalence may, in fact, not differ significantly from that of similar lesions of the general population.17–21
Etiology and Pathogenesis Established knowledge of the pathogenic back- ground of tissue necrosis in NG and NP is limited. One of the most interesting questions is whether less pathogenic organisms can cause tissue necrosis in HIV-infected as compared with non-HIV-infected individuals. Data on the microflora associated with necrotic periodontal lesions are unfortunately com- promised by frequent lack of precise description of the sites from which the microbiologic samples were obtained. There is no doubt that many samples are obtained from deep pockets, and consequently, the findings may not be directly related to tissue necro- sis. No clear distinction can therefore be drawn between NP and other forms of HIV-associated periodontitis in the description of the microbiolog- ic profile. A further complication is that the avail- able information on the microbiology of HIV-asso- ciated NG is very limited. The isolated organisms include Borrelia, gram-positive cocci, b-hemolytic streptococci, and C. albicans.8
The occurrence of P. gingivalis, spirochetes, and motile eubacteria in periodonitis has been found to be the same in HIV-infected patients and in systemically healthy adults.51 Also, the microflo- ra isolated from HIV-associated periodontitis was similar to that of classic adult periodontitis, except
that P. gingivalis was more prevalent in conven- tional periodontitis.33,34,52 Greater numbers of P. gingivalis have been revealed in samples from non-HIV-infected subjects with healthy periodon- tium than in samples from HIV-associated perio- dontitis.51 Other findings have indicated that sub- gingival plaque in acquired immunodeficiency syndrome (AIDS) patients with periodontitis can harbor high proportions of the same periodontal pathogens as are associated with periodontitis in non-HIV-infected individuals, but additional high proportions of other opportunistic pathogens like Clostridium, Enterococcus, and C. albicans.52 The suggestion that the predominant subgingival microflora in HIV-associated periodontitis is in many ways similar to that of progressing periodon- titis lesions in systemically healthy adults has been supported by others.53 On the other hand, this investigation of HIV-associated periodontitis lesions also revealed organisms rarely associated with common types of periodontitis. Higher pro- portions of C. albicans and C. rectus were charac- teristic of HIV-associated periodontitis, the quali- tative profiles of HIV-associated gingivitis and HIV-associated periodontitis being similar and only C. rectus showing major quantitative differ- ences. None of the available studies answer the important question whether other pathogens cause tissue breakdown in HIV-associated disease unlike in non-HIV associated disease. Necrotizing gin- givitis has been associated with peripheral CD4+ lymphocyte depletion in a few studies.6,47 Howev- er, the disease has also been found to be unrelated to immunosuppression, with equal numbers of patients having CD4+ T cell counts above and below 400/mm3.19
The severity of periodontal destruction has been associated with the progression of HIV dis- ease in several studies.20,21,24,25,28,50,54–56 The cause mentioned in these studies is that the progressive depletion of immune effector and regulatory cells in HIV-seropositive patients compromises the local host defense to such an extent that the sus- ceptibility to periodontal disease increases. One study even suggested that NP was a stronger pre- dicator of HIV disease progression and immune suppression than established AIDS defining ill- nesses.50 A temporal relationship between NP and poor survival was also suggested, where almost 60% of patients with NP died within 18 months of the periodontal diagnosis. However, other stud- ies have indicated that the association between HIV-related immune depletion and periodontal destruction is less strong.57–59
HIV Infection and Periodontal Diseases 189
Differential Diagnosis A number of oral mucosal diseases can be con- fused with NG and NP. These include bullous lesions of benign mucous membrane pemphigoid and erythema multiforme exudativum, but the progressive nature and the localized occurrence of NG and NP usually distinguish these diseases from bullous mucosal diseases. Acute forms of leukemia may be associated with necrotizing gin- gival ulcers of the oral mucosa, which sometimes manifest in the marginal gingiva.17,18 The gingi- val lesions are often bluish red and edematous. Medical examination will reveal the cause in sus- pect cases. Since serologic/hematologic examina- tion usually is necessary for patients unaware of a possible HIV infection or another cause of the necrotizing periodontal disease, a possible sup- plementary blood examination to look for leukemia is justifiable.
Treatment The treatment aspects of NG and NP are similar. In HIV-infected patients, the diseases do not rou- tinely respond to conventional treatment with scal- ing and improved oral hygiene.24 However, the adjunctive use of metronidazole in these patients is reported to be extremely effective in reducing acute pain and promoting rapid healing.50,60 Due to the susceptibility of HIV-infected patients to candidal infections,61 simultaneous treatment with appro- priate antimycotic agents may be necessary. Although it has been postulated that healing is delayed in HIV-infected patients and pain may be prolonged,8 other studies did not reveal increased incidence of delayed healing after extraction or other complications even in severely immunocom- promised individuals. Therefore, prophylactic antimicrobials were not recommended.62,63 Fre- quent use of antibiotics may give rise to problems due to microbial resistance; hence a restrictive atti- tude is important.
Follow-up care for HIV-associated necrotizing periodontal diseases is essential to ensure success in treatment. Inadequate plaque control in sites affected by NP is often associated with delayed healing and continued rapid destruction.11 In many cases, extensive tissue destruction results in residual defects, which may make it very difficult for the patient to maintain oral hygiene. Oral hygiene in these areas often requires the use of interproximal devices and soft, smaller brushes. Antibiotic prophylaxis may not be necessary in relation to scaling, since bacteria were recovered from venipuncture 15 minutes after scaling but
were not detectable in samples obtained at 30 min- utes.64 Removal of sequestra does not always appear to require antibiotic coverage.65
LESIONS LESS COMMONLY ASSOCIATED WITH HIV INFECTION
A number of lesions less commonly associated with HIV infection may affect the periodontal tissues. Necrotizing stomatitis is among the most serious, but other important diseases are lesions caused by herpes simplex virus, human papilloma virus, and varicella-zoster virus. These lesions, however, are not included in this chapter.
Necrotizing Stomatitis
Necrotizing stomatitis (NS) is defined as a local- ized, acutely painful ulceronecrotic lesion of the oral mucosa, exposing underlying bone or pene- trating or extending into contiguous tissues. The lesions may extend from areas of NP.15
Diagnosis and Clinical Presentation The clinical aspects of NS resemble those of NG and NP. Necrotizing stomatitis is the most severe and is not as common as NG and NP.5 The exten- sively destructive lesions are rapidly progressive, ulcerative, and necrotizing. In most cases, the lesions extend from the gingiva into the adjacent mucosa and bone, causing destruction of both oral soft tissues and underlying bone. The disease appears to be related to the immune depletion caused by HIV infection.66 Importantly, it may be life threatening,67 and the clinical features of NS resemble noma as described by Tempest.68 Progres- sion of NP to NS may result in progressive osseous destruction,69 with sequestration and/or the devel- opment of oroantral fistula and osteitis.70 The dif- ferential diagnostic and treatment aspects for NS are similar to those of NG and NP.67
LESIONS SEEN IN HIV INFECTION
Individuals infected by HIV may suffer from com- mon forms of periodontal diseases without tissue necrosis or other characteristic features of HIV infection as described above. These diseases with less dramatic clinical features include adult peri- odontitis20,21 and rapidly progressive periodonti- tis.8 The most interesting aspect of these diseases in HIV-infected populations is whether their preva-
190 Periodontal Medicine
lence figures and progression of attachment loss are similar to those encountered in non-HIV-infected individuals.
Conventional Adult Periodontitis/ Rapidly Progressive Periodontitis
Prevalence A number of studies among HIV-seropositive indi- viduals have reported high prevalence figures of severe attachment loss, but others have failed to show differences between HIV-seropositive and HIV-seronegative individuals.32 The reported prevalence figures of periodontitis among HIV- seropositive patients show considerable variation (5 to 69%), the variation being due to differences in study groups. For instance, several studies com- prise groups of patients who are selected on the basis of admission to hospitals or to the dental set- ting, but it is not possible to identify mechanisms of selection in all referred studies.
Severe periodontal destruction was revealed in 11% of 44 HIV-seropositive patients45 and pro- gressive periodontitis comparable with rapidly pro- gressive periodontitis71 was diagnosed with similar frequency among 110 HIV-seropositive patients.8
Twenty-seven percent of 200 HIV-seropositive patients had moderate or advanced adult perio- dontitis.29 In a study of 181 heterosexual men and women with AIDS, 92% of the patients being intravenous drug users, the prevalence was much higher than in other studies. The clinical features were not reported in detail, and figures for patients without tissue necrosis could not be identified. Early periodontitis was found in 24%, moderate in 23%, and advanced in 22%. Significantly increased severity of periodontitis was seen in women as compared with men.26
A number of studies have shown limited prevalence figures. Among 141 HIV-seropositive homosexual males, 5% had severe periodontitis as compared with 0.2% among 606 seronegative homosexual males. The reported prevalence was markedly lower than that reported for severe perio- dontitis in adult males in the United States. No radiographic examination was available.22 Studies based on the registration of periodontal indices have shown that loss of attachment associated with HIV infection is a relatively rare condition, at least in some cohorts of patients.20,21 One of the most recent studies revealed no significant differences in bleeding on probing, pocket formation, or attach- ment loss among HIV-seronegative and HIV- seropositive individuals and AIDS patients in Tan-
zania.52 However, when using clinical attachment loss and radiographic assessment of alveolar bone loss, definite trends are evident pointing to HIV infection being a risk indicator for progression of periodontitis.32
Etiology and Pathogenesis Reports of the microbiology of HIV-associated periodontitis do not always state whether micro- bial samples have been obtained from lesions with or without necrosis. The available microbiologic data are described above in relation to NG and NP.
The reports on the significance of HIV-related immune deterioration and loss of attachment are conflicting. However, most studies have revealed an association between progression of periodontitis and decreased number of peripheral T-helper cells. One study has shown that periodontitis in patients with more advanced stages of HIV infection was related to severity of systemic disease and to decreasing numbers of CD4+ lymphocytes but not to visible plaque index or occurrence of periodon- tal pathogenic microorganisms.54 A 20-month fol- low-up study of 114 homosexual and bisexual men showed relative attachment loss of 3 mm or more occurring 6.16 times more frequently among sub- jects with CD4+ counts < 200 compared with sub- jects with counts of 200 or more. Among individ- uals aged 35 years and over, the incidence (33%) of relative attachment loss of 3 mm or more was sig- nificantly higher in more immunosuppressed indi- viduals compared with the incidence (5%) in less immunosuppressed subjects. In 78 individuals seen at follow-up visits, mean gingival indices increased and were significantly higher in the seropositive subjects compared with the seronega- tive ones, but gingival indices were not related to CD4+ T cell counts within the seropositive group. The study suggested a greater sensitivity to plaque in the seropositive group. The authors concluded that immunosuppression, especially in combina- tion with older age, may be a risk for attachment loss, and HIV seropositivity, independent of CD4+ T cell counts, may be a risk factor for gin- gival inflammation.19 In a study of 29 HIV- seropositive patients and 27 control patients, the HIV-seropositive patients had a higher mean per- cent of sites exhibiting suppuration than the con- trol group.59 Among 312 men with HIV infection, decreased CD4 lymphocyte counts predicted the extent and severity of periodontal attachment loss but not pocketing, which was only related to HIV infection when compared with 260 men without HIV.22 In contrast, a recent report from Tanzania
HIV Infection and Periodontal Diseases 191
did not reveal any significant associations between periodontal indicies with regard to lymphocyte and CD4+ T cell counts among the HIV-infected individuals including AIDS patients.58
Treatment Since deterioration of the immune deficiency may be a risk factor for attachment loss, and HIV- seropositivity may be a risk factor for gingival inflammation, it is particularly important that HIV-infected individuals practice intensive oral hygiene and receive frequent professional preven- tive dental treatment.19 This supports the idea of providing intensive oral care programs to be initi- ated as soon as the diagnosis of HIV infection is established.
REFERENCES
1. WHO End of year annual report on HIV and AIDS. Geneva: WHO; 1998.
2. Chun TW, Stuyer L, Mizell SB, et al. Presence of inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci 1997;94:13193–7.
3. Finzi D, Hermankova M, Peirson T, et al. Identifi- cation of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997;278:1295–300.
4. Leandersson AC, Bratt G, Fredrikson M, et al. Spe- cific T-cell responses in HIV-infected patients after highly active antiretroviral therapy (HAART). Abstract 31142. Geneva: 12th World AIDS Conference; 1998.
5. Glick M, Muzyka BC, Lurie D, Salkin LM. Oral manifestations associated with HIV disease as markers for immune suppression and AIDS. Oral Surg Oral Med Oral Pathol 1994;77:344–9.
6. Ceballos-Salobrena A, Aguirre-Urizar JM, Bagan- Sebastian JV. Oral manifestations associated with human immunodeficiency virus infection in a Spanish population. J Oral Pathol Med 1996;25:523–6.
7. Ficarra G, Berson AM, Silverman S, et al. Kaposi’s sarcoma of the oral cavity: a study of 134 patients with a review of the pathogenesis, epi- demiology, clinical aspects and treatment. Oral Surg Oral Med Oral Pathol 1988;66:543–50.
8. Reichart PA, Gelderblom HR, Becker J, Kuntz A. AIDS and the oral cavity. The HIV-infection: virology, etiology, origin, immunology, precau- tions and clinical observations in 110 patients. Int J Oral Maxillofac Surg 1987;16:129–53.
9. Schiøt M, Pindborg JJ. AIDS and the oral cavity. Epidemiology and clinical oral manifestations of human immune deficiency virus infection: a review. Int J Oral Maxillofac Surg 1987;16:1–14.
10. Scully C, Laskaris G, Pindborg JJ, et al. Oral man- ifestations of HIV infection and their manage- ment. I. More common lesions. Oral Surg Oral Med Oral Pathol 1991;71:158–66.
11. Winkler JR, Robertson PB. Periodontal disease associated with HIV-infection. Oral Surg Oral Med Oral Pathol 1992;73:145–50.
12. Holmstrup P, Westergaard J. Periodontal diseases in HIV-infected patients. J Clin Periodontol 1994; 21:270–80.
13. Holmstrup P, Westergaard J. HIV infection and periodontal diseases. Periodontol 2000 1998;18: 37–46.
14. Robinson PG, Winkler JR, Palmer G, et al. The diagnosis of periodontal conditions associated with HIV infection. J Periodontol 1994;65: 236–43.
15. EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficien- cy Virus. Classification and diagnostic criteria for oral lesions in HIV infection. J Oral Pathol Med 1993;22:289–91.
16. Mealey BL. Periodontal implications: medically compromised patients. Ann Periodontol 1996; 1:256–321.
17. Glick M, Garfunkel AA. Common oral findings in two different diseases—leukemia and AIDS. Part I. Compend Contin Educ Dent 1992;13: 432–50.
18. Garfunkel AA, Glick M. Common oral findings in two different diseases—leukemia and AIDS. Part II. Compend Contin Educ Dent 1992;13: 550–62.
19. Barr C, Lopez MR, Rua-Dobles A. Periodontal changes by HIV serostatus in a cohort of homo- sexual and bisexual men. J Clin Periodontol 1992;19:794–801.
20. Drinkard CR, Decker L, Little JW, et al. Periodon- tal status of individuals in early stages of human immunodeficiency virus infection. Comm Dent Oral Epidemiol 1991;19:281–5.
21. Friedman RB, Gunsolley J, Gentry A, et al. Perio- dontal status of HIV-seropositive and AIDS patients. J Periodontol 1991;62:623–7.
22. Melnick SL, Engel D, Truelove E, et al. Oral mucosal lesions: association with the presence of antibodies to the human immunodeficiency virus. Oral Surg Oral Med Oral Pathol 1989; 68:37–43.
192 Periodontal Medicine
23. Robinson PG, Sheiham A, Challacombe SJ, Zakrzewska JM. The periodontal health of homosexual men with HIV infection: a con- trolled study. Oral Dis 1996;2:45–52.
24. Winkler JR, Grassi M, Murray PA. Clinical descrip- tion and etiology of HIV-associated periodontal disease. In: Robertson PB, Greenspan JS, edi- tors. Oral manifestations of AIDS. Proceedings of First International Symposium on Oral Man- ifestations of AIDS. Littleton: PSG Publishing Company; 1988. p.49.
25. Swango PA, Kleinman DV, Konzelman JL. HIV and periodontal health. A study of military per- sonnel with HIV. J Am Dent Assoc 1991;122: 49–54.
26. Klein RS, Quart AM, Small CB. Periodontal disease in heterosexuals with acquired immuno-deficiency syndrome. J Periodontol 1990;62:535–40.
27. Laskaris G, Hadjivassiliou M, Stratigos J. Oral signs and symptoms in 160 Greek HIV-infected patients. J Oral Pathol Med 1992;21:120–3.
28. Masouredis CM, Katz MH, Greenspan D, et al. Prevalence of HIV-associated periodontitis and gingivitis in HIV-infected patients attending an AIDS clinic. J Acquir Immune Defic Syndr 1992;5:479–83.
29. Riley C, London JP, Burmeister JA. Periodontal health in 200 HIV-positive patients. J Oral Pathol Med 1992;21:124–7.
30. San Martin T, Jandinski JJ, Palumbo P. Periodontal diseases in children infected with HIV [abstract]. J Dent Res 1992;71:366A.
31. Schoen D, Murray P, Jandinski J. Periodontal sta- tus of HIV-positive children [abstract]. J Dent Res 1994;73:2003A.
32. Lamster IB, Grbic JT, Mitchell-Lewiss DA, et al. New concepts regarding the pathogenesis of periodontal disease in HIV infection. Ann Peri- odontol 1998;3:62–75.
33. Murray PA, Grassi M, Winkler JR. The microbiol- ogy of HIV-associated periodontal lesions. J Clin Periodontol 1989;16:636–42.
34. Murray PA, Winkler JR, Peros WJ, et al. DNA probe detection of periodontal pathogens in HIV-associated periodontal lesions. Oral Microbiol Immunol 1991;6:34–40.
35. Tylenda CA, Larsen J, Yeh C-K, et al. High levels of oral yeasts in early HIV-infection. J Oral Pathol Med 1989;18:520–4.
36. Glick M, Pliskin ME, Weiss RC. The clinical and histologic appearance of HIV-associated gingivi- tis. Oral Surg Oral Med Oral Pathol 1990;69: 395–8.
37. Holmstrup P, Schiøtz AW, Westergaard J. Effect of
dental plaque control on gingival lichen planus. Oral Surg Oral Med Oral Pathol 1989;69: 585–90.
38. Pindborg JJ. Atlas of diseases of the oral mucosa. 5th ed. Copenhagen: Munksgaard; 1992. p.246.
39. Heinic GS, Greenspan D, MacPhail LA, Greenspan JS. Oral Geotrichum candidum infection associ- ated with HIV-infection. A case report. Oral Surg Oral Med Oral Pathol 1992;73:726–8.
40. Serio FG, Siegel MA, Slade BE. Plasma cell gin- givitis of unusual origin. A case report. J Peri- odontol 1991;62:390–3.
41. EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Human Immun- odeficiency Virus. An update of the classifica- tion and diagnostic criteria of oral lesions in HIV-infection. J Oral Pathol Med 1991;20: 97–100.
42. Grassi M, Williams, CA, Winkler JR, Murray PA. Management of HIV-associated periodontal diseases. In: Robertson PB, Greenspan JS, edi- tors. Perspectives on oral manifestations of AIDS. Proceedings of First International Sym- posium on oral manifestations of AIDS. Little- ton: PSG Publishing Company; 1988. p.119.
43. Horning GM, Cohen ME. Necrotizing ulcerative gingivitis, periodontitis, and stomatitis: clinical staging and predisposing factors. J Periodontol 1995;66:990–8.
44. Greenspan D, Schiødt M, Greenspan J, Pindborg JJ. AIDS and the mouth. Copenhagen: Munks- gaard; 1990.
45. Porter SA, Luker J, Scully C, et al. Orofacial man- ifestations of a group of British patients infected with HIV-1. J Oral Pathol Med 1989;18:47–8.
46. Schulten EJAM, ten Kate RW, van der Waal I. Oral manifestations of HIV-infection in 75 Dutch patients. J Oral Pathol Med 1989;18:42–6.
47. Thompson SH, Charles GA, Craig DB. Correla- tion of oral disease with the Walter Reed staging scheme for HIV-1–seropositive patients. Oral Surg Oral Med Oral Pathol 1992;73:289–92.
48. Moniaci D, Greco D, Flecchia G, et al. Epidemiol- ogy, clinical features and prognostic value of HIV-1 related oral lesions. J Oral Pathol Med 1990;19:477–81.
49. Barnes GP, Bowles WF, Carter HG. Acute necro- tizing ulcerative gingivitis: a survey of 218 cases. J Periodontol 1973;44:35–42.
50. Glick M, Muzyka BC, Salkin LM, Lurie D. Necro- tizing ulcerative periodontitis: a marker for immune deterioration and a predictor of the diag- nosis of AIDS. J Periodontol 1994;65:393–7.
HIV Infection and Periodontal Diseases 193
51. Gornitsky M, Clark DC, Siboo R, et al. Clinical documentation and occurrence of putative perio- dontopathic bacteria in human immunodeficiency virus-associated periodontol disease. J Perio- dontol 1991;62:576–85.
52. Zambon JJ, Reynolds HS, Genco RJ. Studies of the subgingival microflora in patients with acquired immunodeficiency syndrome. J Periodontol 1990;61:699–704.
53. Rams TE, Andriolo M, Feik D, et al. Microbiolog- ical study of HIV-related periodontitis. J Perio- dontol 1991;62:74–81.
54. Lucht E, Heimdahl A, Nord CE. Periodontal dis- ease in HIV-infected patients in relation to lym- phocyte subsets and specific micro-organisms. J Clin Periodontol 1991;18:252–6.
55. Steigley KE, Thompson SH, McQuade MJ, et al. A comparison of T4:T8 lymphocyte ratio in the periodontal lesion of healthy and HIV-positive patients. J Periodontol 1992;63:753–6.
56. Tomar SL, Swango PA, Kleinman DV, Burt B. Loss of periodontal attachment in HIV-seropositive military personnel. J Periodontol 1995;66:421–8.
57. Martinez-Canut P, Guarinos J, Bagán JV. Peri- odontal disease in HIV seropositive patients and its relation to lymphocyte subsets. J Periodontol 1996;67:33–6.
58. Scheutz F, Matee MIN, Andsager L, et al. Is there an association between periodontal condition and HIV infection? J Clin Periodontol 1997;24: 580–7.
59. Smith GLF, Cross DL, Wray D. Comparison of periodontal disease in HIV seropositive subjects and controls. I. Clinical features. J Clin Perio- dontol 1995;22:558–68.
60. Scully C, Porter SR, Luker J. An ABC of oral health care in patients with HIV-infection. Brit Dent J 1991;171:149–50.
61. Holmstrup P, Samaranayake LP. Acute and AIDS- related oral candidoses. In: Samaranayake LP, MacFarlane TW, editors. Oral candidosis. Lon- don: Wright; 1990. p.133.
62. Robinson PG, Cooper H, Hatt J. Healing after den- tal extractions in men with HIV-infection. Oral Surg Oral Med Oral Pathol 1992;74:426–30.
63. Glick M, Abel SN, Muzyka BC, DeLorenzo M. Dental complications after dental treatment of patients with AIDS. J Am Dent Assoc 1994; 125:296–301.
64. Lucartorto FM, Franker CK, Maza J. Postscaling bacteremia in HIV-associated gingivitis and periodontitis. Oral Surg Oral Med Oral Pathol 1992;73:550–4.
65. Robinson P. The management of HIV. Brit Dent J 1991;171:287.
66. Muzyka BC, Glick M. Necrotizing stomatitis and AIDS. Gen Dent 1994;42:66–8.
67. Williams CA, Winkler JR, Grassi M, Murray PA. HIV-associated periodontitis complicated by necrotizing stomatitis. Oral Surg Oral Med Oral Pathol 1990;69:351–5.
68. Tempest MN. Cancrum oris. Br J Surg 1966;53: 949–53.
69. SanGiacomo TR, Tan PM, Loggi DG, Itkin AB. Progressive osseous destruction as a complica- tion of HIV-periodontitis. Oral Surg Oral Med Oral Pathol 1990;70:476–9.
70. Felix DH, Wray D, Smith GLF, Jones GA. Oro- antral fistula: an unusual complication of HIV- associated periodontal disease. Br Dent J 1991; 171:61–2.
71. Page RC, Altman LC, Ebersole JL, et al. Rapidly progressive periodontitis. A distinct clinical con- dition. J Periodontol 1983;54:197–209.
CHAPTER 12
PERIODONTAL DISEASE AND PERIODONTAL MANAGEMENT IN PATIENTS WITH CANCER Joel B. Epstein, DMD, MSD, FRCD(C)
PATIENTS WITH HEAD AND NECK CANCER
Radiation therapy that includes the oral cavity and salivary glands may have dramatic effects upon oral health. The acute effects of radiation therapy include mucositis, altered salivary gland function, and risk of mucosal infection. The long-term effects include alteration in the vascularity of soft tissue and bone, salivary gland damage, reduction in the cellu- larity of bone and connective tissue, and risk of increased collagen synthesis resulting in fibrosis (Figure 12–1). Cellular damage may lead to reduc- tion in cellularity of tissue, fibrosis of connective tis- sue, and vascular changes with intimal thickening, endarteritis, and thrombosis. These changes result in hypovascular, hypocellular, and hypoxic tissue.1–4
The affected bone has a reduced capacity to remod- el and may be at increased risk of infection.
The periodontium is sensitive to the effects of radiation at high doses.1–11 Blood vessels in the periodontium, periosteum, and the periodontal ligament1,3,7,8 may be affected, leading to widening of the periodontal ligament space.9–11 These changes may result in increased risk of periodontal disease and altered healing with impaired capacity of bone remodeling and repair.1,12,13 Rampant periodontal destruction may occur in the absence of good oral hygiene.12 Because of the effects of therapeutic radiation, periodontal involvement of teeth to be included in the high-dose fields must be assessed prior to radiation therapy to identify teeth that cannot be maintained for a lifetime and may require extraction prior to irradiation.14,15 It has been shown that preradiation extraction of teeth carries a lower risk of osteonecrosis than extraction of teeth following radiation therapy.16
An additional consideration in preradiation treatment planning is the finding that periodontal involvement of teeth in high-dose radiation of some sites can lead to the development of osteo- necrosis.17 Periodontal attachment loss, particular- ly on the buccal aspect of teeth in a high-dose radi- ated field, has been reported to represent a risk fac- tor for the development of osteonecrosis.18
It is important to realize that periodontal attachment loss is greater in teeth in irradiated sites;18 therefore, preradiation treatment planning should include consideration of the impact of additional attachment loss over time on the ability to retain teeth and, in particular, to maintain teeth that may serve as abutment teeth for dental pros- theses. Statistically significant increase in attach- ment loss occurs in teeth in the sites of high-dose irradiation and is reflected in increased mobility of
Figure 12–1. This photograph demonstrates exposure of bone in a patient following head and neck radiation therapy. Radiation changes are seen involving the gingival tissues extending into the floor of the mouth, and the necrotic, stained area of the bone is exposed in the molar region.
196 Periodontal Medicine
these teeth in irradiated fields.18 Also, following radiation therapy, tooth loss is greater in fields of irradiation. The increased periodontal involvement and loss of teeth in the high-dose fraction indicates a local effect on the tissue, likely due to changes in the cellularity, vascularity, and reduced healing/ remodeling potential of the periodontium.
Similarly, decreased saliva volume has been shown in patients with Sjögren’s syndrome to result in increased risk of alveolar bone loss, attachment loss, and increased distance between the cemento- enamel junction and the alveolar bone crest.19 In patients with head and neck cancer and xerostomia, the periodontal breakdown was comparable with the results reported in those with Sjögren’s syn- drome.18 However, more significant periodontal destruction was noted in the teeth within the irra- diated bone, supporting the potential for irradia- tion-induced changes in the periodontium to influ- ence progression of periodontal involvement. Of course, the progression of the periodontal condi- tion is also related to the patient’s home care.
The patient’s current periodontal status and the probability of continuing loss of periodontal attachment in general and greater attachment loss within the fields of high-dose irradiation should be considered in dental treatment planning prior to radiation therapy. A UK study found that only 11.2% of patients who reported regular dental office attendance prior to a diagnosis of oral cancer had no dental conditions that required treatment before radiation therapy.20 The provider must be knowledgeable and understand the basis of radia- tion therapy, the nature of the planned radiation treatment for each patient (radiation dose, sched- ule, and fields) and the oral/dental/periodontal sta- tus in order to develop the best preradiation treat- ment plan.21
Teeth in the high-dose radiation field that should be extracted prior to radiation therapy are those that are nonrestorable, and those with moder- ate to severe periodontal disease that makes their
long-term prognosis questionable or poor (Table 12–1). Periodontal considerations suggesting the possible need for extraction include probing depths or attachment loss of > 5 mm, moderate to advanced alveolar bone loss, or advanced recession with or without mucogingival involvement. In patients with limited past dental care, poor oral hygiene, and evi- dence of past dental/periodontal disease, more aggressive management should be considered. The recommendation for pretreatment extractions may be modified on the basis of the position of the teeth in question and should take into consideration the relative importance of individual teeth for future restoration and function, such as teeth that may serve as abutments for prostheses.
Following radiation therapy, good oral care and compliance with recommendations for oral care are improved with regular post-treatment den- tal visits for reinforcement of oral maintenance.22
Periodontal treatment following radiation therapy must be provided with knowledge of fields of irra- diation. Despite the potential for the development of osteonecrosis in high-dose volumes, if surgical intervention is considered, it has been shown that treatment including periodontal surgery is possi- ble, if necessary, and may be more easily tolerated than extraction.23
PATIENTS RECEIVING HIGH-DOSE CHEMOTHERAPY AND/OR BONE MARROW TRANSPLANT
Periodontal manifestations of leukemia occur in some patients prior to the diagnosis of leukemia. The periodontal findings may occur as early man- ifestations of disease or may develop during cancer therapy (Figures 12–2, 12–3). Patients, especially those with significant platelet dysfunction, may present with gingival bleeding. In some patients, and more commonly in those with monocytic and myelomonocytic leukemia, gingival infiltration may be seen (Figure 12–4). In patients with neu- trophil dysfunction or neutropenia, the inflamma- tory response may be blunted or not seen, leading to nonhealing gingival ulceration and poor response to tissue therapy following dental proce- dures. In patients with reduced red cell produc- tion, the oral tissues may appear pale (Figure 12–5). Thus, the presentation prior to diagnosis and during treatment of leukemia may be variable, ranging from significant oral changes that may lead to the diagnosis of leukemia to minimal findings that are not suggestive of an underlying disease.
TABLE 12–1. Considerations for Preradiation Extraction of Teeth in the High-Dose Fraction
Caries: nonrestorable teeth Active periapical disease: symptomatic teeth Moderate to advanced periodontal disease Lack of opposing teeth, compromised hygiene Partial impaction or incomplete eruption of teeth Extensive periapical lesions (not if chronic or well
localized)
Periodontal Disease and Periodontal Management in Patients with Cancer 197
Prior to medical management, oral health assessment is conducted to identify oral conditions that may become symptomatic during medical therapy, particularly those that may represent risk sites of infection. Studies have shown that oral and periodontal assessment and management reduce the risk of infection and fever associated with oral conditions.24–28 The clinical diagnosis of oral infec- tion depends upon an accurate history of oral symptoms and a thorough examination. Signs and symptoms may be minimized in neutropenic patients, with reduced erythema, swelling, and pain in sites of infection. Careful appraisal of the patient with cancer is needed, with understanding of pre-existing sites of periodontal involvement and careful evaluation that includes an assessment of tissue tenderness. While some have empirically raised concerns that periodontal probing and peri- odontal maintenance procedures may increase the risk of bacteremia in leukemic patients prior to medical management, this has not been seen in studies assessing the risk of fever or bacteremia fol- lowing such procedures.24,25,27,29 Patients may be febrile during neutropenia, and potential oral sources of infection must be carefully considered.
The patient’s underlying systemic disease and its medical management are critical factors in deter- mining the risk for infection. Oral infection is seen in approximately one-third of patients with acute leukemia or chronic leukemia in the blast phase.30
In patients receiving chemotherapy for solid tumors, 10% may develop oral infection.31,32 The complica- tions common in patients on intensive chemothera- py protocols for breast cancer (methotrexate, 5-flu- orouracil, vincristine, and prednisone) include neu- rotoxicity (65%), mucositis (21%, often associated with neutropenia), and candidiasis.32 In immuno-
compromised patients with blood dyscrasias, the frequency and severity of infection increases with the severity and duration of granulocytopenia.33–35
Fifty-four percent of adult patients with leukemia develop oral lesions during chemotherapy.34 The length of hospital stay is greater in patients who develop oral lesions, and in 25% of patients with positive blood cultures, an oral source is probable. Increased length of hospitalization and alpha- hemolytic streptococcal septicemia have been reported in patients with oral ulcerative mucositis consistent with an oral source of infection.36 Thus, the oral cavity is a site of potential systemic infection in neutropenic patients.
Figure 12–2. This figure demonstrates gingival infiltration with minimal inflammatory response and some tissue pallor in a patient with progressive chronic lymphocytic leukemia.
Figure 12–3. This figure represents gingival infiltration with soft tissue necrosis, minimal inflammatory response and some bleeding into tissues in a patient with progressing myelodysplastic syndrome, later diagnosed as chronic myel- ogenous leukemia.
Figure 12–4. This figure demonstrates gingival hyperplasia, with bleeding into the gingival margins, particularly at inter- dental papillae. This was an individual with previous diag- nosis of myelodysplastic syndrome and the gingival involve- ment was the initial finding of progression to acute myel- ogenous leukemia.
198 Periodontal Medicine
Bacteremia due to oral sources has been well doc- umented in immunosuppressed patients.25,26,30,31,34,36
Bacterial infections may arise from oral sources in one-third of patients with acute leukemia. The bac- teria implicated include periodontal flora, strepto- cocci, and staphylococci (Figure 12–6). More recently, an increase in streptococcal bacteremia has been reported in leukemic patients.34,36,37–41 The shift in the organisms identified in bacteremia may be due to use of systemic antibacterial prophylaxis with improved coverage of gram-negative organ- isms. Current antibiotic coverage may have an impact on the potential for exacerbation of pre-
existing periodontal disease. Gingivitis and peri- odontitis due to mixed bacterial infections are also common and have been reported in up to 25% of all infections in patients with acute nonlympho- cytic leukemia.26
Patients with chronic periodontal disease receiv- ing high-dose chemotherapy may develop acute exacerbations at pre-existing sites of disease during periods of neutropenia.42–45 Assessment of the peri- odontal flora during chemotherapy showed that a shift in the flora to increased gram-negative bacilli occurred in less than 50% of patients.46,47 Of these, the Pseudomonas species predominated although Klebsiella pneumoniae was also present.48 Periodon- tal disease and attachment loss was associated with recovery of staphylococci from supragingival sites but no correlation with yeast colonization was seen. In another study, the periodontal flora in leukemic patients were assessed in sites of exacerbation of periodontal disease.44 In 24 patients, exacerbations developed during neutropenia in all but 2 cases. The potential pathogens identified were Staphylococcus epidermidis, Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa in primary infection or mixed culture. The subgingival flora associated with these exacerbations were indigenous when com- pared with noncancer patients. In these patients, inflammatory signs were suppressed, making detec- tion difficult.49,50
Thus, pre-existing periodontal disease may serve as a site for the development of infection in neutropenic patients.25,47,51 An oral source of sep- ticemia was suspected in 25% of patients with acute leukemia who received dental care and scaling prior to chemotherapy, compared with 77% of patients without such dental care prior to chemotherapy.25
The primary sources were pericoronitis or pre-exist- ing periodontal infections. In a study of fever fol- lowing oral examination with and without peri- odontal probing and scaling in leukemic patients, no differences were seen in the incidence of fever or bacteremia between groups.29 Oral preventive care has been shown to not result in increased risk of bacteremia or in fever and is associated with less severe oral mucositis.24 Thus, periodontal evalua- tion and treatment may reduce the potential for septicemia from periodontal sources.
In patients who will become neutropenic, den- tal and periodontal treatment should be completed prior to chemotherapy. It is desirable to have a 2- week healing period prior to the anticipated onset of neutropenia. In patients with solid tumors treated with chemotherapy, the treatment schedules are provided in a planned series, often on a 3 to 4 week
Figure 12–5. This photograph demonstrates mild gingival hyperplasia in interdental regions and isolated areas of the gingival margins. There is tissue pallor and no evidence of hemorrhage. This patient was diagnosed with acute myel- ogenous leukemia (AML) type 4.
Figure 12–6. This patient was undergoing chemotherapy for acute myelogenous leukemia and developed an area of tenderness between the incisors. Clinically, ulceration of the interdental papillae with minimal erythematous reaction and possible extension of the ulceration along the attached gingi- val tissue is seen. A culture identified Staphylococcus bacteria in this region.
Periodontal Disease and Periodontal Management in Patients with Cancer 199
basis for a number of treatments. In patients with solid tumors, chemotherapy may result in a short- term depression in white cell counts. Typically, blood counts improve prior to the next course of chemotherapy. Dental and periodontal treatment should be provided when the white cell counts are not suppressed, which is typically 2 to 3 weeks fol- lowing a course of chemotherapy, just prior to the next dose of chemotherapy. Antibiotic coverage may be considered when the neutrophil counts are less than 500 cells/mL, if the treatment cannot be delayed until counts are higher than 1,000 cells/mL.
Empiric antibiotic therapy for management of the febrile neutropenic patient is well established. The antibiotic must be broad spectrum, bacterio- cidal, and given in appropriate dose and schedule. Metronidazole appears to be an important antimi- crobial in the management of oral infection associ- ated with fever in neutropenic patients.52 In leukemic patients, who remain febrile despite broad-spectrum antibiotics, defervescence may occur when metronidazole is added to the antibi- otic regimen.52
The use of topical agents has not yet been shown to be effective in the prevention of coloniza- tion of the oropharynx and in the prevention of oro- mucosal infections. Chlorhexidine has been shown to reduce plaque formation and disperse established plaque; the agent may assist in managing gingivitis and periodontal involvement, reduce caries risk, and may decrease oral colonization by Candida.53,54
In patients who will become neutropenic, prior to myelosuppressive chemotherapy, elimina- tion of pre-existing foci of infection is desired. The oral cavity, dentition, and periodontium must be examined thoroughly, including radiographic eval- uation, when indicated, on the basis of the find- ings of the examination. If necessary, delaying the myelosuppressive therapy should be considered in order to manage a symptomatic dental infection. If asymptomatic periapical pathosis is present, dental treatment may be completed after chemotherapy, and the patient should be covered by appropriate systemic antibiotic therapy during myelosuppres- sion.55–57 Local irritants such as calculus and rough irregular dental surfaces should be managed to reduce local tissue irritation. Dentures should be cleaned regularly, and removal of the appliance at night is recommended due to microbial coloniza- tion of the denture surface.58 In cancer patients, pretreatment oral/dental management has been shown to decrease the length of hospital stay, and to be associated with reduced oral complica- tions.58,59–61 Good oral hygiene has been reported
to reduce the risk of mucositis and not increase the risk of fever or bacteremia.24
In leukemia/bone marrow transplant (BMT) patients, reactivation of latent herpes simplex virus (HSV) infection occurs in the majority of carriers in the “absence” of viral prophylaxis.62–64 In the mouth, the lesions most commonly affect the ker- atinized mucosa of the gingiva, the palate, and the tongue, frequently beginning on the attached gin- giva as 1- to 2-mm, rounded ulcerations that can extend to form large confluent lesions (Figures 12–7, 12–8). A patient seropositive for HSV has a
Figure 12–7. This patient felt discomfort in the palatal gin- gival tissues. The clinical diagnosis was herpes simplex virus, and increasing acyclovir dose led to resolution. These lesions were confirmed as HSV on viral culture, and exfoliative cytology demonstrated the presence of HSV-like inclusions.
Figure 12–8. A patient during treatment for leukemia, with ulceration involving the gingival tissues, extending from the margin into the vestibular mucosa and bicuspid region, and an extensive ulceration with the development of exophytic mass on the lip. Culture and tissue sampling identified her- pes simplex virus, and treatment with acyclovir was associat- ed with improvement in the lesions.
200 Periodontal Medicine
high probability of viral reactivation during induc- tion chemotherapy for leukemia or during BMT.65–67 Since HSV infections in immunocom- promised patients are severe and can be associated with high morbidity and mortality, chemoprophy- laxis with acyclovir and its analogs has become standard for seropositive patients during BMT.68–72
Acyclovir-resistant HSV during prolonged treat- ment has been reported although when this occurs, increasing the dose of acyclovir or its analogs may be effective, and foscarnet is also available.62,65,72–77
Other antivirals are under development.72,76
Varicella-zoster infection is also common in immunocompromised patients, with the lesions initially confined to the dermatome distribution of the involved nerve branches. Cytomegalovirus (CMV) causes up to 20% of post-transplant deaths, and reactivation occurs in up to 70% of seroposi- tive patients.78 Cytomegalovirus can present as per- sisting oral mucosal ulcers and has been reported to cause gingival enlargement.79–82 Diagnosis requires suspicion of the potential causes of the lesion and is based on clinical findings and positive virus identification in the involved tissue.
Periodontal disease should be assessed and managed prior to medical treatment of oropharyn- geal cancer and in patients in whom neutropenia may develop during treatment. Oral and peri- odontal infection may exacerbate during cancer therapy and may result in oral pain and infection as well as systemic infection that results in morbid- ity and can lead to mortality. Pretreatment assess- ment and management and maintenance of oral hygiene have been shown to be effective in pre- venting oral and systemic complications during treatment of patients with cancer.
REFERENCES
1. Guglielmotti MB, Ubios AM, Cabrini RL. Alveo- lar wound healing after x-irradiation: a histolog- ic, radiographic and histometric study. J Oral Maxillofac Surg 1986;44:972–6.
2. Wright WE. Periodontium destruction with oncol- ogy therapy. Five case reports. J Periodontol 1987; 58:559–63.
3. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 1983; 41:351–7.
4. Marx RE, Johnson RP. Studies on the radiobiology of osteoradionecrosis and their clinical signifi- cance. Oral Surg Oral Med Oral Pathol 1987; 64:379–90.
5. Arcuri MR, Schneider RL. The physiological effects of radiotherapy on oral tissue. J Prostho- dont 1992;1:37–41.
6. Fattore D, Straus R, Bruno J. The management of periodontal disease in patients who have received radiation therapy for head and neck cancer. Spec Care Dent 1987;7:120–3.
7. Pappas GC. Bone changes in osteoradionecrosis and their clinical significance. Oral Surg Oral Med Oral Pathol 1987;64:379–90.
8. Beumer J, Curtis TZ. Radiation therapy of head and neck tumors. In: Beumer J, Curtis TA, Firtell DW, editors. Maxillofacial Rehabilita- tion. St Louis: CV Mosby, 1979. p. 43–89.
9. Fujita M, Tanimoto K, Wada T. Early radiographic changes in radiation bone injury. Oral Surg Oral Med Oral Pathol 1986;61:641–4.
10. Medak H, Burnett GW. The effect of x-ray irradi- ation on the oral tissues of the Macacus rhesus monkey. Oral Surg Oral Med Oral Pathol 1954; 7:778–86.
11. Chambers F, Ng E, Ogden H, et al. Mandibular osteomyelitis in dogs following irradiation. Oral Surg Oral Med Oral Pathol 1958;11:843–59.
12. Silverman S, Chierici G. Radiation therapy of oral carcinomas. I. Effects on oral tissues and man- agement of the periodontium. J Periodontol 1965;36:478–84.
13. Joyston-Bechal S. Prevention of dental diseases fol- lowing radiotherapy and chemotherapy. Int Dent J 1992;42:47–53.
14. Consensus Development Panel. Consensus state- ment: oral complications of cancer therapies. NCI Monogr 1990;9:3–8.
15. Sonis ST, Woods PD, White A. Pretreatment oral assessment. NCI Monogr 1990;9:37–42.
16. Epstein JB, Rea G, Wong FLW, et al. Osteonecro- sis: study of the relationship of dental extraction in patients receiving radiotherapy. Head Neck Surg 1987;10:48–54.
17. Galler C, Epstein JB, Guze KA, et al. The develop- ment of osteoradionecrosis from sites of peri- odontal disease activity: report of 3 cases. J Peri- odontol 1992;63:310–6.
18. Epstein JB, Lunn R, Le N, Stevenson-Moore P. Periodontal attachment loss in patients follow- ing head and neck radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86(6): 673–7.
19. Najera MP, Al-Hashimi I, Plemons JM, et al. Prevalence of periodontal disease in patients with Sjögren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83: 453–7.
Periodontal Disease and Periodontal Management in Patients with Cancer 201
20. Lizi EC. A case for a dental surgeon at regional radiotherapy centres. Brit Dent J 1992;173: 24–6.
21. Stevenson-Moore P. Essential aspects of a pretreat- ment oral examination. NCI Monogr 1990;9: 33–6.
22. Epstein JB, van der Meij EH, Lunn R, et al. Effects of compliance with fluoride gel application on caries and caries risk in patients after radiation therapy for head and neck cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:268–75.
23. Epstein JB, Corbett T, Galler C, Stevenson-Moore P. Surgical periodontal treatment in radiothera- py-treated head and neck cancer patient. Spec Care Dent 1994;14:182–7.
24. Borowski B, Benhamou E, Pico JL, et al. Preven- tion of oral mucositis in patients treated with high-dose chemotherapy and bone marrow transplantation: a randomised controlled trial comparing two protocols of dental care. Europ J Cancer, Oral Oncol 1994;30(B):93–7.
25. Greenberg MA, Cohen SG, McKitrick JC, Cas- sileth PA. The oral flora as a source of sep- ticemia in patients with acute leukemia. Oral Surg Oral Med Oral Pathol 1982;53:32–6.
26. Overholser CD, Peterson DE, Williams LT, Schimpff SC. Periodontal infection in patients with acute nonlymphocytic leukemia: preva- lence of acute exacerbations. Arch Intern Med 1982;142:551–4.
27. Peterson DE, Overholser CD, Schimpff SC, et al. Relationship of intensive oral hygiene to sys- temic complications in acute nonlymphocytic leukemia. Proc Am Fed Clin Res 1981;29:440A.
28. Levy-Polack MP, Sebelli P, Polack NL. Incidence of oral complications and application of a preven- tive protocol in children with acute leukemia. Spec Care Dent 1998;18:189–93.
29. Weikel DS, Peterson DE, Rubinstein LE, et al. Incidence of fever following invasive oral inter- ventions in the myelosuppressed cancer patient. Cancer Nurs 1989;12:265–70.
30. Dreizen S, McCredie KB, Keating MJ, Bodey GP. Oral infections associated with chemotherapy in adults with acute leukemia. Postgrad Med 1982; 71:133–46.
31. Dreizen S, Bodey GP, Valdivieso M. Chemothera- py-associated oral infections in adults with solid tumors. Oral Surg Oral Med Oral Pathol 1983; 55:113–20.
32. McCarthy GM, Skillings JR. Orofacial complica- tions of chemotherapy for breast cancer. Oral Surg Oral Med Oral Pathol 1992;74:172–8.
33. Dreizen S, McCredie KB, Bodey GP, Keating MJ. Quantitative analysis of the oral complications of antileukemia chemotherapy. Oral Surg Oral Med Oral Pathol 1986;62:650–3.
34. Epstein JB, Gangbar SJ. Oral mucosal lesions in patients undergoing treatment for leukemia. J Oral Med 1987;43:132–7.
35. Navari RM, Buckner CD, Clift RA, et al. Prophy- laxis of infection in patients with aplastic ane- mia receiving allogeneic marrow transplants. Am J Med 1984;76:564–72.
36. Ruescher TJ, Sodeifi A, Scrivani SJ, et al. The impact of mucositis on alpha-hemolytic strepto- coccal infection in patients undergoing autolo- gous bone marrow transplantation for hemato- logic malignancies. Cancer 1998;82:2275–81.
37. Donnelly JP. Bacterial complications of transplan- tation: diagnosis and treatment. J Antimicrob Chemother 1995;36(B):59–72.
38. Donnelly JP, Muus P, Horrevorts AM, et al. Failure of clindamycin to influence the course of severe oromucositis associated with streptococcal bac- teraemia in allogeneic bone marrow transplant recipients. Scand J Infect Dis 1993;25:43–50.
39. Donnelly JP, Muus P, Schattenberg A, et al. A scheme for daily monitoring of oral mucositis in allogeneic BMT recipients. Bone Marrow Transplant 1992;9:409–13.
40. Mossad SB, Longworth DL, Goormastic M, et al. Early infectious complications in autologous bone marrow transplantation: a review of 219 patients. Bone Marrow Transplant 1996;18:265–71.
41. Channock SJ, Pizzo PA. Infectious complications of patients undergoing therapy for acute leukemia: current status and future prospects. Semin Oncol 1997;24:132–40.
42. Peterson DE. Pretreatment strategies for infection prevention in chemotherapy patients. NCI Monogr 1990;9:61–71.
43. Overholser CD, Peterson DE, Williams LT, Schimff SC. Periodontal infection in patients with acute nonlymphocytic leukemia: preva- lence of acute exacerbations. Arch Intern Med 1982;142:551–4.
44. Peterson DE, Minah GE, Overholser CD, et al. Microbiology of acute periodontal infection in myelosuppressed cancer patients. J Clin Oncol 1987;5:1461–8.
45. Stansbury DM, Peterson DE, Suzuki JB. Rapidly progressive acute periodontal infection in a patient with acute leukemia. J Periodontol 1988;59:544–7.
46. Minah GE, Rednor JL, Peterson DE, et al. Oral succession of gram-negative bacilli in myelosup-
202 Periodontal Medicine
pressed cancer patients. J Clin Microbiol 1986; 24:210–13.
47. Moore WEC, Holdeman LV, Cato EP, et al. Bacte- riology of moderate (chronic) periodontitis in mature adult humans. Infect Immun 1983;42: 510–155.
48. Reynolds MA, Minah GE, Peterson DE, et al. Peri- odontal disease and oral microbial successions during myelosuppressive cancer chemotherapy. J Clin Periodontol 1989;16:185–9.
49. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966;64:328–40.
50. Sickles EZ, Greene WH, Wiernik PH. Clinical presentation of infection in granulocytopenic patients. Arch Intern Med 1975;135:715–9.
51. Bergman OJ. Oral infections and septicemia in immunocompromised patients with hematolog- ic malignancies. J Clin Microbiol 1988;26: 2105–9.
52. Barrett AP, Schifter M. Antibiotic strategy in orofa- cial/ head and neck infections in severe neu- tropenia. Oral Surg Oral Med Oral Pathol 1994;77:350–5.
53. Fardal O, Turnbull RS. A review of the literature on use of chlorhexidine in dentistry. J Am Dent Assoc 1986;112:863–9.
54. Langslet A, Olsen I, Lie SO, Lokken NP. Chlorhex- idine treatment of oral candidiasis in seriously diseased children. Acta Paediatr Scand 1974;63: 809–11.
55. Overholser CD, Peterson DE, Bergman SA, Williams LT. Dental extractions in patients with acute nonlymphocytic leukemia. J Oral Surg 1982; 40:296–8.
56. Peterson DE, Overholser CD, Williams LT. Endodontic therapy in patients receiving myelo- suppressive chemotherapy. Proc J Dent Res 1982; 61:276.
57. Peters E, Monopoli M, Woo SB, Sonis S. Assess- ment of the need for treatment of postendodon- tic asymptomatic periapical radiolucencies in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 1993;76:45–8.
58. De Paola LG, Minah GE. Isolation of pathogenic microorganisms from dentures and denture soaking containers of myelosuppresed cancer patients. J Prosthet Dent 1983;49:20–4.
59. Epstein JB, Chin EA, Jacobson JJ, et al. The rela- tionship among fluoride, cariogenic oral flora, and salivary flow rate during radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:286–92.
60. Sonis S. Mucositis as a biological process: a new hypothesis for the development of chemotherapy- induced stomatotoxicity. Oral Oncol 1998;34: 39–34.
61. Sonis S, Kunz A. Impact of improved dental ser- vices on the frequency of oral complications of cancer therapy for patients with non-head-and- neck malignancies. Oral Surg Oral Med Oral Pathol 1988;65:19–22.
62. Epstein JB, Sherlock C, Page JL, et al. Clinical study of herpes virus infection in leukemia. Oral Surg Oral Med Oral Pathol 1990;70:38–43.
63. Epstein JB, Scully C. Herpes simplex virus in immunocompromised patients: growing evi- dence of drug resistance. Oral Surg Oral Med Oral Pathol 1991;72:47–50.
64. Epstein JB, Ransier A, Sherlock CH, et al. Acy- clovir prophylaxis of oral herpes virus during bone marrow transplantation. Oral Oncol, Eur J Cancer 1996;32(b):158–62.
65. Barrett AP. A long-term prospective clinical study of oral complications during conventional chemotherapy for acute leukemia. Oral Surg Oral Med Oral Pathol 1987;63:313–6.
66. Meyers JD, Flournoy N, Thomas ED. Infection with herpes simplex virus and cell-mediated immunity after marrow transplant. J Infect Dis 1980; 142:338.
67. Saral R, Ambinder RF, Burns WH, et al. Acyclovir prophylaxis against recrudescent herpes simplex virus infections in leukemia patients: a random- ized double-blind placebo controlled study. Ann Intern Med 1983;99:773–7.
69. Lam MT, Pazin GJ, Armstrong JA, Ho M. Herpes simplex infection in acute myelogenous leukemia and other hematologic malignancies: a prospective study. Cancer 1981;48:2168–71.
70. Rand KH, Kramer B, Johnson AC. Cancer chemotherapy-associated symptomatic stomati- tis: role of herpes simplex virus (HSV). Cancer 1982; 50:1262–5.
71. Wade JC, Newton B, Flournoy N, Meyers JD. Oral acyclovir prophylaxis of herpes simplex virus infection after marrow transplant. Ann Intern Med 1984;100:823–7.
72. Cassady KA, Whitley RJ. New therapeutic approaches to alpha-herpesvirus infections. J Antimicrob 1997;39:119–28.
73. Oakley C, Epstein JB, Sherlock CH. Reactivation of oral herpes simplex virus. Implications for clinical management of herpes simplex virus recurrence during radiotherapy. Oral Surg Oral Med Oral Pathol 1997;84:272–8.
Periodontal Disease and Periodontal Management in Patients with Cancer 203
74. Burns WH, Santos GW, Saral R, et al. Isolation and characterization of resistant herpes simplex virus after acyclovir therapy. Lancet 1982;1:421–3.
75. Crumpacker CS, Schnipper LE, Marlowe SI, et al. Resistance to anti-viral drugs of herpes simplex virus isolated from a patient treated with acy- clovir. N Engl J Med 1982;306:343–6.
76. de Clerq E. In search of a selective antiviral chemo- therapy. Clin Microbial Rev 1997;10:674–93.
77. Wagstaff AJ, Bryson HM. Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic proper- ties and therapeutic use in immunocompro- mised patients with viral infections. Drugs 1994;48:199–226.
79. Zaia JA, Forman SJ. Cytomegalovirus infection in the bone marrow transplant recipient. Infect Dis Clinics N Am 1995;9:879–900.
80. Scully C, Epstein J, Porter S, Cox M. Viruses and chronic disorders involving the human oral mucosa. Oral Surg Oral Med Oral Pathol 1991; 72:537–44.
81. Schubert MM, Epstein JB, Lloid ME, Cooney E. Oral infection due to cytomegalovirus in immunocompromised patients. J Oral Pathol Med 1993; 22:268–73.
82. Epstein JB, Sherlock CH, Wolber RA. Oral mani- festations of cytomegalovirus infection. Oral Surg Oral Med Oral Pathol 1993;75:443–51.
CHAPTER 13
PERIODONTAL CONSIDERATIONS IN PATIENTS WITH BONE MARROW OR SOLID ORGAN TRANSPLANTS Terry D. Rees, DDS, MSD
The science of organ and bone marrow transplan- tation has evolved over the past 30 to 40 years from last-ditch desperate efforts to briefly prolong life, or improve the quality of life, to a sophisti- cated treatment modality that is preferred in the management of a variety of diseases.1 In most instances, the various diseases and disorders which lead to a need for transplantation have oral mani- festations, which may cause the alert dental prac- titioner to refer the affected patient for medical evaluation and appropriate treatment, including transplantation. Improved prognosis following organ transplantation is the direct result of the development of superior methods for obtaining donor-patient tissue matches, transportation solu- tions, and the effective use of immunosuppressant drugs.2 Although transplantation procedures are often beneficial, they are not without complica- tions, which range from life-threatening infections to rejection of the grafted organ. Safe and effective dental therapy in these patients requires an under- standing of the diseases that are best treated by transplantation, their complications, and the after effects of the transplantation procedure. In each circumstance, careful dental protocols must be followed in order to provide this safe and effective care for patients.3 Dental infections and manipu- lation of oral tissues may subject immunosup- pressed patients to infections, which can lead to organ rejection, compromise of other body sys- tems, or even death. This paper will review the systemic conditions that may result in a need for organ or bone marrow transplantation, discuss systemic and oral complications associated with the diseases and their treatment, and provide a protocol for the management of patients who are transplant recipients.
KIDNEY TRANSPLANTATION
Acute and Chronic Renal Failure
Renal failure is a major complication of kidney dis- ease and transplantations, and failure in both native and transplanted kidneys most commonly occurs as a result of chronic renal disease. Progres- sive end-stage renal disease may develop rapidly or may occur many years after the onset of the initi- ating condition. Essentially, renal failure occurs as a result of the accumulation of circulating serum proteins, which, in turn, induce endocytosis of renal vascular epithelial cells and a nephrotoxic effect due to the release of vasoactive and inflam- matory substances into the renal interstitium. Classic phases of failure include inflammation, fibrosis, atrophy, and end-organ damage.4,5
Glomerulonephritis in its various forms was once the most common condition leading to chronic renal failure (CRF). However, due to more success in noninvasive management of glomeru- lonephritis, diabetes mellitus is now the most com- mon cause of chronic failure, followed by pro- longed or progressive hypertension.5–8
Glomerulonephritis usually presents with manifestations of nephrotic syndrome, which may be acute or chronic in nature. This condition is characterized by massive edema, proteinuria, hypoalbuminemia, and susceptibility to intercur- rent infections. Poststreptococcal glomeru- lonephritis is associated with an inflammatory reaction appearing after infection with group A or B hemolytic streptococci or with staphylococci. Nephritis has been associated with skin infections, but its relationship to oral streptococcal bac- teremias is unknown.
206 Periodontal Medicine
Other forms of postinfectious glomeru- lonephritis may occur after a variety of bacterial, viral, or parasitic infections. This type of nephritis may be induced by bacterial endocarditis or infect- ed ventriculoatrial shunts. The severity of nephritis is related to the duration of infection before appro- priate antibacterial therapy is initiated. Control of the causative infection usually leads to the rapid resolution of glomerulonephritis, but irreversible renal failure can occur, especially if initiation of antimicrobial therapy has been delayed. It should be noted, however, that antimicrobial therapy itself may induce acute interstitial nephritis.
Membranoproliferative glomerulonephritis (hypocomplementemia) may occur due to inherit- ed complement deficiencies or in conjunction with other conditions such as systemic lupus erythe- matosus, mixed cryoglobulinemia, systemic sclero- sis, shunt infections, or bacterial endocarditis, all of which are associated with persistent immune complex formation.9 Rapidly progressive glomeru- lonephritis may induce a steady alteration of renal function over a period of weeks or months, poten- tially leading to renal failure. This condition may also be associated with bacterial endocarditis or shunt infection.
Goodpasture’s syndrome features a specific pathologic entity associated with formation of anti- bodies to glomerular epithelial basement membranes (GMB). Other forms of anti-GMB may be associat- ed with pulmonary changes resulting from influenza, abuse of tobacco or illicit drugs, or other conditions that permit circulating antibody complexes access to lung alveoli.4,10 Anti-GMB diseases usually progress to renal failure within 1 year of onset.
Fibrillary glomerulonephritis has recently been described as an idiopathic disorder which features pathognomonic fibril deposition in the glomeruli, which may induce nephrotic effects. At present, there is no known treatment for this disorder.
Immunoglobulin A (IgA) nephropathy (Berg- er’s disease) is usually idiopathic but may occur in association with other diseases such as hepatic cir- rhosis. The condition usually leads to reversible acute renal failure, but some patients experience life-threatening renal failure, sometimes over a peri- od of 20 or more years.4 IgA disease often recurs in patients undergoing kidney transplantation, although resultant graft rejection is rare.11
Hereditary nephritis (Alport’s syndrome) may be accompanied by hepatic impairment. The condition is often progressive, especially in men, leading to end-stage renal failure over a period of years.
Nephrotic syndrome may occur in association with systemic conditions such as amyloidosis, sys- temic lupus erythematosus, and diabetes mellitus and ranges in degree from lipoid nephrosis to renal failure requiring transplantation. Unfortunately, the condition may recur in the transplanted kid- ney.4 More rapid renal deterioration may occur when related to heroin abuse or acquired immun- odeficiency syndrome (AIDS).12 Corticosteroid- resistant patients with nephrotic syndrome may require cyclosporine therapy before renal trans- plantation. Therefore, these individuals are prone to cyclosporine-induced gingival overgrowth, together with more serious drug side-effects.13–16
Cyclosporine may induce toxic nephropathy both before and after kidney transplantation.4,14
Membranous nephropathy may occur idio- pathically or in association with the presence of solid tumors, systemic lupus erythematosus, hepatitis B, and occasionally hepatitis C infection, or with certain medications such as gold salts, penicillamine, or amphotericin B.13 Nephrotic patients may be particularly susceptible to drug- induced rhabdomyolysis.17
Acute renal failure may be associated with ele- vated blood urea nitrogen (BUN) and creatinine concentrations. Acute failure may be induced by a reduction in blood volume due to hemorrhage, severe hypotension, advanced heart failure, or liver disease. Drugs such as angiotensin-converting enzyme (ACE) inhibitors or ACE receptor inhibitors may sustain renal hypotension. Inges- tion of nonsteroidal anti-inflammatory drugs (NSAIDs) may produce similar effects.18 Renal failure can occur as a complication of severe ischemia or hypovolemia or that of a major surgi- cal procedure such as cardiac surgery and may also be induced by sepsis or by obstructive biliary cir- rhosis. Acute renal tubular necrosis is generally reversible, but hemodialysis may be required.19,20
Chronic renal failure is a bilateral, progressive deterioration of functioning nephrons and is often insidious in progression. Acute and chronic renal failure can alter the function of virtually every organ system of the body.8 The uremic syndrome occurs in part due to the accumulation of BUN and other metabolic waste products normally excreted by the kidneys. The condition features azotemia, impaired ability to concentrate urine, polyuria, hypokalemia, hypocalcemia, hyperphos- phatemia, and metabolic acidosis in its late stages. It may be accompanied by hypertension, pericardi- tis, congestive heart failure, coronary artery dis- ease, multiple neuropathies, metabolic encephalo-
Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 207
pathy, osteopenia or osteoporosis, and bleeding disorders due to anemia.18,21
Abnormal hemostasis occurs as a result of pro- longed bleeding time, decreased activity of the platelet receptor complex, abnormal platelet aggre- gation and adhesiveness, and impaired prothrombin consumption. Central nervous system disturbances may first manifest as inability to concentrate, drowsiness, insomnia, memory lapses, and errors in judgment. If untreated, the condition becomes asso- ciated with hiccups, cramps, muscle twitching, asterixis, stupor, seizures, and coma.8,22–24
Gastrointestinal abnormalities include anorex- ia, nausea and vomiting, as well as uremic fetor, which is the uriniferous breath odor resulting from breakdown of the urea in saliva to ammonia. This condition may also be associated with a metallic taste sensation. Mucosal ulcerations may occur at any level of the gastrointestinal tract.
Endocrine-metabolic disturbances include altered parathyroid function, glucose intolerance, and insulin metabolism disorders. Dermatologic disorders may include the pallor of anemia, ecchy- moses and hematomas due to defective hemostasis, calcium deposition in soft tissues, pruritus and excoriations related to secondary hyperparathy- roidism, and/or dehydration. In some circum- stances, the combination of anemia and hemato- logic dysfunction leads to development of a sallow, yellow cast to the skin or to slate-gray-to-bronze discoloration associated with hemochromatosis. In severe uremia, the concentration of urea in sweat and saliva may be sufficient to induce a deposition of a fine white powder (uremic frost) on the skin and mucosa as the result of evaporation.8,21,22,23,25
Renal osteodystrophy occurs in renal failure due to disordered calcium and phosphorus metab- olism and altered vitamin D absorption and metab- olism. The result is a secondary hyperparathy- roidism induced by renal retention of phosphorus, which causes a compensatory release of calcium from bone in an effort to maintain the calcium- phosphorus homeostasis. Skeletal changes include altered bone remodeling, osteopenia, osteomalacia and osteoporosis, osteitis fibrosa cystica, osteoscle- rosis, and central giant cell tumors (the brown tumor of hyperparathyroidism).5,8,21–23,26,27
Individuals with renal failure exhibit increased susceptibility to infection due to altered leukocyte, monocyte, and lymphocyte function. The systemic conditions associated with end-stage renal disease (hyperglycemia, protein malnutrition, serum and tissue hyperosmolarity) further impair infection susceptibility. This susceptibility may continue in
patients receiving dialysis or renal transplantation, due in part to the administration of immunosup- pressant drugs.8
Oral Features of Renal Failure
Renal failure induces many abnormalities in the oral cavity. An increase in salivary calculus formation has been described, probably due to elevated serum cal- cium-phosphate levels. Conversely, caries incidence may be reduced, possibly due to plaque inhibition related to increased levels of salivary urea.28 Uremic stomatitis occurs in two forms (1) the erythemopul- taceous type, which features dry, burning, erythema- tous, and painful oral tissues that may be covered with a thick gray exudate; and (2) the ulcerative form, which is characterized by mucosal ulcerations. Xerostomia may be the most common oral manifes- tation and occurs due to altered salivary production, with or without parotid enlargement or infectious parotitis. Oral dryness may be compounded by nasal congestion resulting from insidious nasal bleeding, which, in turn, initiates mouth breathing. Insidious oral bleeding may induce gingival hemorrhage and hematoma formation in the presence of slight trau- ma. Enamel hypoplasia and brownish discoloration of the teeth may occur in children, and pulpal nar- rowing has been described. Infections may be quite frequent with candidal overgrowth being common, although bacterial, viral, and other fungal infections may also occur. Increased esophageal reflux has been described among dialysis patients, with resultant dental erosion and oral discomfort.21–23,28,29
Secondary hyperparathyroidism may induce fine granular metastatic calcifications in the con- nective tissues of the oral cavity, which may initiate mucosal swelling, pain, and ulceration. Radi- ographic evidence of hyperparathyroidism may include loss of lamina dura around the teeth. This is not a universal finding and may occur more often in the anterior dentition.22,23 A reduced radiodensi- ty of the bones of the jaws may occur in association with osteopenia. This can result in a “ground glass” radiographic osseous appearance, which may be associated with an increased possibility of sponta- neous fractures of the jaws in extreme cases. Extrac- tion sockets tend to retain the lamina dura and scle- rotic radiopacities have been reported. Small unilocular or multilocular cystic lesions of the jaws may denote pseudocyst cavities or giant cell tumors (brown tumor). These lesions may induce loosen- ing of teeth, jaw enlargement, and localized oral pain. Spontaneous gingival hemorrhage, ulcera- tions, and petechial lesions are common.21–23,27,28
208 Periodontal Medicine
Increased mobility of teeth is a common find- ing in osteopenic patients, even in the absence of periodontal pockets. Individuals with osteopenia experience increased tooth loss and more advanced periodontal disease. This may be reversed in women by estrogen therapy or by use of bispho- nates.30–34 Periodontal inflammation is very com- mon among patients with renal failure, and oppor- tunistic infections with or without blood seeding is a constant hazard.25,35,36 Extraction of loose teeth should be avoided because of delays in wound healing. In most instances, mobile teeth can be maintained with splinting.21–23,25,27,37
Dialysis
Hemodialysis may be employed in the management of reversible or irreversible renal failure. Unfortu- nately, dialysis may also adversely affect renal func- tion due to decreased urine output, induction of hypotension, or complement activation.38,39
A variety of drugs commonly used in dentistry may induce acute renal failure through tubular necrosis. These drugs include aminoglycoside antibiotics, acyclovir, sulfonamides, and aceta- minophen.17 The severity of the nephrotoxic effect may relate to dosing frequency and plasma levels achieved, especially in patients with concurrent renal ischemia.40 The presence of sepsis or liver dis- ease, particularly severe obstructive jaundice, may enhance drug-induced nephrotoxicity.
Accumulation of uric acid from gout or other diseases may also induce acute or chronic renal dis- ease and failure. Chronic urate nephrotoxicity is rare today but occasionally results from deposition of sodium urate crystals in the kidney medullary interstitium.41 Fanconi-like syndromes are possible when tetracyclines or other specific drugs are used in patients with pre-existing nephrosis.
Hemodialysis is initiated when a failing kid- ney cannot successfully excrete waste products, regulate acid-base balance, or maintain sodium homeostasis. In this procedure, solutes such as excessive urea or potassium are filtered out of the blood, and excessive extracellular fluid is removed. The procedure is usually performed every 2 to 3 days and requires 3 to 5 hours per session.21 Side effects include severe hypotension, cramping, nau- sea, and vomiting.42
Vascular access is necessary to perform blood purification by dialysis. Today, this is most fre- quently accomplished by the creation of an arte- riovenous fistula, often by anastomosis of the radial artery and cephalic vein of the arm.39,43 To
make this technique efficient, the anastomosis should be in place for 6 to 8 weeks before use to enable vessels to mature and enlarge. Conse- quently, this site is rarely used in the event imme- diate dialysis should be necessary to treat acute renal failure. In such circumstances, a double lumen catheter is inserted in the femoral, internal jugular, or subclavian vein. The dialysis equip- ment enables blood flow through a filtering membrane, resulting in the cleansing of the dialysate solutions. In some circumstances, the membrane may activate complement via the alter- nate pathway or generate interleukin-1 (IL-1), which can induce hypotension and b2-microglob- ulin accumulation. These effects may be mini- mized by use of biocompatible membrane mate- rials. Despite this, dialysis membranes may acti- vate the clotting mechanism within the dialysis system itself. Intersystem clotting is controlled by administration of heparin.39
Indications for hemodialysis include uremia, hyperkalemia, volume overload, acidosis, uremic pericarditis, and other features of uremic syn- drome. Hypotension is the major complication of hemodialysis, usually occurring as the result of excessive filtration and volume depletion. The con- dition is far more likely when vasoconstrictive mechanisms are impaired as a result of medications or of autonomic neuropathy such as that found in diabetics. Chronic anemia may also result due to factors such as decreased erythropoietin produc- tion, iron deficiency, folate deficiency, or hemoly- sis related to the dialysis process.39
Long-term hemodialysis patients may mani- fest musculoskeletal changes such as carpal tunnel syndrome, arthropathies, or amyloidosis, with or without increased tissue levels of b2-microglobu- lin.7 Encephalopathy may occur toward the end of dialysis and may persist even after completion of the therapeutic regime. Symptoms include subtle changes in personality, reduced short-term memo- ry, slurred speech, and myoclonic spasms of the face, arms, legs, and trunk.39
Therapeutic outcomes of hemodialysis have remained constant over the past few years, with a mortality rate of approximately 20 to 25%. Com- plications include cardiovascular disease (stroke, myocardial infarction) and infections. A variety of infections occur due to protein malnutrition and inability to produce antibodies. As a consequence, hemodialysis patients are at increased risk for infectious endocarditis and endoarteritis at the shunt site. The patient’s quality of life is impaired by frequent dialysis that must be performed and
Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 209
the amount of time required to complete the ther- apy although hemodialysis can be performed at home, after a reliable family member has been trained to conduct the procedure.
Peritoneal dialysis is performed by introducing dialysate solution into the peritoneal cavity. The procedure may be continuous (continuous ambula- tory peritoneal dialysis) or periodic (cyclic ambula- tory peritoneal dialysis). It is often the treatment of choice in acute renal failure, obviates the need for heparin, and minimizes marked changes in blood pressure, especially the hypotension associated with conventional dialysis. In this technique, the dialysis solution is infused into the abdominal cavity and drained after sufficient time for collection of toxic waste products and excess fluids. Often three to five exchanges are performed daily but the procedure can be performed at home. The primary complica- tions are infection of the exit port within the catheter or infection in the peritoneal cavity. Other disadvantages include protein loss and glucose absorption into the bloodstream and this procedure also interferes with patient quality of life.44
Most peritoneal infusion infections are caused by gram-positive microorganisms such as Staphylo- coccus epidermitis and Staphylococcus aureus. How- ever, peritonitis may also be induced by gram-neg- ative anaerobic organisms including putative peri- odontal pathogens and by fungi.27,28,44
Renal Transplantation
Renal transplantation offers the best opportunity for resumption of normal daily activities and full rehabilitation in end-stage renal disease (ESRD) although graft rejection and infection remain seri- ous problems. Both living and cadaver organs can be used; however, the best results occur when donors and recipients share compatible ABO blood groups and HLA antigens. No matching of Rh factor is required. Transplantation from identi- cal twins offers the greatest opportunity for suc- cess, and immunosuppressant drugs are usually not required with fully compatible donor-receptors.
Improvements in immunosuppressant proto- cols have resulted in reduced graft rejection even in poorly matched donor-receptors. Unfortunately, immunosuppressant drugs also suppress host defenses against bacterial, viral, and fungal infec- tions.45 When possible, pregraft antibody titers against varicella zoster virus (VZV), cytomegalo- virus (CMV), hepatitis B (HBV), and the human immunodeficiency virus (HIV) should be obtained prior to transplantation.46 Receptor patients who are
seronegative for VZV or HBV should receive vacci- nation prior to transplantation, although anti-CMV antibodies do not always confer protection.44,47
Graft rejection is mediated by both humoral and cellular mechanisms. Acute rejection may occur if the recipient patient has cytotoxic anti- bodies to donor blood group or HLA antigens. Chronic humoral rejection progresses more slowly but inexorably leads to graft loss.
Cardiovascular disease is one of the leading causes of morbidity and mortality in organ recipi- ents and may include congestive heart failure, severe hypertension, or cardiac arrythmias. An increased incidence of infective endocarditis may occur even in patients without known cardiac val- var lesions.21,48 Risk factors include pretransplant cardiovascular disease, diabetes mellitus, elevated serum lipids, hypertension, tobacco or drug abuse, and allograft dysfunction. Patients who have undergone coronary artery angioplasty or bypass surgery are at increased risk of re-stenosis.48 Hyper- tension is very common after renal transplantation, most often due to the direct nephrotoxic effect of cyclosporine or possibly tacrolimus. Hypertension may lead to chronic graft rejection due to reduced renal function or renal artery stenosis.48
Infection is a constant hazard and most often occurs immediately following transplantation. Sur- gical wound infection, blood transfusions before or during organ transplantation (especially hepatitis C transmission), dialysis-related sepsis, urinary tract infection, and aspiration pneumonia infec- tions are most common. The greatest risk of post- transplant infection occurs within the first 6 months, when immunosuppressive therapy is at its peak.37 Delayed infections most often occur due to viral (HSV, CMV, EBV), fungal (Candida albi- cans) or other opportunistic organisms.49–51
Other common post-transplant complications include hyperlipidemia, which may be influenced by hyperinsulinemia or by the use of drugs such as cyclosporine or diuretics. Hyperparathyroidism may persist after renal transplantation and may require initiation of dialysis. Metabolic derangement, hyperkalemia, hypomagnesemia, hyperuricemia, and post-transfusion diabetes mellitus (PTDM) are additional risks. The last may be associated with administration of corticosteroids, but cyclosporine and tacrolimus can also be diabetogenic due to increased insulin resistance, decreased insulin secre- tion, or other mechanisms. Anemia and leukopenia are associated with poor renal function and defi- ciency in the renal production of erythropoeitin, which is essential to red blood cell development.
210 Periodontal Medicine
Liver disease is a common complication fol- lowing renal transplantation. This may be drug- induced (cyclosporine, azathioprine) or due to viral hepatitis.
Immunosuppression therapy is usually provid- ed by various combinations of glucocorticoids, aza- thioprine, cyclosporine, tacrolimus, monoclonal antibody OKT 3, or antilymphocyte globulin. Appropriate cyclosporine or tacrolimus serum lev- els are essential to prevent graft rejection although higher serum levels are associated with more severe adverse side effects. Serum levels can be uninten- tionally increased by simultaneous intake of drugs such as erythromycin, oral contraceptives, and some calcium channel blockers.
Rifampin, phenobarbital, phenytoin, and other anticonvulsant drugs may decrease cyclo- sporine levels, and aminoglycoside antibodies may promote cyclosporine nephrotoxicity. Thus, the prescription of any drug for patients receiv- ing cyclosporine should be preceded by medical consultation.18,48
Cyclosporine is an excellent immunosuppres- sant drug, which is often prescribed following organ transplantation because it selectively suppresses cell- mediated immunity. Complications of the drug include nephrotoxicity, renal vasculopathy, hyper- tension, chronic renal interstitial fibrosis (which is also common in heart transplantation), neurotoxic- ity, gingival overgrowth, and increased susceptibility to malignancies, including B cell lymphoma, squa- mous cell carcinoma of the skin, lip or oral mucosa, or Kaposi’s sarcoma.23,35,52–86 Malignancy may be transmitted from the donor or it may develop de novo post-transplantation,65,87–89 and oral malig- nancies have been reported within sites of cyclosporine-induced gingival overgrowth.82,90
Cyclosporine-induced perioral dermatitis has been described and features red papules, pustules, and scaling of the chin, upper lip, and nasolabial fold.23
Oral hairy leukoplakia may occur in HIV-neg- ative individuals taking cyclosporine, and gingival overgrowth is a common occurrence. This may be especially prevalent in patients with pregraft peri- odontitis.91,92 Nephrotoxicity and neurotoxicity may be more severe in patients immunosuppressed with tacrolimus although gingival enlargement has not been identified in association with this drug.93
Recent evidence indicates that the presence or absence of pretransplant gingival hyperplasia may influence the incidence and severity of drug- induced gingival overgrowth.92 The true incidence of cyclosporine-induced gingival enlargement is difficult to determine since the drug is often used
for organ transplant patients in combination with antihypertensive drugs such as the calcium channel blocking agent, nifedipine, also associated with gin- gival overgrowth.57,94–97 Recent reports indicate that nifedipine-induced gingival overgrowth can be reversed by using alternative calcium channel blocking drugs such as amlodipine or isradip- ine.98,99 Other calcium channel blockers, however, may induce increased plasma levels of cyclosporine while nifedipine does not. This may explain the fre- quent use of nifedipine in postrenal transplant patients.3 Treatment for drug-induced gingival overgrowth includes establishment of effective oral hygiene and discontinuance or reduction in dosage of the causative drug, when possible. Unfortunate- ly, surgical removal of enlarged gingivae is often necessary to facilitate patient oral hygiene measures.
New immunosuppressant drugs (sirolimus and mycophenolate mofetil) are now available as cyclosporine substitutes, when appropriate. These agents appear to induce fewer side effects, and no gingival overgrowth has been reported to date.
Dental Management
No firm protocols have been established for dental management of recipients of solid organ transplants. Periodontal disease was recently reported in 100% of 45 renal dialysis patients studied, suggesting that most patients scheduled for renal dialysis or trans- plantation may have oral infections which could prove life-threatening.100 However, application of common treatment principles should facilitate safe and effective periodontal therapy. Dental and peri- odontal management of patients with ESRD must be carefully coordinated with the patient’s physician. The dentist should participate in treatment planning and provide necessary pretreatment for patients scheduled for elective dialysis or organ transplanta- tion. Under ideal circumstances, all potential oral foci of infection should be eliminated prior to trans- plant placement.37,50,101,102 Teeth that are beyond repair and those that are suspect should be extracted although endodontic therapy may be appropriate in selected circumstances. Patients should be instructed in effective oral physiotherapy, and the use of anti- septic mouthrinses such as chlorhexidine may be appropriate.18,28,37,103,104 Individuals who receive organ transplantation on an emergency basis and who have existing dental infection should be given antibiotics before and after the transplantation until dental treatment can be accomplished.
The potential for oral and systemic infections is quite high after transplantation because of the use of
Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 211
immunosuppressive drug regimens. These drugs may include cyclosporine, tacrolimus, corticos- teroids, azathioprine, antilymphocyte globulin, or combinations of these. Most organ transplant recip- ients are maintained on immunosuppressant drugs for life to attenuate graft rejection.3,50 Immunosup- pressant drugs may mask early manifestations of oral infection, including periodontal disease.18,23 Patients are especially susceptible to urinary tract infections with Escherichia coli. Most vascular access site infec- tions occur from S. aureus. Occasionally, however, the oral cavity is the source of gram-negative enter- coccal infections (Pseudomonas, Proteus, Klebsiella), fungal infections (Candida, Aspergillus, Mucor), or viral infections (herpes simplex, Epstein-Barr, cytomegalovirus, and others), all of which can result in life-threatening systemic sepsis.37 Oral lesions suggestive of infection should be evaluated by cyto- logic examination, culture, and/or biopsy, when indicated.105–107
Medical complications associated with renal dialysis or transplantation must be clearly identi- fied by obtaining a thorough medical and dental history, by evaluation of vital signs, by use of appropriate laboratory screening tests, and by medical consultation.
Drugs often used in dental practice may be retained in blood plasma for prolonged periods of time due to diminished renal function in ESRD patients. Therapeutic administration of these drugs may require adjustment of dosage or lengthening of intervals between administration. The prudent practitioner should consult the patient’s physician prior to the use of any drugs.18,28 Local anesthetics are metabolized in the liver and therefore usually safe for ESRD patients. Acetaminophen and codeine may be appropriate for postoperative anal- gesia, but aspirin and other NSAIDs should be avoided. Antibiotics such as aminoglycosides, tetracyclines, and polypeptides (bacitracin and polymyxin) are nephrotoxic. Potassium penicillins should not be prescribed because of their high lev- els of potassium salts.27
Patients with ESRD should be observed for signs and symptoms associated with long-term glu- cocorticosteroid therapy. These include excessive weight gain, moon facies, buffalo hump, abdominal striae, acne, and mental depression, or psychosis.18
Stressful dental procedures may require cortico- steroid supplementation. Recent evidence, however, suggests that the administration of low-dose corti- costeroids (prednisone, 5 to 10 mg administered every other day) is not likely to induce an adrenal crisis, especially if dental procedures are performed
on the alternate day. Higher levels of corticosteroids will protect the patient from adrenal deficiency and shock. Further protection against adrenal crisis may be attained by following a stress reduction protocol consisting of morning appointments, maintenance of a nonthreatening treatment environment, use of conscious sedation, attainment of profound local anesthesia, and prescription of safe and effective postoperative analgesics. Some authorities recom- mend doubling the usual steroid dose the day before, on the day of, and for 2 days following a stressful dental procedure. As an alternative, the dentist must be prepared to administer intravenous corticosteroid supplementation in the event of an adrenal crisis.23,25,37
Dental treatment should be conservative and noninvasive when possible, especially during the first 3 months after transplantation.23 When an invasive periodontal or surgical procedure is planned, prophylactic antibiotic coverage should be considered, especially if a dialysis shunt or fistu- la is present.18,23,27,28,37 Generally, the recommen- dations of the American Heart Association for the prevention of bacterial endocarditis are considered sufficient.108,109 Infective endocarditis (IE) may occur in dialysis patients with no evidence of pre- vious cardiac valvar damage.28 Therefore, the den- tal practitioner should remain alert for signs and symptoms of IE, which include fever of unknown origin, malaise, unexplained elevation of white blood cells, and others.101
Chlorhexidine rinses prior to soft tissue manip- ulation may reduce the occurrence of orally induced bacteremias.103,108,110 Several authorities have noted, however, that there are no controlled studies that establish the beneficial effect of topical or systemic prophylactic antibiotic therapy in organ transplant patients.2,111,112 They note that antibiot- ic suppression of normal bacterial flora may render the patient more susceptible to enterococcal, fun- gal, or other opportunistic systemic infections.
Care must be taken to avoid trauma to the arteriovenous site in patients who are receiving hemodialysis either before or after renal transplan- tation. The arm with an anastomosis site should not be used for injection of intramuscular or intra- venous medications, and the access site should not be used as a portal for injections.23,28 Blood pres- sure recordings should not be obtained from the involved arm, and the arm should not be placed in a cramped position.23,25
The presence of a hemodialysis access site places the patient at increased risk for endarteritis induced by manipulation of periodontal tissues.
212 Periodontal Medicine
Peritoneal dialysis patients are subject to retrograde staphylococcal or streptococcal infection, but there is only a low risk of orally-induced bacteremia ini- tiating this infection.28,37
Excessive and prolonged bleeding may occur in ESRD in conjunction with dialysis or following transplantation. This may be compounded in patients receiving hemodialysis because heparin is usually administered during the dialysis process to prevent clotting, and warfarin compounds (Coumadin) may be used for management of relat- ed medical complications. Patients with ESRD may have reduced platelet counts and function due to uremia, further increasing bleeding potential.28 For these reasons, any necessary dental procedure likely to induce bleeding should be performed following medical consultation, usually on the day after dial- ysis to allow normal clotting, and to permit partial healing prior to the next dialysis session.27,28 Surgi- cal flaps should be avoided when possible, and appropriate surgical techniques should be per- formed (atraumatic surgery, adequate wound clo- sure with sutures, application of postsurgical pres- sure with or without topical clotting agents such as gelfoam, topical thrombin, oxidized regenerated cellulose or synthetic collagen.)18,21,25,27,28,113–115
Screening laboratory tests should be obtained prior to invasive procedures, including a complete blood count with platelets, a partial thromboplastin time, and a prothrombin time. Drugs such as 1-deamino- 8-D-arginine vasopressin (DDAVP) or conjugated estrogen may be prescribed by the patient’s physi- cian to further control hemorrhage during neces- sary oral surgical procedures.27,28
Liver Diseases
Acute hepatitis may be caused by a variety of viruses, drugs, or toxins. In most circumstances, recovery occurs over time, but hepatitis B virus (HBV) infections may lead to chronic liver disease in 5 to 10% of adults and 80 to 90% of children. Chron- ic liver disease also develops in 70 to 90% of indi- viduals infected with hepatitis C virus (HCV). Infection with HBV has been markedly reduced in the developed countries due to immunization against the virus, appropriate health care for infect- ed individuals, and establishment of universal pre- cautions against disease transmission among health care workers. Hepatitis C virus is primarily trans- mitted by parenteral means (blood transfusion, intravenous drug abuse, or occupational exposure to blood or blood products). In some circum- stances, HCV may be community acquired in
association with risk factors such as household exposure, sexual contact, or multiple sex partners. Transmission of HCV has declined as a result of screening tests, which identify the virus in blood and blood products prior to transfusion.116–118
In most cases, acute viral liver infections are transient although a small percentage of infected individuals will follow a fulminant course leading to hepatic coma or death. The most significant aftermath of acute hepatic viral infection is chron- ic hepatic deficiency, which may lead to end-stage hepatic disease (ESHD) or development of hepat- ic malignancy.
Chronic hepatitis is generally described as hepatic inflammation that lasts longer than 6 months. It is most commonly caused by autoim- mune hepatitis and chronic viral hepatitis.119,120
Alternatively, the condition may be drug induced or initiated by genetic susceptibility (Wilson’s disease), primary biliary cirrhosis, or primary sclerosing cholangitis. On occasion, clinical features are absent, but elevated serum aminotransferase levels may be noted. Common clinical features include fatigue, malaise, abdominal pain, and possibly jaun- dice. The condition may lead to liver failure, and the patient may eventually require organ transplanta- tion. Other causes of ESHD include primary hepa- tocellular carcinoma without metastasis, alcoholic liver disease, acetaminophen overdose, overdose of other drugs, or toxin-induced hepatitis.117,121
Severe recurrent HBV infection can develop in patients suffering from chronic hepatitis B, and recurrent viremia invariably occurs in individuals who undergo transplantation due to chronic hepatitis C.122,123 In addition to recurrent hepatitis, this often leads to liver fibrosis or cirrhosis. Recent evidence suggests that HBV is sequestered in extra- hepatic tissues, especially bone marrow. This may explain why recurrent HBV occurs.124
Liver cirrhosis is the sequela of a wide variety of chronic progressive hepatic diseases that lead to scarring and fatty infiltration of liver tissues and disruption of normal liver architecture and func- tion. To date, no clinical features have been recog- nized that invariably signify liver cirrhosis. Clini- cal indicators, however, include palmar erythema, spider nevi, gynecomastia, testicular atrophy, splenomegaly, ascites, esophageal varices, and xan- thelasmia, and the condition may ultimately lead to hepatic encephalopathy or the hepatorenal syn- drome.12,121,123 Skin bronzing is common in vari- ous types of hepatic diseases but most frequently occurs in specific forms of cirrhosis (alcoholic, pri- mary biliary, or hemochromatosis).123
Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 213
Liver Transplantation
Liver transplantation has become the standard of care for virtually all forms of ESHD. Absolute con- traindications for transplantation include seroposi- tivity for HIV, extrahepatic malignancy, metastatic hepatic malignancy, active sepsis, advanced car- diopulmonary disease, and active alcoholism or substance abuse.116,117,121,123,125,126
To avoid the need for long-term hemodialysis, patients who suffer from severe renal disease may require a combined liver-kidney transplant although individuals with severe neurologic or car- diopulmonary disease cannot withstand the stress of transplantation surgery. Increased vascular peripheral resistance may induce transient myocar- dial dysfunction even in individuals free of pre- existing cardiovascular disease.
Postoperative management after liver trans- plantation includes the use of immunosuppressant drugs (corticosteroids, azathioprine, cyclosporine, tacrolimus, or others) to help prevent organ rejec- tion. Both cyclosporine and tacrolimus can induce nephrotoxicity, hepatotoxicity, neurotoxicity, and diabetes mellitus. Hirsutism and gingival over- growth are not associated with tacrolimus. Patients may continue to suffer from pregraft systemic dis- orders such as severe cardiopulmonary disease or renal dysfunction.127
Complications of hepatic transplantation include nonfunction or compromised function of the implanted liver (5 to 10%), and graft rejection or infection. Candidiasis and aspergillosis infec- tions have a high morbidity rate because they often occur in critically ill patients or those who require extremely high dosages of immunosuppressant drugs. Viral, mycobacterial, parasitic, and bacterial (Nocardia, Legionella, Listeria) infections become more evident a few months following transplanta- tion, and infection with CMV is almost universal in this patient group. Immunosuppressive therapy has resulted in a marked decrease in the prevalence of irreversible graft rejection, especially if high trough levels of cyclosporine or azathioprine are sustained. Recurrent autoimmune hepatitis has been reported when immunosuppressant therapy is reduced.
Osteoporosis is common in individuals with chronic cholestatic liver disease, even following liver transplantation. Recent evidence suggests that increased bone density and elimination of vertebral fractures occurs when administration of intra- venous bisphonates is initiated 3 months before transplantation and maintained for 9 months
thereafter.128
Cyclosporine and tacrolimus are both metabo- lized in the liver and therefore drug interactions may occur. Ketoconazole may increase circulating levels of these immunosuppressant drugs while phenytoin reduces serum levels due to enzyme- induced enhanced metabolism. Hyperuricemia often occurs after liver transplantation, and treat- ment may be difficult because allopurinol alters azathioprine metabolism, and NSAIDs may adversely influence renal function.
Despite these potential complications, the 5- year survival rate for liver transplantation continues to improve. That average is currently above 80%.125
Dental Management
Prior to liver transplantation, the primary goal of dental intervention is to eliminate oral sepsis which could potentially lead to systemic infection and possible transplant rejection or compromise. There are many consequences of ESHD, however, which must be considered when developing a den- tal treatment plan for such patients. For example, the ability of the liver to metabolize drugs may be impaired. Drugs commonly used in dentistry, such as acetaminophen, narcotics, local anesthetics, benzodiazepam, barbiturates, and antibiotics (ery- thromycin, ampicillin), are metabolized in the liver, and these agents should be used with caution. Alternative drugs should be considered, and mini- mal required dosages should be administered fol- lowing consultation with a physician.
Bleeding disorders are very common in patients with ESHD. This may result from a decrease in coagulation factors produced by the liver or from thrombocytopenia due to bone mar- row suppression or hypersplenism. Increased clot fibrolysis may also occur. Patients with ESHD should be screened prior to invasive dental proce- dures by obtaining appropriate blood tests, includ- ing a complete blood count, bleeding time, pro- thrombin time, and partial thromboplastin time. Prothrombin times are important in evaluating the function of the clotting factors manufactured in the liver.129 In recent years, an international refer- ence thromboplastin (IRT) has been developed to facilitate standardized prothrombin results in all medical laboratories.91,101,130–137 Corrected normal prothrombin time has been established with an international normalized ratio (INR) of approxi- mately 1.0, although patients receiving anticoagu- lant medications may be maintained at INR levels ranging from 1.2 to 4.0.131,132 Patients with an
214 Periodontal Medicine
with ESHD or those with liver transplants. Sup- pression of oral bacteria may promote sepsis from opportunistic organisms such as Candida albi- cans.111 In any case, any oral sepsis has the potential to induce life-threatening systemic septicemia. Con- sequently, afflicted patients must be informed of the significance of good oral health to their survival. They must be instructed in effective oral hygiene procedures, and frequent recall intervals of 2 to 3 months should be established. These principles apply both before and after liver transplantation.
In most instances, successful organ transplan- tation reduces the dental treatment risks to those risks described previously in patients taking immunosuppressive drugs. It should be anticipated that solid-organ transplant patients will require these drugs indefinitely.
Pancreatic Transplantation
Pancreas transplantation is occasionally used in the treatment of type 1 diabetes mellitus. The organ is often obtained in conjunction with kidney trans- plantation from the same donor. Postoperative complications often occur, and the need for long- term immunosuppression adversely affects treat- ment outcomes.
Pancreatic transplantation may not reverse pre-existent diabetic microangiopathies, nephropa- thy, or retinopathy but may halt or reverse diabet- ic neuropathy. Under selected circumstances, the procedure may be beneficial, especially in diabetic patients who require renal hemodialysis or kidney transplantation.140
Lung Transplantation
Lung transplantation may be performed unilateral- ly, bilaterally, or as a joint heart-lung transplanta- tion. Treatment outcomes are not yet as successful as those reported for renal and hepatic transplants although they range between 50 and 70%. Indica- tions include emphysema, idiopathic pulmonary fibrosis, primary pulmonary hypertension, cystic fibrosis, and other rare disorders.
Availability of donor lungs is scarce, and therefore the selection of recipient candidates is restricted. Active tobacco smokers or those who inhale or smoke illicit drugs are not accepted, and no other systemic diseases should be present which may result in end-organ damage.10,141
Potential recipients who have significant coronary artery disease, renal insufficiency, hepatic diseases, osteoporosis, or significant neurologic impairment
INR value of 3.5 or lower can usually be managed successfully for invasive dental procedures without lowering the INR level, provided appropriate local hemostatic measures are taken.91,130,131,134,135,137
The use of oral rinses containing tranexamic acid may be sufficient to control hemorrhage in minor surgical procedures in patients with an INR of 4.0 or less. However, extensive surgical procedures in the same patients may require additional hemosta- tic measures.136,138 In ESHD patients, however, all hemorrhagic factors should be taken into consider- ation and those individuals with altered platelet levels (below 50,000) or INR values higher than 3.5 may need vitamin K supplementation, blood transfusion, or infusion of fresh frozen plasma or packed platelets. In all cases, selection and applica- tion of proper surgical techniques should be used as described previously.
Abnormal protein metabolism associated with hepatic failure may result in toxic levels of serum ammonia. This substance may induce asterixis, hepatic encephalopathy, coma, or death. The dental clinician must remain alert for signs or symptoms of these conditions. These may include personality changes, mood alterations, confusion and/or even- tual tonic or clonic muscle activity. Altered protein metabolism may also interfere with normal wound healing. Excessive postoperative bleeding following oral procedures may induce swallowing of blood and thus a possible increase in serum ammonia lev- els. The patient who has undergone nonsurgical or surgical therapy should not be dismissed until clot stabilization has been achieved.115,138
Ascites is the accumulation of fluid in the peri- toneal cavity, secondary to liver failure or portal hypertension. Bacterial peritonitis is potentially life threatening in patients with ascites and may be initiated by transient bacteremia induced by manipulation of oral soft tissues. Consequently, prophylactic antibiotic coverage is indicated for dental procedures likely to induce significant bleeding.112,138 The antibiotic regimen recom- mended by the American Heart Association for prophylaxis against bacterial endocarditis is proba- bly sufficient although some authorities recom- mend broad-spectrum antibiotics or metronida- zole in conjunction with amoxicillin to provide protection against a broader range of bacteria.
With the exception of patients with ascites, the issue of whether or not to administer prophylactic antibiotics to patients with liver disease continues to be controversial.2,111,112,139 No controlled studies are available to suggest that bacteremias induced by dental procedures affect the prognosis for patients
Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 215
are also excluded. Patients with a history of previ- ous malignancy, chronic systemic illnesses (dia- betes mellitus and others), or chronic unresolved infections may also be precluded from receiving lung transplantation.142
Heart-lung transplants may be indicated for irreparable congenital cardiac defects or simultane- ous advanced heart and lung disease. Cystic fibrosis usually requires bilateral lung transplantation while unilateral organ transplants are performed when indicated for more localized pulmonary diseases.
Post-transplant complications include acute graft rejection, usually occurring within the first 3 months after placement. Bronchiolitis obliterans occurs in at least half of all patients receiving lung transplants and is the primary cause of chronic transplant rejection.143,144 Airway stenosis may also adversely affect treatment outcomes. As in all other solid-organ transplants, infection is a major cause of mortality. This is especially true for recipients of lung transplants because the lungs are highly vul- nerable to direct contact with infectious microor- ganisms as well as to hematologic infection. Most infections are bacterial (Staphylococcus), viral (CMV), or fungal (Aspergillus). The immunosuppressive complications previously described for other solid- organ transplants are common. These include nephrotoxicity, hypertension, hyperlipidemia, neu- rotoxicity, osteoporosis, and lymphoproliferative disorders. Recurrence of underlying diseases such as sarcoidosis, lymphangioleiomyomatosis, and inter- stitial pneumonitis have been reported.142,145
Dental protocols have not been established for management of post–lung transplant patients, but putative periodontal pathogenic microorganisms have been implicated in lower respiratory infec- tions.146 Therefore, establishment of periodontal health and elimination of any oral sepsis are imper- ative.146–148 General protocols for patients using immunosuppressive drugs are also applicable.
Heart Transplantation
Cardiac transplantation is limited to patients most likely to survive the procedure and resume normal life functions. As a result, transplants are limited to individuals who have not suffered from other end- stage organ damage, those who do not have signif- icant systemic infections (HIV seropositivity), and those without advanced systemic diseases such as diabetes mellitus or collagen vascular disease.
Tissue cross-matching between the donor and recipient is difficult due to a shortage of sufficient donors. Consequently, organ selection is based on
heart size, ABO blood type matching, negative lymphocyte cross-match, and avoidance of trans- plantation from a CMV-positive donor to a CMV- negative recipient. As a result, prevention of organ rejection while avoiding the adverse effects of immunosuppressive drugs is essential for successful transplantation.
Transplantation may be indicated for any patient with end-stage heart disease and a prognosis for survival of 2 years or less. It is also indicated for patients with severely limited quality of life follow- ing other appropriate medical or surgical therapy. Candidates may include those with congestive heart failure, coronary artery disease (including angina pectoris and myocardial infarction), patients with hypertrophic cardiomyopathy, severe valvar defects, or intractable ventricular tachyarrhythmias.149,150
Exclusion criteria include individuals with active virulent infections, those with recent pul- monary infarction, severe diabetes mellitus with end-organ damage, irreversible pulmonary hyper- tension, active peptic ulcerations, recent or current malignancy, or cerebrovascular disease, those with active alcohol or substance abuse, or severe chron- ic obstructive pulmonary disease.150
Complications are common among post–car- diac transplant recipients. Early complications may include acute graft rejection, right side heart failure and bacterial, viral, or protozial infection. Late complications occur relative to chronic transplant rejection and lifelong administration of immuno- suppressive drugs.
Chronic rejection elicits fibrointimal hyper- plasia which may be aggravated by CMV infection. Successful therapeutic outcomes may allow approximately 70% restoration of maximal cardiac output during resting and exercise stages. The transplanted heart commonly remains denervated resulting in some alterations in cardiac function.101
Angina rarely occurs during subsequent post-trans- plant coronary artery disease, resulting in “silent” myocardial infarction or sudden death. Less serious symptoms of immunosuppression include hyper- trichosis, impotence in men, and painful menstru- ation in women. In general, women experience a significantly higher degree of symptomatic side effects although cyclosporine-related gingival enlargement is frequent in both sexes.151
Dental Management
Dental management of heart transplant patients is consistent with that previously described. Howev- er, strong evidence suggests a positive correlation
216 Periodontal Medicine
between the presence of severe periodontitis and risk of myocardial infarction.152–159 Therefore, achievement of periodontal health may be essential for successful management of recipient patients.
As discussed above, the use of immunosuppres- sant agents alters host response while simultaneous- ly suppressing the inflammatory response.11,54,160–163
Although prolonged corticosteroid therapy may lead to osteoporosis and other abnormalities in bone and periodontal fibrous tissue, available evidence suggests that destructive periodontitis is no more common among patients treated with cortico- steroids than the general population. Such patients may, however, be more susceptible to primary her- petic or other viral or fungal infections.
Immunosuppression may affect bone marrow function. The resulting thrombocytopenia, ane- mia, and neutropenia may lead to oral hemorrhage and severe bacterial, viral, fungal, or mixed infec- tions. The risk of infection is directly proportional to the degree and duration of the drug-induced leukopenia and anemia.54,164–167
Cyclosporine-induced gingival enlargement resembles other drug-induced gingival overgrowth, both clinically and histologically. The labial surfaces of anterior teeth are most frequently affected and the overgrowth usually begins within 3 months of start of treatment. The reaction may be preceded by plaque-related inflammation.35,168 Effective plaque control and removal of local irritants, with or with- out the use of antimicrobial mouthrinses, may diminish the severity of cyclosporine-induced gin- gival enlargement,103,104,169–172 but oral hygiene measures alone do not totally suppress gingival overgrowth.35,61,66,82
Prophylactic antibiotic therapy should be con- sidered for periodontal or oral surgical procedures required during the first 6 months of recuperation following heart transplantation. If the recipient patient achieves maximal restoration of cardiac function, preventive antibiotics for dental therapy may not be required unless a requirement for a high maintenance level of immunosuppression is present.28,112 The medical complications of organ transplantation, however, may put recipient patients at risk of orally acquired systemic sepsis. Close coordination between the patient’s physician and dentist is essential; and, continuance of excel- lent oral health is required.173,174
Bone Marrow Transplantation
Bone marrow transplantation (BMT) is currently used in the treatment of leukemia, lymphoma,
multiple myeloma, neuroblastoma, some solid tumors, and various forms of anemia.76,175–181 In this procedure, autologous stem cells or bone mar- row from a donor is infused into a recipient who may or may not have received chemoradiation ther- apy designed to eliminate the host marrow cells.
Usually, BMT grafts are obtained from a histo- compatible donor, and syngeneic graft material may be taken from an identical twin. On some occasions, the patient’s own marrow cells may be harvested and reimplanted following chemotherapy. It is difficult to obtain true histocompatibility in allogeneic graft procedures. Therefore, allogeneic engraftment usu- ally initiates graft-versus-host disease (GVHD), in which the transplanted marrow cells recognize the new host as foreign and attempt rejection.182–184
Chemotherapy and total body irradiation may be used to destroy malignant marrow cells prior to engraftment although chemotherapy alone is cur- rently preferred in many oncology centers. Chemo- radiation therapy is usually conducted 1 to 2 weeks prior to BMT.183,184 After infusion of donor cells, stem cells, or bone marrow, the patient is isolated for 4 to 6 weeks to minimize the risk of infection while marrow cells are revitalized and host defenses re-established.76,179,182,185–187 Immunosuppressant drugs and granulocyte colony growth factors (GCGF) are started at the time of engraftment, and pancytopenia exists until the absolute neutrophil count exceeds 500 cells/mm3.188–190
Patients who undergo BMT are at high risk for development of opportunistic viral, fungal, and bac- terial infections, including putative periodontal pathogens.191–204 Children may suffer from develop- mental abnormalities.205–209 Epstein-Barr virus has been reported to induce hairy leukoplakia in HIV- negative BMT patients.210 Recipients of BMT may also be susceptible to necrotizing ulcerative gingivi- tis, necrotizing stomatitis, and possibly necrotizing ulcerative periodontitis.106 Lesions of this type dur- ing marrow suppression are best treated with gentle débridement, chlorhexidine, or povidine-iodine mouthrinses, removal of necrotic osseous and soft tissue, and antibiotic therapy administered after consultation with the oncologist.49,169–172,195,211–213
Graft-versus-host disease is a multisystem, potentially life-threatening phenomenon, in which the engrafted marrow reacts against the tissues of the host.185,214 A similar condition may occasional- ly be induced by blood transfusion.215–217 Up to 70% of BMT patients may be affected with acute GVHD within the first 30 days after engraft- ment.218–220 Affected tissues include the liver, lungs, gastrointestinal tract, exocrine glands, skin, and
Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 217
mucosa.218 Acute GVHD may induce painful, ery- thematous or ulcerative oral mucosal lesions. Lesions which persist for more than 1 month are considered chronic although GVHD may appear de novo months or years after engraftment.219,221
Chronic GVHD may present with oral features suggestive of lichen planus, systemic lupus erythe- matosus, scleroderma, or Sjögren’s syndrome.222–224
Diagnosis is based on clinical features and biopsy findings suggestive of the mucocutaneous condi- tions described above.225 Oral signs may range from mild mucosal erythema to severe mucositis, desqua- mative gingivitis, xerostomia, and infections.226–229
Chemoradiation therapy–induced xerostomia may subside over time after cessation of treatment. While present, however, it may promote dental caries and mucositis.218 On occasion, unusual oral side effects may occur, including minor salivary gland retention phenomena, verrucous xanthomas, and atypical pyogenic granulomas.184,226,227,229,230
Cyclosporine or tacrolimus are usually pre- scribed for the prevention and treatment of GVHD although successful treatment of chronic oral lesions with psoralen plus ultraviolet A (PUVA) has recently been reported.231 It is desirable to maintain immunosuppression with the minimal quantity of drug necessary, but in the event of persistent GVHD, the dosage may be increased.
Periodontal management prior to BMT is consistent with the protocols described above. When possible, maximal oral health should be achieved prior to engraftment. However, brushing and flossing are usually discontinued immediately following chemoradiation and re-initiated only after white blood cell counts exceed 2000/mm3.188
In the interim, oral cleansing is performed using cotton swabs, gauze sponges, soft sponge sticks, and chlorhexidine rinses.103,232 After partial recov- ery, patients are managed as described for other recipients of organ transplants. Oral GVHD is usually controlled by meticulous oral hygiene, fre- quent dental recall visits, and use of topical or sys- temic corticosteroids, antifungals, and antivi- rals.184,233 Mucositis may be soothed by rinsing with lukewarm saline or 5% sodium bicarbonate solution to elevate salivary pH. Other soothing mouthrinses containing kaolin, diphenhydramine, and topical anesthetics have been recommended for comfort.234–237
Treatment of oral infections with antibiotic combinations are often indicated to prevent gram- negative bacillary septicemia when oral or peri- odontal tissues must be manipulated during mar- row suppression therapy. Agents such as trimetho-
prim and sulfamethoxazole may be recommended by the patient’s oncologist.119,237–240
REFERENCES
1. Perlroth MG. The role of organ transplantation in medical therapy. In: Rubenstein E, Federman DD, editors. Scientific American medicine. New York: Scientific American Medicine, Inc.; 1986.
2. Glassman P, Wong C, Gish R. A review of liver transplantation for the dentist and guidelines for dental management. Spec Care Dent 1993; 13:74–80.
3. Sakurai K, Drinkwater D, Sutherland DE, et al. Dental treatment considerations for the pre- and post-organ transplant patient. J Calif Dent Assoc 1995;23:61–6.
4. Coggins CH, Rennke HG, Rose BD. Glomeru- lonephritis and the nephrotic syndrome. In: Dale DC, Federman DD, editors. Scientific American medicine. New York: Scientific Amer- ican Medicine, Inc.; 1995.
5. Remuzzi G, Bertani T. Pathophysiology of progres- sive nephropathies. New Engl J Med 1998;339: 1448–56.
6. Appel GB. Preventing or slowing the progression of diabetic nephropathy. BUMC Proc 1999;12: 3–6.
7. Fenves AZ, Stone MJ, Johnson KB. Systemic pri- mary amyloidosis in chronic hemodialysis. BUMC Proc 1999;12:61–4.
8. Lazarus JM, Brenner BM. Chronic renal failure. In: Harrison’s Principles of internal medicine, 14th ed. New York: McGraw-Hill Co.; 1998. p. 1513–20.
9. Donohoe JF. Scleroderma and the kidney. Kidney Int 1992;41:462–77.
10. Cruz R, Davis M, O’Neil H, et al. Pulmonary manifestations of inhaled street drugs. Heart Lung 1998;27:297–305.
11. Bachman U, Biava C, Amend W, et al. The clinical course of IgA nephropathy and Henoch-Schön- lein purpura following renal transplantation. Transplantation 1986;42:511–5.
12. Rees TD. Oral effects of drug abuse. Curr Rev Oral Biol Med 1992;3:163–84.
13. Butler WT, Bennett JE, Alling DW, et al. Nephro- toxicity of amphotericin B: early and late effects in 81 patients. Ann Intern Med 1964;61:175–87.
14. Lee MR. Dopamine and the kidney: ten years on. Clin Sci 1993;83:357–75.
15. Olsen NV, Hansen JM, Ladefoged SD, et al. Renal tubular resorption of sodium and water during
218 Periodontal Medicine
infusion of low-dose dopamine in normal men. Clin Sci 1990;78:503–7.
16. Zager RA. Gentamicin effects on renal ischemia/ reperfusion injury. Circ Res 1992;70:20–8.
17. Black RM. Acute renal failure. In: Dale DC, Fed- erman DD, editors. Scientific American medi- cine. New York: Scientific American Medicine, Inc.; 1995.
18. Naylor GD, Fredericks MR. Pharmacologic con- siderations in the dental management of the patient with disorders of the renal system. Dent Clin N Am 1996;40:665–83.
19. Better OS, Stein JH. Early management of shock and prophylaxis of acute renal failure in trau- matic rhabdomyolysis. N Engl J Med 1990;322: 825–9.
20. Zager RA, Gamelin LM. Pathogenetic mechanisms in experimental hemoglobinuric acute renal injury. Am J Physiol 1989;256:F455–66.
21. Ferguson GA, Whyman RA. Dental management of people with renal disease and renal trans- plants. N Z Dent J 1998;94:125–30.
22. Bookatz BN. Management of oral problems related to kidney disease and dialysis. In: McDonald RD, Hurt WC, Gilmore HW, Middleton RA, editors. Current therapy in dentistry. Vol. 7. St. Louis: C.V. Mosby Co.; 1980. p. 31–6.
23. Cohen SG. Renal disease. In: Lynch MA, Bright- man VJ, Greenberg MS, editors. Burket’s oral medicine, 9th ed. Philadelphia: J.B. Lippincott Co.; 1994. p. 487–509.
24. Pierce TB, Razzuk MA, Razzuk LM, Hoover SJ. A comprehensive review of the physiology of hemostasis and antithrombotic agents. BUMC Proc 1999;12:39–50.
25. Eigner TL, Jastak JT, Bennett WM. Achieving oral health in patients with renal failure and renal transplants. J Am Dent Assoc 1986;113:612–6.
26. Wactawski-Wende J, Grossi SG, Trevisan M, et al. The role of osteopenia in oral bone loss and peri- odontal disease. J Periodontol 1996;67:1076–84.
27. Ziccardi VB, Saini J, Demas PN, Braun TW. Man- agement of the oral and maxillofacial surgery patient with end-stage renal disease. J Oral Maxillofac Surg 1992;50:1207–12.
28. DeRossi SS, Glick M. Dental considerations for the patient with renal disease receiving hemodialysis. J Am Dent Assoc 1996;127:211–9.
29. Glick M. Dental considerations for the patient with renal disease receiving hemodialysis. J Am Dent Assoc 1996;127:211–9.
30. Bando K, Nitta H, Matsubara M, Ishikawa I. Bone mineral density in periodontally healthy and edentulous postmenopausal women. Ann Peri- odontol 1998;3:322–7.
31. Grossi SG. Effect of estrogen supplementation on periodontal disease. Comp Cont Ed Dent 1998; (Suppl)22:S30–6.
32. Jeffcoat MK. Osteoporosis: a possible modifying factor in oral bone loss. Ann Periodontol 1998; 3:312–21.
33. Reddy MS, Weatherford TW III, Smith CA, et al. Alendronate treatment of naturally-occurring periodontitis in beagle dogs. J Periodontol 1995; 66:211–7.
34. Reeves HL, Francis RM, Manas DM, et al. Intra- venous bisphosphonate prevents symptomatic osteoporotic vertebral collapse in patients after liver transplantation. Liver Transplant Surg 1998;4:404–9.
35. Seymour RA, Thomason JM, Nolan A. Oral lesions in organ transplant patients. J Oral Pathol Med 1997;26:297–304.
36. Yamalik N, Avcikurt UF, Caglayan F, Eratalay K. The importance of oral foci of infection in renal transplantation. Aust Dent J 1993;38:108–13.
37. Naylor GD, Hall EH, Terezhalmy GT. The patient with chronic renal failure who is undergoing dialysis or renal transplantation: another consid- eration for antimicrobial prophylaxis. Oral Surg Oral Med Oral Pathol 1988;65:116–21.
38. Alfrey AC. Phosphate, aluminum and other ele- ments in chronic renal disease. In: Schrier RW, Gottschalk CW, editors. Diseases of the kidney, 5th ed. Boston: Little, Brown and Co.; 1991. p. 3153.
39. Tolkoff-Rubin NE. Dialysis and transplantation. In: Dale DC, Federman DD, editors. Scientific American medicine. New York: Scientific Amer- ican Medicine, Inc. 1996.
40. Gotch FA, Sargent JA. A mechanistic analysis of the National Cooperative Dialysis Study. Kid- ney Int 1985;28:526–34.
41. Beck LH. Requiem for gouty nephropathy. Kidney Int 1986;30:280–7.
42. Schulman G, Hakim RM. Complications of hemodialysis. In: Jacobson H, Shaker K, Klahr S, editors. Principles and practice of nephrology, 2nd ed. St. Louis: C.V. Mosby Co.; 1995. p. 673.
43. Brescia MJ, Cimino JE, Appel K, Harwich BJ. Chronic hemodialysis using venipuncture and surgically created arteriovenous fistula. N Engl J Med 1966;275:1089–92.
44. Carpenter CB, Lazarus JM. Dialysis and transplanta- tion in the treatment of renal failure. In: Fauci AS, Braunwald E, Wilson JO, et al, editors. Harrison’s Principles of internal medicine, 14th ed. New York: McGraw-Hill Co.; 1998. p. 1520–9.
45. Ruskin JD, Wood RP, Bailey MR, et al. Compara- tive trial of oral clotrimazole and nystatin for
Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 219
oropharyngeal candidiasis prophylaxis in ortho- topic liver transplant patients. Oral Surg Oral Med Oral Pathol 1992;74:567–71.
46. Schubert MM, Epstein JB, Lloyd ME, Cooney E. Oral infections due to cytomegalovirus in immunocompromised patients. J Oral Pathol Med 1993;22:268–73.
47. Whitley RJ, Blum MR, Barton N, de Miranda P. Pharmacokinetics of acyclovir in humans fol- lowing intravenous administration. A model for the development of parenteral antivirals. Am J Med 1982;73(Suppl 1A):165–71.
48. McCauley J. Medical complications. In: Shapiro R, Simmons RL, Starzl TE, editors. Complications of renal transplantation. Stamford, CT: Apple- ton & Lange; 1997. p. 299–313.
49. Finberg R, Fingeroth J. Infections in transplant recipients. In: Fauci AS, Braunwald E, Wilson JO, et al, editors. Harrison’s Principles of internal medicine, 14th ed. New York: McGraw-Hill Co.; 1998. p. 840–6.
50. Kusne S, Manez R. Infectious complications. In: Shapiro R, Simmons RL, Starzl TE, editors. Complications of renal transplantation. Stam- ford, CT: Appleton & Lange; 1997. p. 315–32.
51. Muzyka BC, Glick M. A review of oral fungal infections and appropriate therapy. J Am Dent Assoc 1995;126:63–72.
52. Aebischer MC, Zala LB, Braathen LR. Kaposi’s sar- coma as manifestation of immunosuppression in organ transplant recipients. Dermatology 1997;195:91–2.
53. al-Sulaiman MH, Mousa DH, Dhar JM, al-Khad- er A. Does regressed post-transplantation Kaposi’s sarcoma recur following reintroduction of immunosuppression? Am J Nephrol 1992; 12:384–6.
54. Bakr MA, Sobh M, el-Agroudy A, et al. Study of malignancy among Egyptian kidney transplant recipients. Transplant Proc 1997;29:3067–70.
55. Bencini PL, Marchesi L, Cainelli T, Crosti C. Kaposi’s sarcoma in kidney transplant recipients treated with cyclosporine. Br J Dermatol 1988; 118:709–14.
56. Bencini PL, Montagnino G, Sala F, et al. Cutaneous lesions in 67 cyclosporine-treated renal transplant recipients. Dermatologica 1986;172:24–30.
57. Blohme I, Larko O. No difference in skin cancer incidence with or without cyclosporine. A 5- year perspective. Transplant Proc 1992;24:313.
58. Bocchi EA, Higuchi ML, Vieira ML, et al. Higher incidence of malignant neoplasms after heart transplantation for treatment of chronic Chagas’ heart disease. J Heart Lung Transplant 1998;17: 399–405.
59. Brambilla L, Boneschi V, Fossati S, et al. Vinorel- bine therapy for Kaposi’s sarcoma in a kidney transplant patient. Dermatology 1997;194: 281–3.
60. Bunney MH, Benton EC, Barr BB, et al. The prevalence of skin disorders in renal allograft recipients receiving cyclosporine A compared with those receiving azathioprine. Nephrol Dialysis Transplant 1990;5:379–82.
61. Eslamboltchi F, Rees TD, Iacopino AM. Cyclospor- ine A-induced gingival enlargement. A compre- hensive review. Quintessence Int 1999 [In press].
62. Euvrard S, Kanitakis J, Pouteil-Noble C, et al. Aggres- sive squamous cell carcinomas in organ transplant recipients. Transplant Proc 1995;27:1767–8.
63. Glover MT, Deeks JJ, Raftery MJ, et al. Immuno- suppression and risk of non-melanoma skin cancer in renal transplant recipients [letter]. Lancet 1997;349:398.
64. Green C, Hawk JL. Cutaneous malignancy related to cyclosporine A therapy. Clin Exp Dermatol 1993;18:30–1.
65. Gruber SA, Gillingham K, Sothern RB, et al. De novo cancer in cyclosporine-treated and non- cyclosporine-treated adult primary renal allo- graft recipients. Clin Transplant 1994;8:388–95.
66. Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth. A col- lective review of current concepts. Periodontol 2000 1999 [In press].
67. Halmos O, Inturri P, Galligioni A, et al. Two cases of Kaposi’s sarcoma in renal and liver transplant recipients treated with interferon. Clin Trans- plant 1996;10:374–8.
68. Hepburn DJ, Divakar D, Bailey RR, Macdonald KJ. Cutaneous manifestations of renal trans- plantation in a New Zealand population. N Z Med J 1994;107:497–9.
69. Hiesse C, Kriaa F, Rieu P, et al. Incidence and type of malignancies occurring after renal transplan- tation in conventionally and cyclosporine-treat- ed recipients: analysis of a 20-year period in 1600 patients. Transplant Proc 1995;27:972–4.
70. Hiesse C, Larue JR, Kriaa F, et al. Incidence and type of malignancies occurring after renal trans- plantation in conventionally and in cyclosporine-treated recipients: single-center analysis of a 20-year period in 1600 patients. Transplant Proc 1995;27:2450–1.
71. Jordan ML. Malignancy after renal transplantation. In: Shapiro R, Simmons RL, Starzl TE, editors. Complications of renal transplantation. Stam- ford, CT: Appleton & Lange; 1997. p. 353–82.
72. London NJ, Farmery SM, Will EJ, et al. Risk of
220 Periodontal Medicine
neoplasia in renal transplant patients. Lancet 1995;346:403–6.
73. Margiotta V, Florena AM, Giuliana G. Primary angiosarcoma of the alveolar mucosa in a haemodialysis patient: case report and discus- sion. J Oral Pathol Med 1994;23:429–31.
74. Margolius I, Stein M, Spencer D, Bezwoda WR. Kaposi’s sarcoma in renal transplant recipients. Experience at Johannesburg Hospital, 1966- 1989. S African Med J 1994;84:16–7.
75. Masuhara M, Ogasawara H, Katyal SL, et al. Cyclo- sporine stimulates hepatocyte proliferation and accelerates development of hepatocellular carcino- mas in rats. Carcinogenesis 1993;14:1579–84.
76. Maxymiw WG, Wood RE. The role of dentistry in patients undergoing bone marrow transplanta- tion. Br Dent J 1989;167:229–34.
77. Maxymiw WG, Wood RE, Lee L. Primary, multi- focal, non-Hodgkin’s lymphoma of the jaws presenting as periodontal disease in a renal transplant patient. Int J Oral Maxillofac Surg 1991;20:69–70.
78. Merot Y, Miescher PA, Balsiger F, et al. Cutaneous malignant melanomas occurring under cyclo- sporine A therapy: a report of two cases. Br J Dermatol 1990;2:237–9.
79. Montagnino G, Bencini PL, Tarantino A, et al. Clinical features and course of Kaposi’s sarcoma in kidney transplant patients: report of 13 cases. Am J Nephrol 1994;14: 121–6.
80. Ozen S, Saatci U, Karaduman A, et al. Kaposi’s sar- coma in a paediatric renal transplant recipient. Nephrol Dialysis Transplant 1996;11:1162–3.
81. Penn I. Cancers in cyclosporine-treated vs azathio- prine-treated patients. Transplant Proc 1996;28: 876–8.
82. Rees TD. Drugs and oral disorders. Periodontol 2000 1998;18:21–36.
83. Regev E, Zeltser R, Lustmann J. Lip carcinoma in renal allograft recipient with long-term immuno- suppressive therapy. Oral Surg Oral Med Oral Pathol 1992;73:412–4.
84. Sabeel A, Qunibi W. Recurrent Kaposi’s sarcoma in a renal transplant recipient maintained on min- imum doses of immunosuppression [letter]. Neph Dialysis Transplant 1998;13:1609–10.
85. Thomas DW, Seddon SV, Shepherd JP. Systemic immunosuppression and oral malignancy: a report of a case and review of the literature. Br J Oral Maxillofac Surg 1993;31:391–3.
86. Veness MS. Cardiac transplant-related cutaneous malignancies in an Australian recipient: immunosuppression, friend or foe? Clin Oncol 1998;10:194–7.
87.Jonas S, Rayes N, Neumann U, et al. De novo malig- nancies after liver transplantation using tacrolimus-based protocols or cyclosporine- based quadruple immunosuppression with an interleukin-2 receptor antibody or antihymo- cyte globulin. Cancer 1997;6:1141–50.
88.Lipkowitz GS, Madden RL. Transmission of Kaposi’s sarcoma by solid organ donation. Transplant Sci 1994;4:9–11.
89.Sheil AG, Disney AP, Mathew TH, Amiss N. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplanta- tion. Transplant Proc 1993;25:1383–4.
90.Varga E, Tyldesley WR. Carcinoma arising in cyclosporine-induced gingival hyperplasia. Br Dent J 1991;171:26–7.
91.Patton LL, Ship JA. Treatment of patients with bleeding disorders. Dent Clin North Am 1994; 38:465–82.
92.Varga E, Lennon M, Mair L. Pre-transplant gingival hyperplasia predicts severe cyclosporine- induced gingival overgrowth in renal transplant patient. J Clin Periodontol 1998;25:225–30.
93.Adams CK, Famili P. A study of the effects of FK506 on gingival tissues. Transplant Proc 1991;23:3193–4.
94.Nery E, Edson R. Prevalence of nifedipine-induced gingival hyperplasia. J Periodontol 1995;66: 572–8.
95.Ryman K, Pharm D, Gurk-Turner C. Pharmacology notes—calcium channel blocker review. BUMC Proc 1999;12:34–6.
96.Thomason JM, Seymour RA, Ellis JS, et al. Deter- minants of gingival overgrowth severity in organ transplant patients. An examination of the role of HLA phenotype. J Clin Periodontol 1996; 23:628–34.
97.Wilson RF, Morel A, Smith D, et al. Contribution of individual drugs to gingival overgrowth in adult and juvenile renal transplant patients treated with multiple therapy. J Clin Periodontol 1998;25:457–64.
98.Jorgensen MG. Prevalence of amlodipine-related gin- gival hyperplasia. J Periodontol 1997;68:676–8.
99.Westbrook P, Bednarczyk EM, Carlson M, et al. Regression of nifedipine-induced gingival hyperplasia following switch to a same class cal- cium channel blocker, isradipine. J Periodontol 1997;68:645–50.
100. Naugle K, Darby ML, Bauman DB, et al. The oral heath status of individuals on renal dialysis. Ann Periodontol 1998;3:197–205.
101. Rees TD, Rose LF. Periodontal management of patients with cardiovascular diseases. J Peri- odontol 1996;67:627–35.
Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 221
102. Slots J. Casual or causal relationship between peri- odontal infection and non-oral disease: [guest editorial] J Dent Res 1998;77:1764–5.
103. Ciancio SG. Expanded and future uses of mouth- rinses. J Am Dent Assoc 1994;125: 29S–32S.
104. Ciancio SG, Bartz NW, Lauciello FR. Cyclosporine-induced gingival hyperplasia and chlorhexidine—a case report. Int J Periodont Restor Dent 1991;11:241–5.
105. MacPhail LA, Hilton JF, Heinic GS, Greenspan D. Direct immunofluoresence vs. culture for detect- ing HSV in oral ulcers: a comparison. J Am Dent Assoc 1995;126:74–8.
106. Rees TD. Periodontal considerations in the man- agement of the cancer patient. J Periodontol 1997;68:791–801.
107. Samaranayake LP, MacFarlane TW, Lamey PJ, Ferguson MM. A comparison of oral rinse and imprint sampling techniques for the detection of yeast, coliform and Staphylococcus aureus car- riage in the oral cavity. J Oral Pathol 1986; 15:386–8.
108. Dajani AS, Taubert KA, Wilson W, et al. Preven- tion of bacterial endocarditis. J Am Med Assoc 1997;277:1794–801, Circulation 1997;96: 358–66.
109. Lamas WP. A study of transient bacteremia fol- lowing an intraoral soft tissue biopsy [MS The- sis]. Baylor College of Dentistry; 1998.
110. Rutkauskas JS, Davis JW. Effects of chlorhexidine during immunosuppressive chemotherapy. A preliminary report. Oral Surg Oral Med Oral Pathol 1993;76:441–8.
111. Douglas LR, Douglass JB, Sieck JO, Smith PJ. Oral management of the patient with end-stage liver disease and the liver transplant patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:55–64.
112. Little JW, Rhodus NL. Dental treatment of the liver transplant patient. Oral Surg Oral Med Oral Pathol 1992;73:419–26.
113. Mulligan R, Weitzel KG. Pretreatment manage- ment of the patient receiving anticoagulant drugs. J Am Dent Assoc 1988;117:479–83.
114. Okamoto GU, Duperon DF. Bleeding control after extractions in a patient with aplastic ane- mia during bone marrow transplantation: report of case. ASDC J Dent Child 1989;56:50–5.
115. Rossmann JA, Rees TD. The use of hemostatic agents in dentistry. Postgrad Dent 1996;3(3): 3–12.
116. Keeffe EB. Chronic hepatitis. In: Dale DC, Feder- man DD, editors. Scientific American medi- cine. New York: Scientific American Medicine, Inc.; 1998.
117. Keeffe EB. Acute hepatitis. In: Dale DC, Federman DD, editors. Scientific American medicine. New York: Scientific American Medicine, Inc.; 1998.
118. Lodi G, Porter SR, Scully C. Hepatitis C virus infection: review and implications for the den- tist. Oral Surg Oral Med Oral Pathol Oral Radi- ol Endod 1998;86:8–22.
119. Semba SE, Mealey BL, Hallmon WW. Dentistry and the cancer patient. Part 2. Oral health man- agement of the chemotherapy patient. Comp Cont Educ Dent 1994;15:1378–88.
120. Sempoux C, Horsmans Y, Lerut J, et al. Acute lob- ular hepatitis as the first manifestation of recur- rent autoimmune hepatitis after orthotopic liver transplantation. Liver 1997;17:311–5.
121. Keeffe EB. Cirrhosis of the liver. In: Dale DC, Federman DD, editors. Scientific American medicine. New York: Scientific American Med- icine, Inc.; 1998.
122. Belli LS, Silini E, Alberti A, et al. Hepatitis C virus genotypes, hepatitis and hepatitis C virus recur- rence after liver transplantation. Liver Trans- plant Surg 1996;2:200–5.
123. Podolsky DK, Isselbacher KJ. Major complica- tions of cirrhosis. In: Fauci AS, Braunwald E, Wilson JO, et al, editors. Harrison’s Principles of internal medicine, 14th ed. New York: McGraw-Hill Co.; 1998. p. 1710–25.
124. Ilan Y, Galun E, Nagler A, et al. Sanctuary of hepatitis B virus in bone marrow cells of patients undergoing liver transplantation. Liver Transplant Surg 1996;2:206–10.
125. Dienstag J. Liver transplantation. In: Fauci AS, Braunwald E, Wilson JO, et al, editors. Harrison’s Principles of internal medicine, 14th ed. New York: McGraw-Hill Co.; 1998. p. 1721–5.
126. Isselbacher KJ, Podolsky DK. Infiltrative and meta- bolic diseases affecting the liver. In: Fauci AS, Braunwald E, Wilson JO, et al, editors. Harrison’s Principles of internal medicine, 14th ed. New York: McGraw-Hill Co.; 1998. p. 1717–20.
127. Sampathkumar P, Lerman A, Kim BY, et al. Post- liver transplantation myocardial dysfunction. Liver Transplant Surg 1998;4:399–403.
128. Ludwig J, Hashimoto E, Porayko MK, Therneau TM. Failed allografts and causes of death after orthotopic liver transplantation from 1985 to 1995: decreasing prevalence of irreversible hepatic allograft rejection. Liver Transplant Surg 1996;2:185–91.
129. Bussey HI, Force RW, Bianco TM, Leonard AD. Reliance of prothrombin time ratios causes sig- nificant errors in anticoagulation therapy. Arch Intern Med 1992;152:278–82.
222 Periodontal Medicine
130. Carr MM, Mason RB. Dental management of anticoagulated patients. J Can Dent Assoc 1992;58:838–44.
131. DeClerck D, Vinckier F, Vermylen J. Influence of anticoagulation on blood loss following dental extractions. J Dent Res 1992;71:387–90.
132. Hirsh J, Dalen JE, Deykin D, Poller L. Oral anti- coagulants. Mechanism of action, clinical effec- tiveness, and optimal therapeutic range. Chest 1992;102(Suppl 4):312s–326s.
133. International Committee for Standardization in Haematology and International Committee on Thrombosis and Haemostasis. ICSH/ICTH recommendations for reporting prothrombin time in oral anticoagulant control. J Clin Pathol 1985;38:133–4.
134. Lippert S, Gutschik E. Views of cardiac-valve prosthesis patients and their dentists on antico- agulation therapy. Scand J Dent Res 1994;102: 168–71.
135. Martinowitz U, Mazar AL, Taicher S, et al. Dental extraction for patients on oral anticoagulant therapy. Oral Surg Oral Med Oral Pathol 1990;70:274–7.
136. Purcell CAH. Dental management of the antico- agulated patient. N Z Dent J 1997;93:87–92.
137. Ramstrom G, Sindet-Pedersen S, Hall G, et al. Prevention of postsurgical bleeding in oral surgery using tranexamic acid without dose modification of oral anticoagulants. J Oral Max- illofac Surg 1993;51:1211–6.
138. Rakocz M, Mazar A, Varon D, et al. Dental extrac- tions in patients with bleeding disorders. Oral Surg Oral Med Oral Pathol 1993;75:280–2.
139. Cutler LS. Evaluation and management of the dental patient with a history of hepatitis, jaun- dice, or liver disease. J Conn State Dent Assoc 1985; 59:115–7.
140. Carithers RL, Perkins JD. Liver and pancreas transplantation. In: Dale DC, Federman DD, editors. Scientific American medicine. New York: Scientific American Medicine, Inc.; 1998.
141. Caiffa WT, Vlahov D, Graham NMH. Drug smoking, Pneumocystis carinii pneumonia, and immunosuppression increase risk of bacterial pneumonia in HIV-seropositive injection drug users. Am J Respir Crit Care Med 1994;150: 1493–8.
142. Maurer JR. Lung transplantation. In: Fauci AS, Braunwald E, Wilson JO, et al, editors. Harrison’s Principles of internal medicine, 14th ed. New York: McGraw-Hill Co.; 1998. p. 1491–3.
143. Hohlfeld J, Niedermeyer J, Hamm H, et al. Sea- sonal onset of bronchiolitis obliterans syndrome
in lung transplant recipients. J Heart Lung Transplant 1996;15:888–94.
144. Sundaresan S, Trulock EP, Mohanakumar T, et al. Prevalence and outcome of bronchiolitis obliter- ans syndrome after lung transplantation. Wash- ington University Lung Transplant Group. Ann Thorac Surg 1995;60:1341–6.
145. Maurer JR, Tewari S. Nonpulmonary medical complications in the intermediate and long- term survivor [review]. Clin Chest Med 1997; 18:367–82.
146. Scannapieco FA, Mylotte JM. Relationships between periodontal disease and bacterial pneu- monia. J Periodontol 1996;67:1114–22.
147. Hayes C, Sparrow D, Cohen M, et al. The associ- ation between alveolar bone loss and pulmonary function: the VA dental longitudinal study. Ann Periodontol 1998;3:257–61.
148. Limeback H. Implications of oral infections on systemic diseases in the institutionalized elderly with a special focus on pneumonia. Ann Peri- odontol 1998;3:262–75.
149. Bourke JP, Loaiza A, Parry G, et al. Role of ortho- topic heart transplantation in the management of patients with recurrent ventricular tach- yarrhythmias following myocardial infarction. Heart 1998;80:473–8.
150. Schroeder JS. Cardiac transplantation. In: Fauci AS, Braunwald E, Wilson JO, et al, editors. Harrison’s Principles of internal medicine, 14th ed. New York: McGraw-Hill Co.; 1998. p. 1298–300.
151. Moons P, De Geest S, Abraham I, et al. Symptom experience associated with maintenance immunosuppression after heart transplantation: patients’ appraisal of side effects. Heart Lung 1998;27:315–25.
152. Beck JD, Offenbacher S, Williams R, et al. Peri- odontitis: a risk factor for coronary heart dis- ease? Ann Periodontol 1998;3:127–41.
153. Herzberg MC, Meyer MW. Dental plaque, platelets, and cardiovascular diseases. Ann Peri- odontol 1998;3:151–60.
154. Herzberg MC, Meyer MW. Effects of oral flora on platelets: possible consequences in cardiovascu- lar disease. J Periodontol 1996;67:1138–42.
155. Joshipura KJ, Douglas CW, Willett WC. Possible explanations for the tooth loss and cardiovascu- lar disease relationship. Ann Periodontol 1998;3:175–83.
156. Kinane DF. Periodontal diseases’ contribution to cardiovascular disease: an overview of potential mechanisms. Ann Periodontol 1998;3:142–50.
157. Lowe GDO. Etiopathogenesis of cardiovascular disease: hemostasis, thrombosis, and vascular medicine. Ann Periodontol 1998;3:121–6.
Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 223
158. Mealey BL. Influence of periodontal infections on systemic health. Periodontol 2000 1999 [In press].
159. Page RC. The pathobiology of periodontal diseases may affect systemic diseases: inversion of a par- adigm. Ann Periodontol 1998;3:108–20.
160. Bader G, Lejeune S, Messner M. Reduction of cyclosporine-induced gingival overgrowth fol- lowing a change to tacrolimus. A case history involving a liver transplant patient. J Periodon- tol 1998;69:729–32.
161. Baldwin L, Henderson A, Hickman P. Effect of postoperative low-dose dopamine on renal func- tion after elective major vascular surgery. Ann Intern Med 1994;120:744–7.
162. Mattsson T, Arvidson K, Heimdahl A, et al. Alter- ations in test acuity associated with allogeneic bone marrow transplantation. J Oral Pathol Med 1992;21:33–7.
163. Niehaus CS, Meiller TF, Peterson DE, Overholser CD. Oral complications in children during can- cer therapy. Cancer Nurs 1987;10:15–20.
164. Bressman E, Decter JA, Chasens AI, Sackler RS. Acute myeloblastic leukemia with oral manifes- tations. Report of a case. Oral Surg Oral Med Oral Pathol 1982;54:401–3.
165. Brown AT, Shupe JA, Sims RE, et al. In vitro effect of chlorhexidine and amikacin on oral gram-negative bacilli from bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 1990;70:715–9.
166. Brown AT, Sims RE, Raybould TP, et al. Oral gram-negative bacilli in bone marrow transplant patients given chlorhexidine rinses. J Dent Res 1989;68:1199–204.
167. Peters E, Monopoli M, Woo SB, Sonis S. Assess- ment of the need for treatment of postendodon- tic asymptomatic periapical radiolucencies in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 1993;76:45–8.
168. Bartold PM. Cyclosporine and gingival over- growth. J Oral Pathol 1988;16:463–8.
169. Ferretti GA, Ash RC, Brown AT, et al. Chlorhexi- dine for prophylaxis against oral infections and associated complications in patients receiving bone marrow transplants. J Am Dent Assoc 1987;114:461–7.
170. Ferretti GA, Hansen IA, Whittenburg K, et al. Therapeutic use of chlorhexidine in bone mar- row transplant patients: case studies. Oral Surg Oral Med Oral Pathol 1987;63:683–7.
171. Flaitz CM, Hammond HL. The immunoperoxi- dase method for the rapid diagnosis of intraoral herpes simplex virus infection in patients receiv- ing bone marrow transplants. Spec Care Dent 1988;8:82–5.
172. Fleming P. Dental management of the pediatric oncology patient. Curr Opin Dent 1991;1: 577–82.
173. Montgomery MT, Redding SW, LeMaistre CF. The incidence of oral herpes simplex virus infection in patients undergoing cancer chemotherapy. Oral Surg Oral Med Oral Pathol 1986;61:238–42.
174. Poland J. Prevention and treatment of oral com- plications in the cancer patient. Oncology 1991;5: 45–50,52,57,61–2.
175. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996;335: 91–7.
176. Berkowitz RJ, Strandjord S, Jones P, et al. Stoma- tologic complications of bone marrow trans- plantation in a pediatric population. Pediatric Dent 1987;9:105–10.
177. Cooper B. New concepts in management of acute leukemia. BUMC Proc 1990;3:31–3.
178. Devine SM, Larson RA. Acute leukemia in adults: recent developments in diagnosis and treat- ment. CA Cancer J Clin 1994;44:326–52.
179. Greenberg MS, Garfunkel A. Hematologic disease. In: Lynch MA, Brightman VJ, Greenbert MS, editors. Burket’s Oral medicine 9th ed. Philadel- phia: J.B. Lippincott Co.; 1994. p. 510–8.
180. Lazarchik DA, Filler SJ, Winkler MP. Dental eval- uation in bone marrow transplantation. Gen Dent 1995;43: 369–71.
181. Vose JM, Kennedy BC, Bierman PJ, et al. Long- term sequelae of autologous bone marrow or peripheral stem cell transplantation for lym- phoid malignancies. Cancer 1992;69:784–9.
182. Armitage JO. Bone marrow transplantation. In: Fauci AS, Braunwald E, Wilson JO, et al, edi- tors. Harrison’s Principles of internal medicine, 14th ed. New York: McGraw-Hill Co.; 1998. p. 724–30.
183. Collins RH, Miller GW, Fay JW. Autologous bone marrow transplantation: a review. BUMC Proc 1991;4:3–12.
184. Rhodus NL, Little JW. Dental management of the bone marrow transplant patient. Comp Cont Educ Dent 1992;13:1042–50.
185. Dahllöf G, Heimdahl A, Modéer T, et al. Oral mucous membrane lesions in children treated with bone marrow transplantation. Scand J Dent Res 1989;97:268–77.
186. Seto BG, Kim M, Wolinsky L, et al. Oral mucosi- tis in patients undergoing bone marrow trans- plantation. Oral Surg Oral Med Oral Pathol 1985;60:493–507.
224 Periodontal Medicine
187. Wescott WB. Dental management of patients being treated for oral cancer. CDA J 1985;13:42–7.
188. American Dental Association. Patients receiving cancer chemotherapy. Chicago: American Den- tal Association; 1989.
189. Birek C, Patterson B, Maximiw WC, Minden MD. EBV and HSV infections in a patient who had undergone bone marrow transplantation: oral manifestations and diagnosis by in situ nucleic acid hybridization. Oral Surg Oral Med Oral Pathol 1989;68:612–7.
190. Childers NK, Stinnett EA, Wheeler P, et al. Oral complications in children with cancer. Oral Surg Oral Med Oral Pathol 1993;75:41–7.
191. Barasch A, Mosier KM, D’Ambrosio JA, et al. Postextraction osteomyelitis in a bone marrow transplant recipient. Oral Surg Oral Med Oral Pathol 1993;75:391–6.
192. Barrett AP, Schifter M. Antibiotic strategy in oro- facial/head and neck infections in severe neu- tropenia. Oral Surg Oral Med Oral Pathol 1994;77:350–5.
193. Cutler LS. Evaluation and management of the den- tal patient with cancer. I. Complications associat- ed with chemotherapy or bone marrow transplan- tation. J Conn State Dent Assoc 1987;61:236–8.
194. Epstein JB, Sherlock CH, Page JL, et al. Clinical study of herpes simplex virus infection in leukemia. Oral Surg Oral Med Oral Pathol 1990;70: 38–43.
195. Kolbinson DA, Schubert MM, Flournoy N, Tru- elove EL. Early oral changes following bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1988;66:130–8.
196. Mattsson T, Heimdahl A, Dahllöf G, et al. Oral and nutritional status in allogeneic marrow recipients treated with T-cell depletion or cyclosporine combined with methotrexate to prevent graft-versus-host disease. Oral Surg Oral Med Oral Pathol 1992;74:34–40.
197. Nikoskelainen J. Oral infections related to radia- tion and immunosuppressive therapy. J Clin Periodontol 1990;17:504–7.
198. Peterson DE, Minah GE, Overholser CD, et al. Microbiology of acute periodontal infection in myelosuppressed cancer patients. J Clin Oncol 1987;5:1461–8.
199. Redding SW, Montgomery MT. Acyclovir pro- phylaxis for oral herpes simplex virus infection in patients with bone marrow transplants. Oral Surg Oral Med Oral Pathol 1989;67:680–3.
200. Schubert MM, Peterson DE, Flournoy N, et al. Oral and pharyngeal herpes simplex virus infection after allogeneic bone marrow transplantation:
analysis of factors associated with infection. Oral Surg Oral Med Oral Pathol 1990;70:286–93.
201. Schuchter LM, Wingard JR, Piantadosi S, et al. Herpes zoster infection after autologous bone marrow transplantation. Blood 1989;74:1424–7.
202. Shearer BH, Hay KD. Hard and soft tissue oral changes following bone marrow transplanta- tion. N Z Dent J 1987;83:103–4.
203. Thurmond JM, Brown AT, Sims RE, et al. Oral Candida albicans in bone marrow transplant patients given chlorhexidine rinses: occurrence and susceptibilities to the agent. Oral Surg Oral Med Oral Pathol 1991;72:291–5.
204. Wade JC, Newton B, McLaren C, et al. Intra- venous acyclovir to treat mucocutaneous herpes simplex virus infection after marrow transplan- tation: a double blind study. Ann Intern Med 1982;96:265–9.
205. Dahllöf G, Barr M, Bolme P, et al. Disturbances in dental development after total body irradiation in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 1988;65:41–4.
206. Dahllöf G, Forsberg CM, Ringdén O, et al. Facial growth and morphology in long-term survivors after bone marrow transplantation. Eur J Orthod 1989;11:332–40.
207. Dahllöf G, Krekmanova L, Kopp S, et al. Cran- iomandibular dysfunction in children treated with total-body irradiation and bone marrow transplantation. Acta Odontol Scand 1994;52: 99–105.
208. Dahllöf G, Modéer T, Bolme P, et al. Oral health in children treated with bone marrow transplan- tation: a one-year follow-up. ASDC J Dent Child 1988;55:196–200.
209. Dahllöf G, Rozell B, Forsberg CM, Borgström B. Histologic changes in dental morphology induced by high dose chemotherapy and total body irradiation. Oral Surg Oral Med Oral Pathol 1994;77:56–60.
210. Epstein JB, Sherlock CH, Wolber RA. Hairy leukoplakia after bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1993;75: 690–5.
211. Ellegaard B, Bergmann OJ, Ellegaard J. Effect of plaque removal on patients with acute leukemia. J Oral Pathol Med 1989;18:54–8.
212. Epstein JB, Vickars L, Spinelli J, Reece D. Effica- cy of chlorhexidine and nystatin rinses in pre- vention of oral complications in leukemia and bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1992;73:682–9.
213. Raether D, Walker PO, Bostrum B, Weisdorf D. Effectiveness of oral chlorhexidine for reducing
Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 225
body irradiation on salivary gland function and caries-associated oral microflora in bone mar- row transplant patients. Oral Surg Oral Med Oral Pathol 1992;73:670–6.
229. Wandera A, Walker PO. Bilateral pyogenic granu- loma of the tongue in graft-versus-host disease: report of a case. ASDC J Dent Child 1994;61: 401–3.
230. Lee L, Miller PA, Maxymiw WG, et al. Intraoral pyogenic granuloma after allogeneic bone mar- row transplant. Report of three cases. Oral Surg Oral Med Oral Pathol 1994;78:607–10.
231. Redding SW, Callander NS, Haveman CW, Leonard DL. Treatment of oral chronic graft- versus-host disease with PUVA therapy: case report and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:183–7.
232. Lefkoff MA, Beck FM, Horton JE. The effective- ness of a disposable tooth cleansing device on plaque. J Periodontol 1995;66:218–21.
233. Wingard JR, Niehaus CS, Peterson DE, et al. Oral mucositis after bone marrow transplantation. A marker of treatment toxicity and predictor of hepatic veno-occlusive disease. Oral Surg Oral Med Oral Pathol 1991;72:419–24.
234. Borowski B, Benhamou E, Pico JL, et al. Preven- tion of oral mucositis in patients treated with high-dose chemotherapy and bone marrow transplantation: a randomized controlled trial comparing two protocols of dental care. Eur J Cancer B Oral Oncol 1994;30B:93–7.
235. Fay JT, O’Neal R. Dental responsibility for the medically compromised patient. J Oral Med 1984;39:148–56.
236. National Institutes of Health. National Institutes of Health consensus development conference statement: oral complications of cancer thera- pies: diagnosis, prevention, and treatment. J Am Dent Assoc 1989;119:179–83.
237. Rosenberg SW. Oral care of chemotherapy patients. Dent Clin N Am 1990;34:239–50.
238. Carl W. Managing the oral manifestations of can- cer therapy. Part II. Chemotherapy. Comp Cont Educ Dent 1988;9:376–86.
239. Cheatham BD, Henry RJ. A dental complication involving Pseudomonas during chemotherapy for acute lymphoblastic leukemia. J Clin Pediatr Dent 1994;18:215–7.
240. O’Sullivan EA, Duggal MS, Bailey CC, et al. Changes in the oral microflora during cytotoxic chemotherapy in children being treated for acute leukemia. Oral Surg Oral Med Oral Pathol 1993;76:161–8.
stomatitis in a pediatric bone marrow transplant population. Pediatr Dent 1989;11:37–42.
214. Eggleston TI, Ziccardi VB, Lumerman H. Graft- versus-host disease: case report and discussion. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:692–6.
215. LeVeque FG. An unusual presentation of chronic graft-versus-host disease in an unrelated bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1990;69:581–4.
216. Williams MC, Lee GT. Childhood leukemia and dental considerations. J Clin Pediatr Dent 1991;15:160–4.
217. Williamson LM. Transfusion associated graft ver- sus host disease and its prevention [editorial]. Heart 1998;80:211–2.
218. Curtis JW Jr, Caughman GB. An apparent unusu- al relationship between rampant caries and graft- versus-host disease. Oral Surg Oral Med Oral Pathol 1994;78:267–72.
219. Heimdahl A, Johnson G, Danielsson KH, et al. Oral condition of patients with leukemia and severe aplastic anemia. Follow-up one year after bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1985;60:498–504.
220. Woo S-B, Lee SJ, Schubert MM. Graft-vs-host dis- ease. Crit Rev Oral Biol Med 1997;8:201–16.
221. LeVeque FG, Ratanatharathorn V, Danielsson KH, et al. Oral cytomegalovirus infection in an unrelated bone marrow transplantation with possible mediation by graft-versus-host disease and the use of cyclosporine A. Oral Surg Oral Med Oral Pathol 1994;77:248–53.
222. Barrett AP. Graft-versus-host disease. A clinico- pathologic review. Ann Dent 1987;46:7–11.
223. Heimdahl A, Mattsson T, Dahllöf G, et al. The oral cavity as a port of entry for early infections in patients treated with bone marrow transplan- tation. Oral Surg Oral Med Oral Pathol 1989;68:711–6.
224. Hiroki A, Nakamura S, Shinohara M, Oka M. Significance of oral examination in chronic graft-versus-host disease. J Oral Pathol Med 1994;23: 209–15.
225. Johnson ML, Farmer ER. Graft-versus-host reac- tions in dermatology. J Am Acad Dermatol 1998;38:369–92.
226. Allen CM, Kapoor N. Verruciform xanthoma in a bone marrow transplant recipient. Oral Surg Oral Med Oral Pathol 1993;75:591–4.
227. Barrett AP. Gingival lesions in leukemia. A classi- fication. J Periodontol 1984;55:585–8.
228. Jones LR, Toth BB, Keene HJ. Effects of total
CHAPTER 14
BLEEDING DISORDERS Spencer W. Redding, DDS, MEd Carl W. Haveman, DDS, MS
The tissues of the oral cavity are supported by a rich and varied blood supply. Therefore, it is com- mon for abnormalities of the hemostatic system to present with manifestations in the oral cavity. Mul- tiple oral manipulations including periodontal surgery, scaling and root planing, extractions, and biopsies require an intact coagulation system for normal hemostasis. Patients with gingivitis and periodontal disease are particularly vulnerable to bleeding disorders because of the increased vascu- larity associated with inflammation. Certainly, sur- gical procedures in these patients subject them to bleeding problems; however, spontaneous bleeding can also occur in sites of significant tissue inflam- mation. Therefore, it is necessary for the periodon- tist to have a good working knowledge of the hemostatic mechanism and be prepared to manage locally and, when necessary, systemically patients with diseases of hemostasis. This chapter will dis- cuss the most common causes of oral bleeding and will include material on the appropriate manage- ment of these patients.
NORMAL HEMOSTASIS
The evaluation and treatment of patients with bleeding disorders or of patients who present with abnormal bleeding require a basic understanding of the normal physiology of hemostasis. This process is quite complex, involving numerous blood and tissue products, but all activity can be divided into three phases: the vascular phase, the platelet phase, and the coagulation phase. These three phases must work together to achieve ade- quate clot formation.
The vascular phase is initiated immediately following injury to a blood vessel. Mediation by the autonomic nervous system results in direct vasoconstriction in the area of the injured vessel.
Adjacent vessels are also involved in this vaso- constriction process. Blood flow to the area is slowed, resulting in a reduction of blood loss fol- lowing injury.1,2
The platelet phase is also initiated after trauma to blood vessels and results in the circulating platelets attaching to the site of injury in a process termed “platelet adhesion.” Other substances that contribute to this process of platelet adhesion include subendothelial collagen, platelet receptors, fibronectin, thrombospondin, and Factor VIII von Willebrand’s. Platelet adhesion initiates a process whereby more circulating platelets clump to the initial group of platelets. This process, termed “platelet aggregation,” requires substances both internal and external to the functioning platelet. These substances include thromboxane A2, adenosinediphosphate (ADP), and thrombin. The platelet phase is extremely critical in stopping bleeding from small vessels as these small platelet plugs formed in this process can occlude vessels up to 50 microns in diameter.1,2
The coagulation phase is the final and most involved of the three phases. It, too, is initiated by the process of vascular injury and results in mul- tiple blood proteins or factors being activated. These factors then activate other factors in a process that is termed the “coagulation cascade.” Thrombin is formed as a result of this cascade, and fibrin is formed from the combination of thrombin and fibrinogen. Fibrin is the substance that makes up the stabilized clot at the end of the coagulation process. Prothrombin is converted to thrombin by activated Factor X which results from two different pathways. The intrinsic path- way involves components contained within the blood itself and includes factors XII, XI, IX, and VIII. The extrinsic pathway is activated by sub- stances that are external to the blood, called tissue thromboplastins and includes factor VII. Integri-
228 Periodontal Medicine
ty of both pathways is necessary for normal clot formation. After a clot is formed and stabilized, it is broken down over a period of time. This process, called “fibrinolysis,” is initiated even while the clot is being formed. A substance from the blood vessel endothelium, called tissue plas- minogen activator (TPA), stimulates the release of plasmin, which dissolves the clot. Both circu-
lating factors and plasmin are inactivated by pro- teins and removed from the circulation by the reticuloendothelial system. This process limits clot formation and lysis to the site of the injury. Figure 14–1 provides a systematic representation of the multiple processes and how they interre- late for normal hemostasis. Even though the three phases of hemostasis are described here as
Figure 14–1. Phases of Normal Hemostasis. With permission from Montgomery MT, Redding SW, editors. Oral-facial emer- gencies. Chicago: Federation of Special Care Organizations in Dentistry; 1994.
Bleeding Disorders 229
separate processes for ease of understanding, it is still imperative to realize that there is multiple interrelation of these three phases. For example, phospholipids released from the platelet phase are necessary for the normal activation of factors in the coagulation phase, and thrombin is required for the smooth functioning of platelet aggregation. All three phases and their interrela- tion are necessary for normal clot formation.
BLEEDING DISORDERS
Vascular Disorders
Any disruption in the three phases of hemostasis or in their interaction can result in a significant bleed- ing disorder.1,2 Vascular disorders other than from trauma are relatively rare. However, the possibility of abnormal and prolonged bleeding must be con- sidered in a person whose hemostatic system is normal but in whom a large vessel has been inad- vertently traumatized leading to copious bleeding. Vascular wall abnormalities do occur and include hereditary hemorrhagic telangiectasia and certain deficiency diseases. Hereditary hemorrhagic telangiectasia is an autosomal-dominant inherited disorder characterized by multiple small vascular malformations found on epithelial surfaces (Figure 14–2). When traumatized, these lesions may bleed. Treatment focuses on topical control of the hem- orrhage. Steroid therapy may reduce the incidence of bleeding.
Long-term systemic steroid use can induce vascular friability. Also, elderly individuals may manifest senile purpura as a result of a loss of pro- tective fat from the cutaneous vascular bed. Many healthy women, especially in the older age group, will complain of easy bruising.2
Platelet Disorders
Platelet disorders can be divided into primary and secondary forms. Primary diseases include idio- pathic thrombocytopenic purpura (ITP), throm- botic thrombocytopenic purpura (TTP), and thrombasthenia.
Idiopathic thrombocytopenic purpura pre- sents as a chronic disease characterized by autoim- mune platelet destruction. Over 50% of all cases of ITP are without known cause, but ultimately it is determined that many patients have underlying autoimmune diseases such as systemic lupus ery- thematosus. It has also been recognized increasing-
ly as a complication of HIV infection. In adults, ITP is a chronic disease that waxes and wanes. However, in children, the disease has an acute and usually self-limiting course. It frequently follows minor viral infections. The onset of bleeding prob- lems in patients with ITP may be either insidious or abrupt. These patients present with a reduced platelet count and easy bleeding. Treatment for ITP usually includes prednisone therapy. Splenec- tomy is performed in patients who fail to respond after 2 to 3 weeks. Another treatment available for ITP is intravenous immune globulin.3,4
Thrombotic thrombocytopenic purpura is a relatively rare form of thrombocytopenia, which results in a decreased platelet number and para- doxically widespread platelet thrombi that form in the microcirculation. Some cases involve infec- tious, genetic or immunologic etiologies, but the cause in most cases is unknown. Major clinical manifestations include thrombocytopenia which may result in severe bleeding, microangiopathic hemolytic anemia, neurologic signs and symptoms including headache, disorientation, seizures, coma, and focal neurologic signs, renal abnormalities including proteinuria and hematuria, and fever. In addition to thrombocytopenia, diagnosis of this disease can be made by looking for microscopic clots in vessels from a gingival biopsy. Unlike ITP, the prognosis for TTP is poor, with up to 50% mortality. Therapy has been highly unpredictable. Initially, prednisone therapy is started, followed by plasmaphoresis with plasma exchange or infusion of fresh frozen plasma. Second-line treatments may
Figure 14–2. Photograph of vascular lesions on fingers asso- ciated with hereditary hemorrhagic telangiectasia. With per- mission from Montgomery MT, Redding SW, editors. Oral- facial emergencies. Chicago: Federation of Special Care Organizations in Dentistry; 1994.
230 Periodontal Medicine
include heparin, aspirin, vincristine, and splenec- tomy. Platelet transfusions are contraindicated since they may exacerbate the thrombotic compo- nent.4,5
Primary functional platelet abnormalities are rare. Thrombasthenia, or Glanzmann’s thrombas- thenia, is an unusual autosomal recessive disease, which shows platelet abnormalities characterized by a structural loss of platelet membrane sub- stances. Platelet count and morphology are normal in this disorder. Treatment of thrombasthenia is often not necessary. However, any platelet-inhibit- ing drugs, including aspirin, should be avoided. Treatment for severe bleeding involves transfusion of normal platelets.4,6
Secondary causes of platelet abnormalities, especially thrombocytopenia, are much more com- mon than primary abnormalities. Any process or condition that either depresses bone marrow func- tion or increases platelet destruction may produce thrombocytopenia. Causes of these abnormalities include antineoplastic chemotherapy, severe liver and renal disease, and nonsteroidal anti-inflamma- tory drugs. Antineoplastic chemotherapy is toxic to normal bone marrow function; thus, megakary- ocyte production is decreased, resulting in lowered platelet counts (Figure 14–3). Patients with severe end-stage liver disease and severe end-stage kidney disease present with both qualitative and quantita- tive platelet defects. Platelet function is affected by continuous ingestion of high amounts of ethanol in chronic alcoholics and by circulating toxins sec-
ondary to liver or kidney failure. Hypersplenism as a result of portal hypertension secondary to alco- holic cirrhosis results in increased splenic sequestra- tion and a drop in platelet count. Nonsteroidal anti-inflammatory drugs, such as aspirin and ibuprofen, block the conversion of arachidonic acid to thromboxane. Thromboxane accelerates the platelets’ release of ADP, which is needed for platelet aggregation; therefore, blocking the forma- tion of thromboxane will reduce the release of ADP and impair platelet aggregation. Nonsteroidal anti- inflammatory drugs thus prolong the bleeding time. It is important to note that aspirin’s effect will be exerted on the platelet for its entire lifespan. However, the effect of drugs such as ibuprofen is only for the duration of drug therapy.4,7
Coagulation Disorders
Hemophilias Three disorders account for more than 95% of congenital disorders of blood coagulation. These include the two sex-linked disorders, hemophilia A or factor VIII deficiency and hemophilia B or fac- tor IX deficiency, and the autosomal von Wille- brand disease.
Hemophilia A is caused by a deficiency of fac- tor VIII. The diagnosis of hemophilia A is often made from observance of clinical bleeding and a prolonged partial thromboplastin time (PTT) and then an abnormal factor VIII assay. Hemarthrosis is the most characteristic disabling hemorrhage in these patients. Multiple hemarthroses tend to lead to joint swelling and ultimately joint collapse, with marked limitation or complete loss of motion. The disease is characterized by clinical bleeding, which is classified as severe, moderate, or mild, depending on the frequency of hemorrhage and the severity. The severity is usually related to the plasma level of fac- tor VIII. Severely affected individuals tend to have two or three bleeding episodes per month which may be profuse unless treated (Figure 14–4). Mod- erately affected individuals tend to bleed five to six times per year and may have prolonged periods of free bleeding. Mildly affected individuals may rarely bleed at all, except with significant trauma or surgi- cal stress. Generally, severe hemophiliacs have less than 1% of normal factor VIII, moderate hemo- philiacs have between 1 and 5%, and mild hemo- philiacs have between 5 and 30%. Inhibitors to fac- tor VIII develop in up to 20% of patients treated with factor VIII. The presence of inhibitors may make it very difficult to treat patients who have bleeds or to provide prophylaxis to patients who are
Figure 14–3. Photograph of hematoma of buccal mucosa in a patient who is severely thrombocytopenic from cancer chemotherapy. With permission from Montgomery MT, Redding SW, editors. Oral-facial emergencies. Chicago: Fed- eration of Special Care Organizations in Dentistry; 1994.
Bleeding Disorders 231
being treated surgically. Inhibitors can often be sup- pressed but if they are high, patients may not respond to any replacement therapy, making clinical bleeding truly life threatening.8,9,10
Hemophilia B—factor IX deficiency or Christmas disease—also results in an increased PTT and a reduced factor IX assay. Types and complications of hemorrhages in hemophilia B are similar to those in hemophilia A. As in factor VIII disease, level of factor IX is indicative of severity of disease, and disease is also described as mild, mod- erate, or severe.8,11
Von Willebrand disease is probably the most commonly diagnosed inherited bleeding disorder in adults because its manifestations are less severe than factor VIII or factor IX disease and often would not have been previously diagnosed. It is an autosomal disease (autosomal dominant in the most common forms but autosomal recessive in the most severe form) and is characterized by reduced levels of factor VIII along with qualitative platelet abnormalities. There are several different molecules related to factor VIII that are important in the understanding of von Willebrand disease. These include factor VIII (VIII), factor VIII von Wille- brand’s (vWf), and factor VIII von Willebrand antigen (vWf:Ag). Factor VIII von Willebrand’s cir- culates in plasma as a complex with factor VIII. It acts as a carrier for factor VIII and helps promote adhesion of the platelets to the subendothelium and to one another. Therefore, in addition to its role in coagulation, vWf plays a significant part in prima- ry hemostasis or the platelet phase. Therefore, von Willebrand disease will be marked by an increased PTT and a prolonged bleeding time. Von Wille- brand disease is divided into three different types, on the basis of the presence of different levels of fac- tor VIII, vWf, and vWf:Ag. (The blood levels of these molecules can vary over time in the same patient. Therefore, testing patients may be needed on more than one occasion to make an accurate diagnosis.) Type I is the most common form of the disease, where patients have reduced levels of all three of the above molecules. Type II variants are marked by differing combinations of normal and reduced levels of these molecules. Bleeding in types I and II is usually much less severe than with severe factor VIII disease. Bleeding from mucous mem- branes, including from the nasal, intestinal and uterine mucosa, is common as is bruising following minor trauma. Bleeding typically follows minor injury or surgery. Therefore, this disease may be first diagnosed in an adult who has had a minor surgical procedure such as dental surgery. In type
III disease, factor VIII levels are below 10% of nor- mal, and both vWf and vWf:Ag are absent. Type III is the most severe of the von Willebrand types clin- ically and may involve bleeding into joints and soft tissue.8,12
Factor XI disease, or hemophilia C, is an inher- ited autosomal recessive disease and is usually found in individuals of Jewish ancestry. In these patients, PTT is prolonged and diagnosis is made with a fac- tor XI assay. Most patients are asymptomatic throughout their lives and are diagnosed following postoperative bleeding. Bleeding after tooth extrac- tion is a common first presenting symptom.8,13
Management of patients with inherited coagulation disorders will be discussed under “Treatment.”
Anticoagulation The number of patients receiving anticoagulation, especially with Coumadin (warfarin sodium), has increased dramatically in recent years. These patients include those with prosthetic heart valves, chronic atrial fibrillation, or a past history of deep vein thrombosis, transient ischemic attacks, or stroke. Coumadin anticoagulation is an effective and convenient therapy because it can be given orally. Coumadin acts by inhibiting the vitamin-K- dependent carboxylation of factors II, VII, IX, and X (the so-called vitamin-K-dependent factors). Carboxylation of these factors is needed because without this activation, these factors are left out of the coagulation process. As will be explained later
Figure 14–4. Photograph of liver clot after tooth extraction in a patient with hemophilia A. With permission from Montgomery MT, Redding SW, editors. Oral-facial emer- gencies. Chicago: Federation of Special Care Organizations in Dentistry; 1994.
232 Periodontal Medicine
under the section on treatment, Coumadin antico- agulation is evaluated by prothrombin time (PT) and international normalized ratio (INR). With the increasing number of patients on Coumadin anticoagulation, the potential complication of abnormal bleeding is significant. Patients respond differently to the same dose of Coumadin and must be monitored routinely to ensure that their PT and INR are within the appropriate range. Patients on Coumadin who present to emergency rooms with abnormal intraoral bleeding secondary to an extraction or chronic periodontal disease are among the most difficult of patients to manage. Patients often do not understand the potential side effects of the drugs they are taking. Therefore, Coumadin anticoagulation problems should be considered in any patient that reports with abnor- mal bleeding.1,8,14
Heparin anticoagulation is commonly used in the inpatient setting. Heparin acts by accelerating antithrombin III, which inhibits coagulation fac- tors throughout the cascade in both the intrinsic and extrinsic pathways. Heparin is administered subcutaneously or intravenously and is monitored by PTT.1
Liver Disease The liver is the site of production of fibrinogen, factors II, VII, VIII, IX, X, XII, and XIII as well as antithrombin III. Severe liver disease may result in reduced synthesis of any or all of these factors. Dis- eases such as alcoholic cirrhosis, chronic hepatitis (especially hepatitis C), and others can result in a significant decrease in these clotting factors. These diseases will be marked by an increase in PT and PTT. The vitamin-K-dependent factors (II, VII, IX, and X) are the most sensitive to liver disease and may be the only abnormalities in mild early hepatic disease. Conversely, factors V and VIII are the most resistant to hepatocellular disease and are only decreased in fulminant hepatitis and severe liver failure. Therefore, a decreased level of factor VIII is an ominous sign.1,8
Hemorrhage in patients with severe liver disease can be overwhelming. Bleeding can occur sponta- neously from mucous membranes, skin, and other sites. Complications of chronic liver disease, such as varices and gastritis, may become life threatening when complicated by abnormalities of hemostasis. Because of coagulation defects and platelet abnor- malities, patients with severe liver disease can be the most difficult to manage with regard to bleeding associated with surgical procedures. In patients with the most severe end-stage liver disease, liver trans-
plantation becomes the only viable therapy. Table 14–1 provides a quick reference for the appropriate characteristics of bleeding disorders.
PATIENT EVALUATION
History
The most important factor in identifying patients with potential defects in hemostasis is patient his- tory. Patients should be asked, through question- naires and interviews, about any past abnormal bleeding. Any patient that presents with abnormal bleeding should be investigated further to try to determine any past history or any incident that is suspicious. Table 14–2 is a group of appropriate questions to ask the patient who presents with abnormal bleeding.1
Laboratory Evaluation
Four screening laboratory tests are commonly used to evaluate patients with suspicion of abnormal hemostasis: PT, PTT, the platelet count, and bleeding time.
Prothrombin time and partial thromboplastin time are commonly ordered together and both evaluate the coagulation phase of hemostasis. Pro- thrombin time evaluates the extrinsic pathway and is commonly elevated in patients taking Coumadin anticoagulant medication. Platelet phospholipid is added to the patient’s blood, and the time is recorded until clotting occurs. Prothrombin time has been standardized in the United States by use of INR, which will be discussed in more detail under “Treatment.” The normal value for PT is usually 11 to 14 seconds and is compared with a standard control. Partial thromboplastin time assesses the intrinsic pathway and is elevated with hemophilia A, B, C, and von Willebrand disease. Tissue phospholipid is added to the patient’s blood, and time is recorded until clotting occurs. The normal range for this test is between 25 and 35 seconds, and the results are also reported in comparison with a standard control. As mentioned earlier, patients who are taking heparin anticoagu- lation are often evaluated with PTT.1,2
The platelet count evaluates the platelet phase of coagulation and indicates the number of platelets present. It does not evaluate qualitative platelet defects but only quantitative ones. Often, a platelet evaluation will be included with a com- plete blood count (CBC) but not a specific platelet
Bleeding Disorders 233
count. Therefore, this may need to be ordered sep- arately from the CBC. The normal platelet count is between 150,000 and 400,000/mm3.1,2
The bleeding time test evaluates the platelet phase of hemostasis and also the vascular phase. This test evaluates the platelet’s ability to clot small vessels up to 50 microns in diameter. Therefore, when it is combined with the platelet count, ques- tions concerning the platelet phase of hemostasis can be answered. This test is performed by making a standardized incision, 1 mm deep and 9 mm long, on the flexor surface of the forearm, distal to a blood pressure cuff on the arm inflated to 40 mm of mercury. Because of the standardization of this test, only smaller vessels are affected. These inci- sions are blotted every 30 seconds until no blood is absorbed. The normal range of the bleeding time is 3 to 9 minutes, and bleeding is normally stopped after 20 minutes if it persists. Bleeding times between 9 and 20 minutes would be prolonged, though functional. Beyond 20 minutes, the platelet phase of hemostasis would be considered incompetent.1,2 In recent years, some authors have questioned the value of the bleeding time in pre-
dicting clinically significant bleeding.15 However, it remains the only screening test for disorders of platelet function and vascular disorders.
If patients present with a history of abnormal bleeding, and the screening tests described above are abnormal, more specific tests need to be ordered to make the diagnosis of the bleeding problem. An abnormal PTT or PT may lead to a further evaluation of levels of coagulation factors using specific factor assays to determine which factor is responsible. The normal range of indi- vidual factor assays is between 50 to 150% of normal and the most commonly ordered factor is factor VIII.1,2
Patients who develop inhibitors to factor VIII are evaluated by the Bethesda assay with the Bethesda Unit (BU) being the standard unit of measurement. Patients with inhibitors are divided into low responders (those who will always have inhibitor levels of less than 20 BU) and high responders (those who will have an inhibitor level of greater than 20 BU at least once). Low respon- ders make up 25% of inhibitor patients, with high responders making up 75%.10
TABLE 14–1. Characteristics of Bleeding Disorders
Dysfunction Signs and Symptoms Laboratory Tests
Platelets Coagulation Gingival
Disorders Number Function Intrinsic Extrinsic Petechiae Ecchymosis Epistaxis Bleeding Hemarthrosis BT PC PT PTT
Platelets ITP + – – – + + + + – + + – – TTP + – – – + + + + – + + – – Thrombasthenia – + – – + + + + – + – – – NSAIDs/Aspirin – + – – + ± + + – + – – – Secondary TP + – – – + + + + – + + – –
Coagulation Hemophilia A – – + – – + ± ± + – – – + Hemophilia B – – + – – + ± ± + – – – + Coumadin – – – + – + ± ± – – – + – Heparin – – + – – + ± ± – – – – +
Coagulation and Platelets
von Willebrand disease – + + – + + + + – + – – +
Alcoholism + + + – + + + + – + + – +
ITP = idiopathic thrombocytopenic purpura; TTP = thrombotic thrombocytopenic purpura; NSAIDs = nonsteroidal anti- inflammatory drugs; TP = thrombocytopenic purpura; BT = bleeding time; PC = platelet count; PT = prothrombin time; PTT = partial thromboplastin time; + = affected by disorder; – = not affected by disorder With permission from Montgomery MT, Redding SW. Oral-facial emergencies. Chicago: Federation of Special Care Organiza- tions in Dentistry; 1994.
234 Periodontal Medicine
TREATMENT
Prevention of untoward bleeding is the best form of “treatment.” Obtaining a good history is the best single screening procedure to identify a patient with a bleeding or clotting disorder. Com- prehensive extraoral and intraoral examinations are likewise important in discovering clinical signs of an occult bleeding or clotting disorder. No surgical procedures should be performed on a patient sus- pected of having a coagulation disorder. Such patients should be referred to a physician for screening laboratory tests and final diagnosis. When a patient is known to have a bleeding or clotting disorder, it is essential that their hematol- ogist be consulted concerning appropriate medical management prior to performing any procedures that could result in bleeding. When periodontal surgical procedures are anticipated, the surgeon must take into consideration the fact that the mucoperiosteal flaps on the lingual aspect of the mandible may open up fascial planes into which blood can accumulate and endanger the airway.
A person with an occult coagulation disorder may not have any subjective or objective findings
suggestive of the condition. The first indication of the problem may be prolonged bleeding following a dental procedure. During any episode of pro- longed bleeding, local measures are the first line of defense to control hemorrhage. These local mea- sures include pressure, topical agents, and stents.1
Pressure
Prior to attempting any local measures, it is critical to visualize the source of the bleeding in a clear field with a good intraoral light source. Once the source and severity of the bleeding have been iden- tified, firm manual pressure should be applied with a moist gauze sponge pack for a minimum of 5 minutes. It is imperative that the pressure be applied to the actual bleeding site and that the size of the gauze pack correspond to the size of the bleeding site. Proper pressure is essential to con- trolling abnormal bleeding. Slowing of the blood flow greatly enhances the process of platelet aggre- gation and the formation of a platelet plug. Placing sutures across wound margins or across extraction sites may assist in maintaining hemostasis by stabi- lizing and providing pressure to the tissue respon- sible for the bleeding. If the bleeding is controlled with pressure, it is advisable to observe the patient for an additional 5 to 10 minutes to confirm hemostasis. Patients should be given both verbal and written postoperative instructions concerning prevention of recurrent bleeding. They should also be supplied with extra gauze packs and instructed on the proper placement and use of the packs.
Topical Agents
Clinicians who treat patients with bleeding disor- ders need to have sufficient local hemostatic agents available to treat the anticipated bleeding and be prepared to deal with any unexpected complica- tions. When local pressure is inadequate to control bleeding, topical hemostatic agents should be employed to augment the pressure. Oxidized cellu- lose (Oxycel®, Surgicel®) is one such agent. Its mechanism of action is unclear; however, it physi- cally absorbs blood and promotes clot formation. It should be applied dry and loosely placed, not packed, into the bleeding site and held in place with sterile gauze for 1 to 8 minutes. It is an absorbable hemostatic agent available as a woven fabric that resorbs in 7 to 14 days. It is also bacte- ricidal in vitro against a variety of both gram-posi- tive and gram-negative organisms. It should be noted that according to some authors the acidic
TABLE 14–2. Hemostasis Questionnaire
1. Have any of the following members of your family ever had a problem with prolonged or unusual bleeding: parents, brothers and sisters, children, grandparents, great grandparents?
2. Have you ever had marked bleeding for up to 24 hours after a surgical procedure (ie, tooth extrac- tion or tonsillectomy)?
3. Have you ever required a blood transfusion after surgery?
4. Women: Do you feel that you have abnormal bleeding during menstruation?
5. Do you get bruises larger than the size of a quarter for which you cannot remember the injury?
6. Do you experience numerous and severe nose bleeds for up to several hours?
7. Do your gums often bleed not related to trauma or brushing?
8. Are you taking any blood thinner (anticoagulant)? 9. Have you taken any medication, such as pills,
powders, or liquids, in the last week? 10. Have you had or do you have any liver disease
such as hepatitis or alcoholic cirrhosis?
With permission from Montgomery MT, Redding SW. Oral- facial emergencies. Chicago: Federation of Special Care Organizations in Dentistry; 1994.
Bleeding Disorders 235
nature of oxidized cellulose agents may result in postoperative pain.16
Another routinely used topical agent is absorbable gelatin sponge (Gelfoam®). It is a water- insoluble, porous, pliable sponge material prepared from purified pig skin. Its hemostatic action occurs because it absorbs the blood and provides an increased area for clot formation. It can be applied dry or moistened with normal saline and it should be pressed into place with finger pressure and held for 1 to 2 minutes. It is absorbed within 6 weeks. Gelatin sponge does not possess bacteriostatic properties and has been reported to act as a nidus for infection and therefore should not be used in the presence of infection. If it is used in an infected extraction site, impregnating it with tetracycline powder may be beneficial.
Additional topical agents consist of absorbable purified bovine collagen. Hemostatic activity is an inherent property of collagen. When it comes into contact with blood, platelets aggregate in large numbers on the collagen and release coagulation factors enabling the formation of fibrin. Several physical forms of purified bovine collagen are avail- able. One such product is Avitene®, which is a microfibrillar collagen available as an off-white, fluffy, finely fibrous, water-insoluble material with a highly open structure. It can be applied directly to the bleeding surface with dry cotton forceps, then pressed and held in place with a sterile sponge. As soon as it comes into contact with blood, it attracts platelets, which triggers further platelet aggregation and initiates the formation of a platelet plug. It is absorbed in 4 to 6 weeks.
Other absorbable purified bovine collagen prod- ucts available specifically for dental surgery are Col- laTape®, CollaCote®, and CollaPlug®. These are soft, white, pliable, nonfriable sponges. They retain their structural integrity even when wet and their application to wounds is easily controlled. They are highly absorbent, holding blood or solution that is many times their own weight. The sponge structure provides a three-dimensional matrix for additional strength of the blood clot. A piece of CollaTape® or CollaCote® large enough to cover the bleeding wound surface should be held in place for 2 to 5 minutes and subsequently can be removed or left in place. If desired, a periodontal packing can be used to hold it in place. A CollaPlug® is bullet shaped and designed to be placed into an extraction site. It can be held in place with gentle pressure using a sterile Q-tip. These products should not be used on infect- ed wounds. They are, however, very valuable for controlling persistent bleeding from tooth sockets.
Another useful topical agent is thrombin (Thrombogen®), supplied as a sterile powder. The powder also contains calcium chloride and comes with a vial of isotonic saline for use as a diluent. Thrombin requires no intermediate physiologic agent for its action. It converts the fibrinogen of the blood directly into fibrin. Its failure to clot blood occurs in the rare case where the primary clotting defect is due to the absence of fibrinogen itself. The speed with which topical thrombin clots blood depends upon its concentration. The desired strength for dental applications is 100 to 1000 U/mL. It is useful wherever any oozing from small vessels is accessible. It can be applied topically either in its powder form or diluted in isotonic saline or sterile water after the bleeding surface has been sponged or blotted free of blood. It must never be injected or otherwise allowed to enter large blood vessels. Wiping or suctioning the treat- ed surface should be avoided in order that the clot remain securely in place.
Thrombin may also be used in conjunction with Gelfoam® or the Colla® products either in the powder or liquid form. When used as a pow- der, the Gelfoam® or Colla® product should be moistened with sterile saline or water and then touched to the powder to pick up a light coating of the particles. When used in the diluted form, the Gelfoam® or Colla® product should be saturated with the thrombin solution. With either method, the combination is then applied to the bleeding area and held in place for about 15 seconds with a sterile Q-tip or a small gauze sponge. Thrombin should not be used with oxidized cellulose since its acidity will render the topical thrombin ineffective.
Suturing with a resorbable material may also be very beneficial to controlling hemorrhage. Primary closure should be achieved, if possible. Even without primary closure, sutures place slight pressure on the tissue and may assist in keeping topical agents in place, especially when placed as a figure-of-eight suture across an extraction site into which Gelfoam®
or a CollaPlug® has been placed. Another local mea- sure to aid in controlling hemostasis is the injection of a local anesthetic with a vasoconstrictor such as lidocaine 2% with 1:100,000 or 1:50,000 epineph- rine. However, caution must be exercised while using this technique as bleeding may resume when the effects of the vasoconstrictor end.
Custom-fabricated acrylic or plastic stents or latex mouthguard appliances may also prove help- ful in controlling hemorrhage and in preventing the mechanical displacement of the clot.1 Care is required during stent construction to avoid exces-
236 Periodontal Medicine
sive pressure on soft tissues, which could result in necrosis. An acrylic or plastic stent can be used to retain CollaTape® or Surgicel® in place over a palatal wound, such as a free gingival or connective tissue graft donor site, while at the same time pro- viding protection of the wound from trauma. When the patient has a known bleeding diathesis, a prefabricated soft latex mouthguard type of appliance may be used to apply a topical agent. Avitene® may be delivered in this type of appliance when generalized bleeding from the gum tissue or gingival sulcus is anticipated. Such an appliance can also be used to hold CollaTape® in place on bleeding sites. These appliances combine the light pressure from the appliance with the hemostatic effects of the topical agents. They should be worn until hemostasis has been maintained for several hours and subsequently only if needed; however, they require cleaning at least once each day because they can promote sepsis.
The choice of a topical agent is somewhat dependent upon the type of bleeding abnormality. Surgicel®, Gelfoam®, and thrombin are useful in most patients with persistent bleeding whereas the absorbable collagen products are more effective for those patients who have a platelet dysfunction or deficiency. It should be noted that many patients are on aspirin anticoagulation therapy, especially those having suffered a heart attack or stroke. Aspirin therapy alone is not usually associated with serious prolonged oral bleeding. In the vast majority of cases, a bleeding tendency from aspirin therapy can be controlled with the local measures cited. If a top- ical agent is necessary, one of the collagen products should be chosen. A listing of the above topical agents, a source for procurement, and the approxi- mate cost for each can be found in Table 14–3.
Anticoagulants
Anticoagulants are needed to prevent thrombosis and embolism. By far the most widely used is war- farin sodium (Coumadin). A consultation with the patient’s physician is essential in the dental man- agement of patients on anticoagulant therapy. Information needed from the physician includes verification of the information obtained from the patient, recent dose modifications, planned dura- tion of anticoagulant therapy, and current labora- tory values. Since the early 1940s, prothrombin time (PT) developed by Quick has been the pri- mary means of monitoring the level of oral antico- agulation control. Hematologists have recom- mended that the level of anticoagulation be one
and a half to three times the control value to pre- vent thrombosis. The ratio of the patient’s PT to a laboratory control PT is termed the prothrombin time ratio or (PTR). Because of the variations in dose response in individual patients during the course of anticoagulant therapy, their dosage must be monitored closely to prevent overdosing or underdosing. In the 1970s, it was found that there were wide differences in the PTR from one labora- tory to another. These differences occurred because of the variation in sensitivity of the thromboplas- tin reagents the laboratories used to perform PT. This meant that some patients were being antico- agulated to a greater extent than others and were prone to having more significant bleeding compli- cations. Because of these variations, the World Health Organization recommended that the PTR be standardized using the International Normal- ized Ratio (INR) that is based on the sensitivity of different thromboplastin reagents (International Sensitivity Index [ISI]). The INR=PTRISI results in the INR being essentially the same, regardless of which thromboplastin reagent a laboratory uses.17
Clinical research supports using the INR over the PTR and it is currently recommended that the INR be used to monitor the level of anticoagula- tion. Table 14–4 gives the recommended therapeu- tic range for oral anticoagulation therapy using INR values.18,19
Patients receiving oral anticoagulation therapy may present challenging management situations. The American Medical Association and the Amer- ican Dental Association previously recommended a PT of between 1.5 and 2.5 times the control PT before performing a surgical procedure. Presently, the literature is undecided on the acceptable INR level to perform extractions. Values between 1.5 and 4.0 have been recommended.19,20 There is concern that reduction or elimination of anticoag- ulant therapy places the patient at an unacceptable risk of thromboembolism. In assessing risk, clini- cians need to weigh the probability of embolism occurring if anticoagulant therapy is reduced. Sub- therapeutic anticoagulation levels in patients with a mechanical valve prosthesis entails a significant risk of valve thrombosis.19 Withdrawal of anticoag- ulant therapy is not needed for most patients to safely undergo most dental procedures. Dental treatment planning dividing full arch procedures into multiple smaller procedures, using infiltra- tion, periodontal ligament, or intraosseous injec- tions in place of block anesthesia, when practical, and using local hemostatic measures can signifi- cantly reduce the risk to the patient by avoiding
Bleeding Disorders 237
anticoagulation therapy modification. Table 14–5 gives our recommendations with regard to dental treatment and degree of anticoagulation as mea- sured by INR values.
A variety of medications can affect anticoagu- lant therapy (Table 14–6). Salicylates and nons- teroidal anti-inflammatory drugs should be avoided entirely in patients on anticoagulant therapy. Even acetaminophen should be used with caution. A recent study found a highly significant dose- response relationship between acetaminophen and Coumadin’s effect. For patients who reported taking at least four 325-mg tablets per day for longer than 1 week, the odds of having an INR greater than 6.0 were increased tenfold compared with those taking no acetaminophen.21 Although some antibiotics can adversely affect Coumadin therapy, antibiotic pro- phylaxis against infective endocarditis is unlikely to affect the patient’s anticoagulation status.19
Patients in whom the risk of thromboem- bolism is less of a problem and who need to have their INR values lowered can be managed by dis- continuation of their Coumadin dose approxi- mately 48 hours prior to the surgery and restarting
it on the day of surgery. The INR should always be checked on the morning of the surgery to ensure it is within an acceptable range. For patients at high risk of thromboembolism, an alternative approach is to discontinue Coumadin and introduce heparin to achieve a PTT of 1.5 to 2.0 times the control, midway between injections. Heparin prevents the conversion of prothrombin to thrombin. It has a short half-life of approximately 90 minutes but its duration of action is dose dependent.22 It should be discontinued for 4 to 6 hours before surgery and resumed 12 to 24 hours after surgery. Coumadin is resumed on the day of surgery and is continued
TABLE 14–3. Topical and Antifibrinolytic Hemostatic Agents
Agent Source Approximate Cost (US dollars)
Surgicel® Johnson and Johnson Medical Inc. $133.00/box of 12 Arlington, TX 76004-3130 (0.5 ´ 2.0 inch) (800-255-2500)
Gelfoam® Pharmacia & Upjohn $23.00/Jar (15 Squares) Kalamazoo, MI 49001 (800-253-8600)
Avitene® Med Chem Products Inc. $43.00/0.5 gram pack Subsidiary of C.R. Bard Inc. Woburn, MA 01801 (800-451-4716)
CollaPlug® Calcitek\ Sulzer Medica $ 63.00/package of 10 CollaTape® 2320 Faraday Avenue $110.00/package of 10 CollaCote® Carlsbad, CA 92008 $ 71.00/package of 10
(800-854-7019) Thrombogen® Johnson and Johnson Medical Inc. $46.00/box (10,000 units)
Arlington, TX 76004-3130 (800-255-2500)
Amicar® Immunex $ 345.00/480 mL bottle 51 University Street Seattle, WA 98101 (800-334-6273)
Cyclokapron® Pharmacia & Upjohn $225.00/10 ampules Kalamazoo, MI 49001 (10mL/100 mg/mL) (800-442-4348)
TABLE 14–4. Recommended Therapeutic Ranges Using INR Values18,19,20
Indication INR Range
Prophylaxis of venous thrombosis 2.0 to 3.0 Treatment of venous thrombosis 2.0 to 3.0 Prevention of systemic embolism 2.0 to 3.0 Treatment of pulmonary embolism 2.0 to 3.0 Mechanical prosthetic heart valves 2.5 to 3.5
238 Periodontal Medicine
until the INR returns to an optimal range. This method usually requires hospitalization and is very expensive. Because heparin can only be adminis- tered parenterally, it is unlikely that patients on heparin therapy will be encountered in other than a hospital-based dental practice.
Of note are the new low-molecular-weight heparins (LMWHs), including ardeparin dal- teparin, and enoxaparin, which represent an impor- tant therapeutic advance in the treatment of patients with venous thromboembolism. They have a lower incidence of heparin-induced thrombocy- topenia, greater bioavailability, longer half-life, and a more predictable anticoagulant response com- pared with standard heparin.23 Because of these benefits, these drugs can be used subcutaneously (patient administered), without laboratory moni- toring, to treat select patients with venous throm- boembolism in the outpatient setting. Periodontists may encounter medically compromised patients in their practices. Because of the predictable anticoag- ulant response to these drugs, the medical manage- ment of these patients to prevent potential bleeding problems should be less complicated compared with patients on Coumadin therapy. Low-molecu- lar-weight heparins are given once or twice daily. If currently used for venous thromboembolism, it would appear reasonable to discontinue the dose prior to any dental surgery and then have the patient resume the next scheduled dose. This should be confirmed with the patient’s physician.
Factor Enhancement
Patients with inherited coagulation defects may require factor replacement to prevent postoperative bleeding complications. Therapies to promote
coagulation carry significant risks and should be carried out by the patient’s hematologist. The type of replacement therapy employed will depend upon the type and severity of factor deficiency. Mild hemophilia A (5 to 25% factor VIII), hemo- philia B or von Willebrand disease (type 1) can usually be managed with local measures alone (topical agents plus antifibrinolytic agents, dis- cussed in the next section). In addition to local measures, moderate hemophilia A (1 to 5% factor VIII) or moderate von Willebrand disease (type II) may be managed with desmopressin 1-deamino-8- D-arginine vasopressin (DDAVP).
Desmopressin is a synthetic analog of vaso- pressin which causes an increased release of endogenous factor VIII and vWf levels by approx- imately fourfold. This mimics replacement therapy with blood products. Desmopressin can be given via nasal spray, subcutaneous injection, or IV infu- sion. A dose of 0.3 to 0.5 µg/kg intravenously pro- duces peak factor levels at 30 to 60 minutes, which tapers to baseline at 24 hours. It is also available for subcutaneous or intranasal use. The optimal intranasal dose is 300 µg for adults and 150 µg for children. After intranasal or subcutaneous admin- istration, factor levels peak at 60 to 90 minutes. The above doses can be repeated at 12-hour inter- vals up to three or four times. Common side effects are facial flushing and headache. In addition, it is a potent antidiuretic and causes the release of the plasminogen activator. Because of the latter effect, adjunctive use of topical tranexamic acid (dis- cussed in the next section) is beneficial. It should be noted that DDAVP does not usually shorten the bleeding time in patients with severe von Willebrand factor deficiency (type III) or dysfunc- tional von Willebrand factor (type II variant).
TABLE 14–5. Managing Patients as Related to Their INR
INR Value Recommendations Concerning Invasive Treatment*
4.0 or greater No surgical treatment until the INR is reduced. 3.5–4.0 Emergency minor surgical procedures only, simple extraction, incision and drainage. Avoid
block anesthesia injections; use local measures for hemostasis. 3.0–3.4 Minor surgical procedures, simple extraction, gingivoplasty; block anesthesia not recommended;
use local measures for hemostasis. 2.5–2.9 Multiple extractions, single bony impaction, quadrant periodontal flap surgery or scaling and
root planing; avoid block anesthesia, if possible, and use local measures for hemostasis. 1.5–2.4 Full-mouth extractions, multiple bony impactions, gingivectomy, multiple quadrant flap
surgery; avoid block anesthesia, if possible, and use local measures for hemostasis.
*Local factors such as periodontitis/gingival inflammation or medications the patient is taking can increase the severity of bleeding. Risk assessment must include all applicable factors.
Bleeding Disorders 239
Severe factor deficiencies usually require con- centrated forms of replacement therapy such as factor VIII concentrate or cryoprecipitate for hemophilia A and some forms of von Willebrand disease (types II and III) and factor IX complex for hemophilia B. For severe hemophilia A (1% or less factor VIII), the therapeutic goal for replacement is 50% of normal. A normal factor VIII level is one unit of factor VIII per one milliliter of blood. To avoid possible hematomas leading to airway obstruction, block injections should not be employed unless at least a 30% level can be achieved.24 The formula for determining the quan- tity of replacement factor needed is the desired fac- tor VIII level minus the patient’s factor VIII level times the plasma volume (approximately 41 mL/kg of body weight).1 For example, a patient with 2% of normal factor VIII has 0.02 units/mL. If the patient weighs 70 kg, the patient has a plasma vol- ume of approximately 2870 mL. In order to raise the patient’s factor VIII level to 30%, the patient should receive approximately 804 units of factor VIII ([0.30 to 0.02] x 2870). Factor VIII has an 8 to 12-hour half-life unless the patient has devel- oped antibodies to it (5 to 20% of patients). It should be given 10 to 30 minutes prior to surgery. All necessary surgery should be performed at one sit- ting to minimize the number of times replacement therapy is needed. Patients with inhibitors to factor VIII can be treated with increased doses of factor concentrate if their inhibitor level is low (below 20 BU). With high inhibitor levels, prothrombin com- plex concentrates (contains factors II, VII, IX, and X) may be used, but the response is highly variable. This product is thought to bypass the factor VIII inhibitor. Unfortunately, some patients with high inhibitor levels will not respond to any form of replacement therapy. All efforts must be made to prevent bleeding episodes in these patients.10
In patients with hemophilia B, a moderate fac- tor IX deficiency can be managed with local mea- sures alone or in combination with fresh frozen plasma. For patients with severe hemophilia B, the therapeutic goal for factor IX replacement is 25% of normal. This can be attained by giving an initial
dose of 50 units/kg of factor IX complex intra- venously followed by 20 units/kg every 12 to 24 hours. Factor IX has a half-life of up to 2 days.
Factor XI deficiency (hemophilia C) can be successfully managed using fresh frozen plasma and local hemostatic measures. The periodontal surgeon must be aware that factor replacement products are very expensive and may carry the risk of transmission of infectious diseases. It is impera- tive that they be used appropriately and only when needed. Patients requiring these products are best managed by a hematologist.
Antifibrinolysis
In addition to the use of local measures and increasing coagulation action, maintenance of clot stability following formation is critical to prevent rebleeding. This can be accomplished via antifibri- nolysis agents such as Amicar (epsilon-aminocaproic acid [EACA]) and Cyclokapron (tranexamic acid). These antifibrinolytics are useful in patients with a broad range of bleeding disorders especially when the bleeding involves mucosal sites. Both these agents block the binding of plasminogen to fibrin and its activation and transformation to plasmin. This results in increased clot stability. Tranexamic acid is about 10 times more potent than amino- caproic acid and has a longer half-life. The half-life of EACA is 4 hours, and it may be given as a tablet or an elixir. The elixir is preferred for oral bleeding because of potential topical effects (plasmin is found on the oral mucosa and in saliva). The rec- ommended oral dose of aminocaproic acid is 50 to 60 mg/kg every 4 hours.25 However, systemic treat- ment with antifibrinolytic agents is prohibited in patients using anticoagulant medication because of the risk of thromboembolism.
Tranexamic acid is preferred over aminocaproic acid as a topical agent. The use of tranexamic acid in conjunction with other local measures will sig- nificantly decrease postoperative bleeding in patients with hemophilia or those who are on anti- coagulation therapy.16,25,26 Saliva has fibrinolytic qualities, which may contribute to postoperative
TABLE 14–6. Medications Affecting Coumadin Therapy18,19,22
Potentiating effect Acetaminophen (underappreciated), cephalosporins, chloral hydrate, cimetidine, ciprofloxacin, corticosteroids, diflunisal, erythromycin, fluconazole, fluoroquinolones, indomethacin, ketoconazole, metronidazole, nonsteriodal anti-inflammatory drugs, penicillins, propoxyphene, salicylates, tetracyclines, trimethoprim/sulfamethoxazole.
Opposing effect Ascorbic acid, barbiturates, carbamazepine, dicloxacillin, nafcillin, penicillin.
240 Periodontal Medicine
bleeding in the oral cavity. The topical use of tranexamic acid appears to neutralize the fibri- nolytic effects of saliva and stabilize the fibrin structure. It has proven effectiveness in eliminating postoperative complications in patients on antico- agulation therapy who have undergone surgical procedures without lowering their anticoagulant therapy.16,26 Additionally, topical antifibrinolytic therapy does not increase the risk of thromboem- bolism. A 1- to 2-minute preoperative rinse with 10 cc of a solution diluted to 50 mg/mL of tranex- amic acid, followed by identical rinses four times per day for 4 to 7 days, is usually effective. Its con- centration in saliva remains high enough to sup- press fibrinolysis for several hours after use. Extrac- tion sites can also be irrigated with the solution during surgery, and postoperative bleeding sites can be treated by pressing with gauze soaked in tranexamic acid. The Colla® products, Gelfoam®
and Surgicel® can also be soaked in the agent prior to use. A listing of the above antifibrinolytic agents, a source for procurement, and the approx- imate cost for each can be found in Table 14–3.
Platelet Transfusions
Postoperative bleeding in patients with mild to moderate thrombocytopenia usually can be man- aged with local measures alone. However, in addi- tion to local measures, platelet transfusion must be considered for severely thrombocytopenic patients (< 20,000 platelets/mm3). Regional block anesthet- ic injections should be avoided when the platelet count is < 30,000/mm3. The goal for these patients is to raise their platelet count to at least 50,000 platelets/mm3 prior to a surgical procedure. This should be increased to 75,000 platelets/mm3 for multiple extractions, multiple quadrants of peri- odontal surgery, or a bony impaction. Platelet trans- fusions are usually performed in a hospital setting. One unit of platelets will raise the average patient’s count by 10,000 platelets/mm3 unless the patient has platelet antibodies. At least 30% of transfusions result in complications, and the incidence of patients developing antibodies to platelets after repeated transfusions is approximately 75%; there- fore, they should be given judiciously. They are usu- ally given six units at a time at a cost of approxi- mately US $300. Platelet transfusions should be done about 30 minutes prior to the surgical proce- dure because platelets are rapidly sequestered. If the patient has antibodies to platelets, a continuous transfusion of platelets will probably be required during the surgical procedure. This can only be
accomplished in a hospital environment. Platelet transfusions also carry the risk of infectious diseases.
CONCLUSION
Dental management of patients with a bleeding or clotting diathesis should be accomplished in con- sultation with the patient’s physician. Most patients with mild to moderate bleeding or clot- ting problems can be safely treated in the dental office using local measures, provided there is prop- er planning, preparation, and a judicious surgical technique. Hospitalization is reserved for those patients with severe defects. Aspirin and other nonsteroidal anti-inflammatory agents used as postoperative analgesics should be avoided or used only with extreme caution in these patients. Mild narcotics such as codeine or hydrocodone and acetaminophen are safer analgesics. Additional hemostatic agents and recombinant products are being investigated as to their effectiveness.
Early human clinical trials involving inter- leukin-11, recombinant human thrombopoietin, or polyethylene glycol conjugated recombinant human megakaryocyte growth and development factor have shown promise in increasing platelet production in bone marrow suppressed patients.27
Recombinant factor VIII, factor IX and activated factor VII are available (Factor VII only in Europe) and are being studied. Clinical studies of recombi- nant von Willebrand factor are also due to begin.25
Fibrin tissue adhesives (fibrin sealants) have also been used clinically with good success.28 These sealants mimic the last phase of blood clotting by means of the conversion of fibrinogen to fibrin. They consist of two components; (1) fibrinogen and plasma proteins, and (2) thrombin and calcium chloride. When the two components are mixed, thrombin converts fibrinogen into fibrin, and the mixture solidifies. These topical agents have not been recommended because objective data on their efficacy and safety are limited.25 Undoubtedly, with all these new agents, there will be continued efforts to advance the clinical management and treatment of patients with bleeding and clotting disorders.
REFERENCES
1. Redding SW. Oral bleeding. In: Montgomery MT, Redding SW, editors. Oral-facial emergencies. Chicago: Federation of Special Care Organiza- tions in Dentistry; 1994.p.103.
Bleeding Disorders 241
2. Olive JA. Disorders of hemostasis. In Tullman MJ, Redding SW, editors. Systemic disease in dental treatment. New York: Appleton Century Crofts; 1982.p.195.
3. Bussel J, Cines D. Immune thrombocytopenic pur- pura, neonatal alloimmune thrombocytopenia, and post-transfusion purpura. In: Hoffman R, Benj EJ, Shattil SJ, et al., editors. Hematology basic principles and practice. 2nd ed. New York: Churchill Livingstone; 1995.p.1849.
4. Schafer A. Thrombocytopenia and disorders of platelet function. In: Stein JH, editor. Internal medicine. 5th ed. Philadelphia: CV Mosby Co.; 1998.p.610.
5. Moake JL. Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. In: Hoff- man R, Benj EJ, Shattil SJ, et al., editors. Hema- tology basic principles and practice. 2nd ed. New York: Churchill Livingstone; 1995.p.1879.
6. Bennett JS. Hereditary disorders of platelet func- tion. In: Hoffman R, Benj EJ, Shattil SJ, et al, editors. Hematology basic principles and prac- tice. 2nd ed. New York: Churchill Livingstone; 1995.p.1909.
7. George JN, Shattil SJ. Acquired disorders of platelet function. In: Hoffman R, Benj EJ, Shat- til SJ, et al, editors. Hematology basic principles and practice. 2nd ed. New York: Churchill Liv- ingstone; 1995.p.1926.
8. White G. Disorders of blood coagulation. In: Stein JH, editor. Internal medicine, 5th ed. Philadel- phia: CV Mosby Co.; 1998.p.617.
9. Brettler DB, Kraus EM, Levine PH. Clinical aspects of and therapy for hemophilia. In: Hoffman R, Benj EJ, Shattil SJ, et al, editors. Hematology basic principles and practice. 2nd ed. New York: Churchill Livingstone; 1995.p.1648.
10. Redding SW, Stiegler KE. Dental management of the classic hemophiliac with inhibitors. Oral Surg Oral Med Oral Pathol 1983:56 (1);145–8.
11. Roberts HR, Gray TF. Clinical aspects of and ther- apy for hemophilia B. In: Hoffman R, Benj EJ, Shattil SJ, et al, editors. Hematology basic prin- ciples and practice. 2nd ed. New York: Churchill Livingstone; 1995.p.1678.
12. White GC, Montgomery RR. Clinical aspects of and therapy for von Willebrand disease. In: Hoff- man R, Benj EJ, Shattil SJ, et al, editors. Hema- tology basic principles and practice. 2nd ed. New York: Churchill Livingstone; 1995.p.1725.
13. Roberts HR, Gray TF. Factor XI and other clotting factor deficiencies. In: Hoffman R, Benj EJ, Shattil SJ, et al, editors. Hematology basic prin- ciples and practice. 2nd ed. New York: Churchill Livingstone; 1995.p.1691.
14. Furie B. Oral anticoagulant therapy. In: Hoffman R, Benj EJ, Shattil SJ, et al, editors. Hematology basic principles and practice. 2nd ed. New York: Churchill Livingstone; 1995.p.1795.
15. De Rossi SS, Glick M. Bleeding time: an unreliable predictor of clinical hemostasis. J Oral Maxillo- fac Surg 1996;54:1119–20.
16. Gaspar R, Brenner B, Ardekian L, et al. Use of tranexamic acid mouthwash to prevent postop- erative bleeding in oral surgery patients on oral anticoagulant medication. Quintessence Int 1997;18:375–9.
17. Meehan S, Schmidt MC, Mitchell PF. The interna- tional normalized ratio as a measure of antico- agulation: significance for the management of the dental outpatient. Special Care in Dentistry 1997;17(3):94–6.
18. Hirsh J, Dalen DE, Deykin D, Poller L. Oral anti- coagulant mechanism of action, clinical effec- tiveness, and optimal therapeutic range. Chest 1992;102(Suppl):312S–26S.
19. Herman W, Konzelman J Jr, Sutley S. Current per- spectives on dental patients receiving coumadin anticoagulant therapy. J Am Dent Assoc 1997; 128:327–35.
20. Beirne OR, Koehler JR. Surgical management of patients on warfarin sodium. J Oral Maxillofac Surg 1996;54:1115–8.
21. Hylek EM, Heiman H, Skates SJ, et al. Aceta- minophen and other risk factors for excessive warfarin anticoagulation. J Am Med Assoc 1998; 279:657–62.
22. Gage TW, Pickett FA. Dental drug reference. 4th ed. Philadelphia: CV Mosby Co., 1999.p.700.
23. Litin SC, Heit JA, Mees KA. Use of low-molecular- weight heparin in the treatment of venous throm- boembolic disease: answers to frequently asked questions. Mayo Clin Proc 1998;73:545–51.
24. Scully C, Cawson RA. Medical problems in den- tistry. 4th ed. Oxford, England: Butterworth- Heinemann; 1998.p.82.
25. Mannucci PM. Hemostatic drugs. N Engl J Med 1998;339(4):245–53.
26. Brandrowshy T, Vorono A, Borris T, Marcantoni H. Amoxicillin-related postextraction bleeding in an anticoagulated patient with tranexamic acid rinses. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:610–2.
27. Kaushansky K. Thrombopoietin. N Engl J Med 1998;339(11):746–54.
28. Bodner L, Weinstein JM, Baumgarten AK. Effica- cy of fibrin sealant in patients on various levels of oral anticoagulant undergoing oral surgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86(4):421–4.
CHAPTER 15
PHARMACOTHERAPY Sebastian G. Ciancio, DDS
Drugs were first used to treat disease when Paul Ehrlich treated syphilis with salvarsan, an organic chemical. Much later, in 1936, sulfonamides were introduced for treating infections and antibiotics became clinically available in 1941. Since then, numerous antibiotics have become available and new antibiotics are constantly being evaluated.
Antimicrobial agents either suppress the growth of microorganisms or destroy them. They are divided into three categories: antibiotics, anti- septics, and sulfonamides. In dentistry, antibiotics and antiseptics are most frequently used.
Pharmacotherapeutic agents of value as adjuncts to periodontal therapy can be classified into agents which are useful for their antimicrobial properties and those which are useful for their abil- ity to improve “host resistance.” In the former cat- egory are antibiotics and antiseptics, and in the lat- ter category are anticollagenase and antiprosta- glandin agents.
A sub-antimicrobial dose of doxycyline hyclate has recently become available for use an as adjunct to mechanical methods of periodontal therapy. This agent arrests the progress of periodontal disease and results in probing depth reduction and attachment gain.1 It produces its effect by reducing the release and activity of matrix metalloproteinases such as collagenase and gelatinase by polymorphonuclear leukocytes. These effects occur without the side effects associated with systemic antibiotic therapy, including the development of bacterial resistance.
ANTIBIOTICS
Antibiotics, which are chemical substances origi- nally produced by microorganisms, either retard the growth of microorganisms or result in their death. Now, some antibiotics are chemically synthesized.
An ideal antibiotic should: (1) be selective and effective against microoganisms without injuring the host; (2) destroy microorganisms (bactericidal action) rather than retard their growth (bacterio- static action); (3) not become ineffective as a result of bacterial resistance; (4) not be inactivated by enzymes, plasma proteins, or body fluids; (5) quickly reach bactericidal levels throughout the body and be maintained for long periods; and (6) have minimal adverse effects.
Depending on the antibiotic, several mecha- nisms of action are possible. They include: (1) inhibition of bacterial cell wall synthesis, (2) alter- ation of bacterial cell membrane permeability, (3) alteration of bacterial synthesis of cellular compo- nents, and (4) inhibition of bacterial cell metabo- lism.
Certain basic terms and concepts are impor- tant in understanding the pharmacology of antibi- otics; they are described below.
Resistance
Microorganisms are sometimes resistant or unaf- fected by an antibiotic. Resistance can be natural, that is, present before contact with drug, or acquired and develop during exposure to the drug. The development of acquired resistance is genetic, with a change in the microorganism’s DNA, and is inherited by each subsequent generation. Once resistance develops to an antibiotic, it persists, and a new antibiotic must be found that will destroy the resistant strain.
Microorganisms resistant to a particular drug frequently are resistant to other chemically related antimicrobial agents. This is referred to as cross- resistance. Occasionally, cross-resistance can also occur between two chemically dissimilar drugs.
Antibiotic resistance usually implies inactiva- tion of the antibiotic by bacterial enzymes and
244 Periodontal Medicine
development by the bacteria of alternative meta- bolic pathways unaffected by the antibiotic, or by biochemical alterations in the bacteria that prevent the uptake or binding of the antibiotic.
Antibiotic effectiveness can be reduced by inadequate therapy. For example, if a drug is given at a late stage of a disease, it may not control the large number of microorganisms that are present.
At other times, no clinical improvement may be seen even when the microorganisms are sensi- tive to the antibiotic, which may result from too low a dose of antibiotic. This has an additional danger in that low doses only destroy the weaker microorganisms and allow the stronger to survive, multiply, and possibly become drug resistant. The antibiotic thus serves to permit the growth of less susceptible microorganisms without the competi- tion of the more susceptible bacteria that have been destroyed by the antibiotic. This phenome- non is called “selective pressure.” The process of selecting increasingly less susceptible or resistant microorganisms occurs in a stepwise manner. Therefore, it is imperative that an antibiotic con- centration be reached at the site of the infection to kill these microorganisms. This can also occur if drug therapy is not long enough. In view of this, it is important that patients take all the medica- tion prescribed to them for the duration pre- scribed. Too often, patients prematurely stop tak- ing an antibiotic because they “feel better.” Lastly, antibiotics can be ineffective if they do not reach therapeutic levels at the site of the infection, or if they are antagonized by their interaction with other drugs.
Spectrum of Activity
This term refers to the different types of microor- ganisms affected by an antibiotic. An antibiotic may affect only a few species of microorganisms and have a limited spectrum of activity or affect a wide variety and have a broad spectrum of activity. Broad-spectrum antibiotics are only necessary if an infection is caused by a variety of microorganisms. Often, an infection caused by one microorganism will even respond more readily to a limited-spec- trum antibiotic that is directed toward that microorganism.
Antibiotic therapy may suppress one group of microorganisms while permitting the growth of another group of bacteria that are normally present but do not cause disease. In large numbers, they can produce a superimposed infection, referred to as a “superinfection.”
Type of Action
Antibiotics are either bacteriostatic or bactericidal.2
Bacteriostatic antibiotics inhibit the growth and multiplication of microorganisms while bactericidal antibiotics kill microorganisms. While bacteriostatic antibiotics alter the metabolic pathways or synthesis of cellular components in microorganisms, bacteri- cidal drugs interfere with the synthesis or function of either the cell wall, cell membrane, or both.
When two bactericidal antibiotics are given together, they may exert a greater effect than when each is given alone. This is called “antibiotic syner- gism.” Sometimes, however, when a bacteriostatic and a bactericidal antibiotic are given together, their effectiveness is negated or reduced. This is called “antibiotic antagonism.” In the majority of dental infections, combination therapy is not usu- ally necessary. However, in the prophylaxis of patients with a history of rheumatic fever, combi- nation therapy for antibiotic synergism is some- times indicated.
Inhibition of Oral Contraceptive Effectiveness
Occasionally, contraceptive failures without obvi- ous cause are reported, and some evidence suggests that these events are related to the concurrent use of certain other drugs, including antibiotics.
It has been suggested that with the trend toward lower steroid dosages in oral contraceptive preparations, there is increased frequency of drug interactions that cause lowered efficacy of oral contraceptives.
Ampicillin and other penicillins were the antibiotics most frequently listed as having the potential to inhibit contraceptives; tetracycyline, although listed less frequently, was also implicated in several cases. In some cases, a combination of penicillin and a tetracycline was taken.3
Contraceptives belong to the steroid class of drugs. Steroid levels in the body are dependent on metabolic action by bacteria in the gastrointestinal (GI) tract. By suppressing the bacterial flora, antibiotics diminish their ability to maintain the required levels of the contraceptive drug in the GI tract. This, in turn, results in less availability of the drug for absorption. Consequently, plasma con- centrations of the steroid are abnormally low, and it is cleared more rapidly from the body than under normal circumstances.
If a patient taking an oral contraceptive is in need of antibiotic therapy as part of dental treat-
Pharmacotherapy 245
ment, the patient should be cautioned about drug interaction and advised to use alternative methods of contraception until cessation of antibiotic therapy.
It should be noted that the clinical importance of this drug interaction is currently being ques- tioned, and ongoing studies may prove it not to be a significant clinical concern.
Antibiotics Used in Periodontics
The most common antibiotics used in periodon- tics are listed in Table 15–1. They are listed accord- ing to frequency of use, with the most commonly used listed first. Dosages vary according to the drug used. However, with oral administration, the initial dose should be double the subsequent doses so that high blood levels are rapidly obtained.
Although systemic antibiotics appear to offer only minimal long-term benefit as pharmacothera- py for adult periodontitis, a number of studies have suggested that they are beneficial in rapidly advancing periodontitis, localized juvenile peri- odontitis, and refractory periodontitis.
Tetracyclines Tetracyclines are the most widely prescribed adjunc- tive agents for periodontal therapy.4 Tetracyclines are broad-spectrum antibiotics that were initially obtained from soil microorganisms.
Types of Tetracyclines. Seven basic types of tetracyclines are currently in use. They are similar chemically and therefore possess similar antibacte- rial spectra and have cross-hypersensitivity. When resistance or hypersensitivity occurs to one tetracy- cline, it will also occur to all in the group. Tetracy- clines are summarized in Table 15–2.
The first tetracyclines developed were chlorte- tracycline, oxytetracycline, tetracycline, and deme- clocycline. The next group of tetracyclines devel- oped were doxycycline, methacycline, and minocy- cline. All these agents have a similar spectrum of activity. However, minocycline appears to be the most effective in the treatment of meningococcal infections. The newer tetracyclines can be admin- istered in smaller doses since they are more rapidly absorbed and more slowly excreted. From Table 15–2, it can be noted that most of the tetracyclines are affected by metal ions but doxycycline and minocycline are affected to a lesser extent. This interaction has also been observed with dairy prod- ucts and antacids because of their calcium content. Tetracyclines bind to the calcium in the GI tract and cannot be absorbed, so minimal therapeutic benefits can be expected. A similar interaction has
been reported with products containing iron, mag- nesium, and aluminum. Therefore, patients should be told to refrain from foods containing these for at least 11/2 hours prior to or following administra- tion of the medication by the oral route.
Mechanism of action. Tetracyclines are bacte- riostatic drugs that retard the growth of susceptible bacteria by inhibiting protein synthesis. Since they all have the same mechanism of action, resistance to one implies resistance to all tetracyclines.
Tetracyclines can block the antibacterial effect of penicillin. Penicillin is most effective on multi- plying, growing bacteria while tetracyclines exert their effect by slowing down the rate of bacterial growth and multiplication. Therefore, concomitant administration of these drugs is contraindicated.
Dosage and Forms. The oral forms include tablets, chewable wafers, capsules, liquids, and oint- ments. The adult dosage for tetracycline, oxytetra- cycline, and chlortetracycline is 250 to 500 mg given four times per day. The adult dosage for demeclocyline and methacycline is 150 mg four times per day, that for doxycycline 100 mg daily, and minocycline 100 mg twice daily.
Spectrum of Activity. Tetrayclines are broad- spectrum antibiotics that are effective against a number of oral gram-negative and gram-positive cocci and bacilli. They are also effective against a few viruses, Treponema, Mycoplasma, Chlamydia, and Rickettsia. Minocycline may be effective against staphylococci that are not susceptible to other tetracyclines.
Metabolism. These drugs are usually admin- istered orally since injections are painful. Peak plas- ma levels are attained slowly, so the daily recom- mended dose is doubled the first day of therapy. These antibiotics pass into most body fluids and tissues. They can also pass through the placenta and occur in low doses in breast milk. However, no adverse effects on the newborn have been reported
TABLE 15–1. Antibiotics of Frequent Use in Periodontal Therapy
Action
Antibiotic Bacteriostatic Bactericidal
Tetracyclines ✓ Metronidazole ✓ Amoxicillin ✓ Clindamycin* ✓ Cephalosporins ✓
*depending on dose, may be bacteriostatic or bactericidal
246 Periodontal Medicine
when the child receives low doses in the mother’s milk. These antibiotics also pass into the gingival crevicular fluid and are therefore in intimate con- tact with the plaque in the gingival crevice. They have an affinity for and are found in higher con- centrations in rapidly growing and metabolizing tissue such as liver, tumors, bone, and teeth.
Tetracyclines are excreted mainly by the kid- neys and can be recovered from the urine in their unchanged form. Treatment with tetracyclines can also adversely alter the normal oral and intestinal flora, resulting in GI problems, such as diarrhea. Some patients have also developed monilial infec- tions of the GI tract, oral cavity, and vagina due to alteration of the flora.
Adverse Effects. The side effects associated with tetracycline therapy are varied. A number of side effects have been related to the use of outdat- ed tetracyclines, and side effects also are more com- mon in pregnant patients (in addition to the fetal tooth-staining problem). These side effects and toxicities are summarized in Table 15–3. As this table indicates, these drugs are contraindicated in all women in the childbearing age group. In these women, the risks involved in therapy are too high to justify their therapeutic value for dental usage.
In one animal study, tetracyclines were found deposited in damaged areas of the heart, particu- larly regions containing calcified deposits. Whether these agents are contraindicated in humans with a history of a cardiac infarct is ques- tionable. Further investigations to clarify this are needed; however, no additional studies since 1962 have been reported relative to this effort. Although the incidence of allergy is low, allergy to one tetra- cycline usually means allergy to all other tetracy-
clines. Unfortunately, there is no diagnostic labo- ratory test for allergy to tetracycline.
Regarding teratogenesis, the effects of tetra- cyclines on the formation of fetal hands and limbs is not established. Other side effects associ- ated with tetracycline therapy are rare and include lymphoepithelioma and simulated systemic lupus erythematosus.
Tetracycline Discoloration of Permanent Teeth. It has been reported that long-term therapy with minocycline (as used for patients with acne) may discolor adult teeth and gingival tissue (Figure 15–1).
In reviewing the cases of discoloration of adult teeth, no pattern of discoloration could be found that was common to all. The tooth discoloration, a gray color, was present at the incisal edge in some cases, the midtooth surfaces in some, and the gin- gival third in others.5,6 Minocycline used for long periods has also been reported to cause a yellow pigmentation of the skull. Similarly, black discol- oration of the thyroid has been observed.7
Permanent tooth-staining can be caused when tetracycline or fluoride is administered dur- ing the time when teeth are developing in utero or after birth. If the drug is given during the time when the development of the crowns is being completed and they are calcifying, the crowns as well as the roots will be stained. However, in all cases studied, the patients (who ranged in age from 18 to 29 years) were over the age of tooth formation, with the exception of the younger patients, whose third molar roots could have been forming at the time of therapy. It should be noted that since tetracyclines become incorporated into dentin, this is a permanent discoloration that can
Table 15–2. Various Tetracyclines
Generic Name Trade Name Route of Administration Affected by Metal Ions
Chlortetracycline HCl Aueromycin po, IV + Demeclocycline HCl Declomycin po + Doxycycline and salts Vibramycin po, IV – Methacycline HCl Rondomycin po +
Minocycline HCl Minocin, Vectrin po, IV -
Oxytetracycline and salts Terramycin po, IM, IV +
Tetracycline and salts Achromycin V, Cyclopar, Panmycin, po, IM, IV + Robitet, SK-Tetracycline, Tetracyn, Sumycin, Tetrex
po = per os (by mouth); IV = intravenous; IM = intramuscular
Pharmacotherapy 247
only be corrected by covering the tooth with restorative materials. Varied reports have appeared in the dental literature suggesting that tetracy- cline-discolored teeth may be partially bleached with long-term concentrated solutions of hydro- gen peroxide sometimes preceded by acid-etching and followed by the application of heat. These findings are not well documented but deserve fur- ther investigation.
Indications. Nondental Conditions. Since their introduction in 1948, tetracyclines have been wide- ly used, particularly in the treatment of acne. This widespread use has led to antibiotic resistance. A number of gram-negative bacilli now carry factors conferring resistance to tetracyclines and to other drugs, thus decreasing their effectiveness.
Several species of Escherichia coli, beta hemolytic streptococci, Streptococcus pneumoniae, Neisseria gonorrhoeae, some Bacteroides, Shigella, and Staphylococcus aureus are resistant to tetracy- clines. Since there is evidence that resistance develops in direct proportion to usage, the preva- lence of these resistant strains may increase in the future. However, tetracyclines remain the drugs of choice for a variety of rarely occurring nondental infections.
Dental Conditions. Clinical studies on humans indicate that use of tetracyclines results in
enhanced bone formation and possibly reattach- ment. In addition, animal studies have suggested beneficial effects of antibiotics in terms of early crestal bone repair and reversal of a unique peri- odontal syndrome in the rice rat. They are valuable in that they not only kill oral pathogens but also diminish the pathogenic potential of these microorganisms. Since plaque is dynamic, a bacte- riostatic drug would retard the growth of certain microbial components of plaque. Therefore, by reducing these pathogens before and following therapy, an enhanced response can be expected. This hypothesis is supported by studies in our lab-
TABLE 15–3. Side Effects and Toxicities of Tetracyclines
Blood urea Elevation of blood urea nitrogen occurs mainly in patients taking diuretics or presenting nitrogen initially with a high blood urea nitrogen. Nausea, vomiting, and their sequelae are associated
with this rise Bone Possible retardation of growth and development—may be transient Gastrointestinal Overgrowth with monilial microorganisms has been reported on a number of occasions in
tract conjunction with tetracycline therapy. However, some articles question this statement. Alteration in absorption of vitamin K may occur, leading to inadequate formation of prothrombin and subsequent bleeding problems
Liver Lethal hepatic toxicity has been reported in conjunction with use in pregnancy and in the nonpregnant state in the presence of renal dysfunction, shock, and sepsis. Abnormal liver function tests have been reported (due to high dose in the presence of renal dysfunction)
Renal Azotemia. Also, renal disorders have been reported following administration during pregnancy. A Fanconi-type syndrome has been associated with the use of outdated or degraded tetracycline. Nephrogenic diabetes insipidus has been reported in conjunction with administration of demeclocycline
Skin Photosensitivity (especially with demeclocycline), rash, onycholysis. Seldom seen with chlortetracycline, minocycline, and tetracycline
Teeth Permanent discoloration and dysgenesis in the offspring due to administration of tetracycline during the last half of pregnancy or the first 6 years of life. Question of discoloration of permanent teeth under study
Teratogenesis These agents may be potential teratogens and result in malformed hands and limbs. Do not use in females of childbearing age range who have missed one or more menstrual periods
Figure 15–1. Minocycline discoloration of adult teeth.
248 Periodontal Medicine
oratories and elsewhere that have shown the pres- ence of tetracyclines in gingival crevicular fluid fol- lowing oral administration. Studies comparing tetracycline HCl and minocycline HCl have shown that the minocycline concentration in gingival crevicular fluid is higher than that of tetracycline HCl.8 Therefore, these antibiotics become an inte- gral part of the crevicular environment and may further exert an effect on plaque and gingival health. They have also been shown to be present in saliva, the level of concentration far below that found in serum.
Although the value of tetracyclines in the treatment of adult periodontitis is questionable, their value is established in the treatment of gener- alized and localized juvenile periodontitis,9–11
refractory periodontitis,12–14 and rapidly progres- sive periodontitis.15
Metronidazole Metronidazole (Flagyl, Metryl) is a unique antimicrobial agent in that it is effective against anaerobic bacteria and parasites but has little or no effect on facultative and aerobic organisms. It was initially developed in 1959 as an antitricho- monal drug.
Spectrum of Action. Metronidazole is most active against obligate anaerobic gram-negative bacilli (Bacteroides sp, Fusobacterium sp, Clostridi- um sp) and certain anaerobic protozoal parasites (Trichomonas, Giardia, Entamoeba). It is the only antimicrobial agent that consistently exhibits bac- tericidal activity against B. fragilis. It is also effec- tive against obligate anaerobic cocci (Peptococcus sp, Peptostreptococcus sp). It has minimal efficacy against Actinobacillus actinomycetemcomitans.
While metronidazole has no in vitro activity against aerobes, it has been shown to be effective in the treatment of mixed infections. The theory is that susceptible bacteria convert metronidazole to metabolites that are effective against the aerobic organisms in a mixed infection. However, despite the effectiveness of the drug against mixed infec- tions, clinical data supporting its use as the sole agent are lacking; therefore, the drug is often used in combination with other microbial agents in the treatment of periodontal infections.
Contraindications. Its main adverse effect is its interaction with alcoholic beverages, which can result in severe nausea and vomiting, metallic taste, gastric discomfort, and diarrhea.
Indications. In dentistry, metronidazole has been used in the treatment of acute necrotizing ulcerative gingivitis (ANUG), and postextraction
anaerobic gram-negative bacteremias and, in com- bination with other antibiotics (primarily peni- cillin), in treating severe odontogenic infections.
Although supportive data are weak, metron- idazole has been shown to be of benefit in treating severe adult periodontitis when the major outcome evaluated is avoidance of surgery.16,17 It has also been reported to be of value in treating refractory periodontitis, with or without combining with other antibiotics such as ciprofloxacin, amoxicillin or doxycycline. Although not effective against A. actinomycetemcomitans, both metronidazole and its hydroxymetabolite act synergistically with amoxicillin. Metronidazole affects most anaerobes and amoxicillin most facultative and aerobic bacte- ria, which makes this combination useful to treat many mixed periodontal infections. The recom- mended dosage for metronidazole is 250 to 500 mg tid for 7 to 10 days.18
Amoxicillin Penicillin, the first antibiotic used in humans, was derived from a number of molds. Although the effect of this derivative from the mold Penicillium notatum was discovered as early as 1928 by Sir Alexander Fleming in London, United Kingdom, therapeutic trials did not take place until 1941. This delay mainly resulted from lack of sufficient quantities of the drug for a clinical trial. Difficul- ties in penicillin production occurred because broth cultures of Penicillium could not be pro- duced rapidly.
Amoxicillin is sometimes called a broad-spec- trum penicillin and is a derivative of ampicillin. For periodontal therapy, it is often combined with clavulanate, which inhibits b-lactamases produced by some bacteria. It is highly acid stable, and pre- dictable blood levels can be attained following oral administration. Over 90% of the dose adminis- tered is absorbed.
Amoxicillin is a bactericidal drug that inhibits the synthesis of bacterial cell walls. The deficient cell walls thus created do not protect bacteria against high osmotic pressure. Fluids enter the cell causing swelling, membrane disruption, and subsequent cell death. The action of the drug also depends on its ability to reach and bind penicillin-binding proteins located in the bacterial cytoplasmic membranes. Because penicillin acts during the synthesis of cell walls, it is most effective against multiplying bacte- ria. The administration of a bacteriostatic drug in conjunction with penicillin therapy could therefore render the penicillin less effective by slowing down the bacterial growth rate.
Pharmacotherapy 249
Metabolism. Penicillin can be administered orally or parenterally. Since absorption following oral administration is influenced by the presence of food in the stomach, more predictable blood levels can be obtained if the drug is taken on an empty stomach. However, the absorption of amoxicillin from the gastrointestinal tract is not affected by the presence of food and therefore is more predictable following oral administration. Alternatively, pre- dictable blood levels are also possible when the drug is given parenterally.
Once absorbed, penicillin is widely distributed throughout the body, and is found in low levels in the saliva and gingival crevicular fluid. It does not cross the blood-brain barrier in normal persons, but in meningitis it does pass through and may be clin- ically effective. Penicillin is rapidly eliminated from the plasma by the kidneys; it can cross the placenta and be found in cord blood and amniotic fluid.
Penicillins are excreted in breast milk in low concentrations. Although significant problems in humans have not been documented, a risk-benefit analysis must be done since the drug may lead to sensitization, diarrhea, and candidiasis in nursing mothers.
Adverse Effects. Penicillin toxicity is extreme- ly low, and except for allergic reactions, it is one of the safest drugs known. However, intrathecal injec- tion or topical application during surgery on the brain has resulted in convulsive reactions.
Patients hypersensitive to one penicillin most likely are hypersensitive to all other penicillins. Also, those with a history of hypersensitivity to cephalosporins, griseofulvin, or penicillamine may show a similar response to penicillins.
Indications. Some studies have suggested that amoxicillin is of value in combination with metronidazole (see “Metronidazole”) for treatment of localized juvenile periodontitis. In addition, as amoxicillin/clavulanate (Augmentin), in doses of 250 to 500 mg tid, it may be of value in treating refractory periodontitis.19,20
Clindamycin Lincomycin, the predecessor to clindamycin, was discovered in 1962 in soil samples from Lincoln, Nebraska. Although lincomycin is no longer pre- scribed because of significant adverse effects, its derivative, clindamycin, is still available since it has fewer adverse effects and its antibacterial action is more effective than that of lincomycin.
Mechanism of Action. This antibiotic inhibits bacterial protein synthesis and is usually bacteriostatic but is bactericidal in high doses. The
mechanism of action of clindamycin is similar to that of erythromycin and identical to that of chlo- ramphenicol. These drugs bind to a specific sub- unit of the bacterial ribosomes, thereby inhibiting their protein synthesis.
Spectrum of Activity. Its antibacterial spec- trum is similar to that of erythromycin. Because of its ability to penetrate bone, however, it is particu- larly useful in treating periodontal disease when bacterial invasion of tissue is suspected.
Levels in the crevicular fluid usually are above the minimum inhibitory concentration for peri- odontal pathogens.21 It is almost completely absorbed from the GI tract and is excreted in urine, feces, and bile, with the biliary route being the most important. Following oral administra- tion, levels in bone are similar to levels in serum.
Adverse Effects. The main adverse effect of clindamycin is diarrhea and gastric upset if taken on an empty stomach. Therefore, it should be taken with food. Ulcerative colitis has been report- ed but the frequency of its occurrence is less than that seen with ampicillin or the cephalosporins. When colitis occurs, it is best treated with metron- idazole (250 mg qid) or vancomycin (500 mg qid). Since colitis can be fatal, patients must be closely monitored for this condition.
Indications. Clindamycin has been shown to be of value in the treatment of refractory peri- odontitis, either alone or in combination with amoxicillin/clavulanate (Augmentin).22–26 The usual dosage is 150 mg tid or qid for 7 to 10 days.
Miscellaneous Antibiotics Spiramycin. Spiramycin is active against
gram-positive organisms and is excreted in high concentrations in saliva. It is used as an adjunct to periodontal treatment in Canada and Europe but is not available in the United States.
This drug has minimal adverse effects. Some studies have suggested its benefit in adult peri- odontitis but data are not convincing.27–29
Ciprofloxacin. Ciprofloxacin is categorized as a fluoroquinolone and was initially developed to treat urinary tract infections. Studies of its value in periodontal therapy are limited, with a possible benefit reported in refractory cases.30,31 In combi- nation with metronidazole, it is effective against A. actinomycetemcomitans.32 The dosage is 500 mg bid for 8 to 10 days.
Adverse effects include gastrointestinal upset, oral candidiasis, headache, restlessness, insomnia, hypersensitivity, hyperpigmentation, and photo- sensitivity.
250 Periodontal Medicine
Antibiotic-Associated Pseudomembranous Colitis
Pseudomembranous colitis is a severe diarrheal dis- ease that can result from virtually any orally or par- enterally administered antibiotic used in dentistry (Table 15–4), but is most commonly associated with ampicillin, cephalosporins, and clindamycin.
The true incidence of this disease from antibi- otic use in dentistry is unknown because definitive diagnosis is based on endoscopic examination of the bowel, and this is rarely performed on patients suffering from diarrhea. However, there are a num- ber of signs and symptoms associated with this dis- ease that should suggest to the dentist that a patient might be suffering from antibiotic-associat- ed pseudomembranous colitis. The majority of patients present with fever, leukocytosis, abundant watery diarrhea, and a crampy abdominal pain beginning on the fourth to ninth day of antibiotic therapy. It is important to note, however, that as many as 40% of these patients do not manifest signs or symptoms until 2 to 10 weeks following the conclusion of antimicrobial therapy.
Etiology Current data suggest that in the majority of cases the disease is confined to the colon and is caused by a toxin produced by Clostridium difficile that is widely distributed in the environment and is a nor- mal inhabitant of the GI tract in approximately 3% of the population. The postulation is that administration of antibiotics alters the normal GI flora, thereby creating an environment more favor- able to the growth of C. difficile and/or the pro- duction and release of its enterotoxin. There is no microbial invasion of the intestinal mucosa, but rather the toxin most likely interacts with the cells lining the lower GI tract, causing cell necrosis and decreased water and electrolyte absorption, and producing a significant diarrhea.
Treatment Treatment depends on the severity of the disease. If it is mild (as it is in most cases), the most impor- tant therapeutic decision is to discontinue the antibiotic (if possible and appropriate) and to rehydrate the patient and replace lost electrolytes. In many patients, this approach usually results in a rapid, complete resolution of symptoms with no further necessary diagnostic tests (endoscopy, or examination of stool to detect C. difficile entero- toxin) or treatment regimens. The medication of choice is orally administered vancomycin or metronidazole. It is important to note that under no circumstances should antidiarrheal agents that decrease GI motility be used. They have been implicated in worsening the symptoms and out- come of the disease.
Most patients with pseudomembranous colitis recover without specific therapy, but the mortality rate in seriously ill patients can approach 30%. Because pseudomembranous colitis is associated with antibiotics that are commonly used in den- tistry, the practitioner should be aware of this potentially serious adverse reaction. Patients should contact their dentist immediately if diarrhea occurs during or after antibiotic therapy because prompt treatment can produce a rapid symptomatic response with essentially 100% recovery.
Antibiotic Combinations in Periodontal Therapy
An approach using a combination of antibiotics in periodontal therapy has recently been studied by var- ious investigators. Van Winkelhoff and colleagues33
reported on the concomitant use of metronidazole and amoxicillin in the treatment of A. actino- mycetemcomitans-associated periodontitis. Their results concluded that this regimen was able to sup- press A. actinomycetemcomitans (also Porphyromonas gingivalis) from being detected from the periodontal pocket for over 1 year. Kornman and colleagues34
have reported some value in the adjunctive systemic use of metronidazole in combination with amoxi- cillin or amoxicillin/clavulanate (Augmentin) in the treatment of patients with refractory periodontitis.
Also, Aitken and colleagues35 indicated that prevention of recurrent periodontitis with metron- idazole may be enhanced by previous treatment with doxycycline. The serial use of doxycycline and metronidazole has also been shown to be of value in reducing periodontal pathogens.36
A more recent study was designed to compare the effect of short-term systemic administration of
TABLE 15–4. Antibiotics Commonly Used in Dentistry that Are Associated with Pseudomembranous Colitis
Most Common Less Frequent Rare
Ampicillin Amoxicillin Aminoglycosides Cephalosporins Cloxacillin Metronidazole Clindamycin Erythromycin Tetracyclines
Penicillin G Penicillin K
Pharmacotherapy 251
a sequential antibiotic treatment therapy using Augmentin and doxycycline with that of a short- term systemically administered doxycycline alone in the treatment of periodontitis caused by A. actinomycetemcomitans and P. gingivalis.37 Doxy- cycline was included in this regimen for both its antibacterial and anticollagenolytic properties.38
In a 25-week study, patients were randomly placed in one of two treatment groups: one group (five patients) was to receive doxycycline (200 mg the first day, then 100 mg each day thereafter for a 10-day period); the second group (six patients) received a combination of Augmentin (500 mg tid for 5 days) and doxycycline (200 mg the first day, then 100 mg each day for a total of 5 days). Each patient received one session (approximately 1 to 2 hours) of local therapy via root planing for one half of the mouth; the other half mouth received no local therapy. No attempt was made to alter the patient’s oral hygiene regimen.
Clinical and microbiologic measurements were recorded at 0, 4, 12, and 25 weeks as follows: gingival index,39 plaque index,40 probing depth and attachment level by using a manual (William’s) probe and a controlled-force probe (Interprobe) at eight selected sites in each patient (four sites root planed and another four without root planing), and bleeding upon probing/suppuration.
The results of the study are summarized as follows:
The doxycycline/Augmentin groups produced significant reduction in probing pocket depth (PPD) at 4, 12, and 25 weeks (1.1, 1.3, and 1.1 mm, respectively). The doxycycline group pro- duced a significant reduction in probing depths only at 4 and 12 weeks (both times 0.8 mm) and a significant gain of 0.8 mm in probing attachment level at the same periods; and the doxycycline/Aug- mentin group in conjunction with root planing produced the most sustained reduction in probing depth and gain in attachment level.
A lower percentage of bleeding sites was noted in the doxycycline/Augmentin group than in the doxycycline group. All sites at 4, 12, and 25 weeks in both groups showed no signs of suppuration, with the exception of one site in the doxycycline group at week 25.
It should be noted that the reductions in prob- ing depths and gains in attachment levels reported were relative to their own baselines and not to each other. When the groups were compared with each other, no intergroup differences were found.
Although there were no significant reductions in the gingival or plaque indexes or the microbial
measurements, there was a trend toward reductions in the doxycycline group, which was better than that in the Augmentin/doxycycline group.
LOCALLY DELIVERED MEDICATIONS
Irrigation represents one of the earliest forms of local delivery of a medication. A major limitation of irrigation is the short duration of application of the medication. However, agents with significant substantivity or strong antibacterial properties may show some benefit, particularly in the treatment of gingivitis.
Water and a variety of chemical agents have been shown to be effective as irrigants in reducing gingivitis. Additionally, subgingival irrigation with a variety of antimicrobial agents has been shown to reduce a number of microorganisms associated with the pathogenesis of periodontal disease. Fur- ther short-term studies have suggested some reduc- tion of pocket depth; however, long-term studies in this area are needed. It is also noteworthy that irrigants, whether supra- or subgingivally deliv- ered, have been shown to be safe whether applied at home or in the office, and have been well received by patients.
Some representative studies on powered irriga- tion will be reviewed in this section.
Irrigation with Antimicrobial Agents
A study in the Journal of Periodontology41 evaluated the effect of in-office irrigation with PerioPik®
(Teledyne Water Pik) followed by at-home subgin- gival irrigation with a Pik Pocket® (Teledyne Water Pik) tip and a Water Pik Oral Irrigator® (Teledyne Water Pik). The in-office and at-home irrigant used was Listerine® (Warner Lambert Company).
Included in this study were 50 patients with adult periodontitis and at least four bilateral sites with probing depths between 4 and 5 mm, which bled upon probing. Following baseline examina- tions, the patients received a half-mouth scaling and prophylaxis and full-mouth subgingival irrigation with either the antimicrobial mouthrinse or control solution professionally delivered. The subjects con- tinued the irrigation at home once daily for 42 days with their assigned rinse delivered via a subgingival delivery system. All sites within the mouth were scored at baseline and at day 42 for supragingival plaque, bleeding on probing, and redness. For the four selected periodontitis sites, probing depth and attachment level were measured at baseline and on
252 Periodontal Medicine
day 42; additionally, supragingival plaque and gin- gival redness were scored on days 7 and 21. Subgin- gival plaque samples for microbiologic analysis were harvested from the selected periodontal sites at base- line and on days 7, 21, and 42. The samples were analyzed for Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium sp, Capnocytophaga sp, Streptococcus sanguis, Porphyromonas loescheii, and Treponema denticola. Microbiologically, irrigation with the antimicrobial mouthrinse resulted in statis- tically significant reductions compared with control in periodontal pathogens, including black pigment- ing species, which persisted at 42 days. Clinically, subgingival irrigation with the antimicrobial mouthrinse produced a significant reduction in supragingival plaque (p < .001), bleeding on prob- ing (p = .019), and redness (p = .017) compared with the control, whether or not a prophylaxis was performed. There were no significant differences between the active and control groups in either probing depth or attachment level (p > .05).
The authors concluded that subgingival deliv- ery of an antimicrobial agent with a powered oral irrigation device can play a potential role in the management of chronic periodontitis by virtue of its significant effects on the subgingival periodon- topathic microflora and supragingival plaque and gingivitis.
In another study at the University of Min- nesota, 74 patients were divided into irrigation and nonirrigation groups.42 Following a periodontal recall visit, the PerioPik® was used in the office to irrigate all gingival crevices with 1.64% stannous fluoride. Subjects were then given a powered pul- sating irrigator with a subgingival delivery tip (the Pik Pocket®) for daily irrigation at home with 200 mL of an iodine-containing solution (tetrahy- drazine hydroperiodide) for 8 weeks. In the irriga- tion group, statistically significant reductions in gingivitis were found compared with the control group and reductions in gingival bleeding com- pared with baseline. These reductions are notewor- thy since the control group was instructed in twice-daily brushing and once daily flossing, fol- lowing their recall visit. This study also demon- strated the safety of at-home subgingival irrigation using the subgingival tip as well as a high degree of acceptability as shown by an 89% compliance rate.
Supragingival Irrigation
Since patients with gingivitis and/or periodontitis rarely demonstrate optimal oral hygiene even when given oral hygiene information and instruction,
supragingival irrigation with water can be expected to have a therapeutic effect in most patients with periodontal disease (Figure 15–2). In a 6-month assessment of patients with gingivitis who per- formed daily supragingival irrigation with water, gingival inflammation was shown to be significant- ly reduced. The therapeutic effects of supragingival irrigation with water corresponded to the effect of twice-daily rinsing with 0.12% chlorhexidine glu- conate solution. However, in this study, supragin- gival irrigation with water influenced neither the supragingival plaque mass nor the composition of the subgingival microflora.43 Thus, it appears pos- sible that supragingival irrigation reduced gingival inflammation without altering the supra- and sub- gingival mass. Although the mechanism responsi- ble for this is not exactly known, it can be assumed that through irrigation there is a dilution or removal of bacterial toxins, which leads to an improvement of gingival health. Also, it has been shown that irrigation changes the morphology of bacteria so that, although present, they appear as cells with ruptured membranes.44
Following scaling and root planing, daily supragingival irrigation with water for 4 weeks leads to an improvement in gingival health that persists for 1 to 3 months.45 A 6-month study in the Journal of Periodontology evaluated the effect of daily water irrigation in 155 patients receiving maintenance periodontal treatment. The study demonstrated that adjunctive supragingival irriga- tion with water can provide meaningful clinical outcomes for patients with periodontitis who are being treated in the maintenance phase of peri- odontal therapy.46 They also found that irrigation with water was significantly better (p < .05) than zinc sulfate irrigation for all parameters measured.
The effect of supragingival irrigation on the subgingival microflora appears to depend on the pocket depth. Supragingival irrigation with water has been shown, in pockets of 5 mm and more, to reduce periodontal pathogenic bacteria, particular- ly P. intermedia, spirochetes, and motile rods.
Further, following supragingival scaling alone, supragingival irrigation with 0.02% stannous fluo- ride solution as an irrigant resulted in a significant improvement of gingival health, compared with supragingival irrigation with water.47
Irrigation with Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid, flurbiprofen, naproxen, and others, offer the possibility of limiting the
Pharmacotherapy 253
destructive side effects of the immune responses that occur in periodontal disease.
However, the therapeutic effect of irrigation with various concentrations of acetylsalicylic acid solution has not been found to be significantly better than irrigation with water.48,49 Further stud- ies with more effective anti-inflammatory agents are needed since they are readily absorbed through oral tissues and may offer beneficial effects on the periodontium.
The various irrigants reviewed are summarized in Table 15–5.
Irrigation around Implants
Powered irrigation has also been shown to be of benefit to improve gingival health around implants. A 3-month study was conducted in 24 men and women between the ages of 35 and 75 years to evaluate the effect of irrigation with 0.06% chlorhexidine (PerioGard®) using a powered oral irrigator (Water Pik®) with a special subgingival irrigating tip (Pik Pocket Subgingival Tip®), com- pared with rinsing with 0.12% chlorhexidine glu- conate once daily.50
The results of this study showed that irrigation with 0.06% chlorhexidine was significantly better than rinsing with 0.12% chlorhexidine for mea- sures of plaque and health (MGI and PI, p < .05) and that the reduction in BI, although not statisti- cally significant, was almost twice as large as that seen in the rinsing group (62% versus 33%). Also, the chlorhexidine-associated stain score was signif- icantly lower in the irrigation group compared with the control (p = .04). Further, it was found that the presence of calculus showed a 22% increase in the rinsing group in contrast to a 42% decrease in the irrigation group.
The results of this study show that powered irrigation with a chemotherapeutic agent such as chlorhexidine is supportive of the health of tissues around implants and minimizes calculus and stain associated with the use of chlorhexidine.
LOCAL DELIVERY OF ANTIBIOTICS
The limitations of systemic therapy have prompt- ed research for the development of alternative delivery systems. Recently, advances in delivery technology have resulted in the controlled release of drugs, usually systemically, for certain medical conditions. The oral cavity offers another relative- ly accessible disease site for localized therapy. The
requirements for treating periodontal disease include a means for targeting an antimicrobial agent to sites of infection and for sustaining its localized concentration at effective levels for suffi- cient lengths of time that, at the same time, evoke minimal or no side effects (Table 15–6).
Tetracycline-Containing Fibers (Actisite®)
The first local delivery product available in the United States and one which has been extensively studied is an ethylene/vinyl acetate copolymer fiber, diameter 0.5 mm, containing tetracycline, 12.7 mg/9 inches (Actisite® tetracycline fiber; manufactured by Alza Corporation, Palo Alto, CA, and distributed by Procter and Gamble Co., Cincinnati, OH) (Figure 15–3). When packed into a periodontal pocket, it is well tolerated by oral tis- sues, and for 10 days it sustains tetracycline con- centrations exceeding 1300 µg/mL, well beyond
Figure 15–2. Powered irrigation device with both supra- and subgingival applicator tips.
TABLE 15–5. Irrigants Showing Benefits as Adjuncts to Periodontal Therapy
Concentration Amount Application (%) (mL) Per Day
Water N/A 500 1 Chlorhexidine 0.06 200 1
digluconate solution
Stannous fluoride 0.02 500 1 solution
Listerine® Undiluted 100 1 Iodine 0.38 200 1
254 Periodontal Medicine
the 32 to 64 µg/mL required to inhibit the growth of pathogens isolated from periodontal pockets.51,52
In contrast, crevicular fluid concentrations of only 4 to 8 µg/mL are reported following systemic tetra- cycline administration, 250 mg four times daily for 10 days (total oral dose, 10 g).53 Thus, controlled site-specific tetracycline delivery can achieve an antibacterial effect at approximately one-thou- sandth of the dose administered systemically.
Studies demonstrate that the tetracycline fibers, applied with or without scaling and root planing, reduce probing depth, bleeding on prob- ing, and periodontal pathogens and provide gains in clinical attachment level. Such effects are signif- icantly better than those attained with scaling and root planing alone or with placebo fibers. In a 2- month study, compared with scaling and root planing, the fibers used alone have provided over a 60% greater improvement in probing depth and clinical attachment level than scaling alone.54 The fibers used in conjunction with scaling and root planing have also provided a statistically significant
improvement in probing depth reduction and clin- ical attachment level gain of over 60% and bleed- ing on probing reductions over scaling and root planing alone at 6 months after therapy.55
Among the tested putative periodontal pathogens, no change in antibiotic resistance to tetracycline has been found following tetracycline fiber therapy.56 Disadvantages of the fiber include the length of time required for placement (10 min- utes or more per tooth), the considerable learning curve required to gain proficiency at placement, and the need for a second appointment 10 days after placement for removal of the fiber. Also, placement of fibers around 12 or more teeth has resulted in oral candidiasis.
Another study suggested that rinsing with 0.12% chlorhexidine (Peridex®, Zila Pharmaceuti- cals, Inc., Phoenix, AZ) following fiber placement had a synergistic effect, enhancing the reduction of bacterial pathogens.57 It is possible that at-home irrigation with an antimicrobial agent following fiber removal could prolong this synergistic effect.
Evaluation of the effect of tetracycline fibers on root surfaces, using fluorescent light and scanning electron microscopy,58 showed superficial penetra- tion of tetracycline, with minor penetration into the dental tubules, and a few areas of demineralized root surface. Scanning electron microscopic obser- vations made in this study also revealed reductions in the subgingival microbial flora on the root sur- faces of teeth treated with the fibers versus the con- trol specimens. Many of the residual microbes observed in the fiber-treated teeth appeared nonvi- able, in contrast to the residual microbes found on the root-planed and control specimens.
Subgingival Delivery of Doxycycline (Atridox®)
Atridox® (manufactured by Atrix Laboratories, Fort Collins, CO; licensed for marketing by Block Drug, Inc., Jersey City, NJ) is a gel system that incorporates the antibiotic doxycycline (10%) in a syringeable gel system (Figure 15–4).
A 9-month multicenter study in 180 patients was designed to study the effects of subgingivally placed doxycycline compared with subgingival place- ment of the vehicle and a herbal agent (sanguinaria). Patients with initial probing depth of > 5 mm in selected sites were included in this study.59 The patients were instructed in oral hygiene and ran- domly assigned to one of three groups: vehicle con- trol, 5% sanguinaria in the vehicle control, and 10% doxycycline in the vehicle control. No scaling
TABLE 15–6. Desirable Characteristics for Locally Delivered Antimicrobials for Periodontal Therapy
Reaches site of disease (base of pocket) Achieves adequate drug concentrations Maintains sufficient duration of treatment Effective against periodontal pathogens Clinically effective as an adjunctive therapy Safe for teeth and soft tissues Minimal adverse side effects No bacterial resistance Easy application Biodegradable
Figure 15–3. Actisite® fiber being placed.
Pharmacotherapy 255
or root planing was performed in any of the groups, and there was no untreated group. Therefore, the study’s objective was to evaluate the effect of the various agents, compared with the vehicle when used as a monotherapy.
Treatment with doxycycline was more effective than the other treatments at all time periods with the exception of the 3-month clinical attachment level value. Also, on evaluation of the effect based on initial probing depth, the differential effect in the doxycycline group in comparison with the other two groups was greater as pretreatment prob- ing depth increased. For the doxycycline group, the reduction in clinical attachment level at 9 months showed a gain of 0.4 mm compared with vehicle control, the reduction in probing depth was 0.6 mm greater than vehicle control, and the reduction of bleeding on probing was 0.2 units greater than vehicle control. The differences were small but they were statistically significant. Although resis- tance was not evaluated in this study, the local application of doxycycline has previously been reported to have shown transient increases in resis- tance in oral microbes and no overgrowth of for- eign pathogens.60
Data from two multicenter clinical trials have also been reported, each studying 411 patients with moderate to severe periodontitis.61 At base- line, patients were randomized to one of four treat- ment groups: doxycycline, vehicle control, oral hygiene only, and scaling and root planing. Sites with probing depth ³ 5 mm that bled on probing were treated at baseline and then again with the same treatment at 4 months. Clinical assessments were made at months 1, 2, 4, 5, 6, 8, and 9 by measuring clinical attachment level, probing depth, and bleeding on probing. All treatment groups in both studies showed clinical improve- ments from baseline over the 9-month period. The results for all parameters measured were signifi- cantly better in the doxycycline group compared with the vehicle-control and oral-hygiene-only groups. Compared with scaling and root planing, the effects of doxycycline on clinical attachment level gain and probing depth reduction were equiv- alent. This product has been approved by the FDA for sale in the United States.
Subgingival Delivery System for Minocycline (Dentamycin®, Perio Cline®)
A subgingival delivery system of 2% (w/w) minocycline hydrochloride (Dentamycin®, Perio Cline®; Cyanamid International, Lederle Division,
Wayne, NJ, and SunStar, Osaka, Japan) is available in a number of countries for use as an adjunct to subgingival débridement. This system is a syringe- able gel suspension delivery formulation.
In a four-center, double-blind, randomized trial, patients with periodontal pockets at least 5 mm deep were selected, and either 2% minocy- cline gel or vehicle was applied once every 2 weeks four times.62 Treatment followed initial subgingival débridement in both treatment groups. Microbio- logic assessments were made at baseline and at weeks 2, 4, 6, and 12, with clinical assessments at baseline and weeks 4 and 12. A total of 103 patients were treated and 90 were evaluable for efficacy, of which 48 had been treated with minocycline gel and 42 with vehicle.
A total of 343 teeth (976 sites) were included in the minocycline group with 299 teeth (810 sites) in the control group. The microbiologic analysis in this study focused on three relevant plaque species: P. gingivalis, P. intermedia and A. actinomycetemcomitans.
Reductions in P. gingivalis and P. intermedia at weeks 2, 4, 6, and 12 and at weeks 6 and 12 for A. actinomycetemcomitans were statistically signifi- cant. These results demonstrated the advantages of supplementing standard subgingival débridement with minocycline gel application.
The three primary clinical efficacy variables in this study were probing depth, clinical attachment level, and bleeding index. There was a trend toward clinical improvement in both treatment groups for all three measures, and the reduction in probing depth was significantly greater with minocycline gel.
When sites with probing depth of at least 7 mm and significant bleeding at baseline were consid- ered, the improvements were greater than with 5
Figure 15–4. Atridox® being placed into a pocket.
256 Periodontal Medicine
mm pockets. The improvements with minocycline were statistically significantly better than the vehi- cle-control group.
In a 3-month study, 2% minocycline was also evaluated in 30 patients.63 Patients received oral hygiene education and root planing with local anes- thesia. Active or placebo gel was placed subgingi- vally at planed sites in each subject according to a double-blind protocol, immediately after instru- mentation and 2 and 4 weeks later. A periodontal examination was made with a constant force probe before instrumentation and 6 and 12 weeks later. Two subjects failed to complete the study; their pairs were therefore not included in the analysis. Results were tested with an analysis of covariance. The differences between the groups in mean prob- ing depth did not reach statistical significance at any visit, but mean clinical attachment levels were different in favor of the minocycline group (p < .05) at both reassessments. There was also a difference in the number of sites that bled after deep probing at 12 weeks, favoring the minocycline group (p < .05). This trial showed that adjunctive minocycline gel provided a more advantageous outcome for non- surgical periodontal treatment in terms of clinical attachment level and bleeding on probing. This product is not available in the United States.
A topical medication (Elyzol®; Dumex, Copenhagen, Denmark) containing an oil-based metronidazole 25% dental gel (glyceryl mono- oleate and sesame oil) has been tested in a number of studies.64 It is applied in viscous consistency to the pocket, where it is liquidized by the body heat and then on contact with water hardens again, forming crystals. As a precursor, the preparation contains metronidazole-benzoate, which is con- verted into the active substance by esterases in the crevicular fluid. Two 25% gel applications at a 1- week interval have been used in clinical studies.65
Studies of the metronidazole gel have shown it to be equivalent to scaling and root planing but have not shown adjunctive benefits in conjunction with scaling and root planing. For example, a recent 6- month study in 30 patients showed the following results.66 The treatment consisted of two applica- tions of the dental gel in two randomly selected quadrants (on days 0 and 7) as well as simultaneous subgingival scaling of the remaining quadrants. Oral hygiene instructions were given on day 21. The average probing depth and the average frequency of bleeding on probing were calculated for all sites with an initial probing depth of 5 mm or more; this was continued at each examination, using the same sites. The statistical analysis showed that both treatments
were effective in reducing probing depth and bleed- ing on probing over the 6-month period. At the end of the follow-up period, the mean reduction in probing depth was 1.3 mm after gel treatment and 1.5 mm after subgingival scaling. Bleeding on prob- ing was reduced by 35% and 42%, respectively. No significant differences between the two treatments were detected. Dark-field microscopy showed a shift toward a seemingly more healthy microflora for both treatment modalities; this effect persisted throughout the 6-month period.
A large multicenter study of 206 subjects investigated two applications of this gel in two ran- domly selected quadrants versus two quadrants of scaling.67 As in the study described above, probing depths were reduced by 1.2 mm in the gel and 1.5 mm in the scaling group. At 6 months, the differ- ences between treatments were statistically but not clinically significant. Also, bleeding on probing was reduced by 88% in both treatment groups.
LOCAL DELIVERY OF AN ANTISEPTIC AGENT
Chlorhexidine Delivery System (PerioChip®)
The PerioChip® (manufactured by Perio Products Ltd., Jerusalem, Israel; distributed by Astra USA, Inc., Westborough, MA) is a small chip (4.0 ´ 5.0 ´ 0.35 mm) composed of a biodegradable hydrolyzed gelatin matrix, cross-linked with glutaraldehyde and also containing glycerin and water, which has been incorporated into a chip containing 2.5 mg chlorhexidine gluconate (Figure 15–5). It is rounded at one end and inserts easily, in less than a minute, into periodontal pockets that are 5 mm or greater in depth. The PerioChip® releases chlorhexidine and maintains drug concentrations in the gingival crevic- ular fluid greater than 100 µg/mL for at least 7 days,68 concentrations well above the tolerance of most oral bacteria.69 Because the PerioChip® biode- grades in 7 to 10 days, a second appointment for removal is not needed.
Two multicenter, randomized, double-blind, parallel-group, controlled clinical trials of the Perio- Chip® were conducted in the United States with a total of 447 patients in 10 centers.70 In these stud- ies, patients received a supragingival prophylaxis for up to 1 hour, followed by scaling and root plan- ing for 1 hour. Chips were placed in target sites with a probing depth 5 to 8 mm at baseline that bled on probing and again at 3 and 6 months if the
Pharmacotherapy 257
probing depth remained 5 mm or greater. Sites in control-group subjects received either a placebo chip (inactive) plus scaling and root planing or scaling and root planing alone. Sites in test-group subjects received either a chlorhexidine chip (active) plus scaling and root planing or scaling and root planing alone (to maintain the study blind). Examinations were performed at baseline and at 3, 6, and 9 months.
At 9 months, significant decreases were observed in probing depth from baseline favoring the active chip compared with controls (chlorhexi- dine chip plus scaling and root planing, –0.95 ± 0.05 mm; placebo chip plus scaling and root plan- ing, –0.69 ± 0.05 mm [p =.001]; scaling and root planing alone –0.65 ± 0.05 mm [p =.00001]). The proportion of pocket sites with a probing depth reduction of 2 mm or more was increased in the chlorhexidine chip group (30%), compared with scaling and root planing alone (16%), a difference which was statistically significant on a per-patient basis (p < .0001). Improvements favoring the chlorhexidine chip compared with controls were also observed for clinical attachment levels at 9 months, improvements which were significant when the data were pooled (p < .05). Bleeding on probing was reduced in the active chip group com- pared with both controls, differences which were significant in one of the two studies (p < .05) and also when the data were pooled (p =.012). These data indicate that the biodegradable chlorhexidine chip, when used as an adjunct to scaling and root planing, significantly reduces probing depth and maintains clinical attachment levels when com- pared with scaling and root planing alone.
Another study was reported that evaluated the results of a 6-month clinical trial using the Perio- Chip®.68 The study was a randomized, blinded, controlled, split-mouth, multicenter study con- ducted with 118 patients in three study centers outside the United States. Patients, aged 30 to 65 years, with moderate periodontitis and in good general health were studied. Patients received a full-mouth scaling and root planing. The subgingi- val instrumentation was performed after baseline measurements were recorded. The two quadrants of the maxillary arch were randomized to the two treatment arms—scaling and root planing alone (control quadrant) or scaling and root planing plus PerioChip® (test quadrant). All remaining maxil- lary pockets with a probing depth between 5 and 8 mm at the baseline visit were entered into the study. The PerioChip® was inserted into each pocket measuring 5 to 8 mm in the designated
quadrant. Clinical measurements, including prob- ing depth, clinical attachment level, and bleeding on probing, as well as gingivitis, plaque, and stain- ing indices, were recorded at baseline and at 1, 3, and 6 months. At the 3-month visit, a full-mouth supragingival prophylaxis was undertaken accord- ing to clinical needs, and a chlorhexidine chip was inserted into each test pocket with a remaining depth of 5 to 8 mm.
The average probing depth reduction in the scaling and root planing plus PerioChip®-treated sites was significantly greater than in the sites receiving scaling and root planing alone, at both 3 and 6 months, with a mean difference of 0.42 mm (p < .01) at 6 months. Improvement in clinical attachment levels at the treated sites was greater than at sites that received scaling and root planing alone although the difference was statistically sig- nificant at the 6th-month visit only (p < .05). An analysis of patients with initial probing depths of 7 to 8 mm (n = 56) revealed an even greater improvement in both probing depth and attach- ment level in those pockets adjunctively treated with PerioChip® compared with scaling and root planing alone, at both 3 and 6 months, suggesting that the deeper the initial probing depth, the greater is the clinical improvement. The mean dif- ferences between test and control sites at 6 months for these deeper pockets were 0.71 mm and 0.56 mm for probing depth and clinical attachment lev- els, respectively.
Relative to bleeding on probing, the scaling and root planing plus PerioChip® sites showed con- sistently less bleeding on probing than control sites with a significant difference (p < .05) between the treatment groups occurring at the 3-month exami- nation. The test quadrants showed a significant decrease (p < .05) in gingival index when compared with control quadrants at 3 and 6 months.
Figure 15–5. PerioChip® compared to tip of a pencil.
258 Periodontal Medicine
No signs of staining were noted in any of the above three studies as a result of the chlorhexidine chip treatment as measured by a stain index. Adverse effects were minimal with a few patients who complained of slight pain and swelling in the first 24 hours after chip placement.
HOST MODULATION
The US Food and Drug Administration recently granted marketing approval for Periostat® for the adjunctive treatment of periodontitis. Periostat®, available as a 20 mg capsule of doxycycline hyclate, is prescribed for use by patients twice daily. The mechanism of action is by suppression of the activ- ity of collagenase, particularly that produced by polymorphonuclear leukocytes. The role of colla- genase in the pathogenesis of periodontal disease is illustrated in Figure 15–6. Although this drug is in the antibiotic family, it does not produce any
antibacterial effects since the dose of 20 mg twice daily is too low to affect bacteria. As a result, resis- tance to this medication cannot develop.
Four double-blind clinical multicenter studies in over 650 patients have demonstrated that Perio- stat® improves the effectiveness of professional periodontal care and slows the progression of the disease process.
The results of the first three studies showed that Periostat® resulted in approximately a 50% improvement in clinical attachment level (CAL) in pockets with probing depths of 4 to 6 mm and a 34% improvement in pockets with probing depths ³ 7 mm. It was also noted that attachment loss was prevented in sites with normal probing depths (0 to 3 mm) while the placebo groups lost 0.13 mm at 12 months (p = .05).71,72
The improvement in pocket depth generally paralleled the improvement in CAL after treatment for 12 months. Tooth sites with a baseline pocket probing depth (PPD) of 4 to 6 mm improved by
Host response to bacterial antigens produces periodontal breakdown
Bacterial MMPs (Collagenase)MMPs
(Collagenase) MMPs
(Collagenase)
Pro-Collagenase
Bacterial Antigens
Bacteria in Gingival Sulcus
Pro-Collagenase
Infiltrating Cells of the Periodontium
Resident Cells of the Periodontium
MMPs Play a Prominent Role
ACTIVATORS
CYTOKINES AND INFLAMMATORY MEDIATORS
Breakdown of Collagen Matrix in Gingiva, Periodontal Ligament and Alveolar Bone
Figure 15–6. Collagenase and the pathogenesis of periodontal disease.
Pharmacotherapy 259
over 50%. Sites with a baseline probing depth ³ 7 mm, improved by Periostat® by 45%.
Incidences of Rapid Progression
Attachment loss of 3 mm or more occurring dur- ing the first 6 months of the three 12-month stud- ies that required interventions by scaling and root planing (SRP) occurred in 52 tooth sites in a total of 9 patients receiving placebo versus 14 tooth sites in a total of 9 patients in the Periostat®-treatment group. Thus, there was a 73% reduction in the incidence of rapid progression of periodontitis associated with Periostat® and scaling treatment. Furthermore, in patients with incidences of rapid progression who received SRP treatment at 6 months, CAL improved by 2.16 mm after treatment with Periostat® plus SRP for an additional 6 months. In comparison, in patients who received placebo plus SRP at 6 months, CAL improved by only 0.78 mm after an additional 6 months (p = .005).
Adjunct to Scaling and Root Planing
A fourth study was conducted over a 9-month period in 190 patients who had at least two sites in each of two quadrants with CAL and PPD between 5 mm and 9 mm.73 The study design was similar to the first three studies with the exception that Periostat® was evaluated as an adjunct to sub- gingival SRP. All data were analyzed by appropriate statistics as in the previous studies but also includ- ed a per-patient analysis of variance (ANOVA).
The results of this study showed that there was a consistent improvement of CAL of approximately 20% (1.03 mm versus 0.86) in patients with a probing depth of 4 to 6 mm (p < .05) and approx- imately 30% (1.55 vs 1.17) in those with probing depths of ³ 7 mm (p < .05). It is also noteworthy that sites with a probing depth of 4 to 6 mm at baseline showed statistically significant improve- ments in CAL after 3, 6, and 9 months of treat- ment with Periostat® and SRP (p < .05) compared with treatment with SRP and placebo.
Similarly, for sites with a probing depth ³ 7 mm at baseline, treatment with Periostat® significantly augmented the efficacy of SRP compared with SRP and placebo. Statistically significant improvements in CAL with Periostat® were observed after 3 months (p < .01), and after 6 and 9 months (p < .05).
Reductions in PPD were similar to those seen for gains in CAL. For sites with a baseline PPD of 4 to 6 mm, a statistically significant reduction was demonstrated after 3, 6, and 9 months in patients
receiving Periostat® and SRP compared with patients receiving SRP and placebo (p < .001). A mean reduction of 0.96 mm was observed after 9 months of treatment with Periostat® whereas treat- ment with SRP and placebo resulted in a mean reduction of 0.71 mm (p < .001) representing a benefit of over 30%. Likewise, PPD at more severe sites (PPD ³ 7 mm at baseline) improved signifi- cantly after 3 (p < .001), 6 (p < .001), and 9 months (p < .01) of treatment with Periostat® compared with SRP and placebo treatment. A mean reduction of 1.68 mm was seen after 9 months of treatment with Periostat® whereas SRP and placebo treatment resulted in a mean reduction of 1.21 mm (p < .01), representing a benefit of almost 40%.
Results of safety studies showed the use of Periostat® 20 mg bid, either with or without mechanical therapy (SRP), did not exert an antimicrobial effect on the periodontal microflora and did not result in a detrimental shift in the nor- mal flora and the colonization or overgrowth of the periodontal pocket by bacteria resistant to doxycy- cline, tetracycline, minocycline, amoxicillin, ery- thromycin, or clindamycin. In addition, there was no evidence of any tendency toward the acquisi- tion of multiantibiotic resistance.74,75
Although no product is available at this time, host modulation by inhibition of prostaglandins may be of value in the future treatment of peri- odontal disease. The drugs of interest in this catego- ry are the nonsteroidal anti-inflammatory agents.76
Agents for Oral Fungal Infections
Oral fungal infections can be expected to increase with an aging population; with increasing age, Candida albicans, the agent responsible for these infections, flourishes due to a decrease in salivary flow that may be physiologic, psychological, or medication induced.
Fungal infections may occur as a side effect of antibiotic therapy or during chronic medication with tranquilizers, sedatives, and anticholinergic drugs. If these infections occur in patients wearing full or partial dentures, therapy includes not only medicating the patients but also having them soak their prosthesis in the medication for the duration of the oral therapy. In some cases, the acrylic por- tions of the appliances must be remade since fungi may be present in its pores. Some common anti- fungal agents are reviewed below.
Nystatin Nystatin (eg, Mycostatin) was discovered in 1954 and is an excellent antibiotic for the treatment of
260 Periodontal Medicine
fungal infections. It is most useful in the treatment of both oral and vaginal moniliasis (thrush, can- didiasis). This drug binds to the covering mem- brane of susceptible fungi, altering the permeabili- ty of the cell membrane and leading to cell death. It is both fungistatic and fungicidal.
Metabolism. This drug can be given orally but is poorly absorbed from the gastrointestinal tract, and large amounts are found in feces. Also, it is not absorbed from the skin and mucous membranes and is therefore not given parenteral- ly. It exerts its main effect via the topical route in most cases.
Adverse Effects. Adverse effects are rare and include nausea, vomiting, and diarrhea following oral administration. However, no adverse effects have been reported via the topical route. Hypersensitivity reactions have not occurred, nor has resistance. It also appears to be safe for use during pregnancy.
Dosage and Dosage Forms. This antibiotic is available as a tablet or liquid for oral or vaginal use and as an ointment and cream for topical and vagi- nal use. Since it is not absorbed when swallowed, it has a topical effect in the gastrointestinal tract. For oral candidiasis, a rinse of 400,000 to 600,000 units daily is usually effective. For vaginal condi- tions, a dose of 100,000 to 200,000 units daily for 2 weeks is indicated.
Ketoconazole Ketoconazole (Nizoral) is classified as an imida- zole, and its oral administration is approved for the treatment of systemic fungal infections. It is also useful for the treatment of oral and vaginal can- didiasis (thrush).
Mechanism of Action. Ketoconazole inter- feres with the synthesis of chemicals needed to form the plasma membrane of fungi, resulting in disorganization of the membrane.
Metabolism. Its absorption from the gas- trointestinal tract is better than that of nystatin. It is metabolized in the liver, and only small amounts are found in urine and feces. Since data for its use in pregnancy are lacking, it is not recommended for pregnant women. The presence of the drug in breast milk has been recognized.
Adverse Effects. The most common adverse effects are nausea and pruritus. Headache, dizzi- ness, gastrointestinal problems, nervousness, and liver dysfunction occur less often. Gynecomastia has been reported in 10% of men treated with ketoconazole. Since this medication has some liver toxicity, if it is used for more than 2 weeks, liver function tests should be performed.
Dosage and Dosage Forms. It is available in tablet form in 200 mg doses and also as an oint- ment. For oral candidiasis, the usual dose is 200 mg daily for 10 days.
Miconazole (Monistat) This drug is classified as an imidazole and has the same mechanism of action as ketoconazole. Howev- er, it is used mainly as an antifungal vaginal prepa- ration and as a skin medication applied topically.
Its main side effects are irritation, burning, or maceration. It is considered safe for use in preg- nancy because absorption is less than 1% when applied topically. Studies relative to its use in den- tistry are minimal.
Clotrimazole (Lotrimin, Mycelex) This drug is chemically similar to miconazole. It is available as a topical and systemic agent and is used more widely in Europe than in this country. Since it is more toxic than the other antifungal agents, it should be used when the others have not been suc- cessful topically.
Adverse Effects. Its main side effects after topical use are the same as those of miconazole. Also, after topical or systemic use, it may cause hal- lucinations, gastrointestinal disturbances, and abnormal liver function. Since abnormal liver function has occurred in 15% of patients using the troche, periodic liver function tests are indicated if therapy exceeds 2 weeks.
Dosage and Dosage Forms. A 10-mg troche is available for oral topical use every 3 hours. Studies have shown that if the troche is allowed to dissolve in the mouth for 30 minutes, therapeutic levels can be found in saliva for up to 3 hours. Apparently, this is due to release of the drug from sites in the oral mucosa to which it binds. Since the amount absorbed systemically by this route has not been determined, signs of adverse reactions associated with systemic administration must be monitored. Its safety in pregnancy has not been determined.
Mouthrinses and Dentifrices Mouthrinses and dentifrices have been shown to be of value mainly in the reduction of plaque and gingivitis. Some of these agents have been shown to have a significant effect in the reduction of gin- givitis, and they have received the American Den- tal Association (ADA) Seal of Acceptance.
Listerine Antiseptic®, Cool Mint Listerine®, FreshBurst Listerine®, chlorhexidine gluconate (Peridex®), and two generic equivalents of Lister- ine Antiseptic® and triclosan have been granted the
Pharmacotherapy 261
ADA Seal of Acceptance. These antimicrobial mouthrinses provide a standard of comparison for all other available products.
The phenolic compound Listerine® showed a reduction of 20 to 34% in plaque and a reduction of 28 to 44% in gingivitis in two 6-month studies and one 9-month study.77–79 The bis-biguanide chlorhex- idine (0.12%) has also proven effective in the reduc- tion of both plaque and gingivitis.80 Chlorhexidine, however, has been associated with staining of teeth, altered taste, and increased levels of calculus forma- tion and is available by prescription only. A further consideration is that a patient should rinse and/or irrigate with this preparation at least 30 minutes after brushing because of a decrease in efficacy due to an interaction with the positively charged sodium lauryl sulfate, the detergent component of dentifrices.81
Similarly, the negatively charged fluoride ion may interact with chlorhexidine and also greatly reduce its efficacy. This cationic nature, however, is the basis for the substantivity of chlorhexidine. This property allows chlorhexidine to bind to negatively charged ions and proteins of the mucous membranes and teeth, and to maintain that contact for some time.82
There are several other antimicrobial mouthrinses available that have not yet received the ADA Seal of Acceptance. The quaternary ammonium compounds such as Cepacol®, Scope®, and New Viadent® have some degree of substan- tivity but less than that of chlorhexidine.83
Sanguinaria, an herbal extract, has not been shown to produce significant reductions in plaque and gingivitis in 6-month studies. The recent addi- tion of zinc chloride to the dentifrice and mouthrinse formulations, however, has helped to produce a significant reduction in both plaque and gingivitis.84 In the United States, the sanguinaria products are available as original formula in Viadent® mouthrinse and toothpaste. To date, however, the ADA Seal of Acceptance has not been awarded to the Viadent® products.
Plax®, a popular prebrushing rinse, has not been shown to reduce plaque and gingivitis exten- sively enough to receive the ADA Seal of Accep- tance. Clinical studies regarding the efficacy of Plax® have yielded equivocal results.85–92
Triclosan Triclosan (2,4,4'-Trichloro-2' – hydroxydiphenyl ether) is a new antiplaque/antigingivitis agent avail- able in dentifrices marketed throughout the world. The addition of a co-polymer (polyvinylmethyl- ether maleic acid [PVM/MA]) has been shown to improve the effectiveness of triclosan by enhancing
its retention (substantivity) onto hard and soft oral surfaces. This formula, found in Colgate Total®, has been cleared by the U.S. Food and Drug Adminis- tration (FDA) for sale in the United States and is also ADA accepted. Formulas without the co-poly- mer are not cleared for sale by the FDA. Therefore, formulations by Unilever and Procter & Gamble are only available outside the United States.
The clearance given by the FDA was based on data from two pivotal studies conducted in approx- imately 600 patients. Both studies were conducted at independent research centers and followed a sim- ilar protocol.93,94 Both these long-term clinical studies provided statistically significant differences (p < .01) in gingivitis in favor of the 0.3% triclosan and 2.0% PVM/MA0 co-polymer dentifrice (in a sodium fluoride/silica base). The reduction in gin- givitis averaged 24.3%. The Gingivitis Severity Index showed an average reduction of 60.6%. These two pivotal studies provided statistically sig- nificant differences (p < .01) in supragingival plaque accumulation in favor of the 0.3% triclosan and 2.0% PVM/MA co-polymer dentifrice (in a 0.243% sodium fluoride/silica base) as compared with a placebo dentifrice (in a 0.243% sodium flu- oride/silica base). The Quigley-Hein Plaque Index efficacy results showed an average efficacy score of 15%. The Plaque Severity Index results averaged a 19% reduction.
Seven other studies showed a reduction in gin- givitis for the Colgate Total® formulation, ranging from 19.7 to 81.5%, with an average reduction of 25.3%. The reduction in Gingivitis Severity was 56%. Reductions in plaque in these studies ranged from 12.7 to 58.9%, with an average reduction of 30.2%. The average reduction in Plaque Severity was 54.9%.95–101
In all the studies carried out (in a total of over 1,400 patients), no extrinsic staining was observed, there were no serious adverse effects associated with the triclosan containing dentifrice (Colgate Total®), and there were no complaints of taste alterations or unpleasant taste. Additionally, reduc- tions in calculus averaging 35% have been report- ed in studies with durations ranging between 3 and 6 months.102
A recent study evaluated the effect of a denti- frice containing triclosan/co-polymer on the microflora and clinical signs characteristic of recur- rent adult periodontitis.103 Sixty patients (mean age of 55 years) previously treated for advanced periodontal disease were included in this 36- month study. During a 3- to 5-year period follow- ing active therapy, the patients had been enrolled
262 Periodontal Medicine
in a supportive periodontal therapy program and were on a 3-month recall interval. All patients who were enrolled had, at various intervals during the preceding 3 to 5 years, exhibited signs of recurrent periodontitis, such as deepened pockets and addi- tional loss of attachment (> 2 mm) and alveolar bone. All subjects presented with moderate gin- givitis and exhibited lesions characterized by prob- ing pocket depth of > 5 mm in eight sites (at least two in each quadrant), and loss of interproximal alveolar bone (> 40% of original height), as seen in radiographs. Standardized radiographs were taken at baseline and 36 months. In a subset of 40 patients, the deepest pocket site in each quadrant (ie, four sites per subject) was selected, and samples of the subgingival bacteria were taken. The test group included 30 individuals who used a denti- frice containing triclosan/co-polymer/fluoride, that is, 0.3% triclosan, 2% co-polymer, and 1100 ppm F from 0.243% sodium fluoride. The control group also included 30 subjects who used a denti- frice identical to the one used in the test group but without the triclosan/co-polymer content. No pro- fessional subgingival therapy was delivered between the baseline and the 36th-month exami- nations. The subjects were recalled every 3 months. Re-examinations were performed after 6, 12, 24, and 36 months of the trial.
The clinical results of this study showed that for bleeding on probing (BOP), in both groups between the baseline and the 36th-month examination, there was a small but insignificant decrease in the number of BOP-positive sites (test group 4% and control group 8%). For probing depth, in the test group, the PPD value gradually decreased between examina- tions. The mean reductions in PPD between baseline and the 6th-, 12th-, 24th-, and 36th-month exami- nations were 0.02 mm, 0.05 mm, 0.03 mm, and 0.14 mm, respectively. In the control group, the mean PPD gradually increased, and the correspond- ing mean PPD increases at the 6th-, 12th-, 24th-, and 36th-month examinations were 0.03 mm, 0.10 mm, 0.17 mm, and 0.19 mm, respectively. The dif- ference in PPD change (mean 0.33 mm) between the test and control groups during the 36th-month interval was statistically significant (p < .01). It was also noted that in the test group the frequency of sites with shallow pockets (< 3 mm) increased between baseline and 36 months (from 57 to 61%), the medium deep pockets (4 to 5 mm) decreased from 31 to 27% while the percentage of sites with deep pock- ets (6 mm) remained unchanged (12%). In the con- trol group, the frequency of shallow pockets decreased with an average of 2% while sites with
deep pockets increased with an average of 2%. For CAL, the mean value increased between the base- line and the 36th-month. In the test group, the mean additional CAL loss amounted to 0.11 mm (12 months), 0.14 mm (24 months), and 0.18 mm (36 months). The corresponding additional loss in the control group was 0.22 mm (12 months), 0.35 mm (24 months), and 0.52 mm (36 months). The additional loss in probing attachment that occurred between baseline and the 24th- and 36th-month examinations was sig- nificantly higher in the control group than in the test group (p < .05 and p < .01, respectively). In all three intervals (0 to 12 months; 12 to 24 months; 24 to 36 months), the test group exhibited fewer sites with additional attachment loss than did the control group. Thus, between baseline and the 12th month, in the test group, there were 48 loser sites compared with 67 sites in the controls. The corresponding numbers for period 2 (12 to 24 months) were 37 and 59, and for period 3 (24 to 36 months) were 72 and 197.
The microflora analysis showed that the total viable count (TVC) of bacteria decreased in both groups between the baseline examination and the re-examination after 36 months. In the control group, the TVC value was reduced from 15 ´ 106
to 12 ´ 106 (not significant). In the test group, the corresponding reduction was more pro- nounced (from 17 ´ 106 to 9 ´ 106) and statisti- cally significant (p < .05). It was also noted that for periodontal pathogens, the reductions were greater in the triclosan/co-polymer group than in the control group.
The results of this study suggest that use of a triclosan/co-polymer dentifrice reduced the fre- quency of deep periodontal pockets and the num- ber of sites that exhibited additional probing attachment and bone loss. This finding may be related to the fact that a number of studies have shown that supragingival plaque reduction has a strong influence on the quantity and quality of the subgingival microflora.104,105 It has been shown that thorough removal of supragingival plaque results in a reduction in the TVC of subgingival microflora and in the number of periodontal pathogens in shallow (< 3 mm) as well as moder- ately deep pockets (4 to 6 mm).106,107
Triclosan is marketed in Europe as a mouth- rinse (Plax®) as well. The European formula differs from the U.S. formula because of the inclusion of triclosan. This triclosan-containing mouthrinse has been shown to significantly reduce plaque and gingivitis with minimal side effects.
Pharmacotherapy 263
EFFECTS OF MEDICATIONS
The Periodontium
Medications can have both beneficial and adverse effects on periodontal tissues. Some of these effects are discussed below.
In terms of their relationship to tissues, medica- tions should be categorized on the basis of the fol- lowing: alteration of methods in behavior and oral hygiene, alteration of plaque composition, alteration of salivary pH, effect on salivary flow, effect on gin- gival tissues, effect on alveolar bone, and effect on gingival crevicular fluid. Some effects of medications may increase the risk of dental diseases while some others may actually decrease the risk.
Behavioral Alteration of Oral Hygiene Practice Patients who are on medications that have a depressant effect on the central nervous system, such as sedatives, tranquilizers, narcotic analgesics, antimetabolites, and antihypertensives, may become careless about their oral hygiene practices; therefore, they have a tendency toward increased plaque formation. The basis for the change in a patient’s attitude or behavior must be understood, and an oral hygiene program must be designed on the basis of these changes.
Two of the top 20 prescription drugs in the United States act directly as mood-altering drugs; alprazolam (Xanax) and fluoxetine (Prozac) may make patients more amenable to improving their oral hygiene.108 However, since drowsiness is a side effect of these medications, motivation may still be a problem. Two other drugs that alter moods as a side effect of their antihypertensive action, enalapril maleate (Vasotec) and captopril (Capoten), may make patients less amenable to following oral hygiene procedures.
Plaque Composition and Salivary pH Plaque composition and pH as well as salivary pH may be altered by the dosage of medications. Over- the-counter (OTC) medications and liquid pharma- ceutical preparations are used daily by some people. Although the active ingredients in these medicines are sometimes necessary for improvement or main- tenance of health, some inactive ingredients pose hidden dangers. For example, many liquid or chew- able pharmaceutical preparations for children are made palatable by the addition of sucrose, glucose, or fructose as sweeteners. Sugars are the sweetening agents in orally administered antifungal prepara- tions. Since these medications come as lozenges,
troches, and oral solutions and are kept in the mouth for extended periods, they may place patients at a significant risk for caries. Antacid tablets also contain large amounts of sugar and, in the older adult, may result in increased caries of root surfaces. The readily fermentable carbohydrates in thick liq- uid preparations may add significantly to alteration of plaque pH and composition. Although the risk of caries has been shown to increase with the use of these medications,109 their effects on the periodon- tal pathogens has not been evaluated.
Sugars, metabolized by bacteria to acid end- products, lower salivary pH as well as the pH with- in an adherent bacteria-rich plaque that is relative- ly unavailable to salivary buffering. This lowered pH near the tooth surface can cause ionic dissolu- tion from the hydroxyapatite crystals, increase sur- face roughness, and enhance the plaque’s ability to be more adherent and to initiate caries. It has been shown that human plaque pH decreased signifi- cantly after administration of liquid iron supple- ments110 and cough syrups.111
A controlled clinical study of patients on chron- ic doses of medication reported a significant increase in both dental caries and gingivitis in a population of children taking liquid or chewable medications continuously for a minimum of 6 months.112
The alteration of plaque composition and plaque retention to tooth surfaces may have peri- odontal implications that must be considered in patients with excess plaque.
Salivary Flow
Adequate salivary flow is critical to the maintenance of the health of oral soft tissues.113 It has been sug- gested that “mouthbreathers” have modified plaque accumulations and associated soft-tissue changes. A number of medications that decrease salivary flow (xerostomia) mimic mouthbreathing.114 For exam- ple, a study at our research center evaluated the effect of anticholinergic agents on plaque and oral health in patients who had gastrointestinal ulcers and were receiving such medications.115 It was found that these patients had a tendency to accu- mulate more plaque after dental prophylaxis and oral hygiene instructions and had a slower rate of resolution of gingivitis following scaling and root planing. In this short-term study, it was found that a statistically significant reduction occurred in the control patients in all clinical measures of gingival health other than pocket depth, but no significant reductions were observed in the medicated patients. Agents that produce xerostomia include antihyper-
264 Periodontal Medicine
tensives, narcotic analgesics, some tranquilizers, quinolones, antimetabolites, antihistamines, seda- tives, and even vitamin D in large doses.116 In addi- tion to the effect of xerostomia on oral soft tissues, root surface caries may be more prevalent in those taking such medications.117
Long-term tranquilizing agents, especially the phenothiazines and meprobamate, have been report- ed to produce xerostomia and, in some situations, an overgrowth of C. albicans in the oral microflora.118
Patients on long-term phenothiazines have also shown a tendency to developing less calculus.
Gingival Tissue
A number of medications may cause gingival enlargement. Phenytoin (Dilantin) was the first drug reported to produce this effect with the inci- dence ranging between 3 and 62% (mean 50%). A number of investigations have suggested a causal relationship between inflammation and gingival hyperplasia, the implication being that this hyper- plasia could be minimized or prevented if gingival inflammation were eliminated.119,120 It is possible that, if patients are placed on a strict program of oral hygiene within 10 days of the initiation of therapy with medications promoting gingival enlargement, its occurrence can be minimized.121,122
Although the occurrence of gingival enlarge- ment due to phenytoin has been clearly established, its cellular and molecular mechanisms of action for this effect are unclear. A recent study suggests that phenytoin augmented the expression of the gene for platelet-derived growth factor-B (PDGF-B).123
In this study, the authors also showed that gingival macrophages exposed to phenytoin secrete increased amounts of PDGF. This may increase not only the proliferation of gingival cells but also alve- olar bone cells. A recent report suggests that pheny- toin has the ability to stimulate bone cell prolifera- tion and differentiation and may mature osteoblas- tic activities to stimulate bone formation.124 If so, this may explain the authors’ clinical impression of minimal bone loss in patients with phenytoin- induced gingival hyperplasia. The effect on PDGF may also explain an early report in which a patient being medicated with phenytoin underwent ortho- dontic tooth movement; and with no special rapid movement planned, the teeth moved in half the time with no adverse effects on bone or shortening of the roots.125 In this case, phenytoin may have favored bone remodeling. It is possible that although phenytoin produces an increased risk fac- tor for gingival enlargement and the associated gin-
givitis, it may result in a decreased risk factor for bone loss found in periodontitis.
Gingival enlargement has also been associated with a number of calcium channel blockers, including nifedipine (Procardia), verapamil (Calan), diltiazem (Cardizem), and isradipine (DynaCirc). Gingival enlargement is seen in 5 to 20% of patients taking these medications.
A proposed mechanism of action relates inflammatory factors within the gingival tissue to gingival enlargement. It has been shown that the histology in a nifedipine patient resembled an inflammatory-type hyperplasia similar to that described for phenytoin, in which numerous inflammatory cells replaced collagen in connective tissue.126 This paper supports the concept that alteration of the intracellular calcium level in gin- gival cells by nifedipine in combination with appropriate local inflammatory factors is impor- tant in eliciting gingival enlargement.
It has also been shown that if nifedipine could not be discontinued, gingival enlargement did not recur after gingivectomy when thorough plaque control was carried out, again supporting earlier reported findings of the role of inflammation and plaque.127
Gingival enlargement has also been reported with cyclosporine, with an incidence of approxi- mately 25%.128 There are a number of similarities between the clinical and histopathologic changes seen in cyclosporine- and phenytoin-induced gin- gival enlargement. Also, both drugs are known to have an effect on the immune system, including the induction of lymphoid hyperplasias and lym- phomas. For these patients, meticulous plaque control, as a preventive measure upon initiation of and throughout cyclosporine therapy and as a cor- rective procedure after completion of therapy, may be of value as in the case of patients on phenytoin therapy.129,130 Also, it has been postulated that cyclosporine alters fibroblastic activity. The role of plaque in this process has not been clearly estab- lished, and conflicting results have been reported.
Alveolar Bone
In addition to their antibacterial effects, tetracy- clines are now known to inhibit pathologically excessive host-derived matrix metalloproteinase activity during periodontal and other diseases. The discovery of the anticollagenolytic properties of the tetracyclines was made using an animal model of both pathologically excessive collagenase activity in gingival tissues and periodontal breakdown.131,132
Pharmacotherapy 265
A recent study showed that treating germ-free and pathogen-reduced rats, inoculated with Porphy- romonas gingivalis, by the oral administration of a nonantimicrobial dose of a tetracycline (as dis- cussed earlier in this chapter) or a chemically mod- ified nonantimicrobial tetracycline significantly inhibited periodontal bone loss.133
Although the mechanisms of this drug effect are not yet clear, tetracyclines can also directly inhibit osteoclast-mediated bone resorption and the pro- duction of collagenase and gelatinase.134 It is not yet known whether this therapeutic effect reflects a direct inhibition of bone resorption longitudinally, the inhibition of episodes of bone resorption in its early stages, or the proanabolic effects on bone for- mation. These issues as well as others such as the temporal relationship of matrix metalloproteinase (collagenase, gelatinase) induction and bone loss should be addressed in future studies.
Antibiotics have also been shown to be of value in arresting bone loss in special types of peri- odontal disease, such as rapidly advancing peri- odontitis, localized juvenile periodontitis, and refractory periodontitis, with the mechanism of action related to the drug’s antimicrobial effects.135
Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce bone loss in both animal and human models, with a variety of agents show- ing some effect.136 Epidemiologic studies of the periodontium of patients receiving NSAIDs on a long-term basis for arthritis suggested that they had less alveolar bone loss than a similar popula- tion not receiving these medications.137 The mech- anism of action of these agents appears to be relat- ed to their effect on prostaglandins.
Gingival Crevicular Fluid
An increase in gingival crevicular fluid (GCF) flow may be responsible for more rapid plaque forma- tion. With the increasing severity of gingivitis, the GCF flow also increases, which may contribute to an increased amount of plaque.138 This relation- ship was first observed when more plaque was seen to have formed as the gingivitis became more severe. A possible mechanism may be that GCF has higher levels of calcium, which may act as a binding agent favoring bacterial aggregation and precipitation of salivary proteins.139 Also, it has been noted that plaque wettability increases with disease and that this factor may be affected by GCF. Following this reasoning, since anti- inflammatory drugs decrease gingival inflamma- tion, if an associated decrease in GCF occurs,
one might expect less plaque to be present in these patients. However, in contrast, an earlier study reported that, although GCF flow decreased with topical steroid application of flu- ocinonide (Sulindac), a systemic nonsteroidal anti-inflammatory drug, this had no plaque- reducing effect.140 Noting that the same amount of plaque was present in both groups of patients, they concluded that GCF flow may not have an effect on plaque accumulation.
Change in Crevicular Fluid Content Since GCF is in intimate contact with plaque, alterations in its content and pH deserve investiga- tion. Do anti-inflammatory and other systemic drugs change the pH and composition of this fluid? Are the changes significant to plaque accu- mulation and metabolism? It has been demonstrat- ed that glucose is present in GCF in levels higher than those found in saliva.141 An unanswered ques- tion is, “Does this level change when oral hypo- glycemics or insulin are administered?” Soluble gold salts decrease the number of inflammatory cells in gingival tissues;142 since metals like gold have antibacterial properties, can their administra- tion improve periodontal health?
Antibiotic Resistance Since antibiotics have been extensively discussed in this chapter, consideration must be given to the development of resistance to them. Resistance to mouthrinse and dentifrice ingredients or to locally delivered medications has not been demonstrated with one exception. S. sanguis resistance to chlor- hexidine has been reported after 2 years of use of the drug. However, the clinical significance of this finding is unclear at this time since oral disease has not been associated with S. sanguis, although bac- terial endocarditis has been caused by this microbe.
However, resistance to systemically adminis- tered antibiotics is increasing, and a brief review of this topic follows.
Penicillin was first discovered in 1896 by a French medical student, but at the time the dis- covery was not evaluated for its true meaning. In 1928, it was rediscovered by Fleming, a Scottish physician. However, penicillin was not mass pro- duced by drug companies until 1943. Shortly after the introduction of penicillin, Staphylococcus aureus resistance to it developed, sending manufacturers rushing to produce forms of penicillin that could overcome this resistance.
The development of antibiotic resistance has been dramatic. In 1967, the resistance of Streptococ-
266 Periodontal Medicine
cus pneumoniae and Neisseria gonorrhoeae was docu- mented. In 1983, another penicillin-resistant bac- terium, Enterococcus fecrisa, developed in hospital settings. Between 1979 and 1987, only 0.02% of pneumococcal strains infecting a large number of patients surveyed by the Centers for Disease Con- trol and Prevention (CDC) were penicillin resistant. The CDC survey included 13 hospitals in 12 states in the United States.143 Today, 6.6% of pneumococ- cal strains are resistant.144 In 1992, 13,300 hospital patients in the United States died of bacterial infec- tions that were resistant to antibiotic treatment.
Although antibiotics themselves do not directly cause resistance, they do create situations that allow an existing variant strain of bacteria to flour- ish. This results in the development of resistance to the antibiotic. A patient can develop a drug-resis- tant infection either by contracting a resistant microorganism before treatment or by having a resistant microbe emerge in the body in the course of antibiotic treatment. Drug-resistant infections not only increase the risk of death but are also often associated with prolonged hospital stays and even medical complications. These infections could necessitate removing part of a ravaged lung, or replacing a damaged heart valve.
In another example of the natural development of resistance, erythromycin attacks ribosomes with- in a cell, enabling it to make proteins. Resistant bac- teria have slightly altered ribosomes to which the antibiotic cannot bind. The ribosomal route is also how bacteria become resistant to other antibiotics such as tetracycline, streptomycin, and gentamicin.
Antibiotic resistance can occur in three ways: spontaneous mutations of a bacterium’s own genetic material (DNA), acquisition of DNA from another bacterium through transformation, and acquisition via plasmid transmission. Though bac- terial antibiotic resistance is a natural process, as outlined above, other factors also contribute to the problem (eg, increased infection transmission cou- pled with inappropriate antibiotic use).
Today, more people are contracting infections. Sinusitis among adults is on the rise, as are ear infections in children. Nearly 6 million antibiotic prescriptions for sinusitis were written in 1985 and nearly 13 million in 1992. For middle-ear infec- tions, the numbers of prescriptions are 15 million in 1985, and 23.6 million in 1992.
Clearcut reasons for the dramatic rise in infec- tions are not available; however, suggested causes include an increase in communal living situations (day-care centers for children and adults, senior citizen centers, homeless shelters, and nursing
homes) and increased use of medications (for immunocompromised patients, transplantation patients, and patients on cancer chemotherapy), which make people more prone to infection. Addi- tionally, the aging of our population is an added risk factor for infection.
ANTIBIOTICS IN POULTRY AND OTHER MEATS
Although the FDA limits the amount of antibiotic residue in meats, the question arises as to whether these foods are a source of low-dose antibiotics, subsequently resulting in resistance. The FDA is also evaluating whether bacterial resistance to quinolone antibiotics can emerge in animals slaughtered for food and consequently cause dis- ease in humans. Although thorough cooking great- ly reduces the likelihood of antibiotic-resistant bac- teria surviving in meat and infecting a human, the possibility remains. There have been sporadic reports of pathogens resistant to drugs other than fluoroquinolones surviving in cooked meat and infecting a human. For example, in 1983, 18 peo- ple in four midwestern states suffered multidrug- resistant Salmonella food poisoning after eating beef from cows fed antibiotics. Eleven of the peo- ple were hospitalized and one died.
ANTIBIOTIC RESISTANCE AND HUMAN USE
A study of the development of antibiotic resistance in humans shows that the increase in antibiotic resistance parallels the increase in antibiotic use. This study examined a large group of cancer patients given fluoroquinolones to prevent infec- tion. The patients’ white blood cell counts were very low as a result of their cancer treatment, leaving them open to infection. Between 1983 and 1993, the percentage of such patients receiving antibiotics rose from 1.4 to 45%. During these years, researchers isolated Escherichia coli annually from the patients and tested the microbes for resistance to five types of fluoroquinolones. Between 1983 and 1990, all 92 E. coli strains tested were easily killed by the antibiotics. But from 1991 to 1993, 11 of the 40 tested strains (28%) were resistant to all five drugs. Resistance is also occurring to vancomycin, which has been the “last resort” antibiotic for many infec- tions, including Staphylococcus. Vancomycin-resis- tant enterococci were first reported in England and France in 1987, and appeared in one New York City
Pharmacotherapy 267
hospital in 1989. By 1991, 38 hospitals in the Unit- ed States reported the pathogen. By 1993, 14% of patients with enterococci infections in intensive-care units in some hospitals had vancomycin-resistant strains, a 20-fold increase from 1987. In 1992, a British laboratory observed the transfer of a van- comycin-resistant gene from Enterococcus to Staphy- lococcus aureus in the laboratory. The fear now is that if vancomycin-resistant enterococci can transfer their resistance, anti-Staphylococcus antibiotics will no longer be of value.
In view of the rapid rise in antibiotic resistance in recent years, all dental prescriptions for antibi- otics should be accompanied by careful instruc- tions to the patient regarding proper dosage and taking the full prescription. All antibiotics should be prescribed in situations where their value is well established so that unnecessary prescribing against “normal” bacteria does not occur. These simple safeguards can help us all win the battle against resistant strains.
REFERENCES
1. Ciancio SG. FDA Approves periostat marketing. Biol Ther Dent 1998; 14:21–2.
2. Ciancio SG, Bourgault PC. Clinical pharmacology for dental professionals. 3rd ed. St. Louis (MO): C.V. Mosby Co.; 1989. p.58.
3. Barnett ML. Inhibition of oral contraceptive effec- tiveness by concurrent antibiotic administra- tion. J Periodontol 1985;56(1):18–21.
4. Preus HR, Lassen J, Aass AM, Christersson LA. Prevention of transmission of resistant bacteria between periodontal sites during subgingival application of antibiotics. J Clin Periodontol 1993;20:299–303.
5. Poliak SC, DiGiovanna JJ, Gross EG, et al. Minocycline-associated tooth discoloration in young adults. JAMA 1985;254:2930–2.
6. Salman RA, Salman DG, Glickman RS, et al. Minocycline-induced pigmentation of the oral cavity. J Oral Med 1985;40:154–7.
7. Attwood HD, Dennett X. A black thyroid and minocycline treatment. Br Med J 1976;2: 1109–10.
8. Ciancio SG, Slots J, Reynolds HS, et al. The effect of short-term administration of minocycline HCl on gingival inflammation and subgingival microflora. J Periodontol 1982;9:557–61.
9. Hayes C, Antczak Bouckoms A, Burdick E. Quali- ty assessment and meta-analysis of systemic tetracycline use in chronic adult periodontitis. J Clin Periodontol 1992;19:164–8.
10. Kornman KS, Robertson PB. Clinical and micro- biological evaluation of therapy for juvenile periodontitis. J Periodontol 1985;56:443–6.
11. Lindhe J, Liljenberg B. Treatment of localized juve- nile periodontitis. Results after 5 years. J Clin Periodontol 1984;11:399–410.
12. Papli R, Lewis JM. Refractory chronic periodonti- tis: effect of oral tetracycline hydrochloride and root planing. Aust Dent J 1989;34:60–8.
13. Kornman KS, Karl E. The effect of long-term low- dose tetracycline therapy on the subgingival microflora in refractory adult periodontitis. J Periodontol 1982;53:604–10.
14. Shapiro A. Healing potential of periodontal osseous defects treated by scaling and root plan- ing. J Dent Que 1990;27:587–92.
15. Preus H. Treatment of rapidly destructive peri- odontitis in Papillon-Lefèvre syndrome. Labora- tory and clinical observations. J Clin Periodon- tol 1988;15:639–43.
16. Loesche WH, Schmidt E, Smith BA, et al. Effects of metronidazole on periodontal treatment needs. J Periodontol 1991;62:247–57.
17. Loesche WJ, Giordano JR, Hujoel PP, et al. Metronidazole in periodontitis: reduced need for surgery. J Clin Periodontol 1992;19:103–12.
18. Loesche WJ, Giordano JR. Metronidazole in peri- odontitis V: debridement should precede med- ication. Compendium Cont Educ Dent 1994; 25:1198–2001.
19. van Winkelhoff AJ, de Graaff J. Microbiology in the management of destructive periodontal dis- ease. J Clin Periodontol 1991;18:411–20.
20. Collins JG, Offenbacher S, Arnold RR. Effects of a combination therapy to eliminate Porphyromonas gingivalis in refractory periodontitis. J Periodon- tol 1993;64:998–1007.
21. Walker CB, Gordon JM, Cornwall HA, et al. Gin- gival crevicular fluid levels of clindamycin com- pared with its minimal inhibitory concentra- tions for periodontal bacteria. Antimicrob Agents Chemo 1981;19:867–71.
22. Walker CB, Gordon JM, Magnusson I, Clark WB. A role for antibiotics in the treatment of refractory periodontitis. J Periodontol 1993;64:772–81.
23. Magnusson I, Clark WB, Low SB, et al. Effect of non-surgical periodontal therapy combined with adjunctive antibiotics in subjects with “refractory” periodontal disease: I. Clinical results. J Clin Periodontol 1989;16:647–53.
24. Magnusson I, Marks RG, Clark WB, et al. Clinical, microbiological and immunological characteris- tics of subjects with “refractory” periodontal dis- ease. J Clin Periodontol 1991;18:291–9.
268 Periodontal Medicine
25. Magnusson I, Low SB, McArthur WP, et al. Treat- ment of subjects with refractory periodontal dis- ease. J Clin Periodontol 1994;21:628–37.
26. Walker C, Gordon J. The effect of clindamycin on the microbiota associated with refractory peri- odontitis. J Periodontol 1990;61:692–8.
27. Quee TC, Clark C, Lautar-Lemay C, et al. The role of adjunctive Rodogyl therapy in the treatment of advanced periodontal disease. A longitudinal clinical and microbiologic study. J Periodontol 1987;58:594–601.
28. Quee TC, Al-Joburi W, Lautar-Lemay C, et al. Comparison of spiramycin and tetracycline used adjunctively in the treatment of advanced peri- odontitis. J Antimicrob Chemother 1988;22 (Suppl B):171–7.
29. Bain CA, Beagrie GS, Bourgoin J, et al. The effects of spiramycin and/or scaling on advanced peri- odontitis in humans. J Can Dent Assoc 1994; 60:209–17.
30. Slots J, Rams TE. Rational use of antibiotics. J Calif Dent Assoc 1990;18:21–3.
31. Slots J, Feik D, Rams TE. In vitro antimicrobial sensitivity of enteric rods and pseudomonads from advanced adult periodontitis. Oral Micro- bial Immunol 1990;5:298–301.
32. Pavicic M, van Winkelhoff A, de Graaff J. Synergis- tic effects between amoxicillin, metronidazole, and the hydroxymetabolite of metronidazole against Actinobacillus actinomycetemcomitans. Antimicrob Agents Chemother 1991;35:961–6.
33. van Winkelhoff AJ, Rodenberg JP, Goene RJ, et al. Metronidazole plus amoxicillin in the treatment of Actinobacillus actinomycetemcomitans-associ- ated periodontitis. J Clin Periodontol 1989;16: 128–31.
34. Kornman KS, Newman MG, Flemmig TF, et al. Treatment of refractory periodontitis with metro- nidazole plus amoxicillin or Augmentin (Abstract 403). J Dent Res 1989;68(Spec Issue):917.
35. Aitken S, Birek P, Kulkarni GV, et al. Serial doxy- cycline and metronidazole in prevention of recurrent periodontitis in high-risk patients. J Periodontol 1992;63:97–102.
36. Birek D, Kulkarni GV, Lee WK, et al. Effect of ser- ial doxycycline/metronidazole on recurrent peri- odontitis pathogens (Abstract 864). J Dent Res 1989;68(Spec Issue):373.
37. Matisko MW, Bissada NF. Short-term sequential administration of amoxicillin/clavulanate potas- sium and doxycycline in the treatment of recur- rent/progressive periodontitis. J Periodontol 1993;64:553–8.
38. Golub LM, Ramamurthy N, McNamara TF, et al.
Tetracyclines inhibit tissue collagenase activity. A new mechanism in the treatment of periodontal disease. J Periodontal Res 1984;19:651–5.
39. Löe H, Silness PJ. Periodontal disease in pregnancy. I. Prevalence and severity. Acta Odontol Scand 1953;21:533–51.
40. Silness PJ, Löe H. Periodontal disease in pregnan- cy. II. Correlation between oral hygiene and periodontal condition. Acta Odontol Scand 1964;22:121–35.
41. Fine JB, Harper DS, Gordon JM, et al. Short-term microbiological and clinical effects of subgingi- val irrigation with an antimicrobial mouthrinse. J Periodontol 1994;65:30–6.
42. Wolff LF, Bakdash MB, Pihlstrom Bl, et al. The effect of professional and home subgingival irrigation with antimicrobial agents on gingivitis and early periodontitis. J Dent Hygiene 1989;63:222–6.
43. Flemmig TF, Newman MG, Doherty FM, et al. Supragingival irrigation with 0.06% chlorhexi- dine in naturally occurring gingivitis. I. 6 month clinical observations. J Periodontol 1990;61: 112–7.
44. Cobb CM, Rodgers RL, Killoy WJ. Ultrastructur- al examination of human periodontal pockets following the use of an oral irrigation device in vivo. J Periodontol 1988; 59:155–9.
45. Aziz-Gandour IA, Newman HN. The effects of a simplified oral hygiene regimen plus supragingi- val irrigation with chlorhexidine or metronida- zole on chronic inflammatory periodontal dis- ease. J Clin Periodontol 1986;13:228–36.
46. Newman MG, Cattabriga M, Etienne D, et al. Effectiveness of adjunctive irrigation in early periodontitis—multicenter evaluation. J Perio- dontol 1994;65:224–9.
47. Boyd RL, Leggott P, Quinn R, et al. Effect of self- administered daily irrigation with 0.02% SnF2 on periodontal disease activity. J Clin Periodon- tol 1985;12:420–31.
48. Drisko C, Forgas L, Killoy WJ. Subgingival irriga- tion with effervescent buffered aspirin solution in gingivitis and periodontitis (Abstract 1257). J Dent Res 1994;73.
49. Flemmig TF, Funkenhauser Z, Epp B, et al. Adjunctive supragingival irrigation in periodon- titis treatment (Abstract 554). J Dent Res 1992;72 (Spec Issue):584.
50. Felo A, Shibly O, Ciancio SG, et al. Effects of sub- gingival chlorhexidine irrigation on peri- implant maintenance. Am J Dent 1997;10: 107–10.
51. Tonetti M, Cugini AM, Goodson JM. Zero order delivery with periodontal placement of tetracy-
Pharmacotherapy 269
cline loaded ethylene vinyl acetate fibers. J Peri- odontal Res 1990;25:243–7
52. Walker CB, Gordon JM, McQuilkin SJ, et al. Tetracycline: levels achievable in gingival crevice fluid and in vitro effect on subgingival organ- isms. Part II. Susceptibilities of periodontal bac- teria. J Periodontol 1981;52:613–6.
53. Gordon JM, Walker CB, Murphy CJ, et al. Tetra- cycline: levels achievable in gingival crevice fluid and in vitro effect on subgingival organisms. Part I. Concentrations in crevicular fluid after repeated doses. J Periodontol 1981;52:609–12.
54. Goodson JM, Cugini MA, Kent RL, et al. Multi- center evaluation of tetracycline fiber therapy: II. Clinical response. J Periodontal Res 1991;26: 371–9.
55. Newman MG, Kornman KS, Doherty FM. A 6- month multi-center evaluation of adjunctive tetracycline fiber therapy used in conjunction with scaling and root planing in maintenance patients: clinical results. J Periodontol 1994;65: 685–91.
56. Goodson JM, Tanner A. Antibiotic resistance of the subgingival microbiota following local tetra- cycline therapy. Oral Microbiol Immunol 1992; 7:113–7.
57. Niederman R, Holborow D, Tonetti M, et al. Rein- fection of periodontal sites following tetracy- cline fiber therapy (Abstract 1345). J Dent Res 1990;69:277.
58. Morrison SL, Cobb CM, Kazakos GM, Killoy WJ. Root surface characteristics associated with sub- gingival placement of monolithic tetracycline- impregnated fibers. J Periodontol 1992;63: 137–43.
59. Polson AM, Garrett S, Stoller NH, et al. Multi- center comparative evaluation of subgingivally delivered sanguinarine and doxycycline in the treatment of periodontitis. II. Clinical results. J Periodontol 1997;68:119–26.
60. Larsen T. Occurrence of doxycycline-resistant bac- teria in the oral cavity after local administration of doxycycline in patients with periodontal dis- ease. Scand J Infect Dis 1991;23:89–95.
61. Garrett S, Adams D, Bandt C, et al. Two multicen- ter clinical trials of subgingival doxycycline in the treatment of periodontitis (Abstract 1113). J Dent Res 1997;76:153.
62. Van Steenberghe D, Bercy P, Kohl J. Subgingival minocycline hydrochloride ointment in moder- ate to severe chronic adult periodontitis: a ran- domized, double-blind, vehicle-controlled, mul- ticenter study. J Periodontol 1993;64:637–44.
63. Graca MA, Watts TLP, Wilson RF, Palmer RM. A
randomized controlled-trial of a 2% minocycline gel as an adjunct to non-surgical periodontal treatment, using a design with multiple matching criteria. J Clin Periodontol 1997;24:249–53.
64. Ainamo J, Lie T, Ellingsen BH, et al. Clinical responses to subgingival application of a metronidazole 25% gel compared to the effect of subgingival scaling in adult periodontitis. J Clin Periodontol 1992;19 (Part II):723–9.
65. Klinge B, Attström R, Karring T, et al. Three regi- mens of topical metronidazole compared with subgingival scaling on periodontal pathology in adults. J Clin Periodontol 1992;19 (Part II): 708–14.
66. Stelzel M, Flores-de-Jacoby L. Topical metronida- zole application compared with subgingival scal- ing. A clinical and microbiological study on recall patients. J Clin Periodontol 1996;23: 24–9.
67. Ainamo J, Lie T, Ellingsen BH, et al. Clinical responses to subgingival application of a metronidazole 25% gel compared to the effect of subgingival scaling in adult periodontitis. J Clin Periodontol 1992;19(Part I):723–9.
68. Soskolne WA, Heasman PA, Stabholz A, et al. Sus- tained local delivery of chlorhexidine in the treatment of periodontitis: a multi-center study. J Periodontol 1997; 68:32–8.
69. Briner WW, Kayrouz GA, Chanak MX. Compara- tive antimicrobial effectiveness of a substantive (0.12% chlorhexidine) and a nonsubstantive (phenolic) mouthrinse in vivo and in vitro. Com- pend Contin Educ Dent 1994;15:1158–68.
70. Jeffcoat M, Bray KS, Ciancio SG, et al. Adjunctive use of a subgingival controlled-release chlorhex- idine chip reduces probing depth and improves attachment level compared with scaling and root planing alone. J Periodontol (In press).
71. Caton J, Bleiden T, Adams D, et al. Subantimicro- bial doxycycline therapy for periodontitis (Abstract). J Dent Res 1997;76:1307.
72. Ciancio SG, Adams D, Blieden T, et al. Suban- timicrobial dose doxycycline: a new adjunctive therapy for adult periodontitis. Presented at the Annual Meeting of The American Academy of Periodontology, Boston, MA, September 1998.
73. Caton JG, Ciancio SG, Crout RJ, et al. Post-treat- ment effects of adjunctive sub-antimicrobial dose doxycycline therapy. J Periodontology 1999 [Submitted].
74. Walker C, Thomas J. The effect of subantimicro- bial doses of doxycycline on the microbial flora and antibiotic resistance in patients with adult periodontitis. Presented at The American Acad-
270 Periodontal Medicine
emy of Periodontology Meeting, Boston, MA, September, 1998.
75. Crout R, Adams D, Blieden T, et al. Safety of doxy- cycline hyclate 20 mg BID in patients with adult periodontitis. Presented at The American Academy of Periodontology Meeting, Boston, MA, September, 1998.
76. Howell TH, Williams RC. Non-steroidal anti- inflammatory drugs as inhibitors of periodontal disease progression. Crit Rev Oral Biol Med 1993;4:177–96.
77. Lamster IB, Alfano MC, Seiger MC, et al. The effect of Listerine antiseptic on reduction of existing plaque and gingivitis. Clin Prev Dent 1983;5:12–6.
78. Gordon JM, Lamster IB, Seiger MC. Efficacy of Listerine antiseptic in inhibiting the develop- ment of plaque and gingivitis. J Clin Periodon- tol 1985;12:697–704.
79. DePaola LG, Overholser CD, Meiller TF, et al. Chemotherapeutic inhibition of supragingival dental plaque and gingivitis development. J Clin Periodont 1989:16:311–5.
80. Löe H, Schiott CR. The effect of mouthrinses and topical application of chlorhexidine on the development of dental plaque and gingivitis in man. J Periodontal Res 1970;5:79–83.
81. Barkvoll P, Rolla G, Svendsen AK. Interaction between chlorhexidine digluconate and sodium lauryl sulfate in vivo. J Clin Periodontol 1989; 16:593–5.
82. Mandel ID. Chemotherapeutic agents for control- ling plaque and gingivitis. J Clin Periodontol 1988;15:488–98.
83. Davies RM. Rinses to control plaque and gingivi- tis. Int Dent J 1992;42(Suppl):276–80.
84. Wennstrom J, Lindhe J. Some effects of a san- guinarine-containing mouthrinse on developing plaque and gingivitis. J Clin Periodontol 1985; 12:867–72.
85. O’Mahony G, O’Mullane DM. Evaluation of Plax pre-brushing rinse in reducing dental plaque (Abstract). J Dent Res 1990;69:246.
86. Patters MR, Shiloah J. A method for evaluating the effect of a pre-brushing rinse in reducing dental plaque [Abstract]. J Dent Res 1991;70:323.
87.Singh SM. Efficacy of Plax pre-brushing rinse in reducing dental plaque. Am J Dent 1990;3:15–6.
88.Freitas Bastos L, Collaert B, Attström R. Plaque removing efficacy of the pre-brushing rinse Plax [Abstract]. J Dent Res 1991;70:768.
89.Balanyk T, Sharma N, Galustians J. Antiplaque effi- cacy of Plax pre-brushing rinse: plaque mass/ area analysis [Abstract]. J Dent Res 1991;70:374.
90.Rustogi KN, Petrone DM, Singh SM, et al. Clinical study of a pre-brush rinse and a triclosan/co- polymer mouthrinse: effect on plaque forma- tion. Am J Dent 1990;3:S67–9.
91.Cronin MJ, Kohut BE. A two-phase clinical efficacy study of Plax pre-brushing rinse. J Clin Dent 1991;3:19–21.
92.Chung L, Smith SR, Joyston-Bechal S. The effect of using a prebrushing mouthwash (Plax) on oral hygiene in man. J Clin Periodontol 1992;19: 679–82.
93.Mankodi S, Walker C, Conforti N, et al. Clinical effect of a triclosan-containing dentifrice on plaque and gingivitis: a six-month study. Clin Prevent Dent 1992;14:4–10.
94.Bolden TE, Zambon JJ, Sowinski J, et al. The clini- cal effect of a dentifrice containing triclosan and a co-polymer in a sodium fluoride/silica base on plaque formation and gingivitis: a six-month clinical study. J Clin Dent 1992;4:125–31.
95.Garcia-Godoy F, Garcia-Godoy K, DeVizio W, et al. Effect of a triclosan/co-polymer/fluoride denti- frice on plaque formation and gingivitis: a 7- month clinical study. Am J Dent 1990;3:S15–26.
96.Cubells AB, Dalmau L, Petrone ME, et al. The effect of a triclosan/co-polymer/fluoride dentifrice on plaque formation and gingivitis: a six-month clinical study. J Clin Dent 1991;2:63–9.
97.Deasy MJ, Singh SM, Rustogi KN, et al. Effect of a dentifrice containing triclosan and a co-polymer on plaque formation and gingivitis. Clin Pre- vent Dent 1991;13:12–9.
98.Denepitiya JL, Fine D, Singh SM, et al. Effect upon plaque formation and gingivitis of a triclosan/ co-polymer/fluoride dentifrice: a 6-month clini- cal study. Am J Dent 1992;5:307–31.
99.Palomo F, Wantland L, Sanchez A, et al. The effect of three commercially available dentifrices con- taining triclosan on supragingival plaque forma- tion and gingivitis: a six-month clinical study. Int Dent J 1994;44 (Suppl 1):S75–81.
100. Triratana T, Tuongratanaphan S, Kraivaphan P, et al. The effect on established plaque formation and gingivitis of a triclosan/co-polymer/fluoride dentifrice: a six-month clinical study. J Dent Assoc Thailand 1993;43:19–28.
101. Lindhe J, Rosling B, Socransky SS, Volpe AR. The effect of a triclosan containing dentifrice on established plaque and gingivitis. J Clin Peri- odontol 5:327–34.
102. Ciancio SG. Calculus reduction of a triclosan/ co-polymer/fluoride dentifrice. Biol Ther Dent 1997;13.
103. Rosling B, Wannfors B, Volpe AR, et al. The use
Pharmacotherapy 271
of a triclosan/co-polymer dentifrice may retard the progression of periodontitis. J Clin Peri- odontol 1997;24:873–80.
104. Smulow JB, Turesky SS, Hill RG. The effect of supragingival plaque removal on anaerobic bac- teria in deep periodontal pockets. J Am Dent Assoc 1983;107:737–42.
105. Hellstrom MK, Ramberg P, Krok L, Lindhe J. The effect of supragingival plaque control on the subgingival microflora in human periodontitis. J Clin Periodontol 1996;23:934–40.
106. Dahlen G, Lindhe J, Sato K, et al. The effect of supragingival plaque control on the subgingival microbiota in subjects with periodontal disease. J Clin Periodontol 1992;19:802–9.
107. McNabb H, Mombelli A, Lang NP. Supragingival cleaning three times a week: the microbiological effects in moderately deep pockets. J Clin Peri- odontol 1992;19:348–56.
108. Wynn RL. The top 20 medications prescribed in 1993. General Dentistry. 1995; March–April: 114–9.
109. Bosco JA, Pearson RE. Sugar content of selected liquid medicinals. Diabetes 1973;22:776–8.
110. Lokken P, Birkeland JM, Sannes E. pH changes in dental plaque caused by sweetened, iron-con- taining liquid medicine. Scand J Dent Res 1975;83:279–83.
111. Imfeld TH. Kariogene hustenspezialitaten. Schweiz Mschr Zahnheilk 1977;87:774–7.
112. Roberts IF, Roberts GJ. Relation between medi- cines sweetened with sucrose and dental disease. Br Med J 1979;2:14–6.
113. Ship JA, Fox PC, Baum BJ. How much saliva is enough? ‘Normal’ function defined. JADA 1991;122:63–69.
114. Sreebny LM, Schwartz SS. A reference guide to drugs and dry mouth. Gerodontology 1986;5:75–99.
115. Ogle RE, Ciancio SG. The effect of anticholiner- gic agents on the periodontium. J Periodontol 1971;42:280–2.
116. The United States Pharmacopeia, 21st revision. Rockville, MD: United States Pharmacopeial Convention, Inc.; 1984.
117. Beck R, Kohout FJ, Hunt RJ, et al. Root caries: physical, medical and psychosocial correlates in an elderly population. Gerodontics 1986;3: 242–7.
118. Accepted dental therapeutics. 39th edition. Chica- go: American Dental Association; 1982.
119. Ziskin DE, Stowe LR, Zegarelli EV. Dilantin hyper- plastic gingivitis. Am J Orthod 1941;27:350.
120. Baden E. Sodium dilantin gingival hyperplasia and conservative treatment: a case report. J Dent Med 1950;5:46.
121. Ciancio SG, Yaffe SJ, Catz CC. Gingival hyper- plasia and diphenylhydantoin. J Periodontol 1972; 43:411–14.
122. Hall WB. Prevention of dilantin hyperplasia: a pre- liminary report. Bull Acad Gen Dent 1969;20.
123. Dill RE, Miller EK, Weil T, et al. Phenytoin increases gene expression for platelet-derived growth factor B chain in macrophages and monocytes. J Periodontol 1993;64:169–73.
124. Nakade O, Baylink DJ, Lau K-HW. Phenytoin at micromolar concentration is an osteogenic agent for human-mandibular-derived bone cells in vitro. J Dent Res 1995;74(1):331–7.
125. Cunat JJ, Ciancio SG. Diphenylhydantoin sodi- um: gingival hyperplasia and orthodontic treat- ment. Angle Orthod 1969;3:192–5.
126. Nishikawa SJH, Tada H, Hamasaki A, et al. Nifedipine-induced gingival hyperplasia: a clin- ical and in vitro study. J Periodontal Res 1991; 52:30–5.
127. Nuki K, Cooper SH. The role of inflammation in the pathogenesis of gingival enlargement during the administration of diphenylhydantoin sodi- um in cats. J Periodontal Res 1972;78:102–10
128. Stone C, Eshenaur A, Hassell T. Gingival enlarge- ment in cyclosporine treated multiple sclerosis patients. J Dent Res 1989;68:285–9.
129. Seymour RA, Smith DG. The effect of a plaque control program on the incidence and severity of cyclosporine induced gingival changes. J Clin Periodontol 1991;18:107–10.
130. Ciancio SG, Bartz NW, Lauciello FR. Cyclo- sporine-induced gingival hyperplasia and chlorhexidine: a case report. Int J Periodont Restor Dent 1991; 3:241–5.
131. Golub LM, Lee HM, Lehrer G, et al. Minocycline reduces gingival collagenolytic activity during diabetes: preliminary observations and a pro- posed new mechanism of action. J Periodontal Res 1983;18:516–26.
132. Golub LM, McNamara TF, D’Angelo G, et al. A non-antimicrobial chemically-modified tetracy- cline inhibits mammalian collagenase activity. J Dent Res 1987;66:1310–4.
133. Golub LM, Evans RT, McNamara TF, et al. A non-antimicrobial tetracycline inhibits gingival matrix metalloproteinases and bone loss in Por- phyromonas gingivalis-induced periodontitis in rats. Ann N Y Acad Sci 1994;732:96–110.
134. Delaisse JM, Eeckhout Y, Neff L, et al. (Pro) col- lagenase (matrix metalloproteinase-1) is present in rodent osteoclasts and in the underlying bone resorbing compartment. J Cell Sci (HNK) 1993;106:1071–82.
272 Periodontal Medicine
135. Ciancio SG, Genco RJ. The use of antibiotics in periodontal disease. Int J Periodont Restor Dent 1990;17:479–93.
136. Williams RC, Jeffcoat MK, Howell TH, et al. Altering the course of human alveolar bone loss with the non-steroidal anti-inflammatory drug flurbiprofen. J Periodontol 1989;60:485–90.
137. Feldman RS, Szeto B, Chauncey HH, Goldhaber P. Non-steroidal anti-inflammatory drugs in the reduction of human alveolar bone loss. J Clin Periodontol 1983;10:131–6.
138. Saxton CA. Scanning electron microscope study of the formation of dental plaque. Caries Res 1973;7:102–19.
139. Hillman DG, Hull PS. The influence of experi- mental gingivitis on plaque formation. J Clin Periodontol 1976;4:56–61.
140. Vogel RI, Copper SA, Schneider LG, Goteiner D. The effects of topical steroidal and systemic nonsteroidal anti-inflammatory drugs on exper- imental gingivitis in man. J Periodontol 1984; 55:247–51.
141. Hara K, Löe H. Carbohydrate components of the gingival exudate. J Periodont Res 1969;4:202 –7.
142. Freeman E, Novak MJ, Polson AM. Effects of gold salts on experimental periodontitis. III. Ultra- structural observations. IADR Program Abstracts; 1984.
143. Lewis R. The rise of antibiotic-resistant infections. FDA Consumer 1995;9:11–5.
144. Breiman RF, Butler JC, Tenover FC, et al. Emer- gence of drug-resistant pneumococcal infections in the United States. JAMA 1994;271:1831–5.
CHAPTER 16
MEDICOLEGAL ISSUES Edwin J. Zinman, DDS, JD
The dental practitioner has the responsibility to provide patients with treatment that meets the cur- rent standards of care. In managing patients with significant systemic conditions or patients whose periodontal disease may adversely affect systemic health, thorough examination and review of rele- vant medical history are paramount. This chapter reviews important medicolegal issues involving all those that are primarily involved in providing health care: the patient, the physician, and the dental practitioner.
STANDARD OF CARE
Two essential ingredients comprise the standard of care. First, the practitioner must possess that degree of skill and learning ordinarily possessed by prudent practitioners. Second, the practitioner must exercise or use the requisite skill and learning in a reasonably prudent manner.1
In recent years, legal standards of care have been influenced by the various specialty organiza- tions that establish parameters of care. Such para- meters are peer reviewed, based upon existing sci- entific literature, and periodically updated. A rea- sonably prudent practitioner usually adheres to such guidelines. Some organizations include a caveat that parameters of care are not to be equat- ed with the legal standard of care.2 Nevertheless, an expert witness may reasonably rely upon these parameters in offering expert opinion. Therefore, as a practical matter, a specialty organization’s para- meters of care are usually consonant with prudent practice, which is also termed “due care.”
The standard of care is not average care but rather represents the minimum standards of a rea- sonably prudent practitioner. Although most prac- titioners adhere to the standard of care, the medi- an or statistically average practitioner does not exclusively dictate the standard of care. Fifty per- cent of practitioners do not automatically practice
below the standard of care merely because they render below statistically average care. Nor do fifty percent of practitioners statistically automatically comply with the standard of care merely because they render care above the statistical average.
The standard of care represents what a reason- ably prudent practitioner should do under the same or similar circumstances. It is no defense or excuse for a negligent practitioner that other negli- gent practitioners (even a majority) follow similar negligent practices, or that only a minority of prac- titioners follow the reasonably prudent approach.
NEGLIGENT CUSTOM
A negligent custom, even if practiced by the major- ity of practitioners, violates the standard of care. By lay analogy, jaywalking, seatbelt avoidance, speed- ing, inattention due to car phone use, and going through stop signs are often tolerated traffic viola- tions, except in a court of law, if injury results from such customarily negligent practices.
Examples of negligent dental practice customs include (1) failing to monitor dental unit water- lines for bacterial counts to assure compliance with the American Dental Association’s recommended standards of 200 CFU/mL or potable water of 500 CFU;3 (2) routinely performing endodontics with- out a rubber dam;4 (3) failing to record pathologic periodontal probe measurements;5 (4) prescription periodontics for abutment teeth only while ignor- ing periodontal disease elsewhere in the mouth;6
(5) blindly adhering to managed-care guideline restraints which delay, or deny, necessary care and constrain specialty referrals;7 (6) unnecessary radi- ation exposure with D-speed film, rather than E- speed film as well as use of short round collimators, rather than long-cone rectangular collimators, for intraoral radiography;8,9 (7) using a glass-bead or chemiclave sterilizer for terminal sterilization of instruments;10 and (8) employing cold chemical
274 Periodontal Medicine
solution sterilization without adhering to the man- ufacturer’s recommendations for development time, temperature, and dilution.11
DUTY TO REFER TO SPECIALIST
While a dental license provides a dentist with the right to perform all dental procedures, few gener- alists actually possess the knowledge, training, and skill to perform every procedure within the requi- site standard of care. Possession of a dental license does not alone prove competency or prudence. For instance, general practice physicians usually lack sufficient training to perform open heart or sophis- ticated brain surgery. Likewise, general dentists often lack training to perform mandibular fracture reduction, or periodontal regenerative surgery such as membrane grafting or bone augmentation.
A general dentist has the duty to refer a patient to a specialist in situations where other reasonable general dentists would make a referral under similar circumstances.12 If specialist training and experience are specifically required, the general dentist would be considered negligent for attempting to diagnose or treat and will be held to the specialist’s standard of care12 (ie, what the reasonable and prudent spe- cialist would have done in similar circumstances).
A specialist’s treatment failure may be justified as an inherent treatment risk. By contrast, in the case of the general dentist, who does not have ade- quate training and therefore should not have attempted sophisticated therapy, such failure is considered a negligently caused avoidable risk. Lack of availability of specialists in a certain local- ity does not justify failure to refer when a referral is indicated. It is the patient’s choice whether or not to travel to a distant specialist.
The duty to refer is not limited to general den- tists only. Specialists also routinely encounter clin- ical conditions that are best treated by a more expe- rienced specialist in their discipline or by specialists in another discipline. Competency includes not only knowledge and training but also sufficient experience and mastery. For sophisticated thera- pies, the standard of care may require mastery even to attempt the therapy.
The referring dentist is not responsible for the treatment results obtained by the specialist, pro- vided the specialist acted independently, without the referring dentist’s participation or control. However, the referring dentist may be liable for the specialist’s care, if he or she actively participated in or controlled the specialist’s treatment. For exam-
ple, a referring general dentist who prescribes only limited periodontal therapy for a patient who requires comprehensive therapy may be liable if the specialist acquiesces and both the referring dentist and periodontist fail to diagnose and adequately treat all of the patient’s periodontal disease.
The referring dentist’s chart should reflect a reasonable attempt to determine if the referred patient consulted the specialist and obtained rec- ommended treatment. The chart should also note reminders to the patient about the need to follow through with the referral and the consequences of not doing so. This may be accomplished when the patient returns for a visit to the referring dentist’s office. The prudent referring practitioner should check with the patient to ensure that the patient’s appointment with the specialist has been kept. Noncompliance, with either consultation or treat- ment, should be recorded.
UPDATING SKILLS AND LEARNING
The standard of care requires that dentists possess the necessary level of skill and learning ordinarily possessed by prudent practitioners. Most profes- sional negligence suits involve failure by an other- wise qualified practitioner to maintain the requi- site skill and learning. Experience alone is insuffi- cient to comply with the standard of care. Dentists with many years of experience who only repeat each year the skills and learning present in their first year of practice are likely perpetuating outdat- ed methods.
A prudent practitioner constantly replaces outdated methods with improved and advanced therapies. It is estimated that following graduation, scientific advances surpass even the most up-to- date educational training provided only 5 years earlier.13 Accordingly, to comply with the standard of care, prudent practitioners should update cur- rent knowledge, skill, and learning by subscribing to scientific journals and attending continuing education courses.
The standard of care does not require that every practitioner adopt each and every new tech- nology or device. A prudent practitioner would not incorporate technologic advancements until they are scientifically proven with sufficient studies and are generally accepted in the scientific com- munity. It is not necessary to be the first to adopt the latest technology; nor should a dentist be the last to adopt generally accepted, scientifically proven technologic advances.
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GOVERNMENTAL AGENCY STANDARDS VERSUS STANDARDS OF CARE
Merely because a device or drug has received gov- ernmental approval, the practitioner who uses, rec- ommends, or prescribes it is not necessarily insu- lated from liability. Governmental health care agencies, such as the Food and Drug Administra- tion (FDA), set their own minimum standards. Such standards on occasion may still fall short of reasonably prudent practice.
For instance, some newer, unapproved implant devices may be better suited because of their size or maneuverability than some older FDA-approved implant systems, particularly where there is risk of injury to vital structures. Avoiding a permanent injury to a nerve may depend on whether the clin- ician used a contraindicated FDA-approved implant or an indicated but nonapproved implant. Similarly, manufacturers frequently defend a defec- tive product by underscoring compliance with industry or government standards. However, “com- pliance with a legislative enactment or an adminis- trative regulation does not prevent a finding of neg- ligence where a reasonable (person) would take additional precautions.”14
Regulations by the FDA provide that a manu- facturer may change an approved drug label before approval if the change is intended to add or strengthen warnings or instructions or delete false or misleading claims for use or effectiveness. The FDA has the authority to take actions that avoid the use of false or misleading labels on drugs. The FDA’s Labeling and Nomenclature Committee (LNC) was established to facilitate trademark review for products, as well as the labeling of prod- ucts that are brought before the FDA for approval.
The FDA does not perform its own drug test- ing. Instead, the FDA relies on each manufacturer’s candor and integrity in submitting drug data both before and after approval. Before being marketed, prescription drugs must be proven safe and effec- tive in double-blinded clinical studies authorized by the FDA (21 United States Code, section 321).
INFORMED CONSENT VERSUS MISREPRESENTATION
The dentist has a duty to disclose all material infor- mation to enable the patient to make an informed decision regarding proposed procedures or treat- ment. This would comprise information that the dentist knows or should know and would be
regarded as significant by a reasonable person in the patient’s position when deciding to accept or reject a recommended procedure or treatment. The dentist is not bound to discuss the minor risks inherent in common procedures, when such pro- cedures very seldom result in serious ill effects.15
The prudent practitioner’s goal is to serve and protect the patient’s best interests to preserve health. Consequently, a practitioner’s fiduciary obligation to his or her patient should not be sole- ly guided by the limitations set by the patient’s insurance carrier and by managed care guidelines; nor should the practitioner recommend only the most profitable procedure when reasonably conser- vative alternative therapies are an option as well.
Honesty is the best policy, which is embodied in the legal obligation of a practitioner to warn patients of inherent, but reasonably unavoidable, therapeutic risks. Before embarking on any proce- dure that involves the inherent risk of serious injury or death, a practitioner must provide the patient with informed choices of the benefits, risks, and consequences of treatment as well as those of nontreatment, and a similar analysis for reasonable alternative therapies. A practitioner who fails to provide such information to aid informed consent of the patient may be judged negligent.16,17
In a failure-to-inform case, the dentist’s mis- conduct is nonfeasance (ie, nonperformance) rather than misfeasance (ie, improper perfor- mance). In most states, failure to inform a patient of a material risk constitutes a legal cause for the patient’s injury if a reasonably prudent patient, when fully informed of the material risks, would have avoided the risk by not consenting to the pro- posed therapy. Accordingly, informed consent is tested objectively, ie, what would a reasonably pru- dent person in the patient’s position have decided if adequately informed of all significant perils?15
Whether a dentist’s failure to inform causes injury turns not on biomechanical principles, but rather on human factors measuring reasonable risk avoid- ance when adequately informed.
Merely because a dentist adequately informs a patient of the material risks of a procedure does not necessarily relieve the dentist of liability if the risk subsequently materializes. Informed consent is not an “affirmative defense” to negligent treat- ment.16,17 That is, it is immaterial that the dentist warned the patient of a material risk if the dentist performs negligent treatment. Adequate informed consent avoids liability only when treatment is per- formed non-negligently, and a previously disclosed material risk subsequently manifests.
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If the practitioner intentionally misrepresents known therapeutic goals, limitations, or risks, the practitioner may be subject to a fraud claim for intentionally deceiving the patient. Fraudulent mis- representations may include intentional overstate- ment of surgical success while minimizing risks, claiming another’s success as one’s own, or quoting national success statistics when the quoting practi- tioner’s own success rate is substantially lower.18,19
Negligent misrepresentations involve state- ments that have no reasonable basis (eg, a state- ment to a 30-year-old patient that her newly placed upper anterior crown should last a lifetime).
Professional liability insurance carriers will defend a suit which claims both negligence and fraud and will indemnify or reimburse the dentist for negligent acts. However, carriers are usually prohibited from indemnifying or reimbursing intentional acts, such as fraud, as contrary to pub- lic policy, since liability insurance is intended to cover only unintentional (ie, negligent) conduct (California Insurance Code section 533).20 The practitioner is generally responsible for payment of any judgments for the portion arising from inten- tional misdeeds such as fraud.
REFUSAL TO TREAT
Dentists are not obligated to render treatment that is not in the patient’s best interest, regardless of the patient’s requests. In other words, if the patient requests treatment which the dentist knows to be improper or contraindicated, the practitioner should not accede to a patient’s request for negligent care.16 Rather, the dentist should refuse to treat.
A dentist is also not obligated to treat a patient when there is professional disagreement. When the dentist declines to begin or continue treatment, the patient should be advised in writing and provided with names and addresses of other dentists the patient could go to for treatment. A patient may be discharged after reasonable notice so long as the dentist’s refusal to continue treatment does not jeop- ardize the patient’s dental or physical health before the patient’s appointment with a new dentist.
A dentist’s refusal to treat may not be based on discriminating reasons for protected classes, such as the disabled, or for racial reasons.21,22
PHYSICIAN CONSULTATIONS
A dentist should consult the patient’s physician whenever the proposed dental procedure or treat-
ment may adversely affect the patient’s general health. Discussions with the patient’s physician should be documented and confirmed by facsimile or letter.
The dentist who blindly follows the physician’s recommendation, even when it conflicts with his own professional judgment, probably violates the standard of reasonable care. Each independent practitioner is ultimately responsible for treatment decisions and should not rely on unreasonable rec- ommendations that are contrary to established specialty parameters of care. When the treatment decisions conflict with each other, allowing the patient to choose is permissible provided that both the dentist’s and the physician’s treatment recom- mendations are reasonable.
PERIODONTAL EXAMINATION AND RE-EVALUATION
The American Academy of Periodontology recom- mends that its Parameters on Comprehensive Peri- odontal Examination (1995) be regarded as the “standard of care for periodontal examinations.”
Periodic re-evaluation following therapy is essential to assess stability or further breakdown. Both host resistance and local factors can affect long-term maintenance. If disease deterioration occurs, the patient must be reassessed for both host resistance and local factors. A practitioner who fails to properly re-evaluate the patient’s disease state cannot appreciate whether or not the patient’s health is being adequately maintained and there- fore fails to make adequate diagnostic or therapeu- tic decisions. The American Academy of Periodon- tology Professional Policy Statement on Periodon- tal Disease Detection states: “Following treatment, the patient must be carefully monitored by the periodontist and the dentist for recurrence of any diseases. Periodic periodontal examinations must be performed, and the records compared to post- treatment recordings. This is essential in order to monitor the effectiveness of therapy during this professional maintenance phase. This maintenance phase is essential to ensure long-term periodontal health and the retention of natural teeth.”
If the patient is presently periodontally disease free, the statement also recommends the following long-term care parameters: “All patients must be screened for the presence of periodontal diseases on a regular basis. When periodontal diseases are detected, a comprehensive charting record must be completed and effective treatment should be ren- dered promptly.”
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RISK FACTORS
The standard of care requires practitioners to be aware of risk factors and to diagnose the patient’s risk susceptibility in order to control or eliminate the risk factor. Failure to do so or to counsel a patient regard- ing such factors may render the practitioner liable.
Risk factor testing is standard practice since prevention of serious disease is the hallmark of modern medicine. A careful medical history identi- fies risk factors and the need for a follow-up inter- view or testing. For example, although the cause of heart disease may be multifactorial (including diet, blood pressure, stress, and myriad other factors), a physician must identify, counsel, and appropriately refer for risk factor reduction, particularly when failure to do so may have fatal complications or cause serious injury. One well-known example involves the relationship between cholesterol level and heart disease. Elevated cholesterol levels have a risk ratio of 2.4.23 Physician identification, counsel- ing, and public awareness have resulted in changed diets and increased exercise to lower cholesterol lev- els and thereby reduce the cholesterol risk factor.
This same medical model is increasingly being applied to dentistry, in general, and periodontics, in particular. Many risk factors can be identified and communicated to patients, and their elimination can be incorporated into periodontal therapy. Peri- odontal disease risk factors may include (1) inherit- ed risk factors (genetic predisposition), (2) systemic risk factors, such as metabolic diseases, (3) acquired risk factors, such as diet or excessive smoking, and (4) local risk factors, such as plaque and calculus. Most acquired and local risk factors can be modi- fied or eliminated after the dentist first assesses a patient’s potential risk factors and provides or rec- ommends appropriate counseling and/or therapy.
Statistical associations or risk factors identify at- risk patients who exhibit increased susceptibility to the initiation or progression of periodontitis. Although the standard of care requires the prudent practitioner to both identify and minimize such risk factors, whether the failure to do so actually caused or aggravated periodontitis may be difficult to prove in a legal case. By analogy, not all smokers develop lung cancer. Nor do all hypertensive patients inevitably suffer strokes or myocardial infarcts.
In the 18th century, Benjamin Rush, a Penn- sylvania physician and signer of the Declaration of Independence, reported that arthritis sufferers found relief after their infected teeth were extract- ed. This theory of foci of infection, now aban- doned, promoted unnecessary and wholesale teeth
extraction for over 100 years.24 Linkage of oral and systemic disease with anecdotal unscientific research risks unnecessary treatment. For example, attributing systemic illness to dental amalgam is another example of misstated science since, except in the extremely rare instances of mercury allergies, there is no proven connection between dental amalgam, mercury vapors, and systemic disease.25
Inherited Risk Factors: Genetic Predisposition
A patient’s genetic composition is unchangeable. However, knowledge of genetic predisposition may affect treatment decisions and prognosis. Perio- dontal disease occurs only in susceptible individuals. Therefore, knowledge of the unchangeable elements of disease susceptibility help the practitioner in determining which factors of host resistance to dis- ease are changeable and which are unchangeable.
According to one study, IL–1–genotype-posi- tive patients have a 6.8-fold increased risk for severe periodontal disease.23 Awareness of the genetic marker for periodontal disease may allow the prac- titioner to be aware of susceptibility to severe peri- odontal disease. Earlier onset and more rapid pro- gression of periodontal pathology are postulated but, to date, it is known only that IL–1–positive subjects have been shown to be at greater risk for severe periodontitis in cross-sectional studies. Lon- gitudinal data to show greater disease progression in genotype-positive subjects are being gathered. Therefore, a genetic risk factor assessment may help the practitioner and patient choose treatment options and determine whether increased frequen- cy of monitoring is warranted. Informed consent reflects the patient’s choice after disclosure of mate- rial therapeutic risks. The more informed both patient and practitioner become in determining disease prognosis and susceptibility, the more informed they become regarding the level of accept- able risks each is willing to assume in treatment planning. For instance, a practitioner may prudent- ly advise a young genotype-positive patient that a maxillary molar with moderate to severe periodon- titis may have a relatively poor prognosis. If that molar required extensive restorative treatment, the patient might elect extraction and replacement with a fixed partial denture. Another useful example of knowledge of genetic predisposition is a young patient with root resorption secondary to ortho- dontics performed during the patient’s teen years. The prognosis will be affected by whether this patient will ever suffer periodontitis since the
278 Periodontal Medicine
crown-root ratio is already diminished. Long-term studies extend up to only 15 years.26 Thus, know- ing whether a 25-year-old patient is likely to suffer loss of periodontal attachment after 15 years, at age 40, because of a genetic positive risk factor, would aid prognosis and evaluation.
Genetic testing is an optional diagnostic aid. If improved technology can aid treatment decisions, it is the patient’s right to know of newer diagnostic technology in order to make an informed refusal decision or elect such testing. The PST™ test is based on the research premise that 30% of the population has an interleukin-1 gene polymorphism causing such individuals to produce greater IL-1 levels as a host response to bacterial plaque.27 Not all popula- tions have a similar prevalence of this IL-1 genotype. Genetic testing of a Chinese population group revealed only 2% genopositive rather than the 30% prevalence on which the PST™ test is premised.28,29
Genetic testing must be done with the full knowledge and consent of the patient since surrep- titious genetic testing, even for experimental rea- sons, violates the patient’s constitutional privacy rights, as well as the fourth amendment protection against illegal searches.30
Systemic Risk Factors
Diabetes Diabetes is a recognized risk factor for periodontal disease progression primarily when metabolic con- trol if poor. Conversely, if the diabetes is con- trolled, diabetic patients are generally not at risk for increased disease progression.
Findings that periodontal disease adversely affects diabetic control suggest a two-way street between certain metabolic systemic diseases and periodontal disease. Elimination or reduction of oral infection has resulted in improved metabolic control of diabetes.31 If further studies substantiate these present research studies, both the physician and dentist may reduce the risk for diabetic com- plications by proper periodontal disease control.
Both the systemic condition and the localized periodontal disease must be controlled for optimal health. Therefore, physicians and dentists need to interact in the overall management of patients to ensure that neither the periodontitis nor the diabetes spirals out of control and adversely affect each other.
Osteoporosis The linkage between periodontal disease and osteoporosis may represent different aspects of the bone loss process: oral bone loss and systemic bone
loss. Postmenopausal patients may demonstrate changed bone density following periodontal dis- ease elimination.32 Further longitudinal studies are required to explore the extent of the linkage between periodontitis and osteoporosis.
Acquired Risk Factors
Smoking Smoking and other types of tobacco use are regard- ed as one of the primary proven risk factors for periodontal disease. Physicians and dentists alike are obligated to counsel patients to curtail or elim- inate tobacco use because of the myriad associated health risks. Since tobacco is addictive, counseling patients as close to the onset of the smoking habit as possible is essential.33
Excessive smoking is an important considera- tion in periodontal disease management. The diffi- culty in controlling this risk factor is due to the patient’s addiction, which limits a patient’s voli- tional control. Nevertheless, it is the practitioner’s obligation to counsel the patient to discontinue tobacco use and to alert the patient that continued presence of the risk factor may adversely affect treatment outcomes.
Oral Hygiene Patients with significant pathologic periodontal pockets have demonstrated periodontal disease susceptibility and require constant periodontal maintenance procedures (PMP) at frequent (usual- ly quarterly) intervals. Regular and frequent PMP can maintain the oral health of even patients with less than adequate oral hygiene.34–37
Stress Stress has become an inescapable component of daily life and a periodontal disease risk factor. However, only those patients who are unable to successfully cope with or overcome life’s stresses are at increased risk for periodontal disease.38 Dentists should consider heightened stress levels when assessing risk factors for periodontitis.
Most dentists, however, lack sufficient training to assess a patient’s stress level and/or ability for stress management. A referral to a psychotherapist for stress reduction may be appropriate for some patients, for example, in the patient with refracto- ry periodontal disease when disease progression defies conventional local therapy management. A simple screening device (Figure 16–1), incorporat- ed into the health history questionnaire, may assist the dentist in identifying a patient’s stress level.
Medicolegal Issues 279
If the patient answers “No” to the coping skills and “Yes” to counseling needs, the practitioner should consider referral to a trained professional in stress management. This will assist in the control of periodontitis, particularly if it is refractory or subject to frequent recurrence as determined at PMP visits.
Cardiovascular Disease Since cardiovascular disease is the leading cause of death, any reduction in cardiac disease is of vital health care concern. Preliminary research evidence suggests a linkage between periodontal disease and cardiovascular status.39 Whether a causal relation- ship exists or there is a predisposed patient group at risk for both periodontal and cardiac disease remains a further research challenge.
Current scientific studies seek to confirm the association between periodontitis and heart disease. Links have been discovered between oral health and systemic medical problems. However, the major issue is distinguishing a causal relationship from a coincidental connection between oral and systemic diseases of a patient susceptible to both diseases. Evidence to date does not conclusively prove a cause-and-effect link between periodontal and car- diovascular diseases. Rather, preliminary research suggests that periodontal disease may increase the risk of cardiovascular disease.40 However, scientifi- cally, it is premature for a dentist to advise a patient that periodontal disease will lead to a greater risk of stroke and heart attack since the definite causative linkage requires research studies with greater statis- tical power. Nor can prudent practitioners state that periodontitis is frequently associated with cardiac disease since a definite causal link has not been con- clusively established. Rather, periodontal disease may be one of many potential risk factors for car- diovascular disease.
One plausible explanation of the association between cardiovascular and periodontal diseases may be that the same patient group susceptible to heart disease may also be susceptible to periodon- tal disease, rather than one disease triggering the other disease. Another unproven theory is that periodontal disease may represent an early mani- festation of a broader systemic disease component which will continue to progress to the more seri- ous cardiac disease unless the same contributing risk factors are controlled, such as smoking or excessive stress. Further research may determine whether periodontal disease is the prognostic pre- cursor to cardiovascular disease or if periodontitis acts as an aggravating factor in cardiac disease management.
Preterm Birth The relationship between periodontal disease and preterm low-birth-weight (PLBW) babies deserves further study of the connecting links of this associ- ation chain. Preterm birth is frequently considered multifactorial since its causes are multiple and diverse. Risk factors include malnutrition, drug abuse, smoking, and lack of prenatal care. Recent periodontal research preliminarily suggests severe periodontal disease as a risk factor.45
Maternal infections predispose to preterm labor, membrane rupture, and spontaneous birth of low-birth-weight babies. Preliminary research with a relatively small case-control study population assessed an added risk of more severe periodontal disease associated with primiparous (first live birth) mothers and small preterm birth (SPB). Whether this is a true interactive risk factor or an indepen- dent incident awaits future study of research groups with greater statistical power. Therefore, it is pre- mature to definitively link premature births and periodontal disease; if proven, however, it would mandate counseling pregnant women to control periodontal disease to avoid the risk of SPB.
Identifying a single risk factor and eliminating it does not always reduce disease incidence. For instance, when measuring the effect of eliminating single risk factors, such as malnutrition and prena- tal care, on rates of premature birth when studied in isolation, elimination of such single risk factors has not resulted in a decline in preterm birth.41
Thus, data from multiple trials of single risk fac- tors have provided substantial evidence that con- trolling only one single factor failed to reduce preterm birth rates.42
Controlling preterm delivery and low birth weight has proven an often insurmountable obstet-
Yes No
1. Are you generally able to ■■ ■■ adequately manage or cope with daily emotional stress?
2. Do you feel that for the past ■■ ■■ year you have been unable to adequately manage or cope with daily emotional stress?
3. Do you desire professional ■■ ■■ counseling for emotional stress management?
Figure 16–1. A simple screening questionnaire.
280 Periodontal Medicine
rical challenge since the 10% risk of SPB has not changed in the past 40 years despite improved pre- natal care.47 On the other hand, neonatal medicine has improved survival rates of premature births. Further research will establish whether periodonti- tis disease severity is a marker for a risk factor, which can prognosticate a preterm delivery suscep- tibility. If proven, clinical periodontal parameters or periodontal gingival crevicular fluid testing may prove to be valuable screening tests for SPB risk assessment.
Local Risk Factors
Bacterial plaque is regarded as the primary causative agent for periodontitis. Nonetheless, not all patients with heavy plaque deposits develop severe periodontitis. Consequently, plaque is a risk factor which only causes periodontal disease mani- festation in a susceptible host.
SUBACUTE BACTERIAL ENDOCARDITIS
The mouth is a well-known reservoir of more species of organisms than any other area of the body. Many cases of subacute bacterial endocarditis (SBE) have no known causative precipitating event. However, no studies have shown that procedures such as brushing and flossing can create a bacterial inoculum of sufficient size to establish infective seeding of existing endocardial vegetations. It is therefore scientifically unsound and unproven to recommend that patients at risk for SBE cease or curtail daily oral hygiene procedures to avoid pre- cipitating bacteremias. On the other hand, both the American Dental Association (ADA) and the American Heart Association (AHA) strongly rec- ommend that SBE-susceptible patients maintain impeccable oral hygiene. Elimination or control of periodontal pockets reduces the potential that large numbers of bacteria will invade the bloodstream and thus reduces the potential for periodontal pathogens to contribute to an SBE exacerbation.
The AHA recommends that any dental proce- dure capable of producing “significant” bleeding has the potential of introducing oral bacteria into the bloodstream and, as such, requires prophylaxis with an appropriate antibiotic for at-risk SBE patients.43 The AHA notes in its recommendations that the clinician’s judgment may supersede a given recommendation. However, unless good cause exists for deviation, the standard of care requires
conformance with the AHA guidelines. Antibacterial mouthrinse products such as
chlorhexidine have proven effective in decreasing the overall oral quantity of bacteria and reducing the incidents of bacteremia associated with third molar extractions as well as localized alveolitis.44–50 Use of these mouthrinse products prior to surgery makes empirical sense and is endorsed by the British antimicrobial societies. However, antibacterial rinses are not proven as an efficacious substitute for administration of systemic antibiotic prophylaxis where otherwise indicated for SBE-at-risk patients.
Mechanical irrigation devices can cause bac- teremias, especially in the presence of chronic or acute periodontal infective states associated with poor oral hygiene. These devices have the potential for introducing larger bacteria boluses than brush- ing or flossing and therefore are not generally rec- ommended for at-risk SBE patients.
The FDA removed from the market Fen (fen- fluramine aka Pondimin), as well as the chemically related drug dexfenfluramine (aka Redux) after reports linked these medications to heart valve abnormalities. The benefit of suppressing appetite did not outweigh the risk of valvular heart defects associated with the altered metabolism of serotonin related to these drugs and their off-label prescription.
Both the AHA and the American College of Cardiology (ACC) now recommend that patients who have taken these drugs should undergo a stethoscope examination for heart valvular defects and a follow-up examination in 6 to 8 months. Patients with symptoms of shortness of breath, chest pain, or heart murmurs should have an echocardiographic examination. Asymptomatic patients may have echocardiography depending upon the physician’s clinical judgment.
Although the incidence of valvular heart defects appears to be a function of the length of time that the patient takes the medication, the standard of care obligates the dentist to obtain a history of such diet drug usage. A medical consul- tation is necessary (if not previously obtained) for all patients who have taken diet drugs, including those that are not at risk for SBE.
DRUG SIDE EFFECTS
Prudent periodontics carefully weighs risks against benefits of any prescribed or performed therapy. Newer local delivery drugs enjoy the benefit of sus- tained local release of the drug over a period of days or weeks, rather than hours. Tetracycline
Medicolegal Issues 281
fibers may be impractical in many instances for routine clinical application because it is time con- suming to place and maintain the fibers in the pocket during the recommended period of use. On the other hand, second generation delivery agents, such as gels or chips, are both patient and dentist friendly and less time consuming to apply.
Packet inserts for local delivery drugs list con- traindications, including allergies. The practitioner may be liable for failure to follow or advise patients of these warnings on drug packet inserts. Liability may also result from failure to follow Physician Desk Reference recommendations. However, these failures alone do not establish violation of the stan- dard of care unless an expert so testifies.51
For instance, the packet insert for Periostat (doxycycline hyclate) capsules warns of tetracycline hypersensitivity and possible discoloration of per- manent teeth if used during the latter half of preg- nancy, or up to age 8 years. Discoloration is more common during long-term use, but may also occur during repeated short-term courses.
The manufacturer of doxycycline warns that the drug may cause harm to the fetus. The manu- facturer also advises that “concurrent use of tetracy- cline may render oral contraceptives less effective.” An increased risk of a wrongful life lawsuit (birth of unplanned child) may occur if the patient is pre- scribed doxycycline but is not adequately advised of any increased risk of unwanted pregnancy and the oral contraceptive dosage is not adjusted or alterna- tive birth-control methods advised.
Since photosensitivity has also been associated with the tetracyclines, patients taking these drugs, including doxycycline, should be cautioned regard- ing excessive exposure to direct sunlight or any ultraviolet light. Tetracyclines have also been shown to depress plasma prothrombin activity. Thus, patients taking anticoagulant therapy may require a downward adjustment of their anticoag- ulant dosage.
Although the doxycycline dosage in Periostat is below the concentration required to inhibit peri- odontitis-associated microorganisms, the lower dosage does not eliminate contraindications, drug interactions, allergies, or potential teratogenic effects. Since the dosage of these newer drugs is lower than the dosage used to treat other infections, the development of resistant strains of microorgan- isms is reduced. Other local delivery tetracycline drugs, such as minocycline, are in clinical trials and should be marketed in the near future.
Mechanical instrumentation with scaling and root planing has proven effective in the treatment
of adult periodontitis. Accordingly, the routine use of local delivery agents with scaling and root plan- ing is usually not justified and is presently an off- label use. Local delivery agents are most often used as adjunctive therapy to conventional care for non- responding sites with moderate pocket depth or in patients who have recurrent disease despite repeat- ed scaling and root planing. Long-term studies are needed to verify the efficacy of combined therapy even in these instances
Fiberoptic illumination, which provides in- creased visual access to the subgingival space, increases the effectiveness of calculus removal on root surfaces. Complete removal of subgingival cal- culus is limited during root planing. Greater pock- et depths often result in increased residual calculus due to the increased area of root surface to be scaled and the increased number of irregularities found on the root surface. Deep narrow pockets impede accessibility to root irregularities.
Flap exposure surgery of root surfaces also greatly enhances the effectiveness of scaling and root planing. In one study, an average of 20% of postsurgery surfaces had residual calculus.52 Non- surgical pocket distention procedures resulted in approximately 40% of the root surfaces having residual calculus.57 If flap exposure or pocket dis- tension procedures were not used, 64% of the root surfaces had residual calculus.57
Pocket distention following tetracycline fiber removal provides improved visual detection of resid- ual calculus. Thus, a possible added advantage to the use of the tetracycline fiber local delivery system is the increased visual access immediately following fiber removal, which aids root calculus removal.
No studies have addressed the use of local drug delivery in specific types of periodontal bony defects such as intrabony defects or class II furca- tions. Results from studies assessing local drug delivery systems have not justified extending the time interval between supportive PMP visits by substituting them with local delivery therapies.
Local delivery agents should be used as thera- peutic adjunctive aids rather than as monotherapy. Contraindications for using local delivery drugs include using them as (1) a replacement for thor- ough scaling and root planing, and (2) full-mouth treatment rather than specific local sites.
Efficacious therapies that benefit the patient’s health should be the practitioner’s first considera- tion rather than the financial gain from it. There- fore, a third-party insurance carrier’s allowance of insurance benefits for local delivery agents should not compromise necessary therapy, nor decrease
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the frequency of the scaling and root planing pro- cedures. Prudent practitioners are primarily oblig- ated to treat the patient’s periodontal pockets rather than comply with the insurance carrier’s dic- tates, or financial pockets.
BURDEN OF PROOF
“Burden of proof” refers to one party’s obligation to produce sufficient evidence to prove the fact or contention proffered. “A party has the burden of proof as to each fact, the existence or nonexistence of which is essential to the claim for relief or defense that he is asserting.” (California Evidence Code section 500)
In a civil case, the burden of proof must be established by a preponderance of the evidence. Preponderance implies the greater weight of the evidence, ie, a probability (versus a possibility) of truth or an event that is more likely than not to have occurred or be true. Vague, inconclusive, or uncertain evidence fails to meet the burden of proof and is considered conjectural or speculative.
A patient-plaintiff bringing a professional neg- ligence lawsuit generally bears the burden of prov- ing by a preponderance, or greater weight, of the evidence the following elements: (1) negligence, (2) causation, and (3) damages. A defendant-den- tist bears the burden of proving by a preponder- ance of the evidence any affirmative defense, such as lack of adequate oral hygiene, missed mainte- nance, or refused specialist referral.
Stated otherwise, the patient-plaintiff must prove by at least a 51% or greater likelihood that (1) the defendant-dentist violated the standard of care, (2) that the defendant’s negligence caused or aggravated the plaintiff ’s periodontitis, and (3) injury or damages resulted. For example, the patient-plaintiff may be able to prove that the den- tist violated the standard of care by not informing the patient of the potentially deleterious effects of stress on the patient’s periodontal health. However, if the patient-plaintiff cannot prove that stress aggravated his periodontitis, the evidence may be speculative that in his individual case the particular risk factor (stress) was the causative culprit. Con- versely, if the defendant-dentist contended that the patient-plaintiff was at fault because of his smok- ing, the defendant bears the burden of proving the plaintiff ’s smoking aggravated his periodontitis.
As only a minority of the population develop severe pathologic periodontal pockets that cause premature tooth loss, a risk factor of only 15%
doubled or tripled still does not reach the 51% or higher proof threshold. It is difficult to prove that a particular risk manifested in any one patient caused severe or worsened periodontitis. Thus, epi- demiologic data of increased risk in the general population does not prove individual causation. Accordingly, a practitioner who fails to recognize or reduce the risk factors (thereby violating the standard of care) may yet avoid liability if the patient-plaintiff cannot prove by a preponderance of the evidence that the nonrecognition or non- treatment of a particular risk factor caused or aggravated the particular disease at issue.
If scientific evidence cannot establish the greater weight of evidence in a particular case, the plaintiff may not prevail since the plaintiff will have failed to provide the burden of proof neces- sary to establish causation despite epidemiologic evidence of the increased disease incidence in the general population.
Epidemiologic research does not establish individual cause and effect but only suggests a potential relationship. Epidemiologic studies best identify very powerful associations, such as in a cohort study in which large groups of people are followed up for a long time. One research study alone does not establish the gold standard of care. The hallmark of science is experimental replication in other independent studies that proves the hypo- thetical or premised postulate. However, a multi- center study does not always ensure scientific accu- racy if a flawed research methodology is repeated at multiple centers.53–58
Defense attorneys are particularly skillful in exploring other causes of diseases, which can be multifactorial. Tobacco companies have, for many years, successfully defended lung cancer cases since a particular patient’s etiology for lung cancer may be explained by factors other than tobacco, such as environmental, work-related, or idiopathic causes. Tobacco companies also argue that they should not be held accountable for the well-publicized risks of cigarettes which was well-known for years and further argue that there is no fraud to attempt to hide something already known, such as risks of using tobacco.
Similarly, defense counsel defending periodon- tal negligence actions have been able to establish that risk factors such as smoking, poor oral hygiene, stress, or systemic diseases caused or aggravated a patient’s periodontal disease, rather than the dentist-defendant’s negligence. Although earlier periodontal literature was equivocal on the role of tobacco and periodontal disease,59 recent
Medicolegal Issues 283
literature has established tobacco’s role as one of the most significant risk factors.60
Although in some states advising the patient of the greater risk, such as death, absolves the practi- tioner from failing to advise of the lesser risk, other states (eg, Minnesota) require the practitioner to advise patients of virtually all risks, such as impo- tence which is a long-term health risk secondary to smoking (88 ALR 3rd 1008). A practitioner should also include long-term risk assessment as part of a patient’s comprehensive health care eval- uation or re-evaluation. Comprehensive care should include not only diagnosis of existing dis- eases but also health care warnings of known risk factors as part of a preventive health care measure. Periodontal disease represents a non–life-threaten- ing disease associated with smoking.
After first consulting with the patient’s physi- cian, the patient may be cautioned that the smok- ing is not only beginning to manifest as oral dis- ease, which is one of many predictable diseases associated with smoking, but that continuation can cause other more serious diseases as well since the patient has already demonstrated weakened host resistance and disease susceptibility. Alerting the patient’s physician of oral evidence (eg, peri- odontitis) of the patient’s host resistance beginning to break down may serve as an early warning that other more serious systemic diseases may occur in the future. Thus, a prudent practitioner should not only diagnose early warning signs of known dis- eases but also consider alerting the patient to con- sult with the patient’s physician to determine if the current manifestations of less serious diseases por- tend the worsening of these diseases and the likely development of more serious diseases linked with the same risk factor.
CIRCUMSTANTIAL EVIDENCE
Evidence is either direct or circumstantial. Direct evidence proves a fact without the need for any inferences. Circumstantial evidence, on the other hand, proves a fact or facts from which an infer- ence of the existence of another fact may be drawn. For example, the fact that a child was taking cook- ies from the cookie jar can be established if the child was seen taking a cookie from the jar, which is direct evidence. If, on the other hand, the only visual evidence is a half-empty cookie jar, a trail of cookie crumbs to the child’s bedroom, and an unhungry child at dinner that night, it is circum- stantial evidence which infers the fact that the
child took cookies from the cookie jar, even though the act was not seen.
Circumstantial evidence is legally accepted as equally convincing as direct testimony.61 It is pos- tulated that periodontal disease is episodic and consists of bursts of activities; however, rather than showing linear progression,62 circumstantial evi- dence may help establish a causative link with par- ticular risk factors if significant periodontal disease progression coincided with risk factors such as periods of uncontrolled diabetes or excessive smok- ing, and disease activity ceased when the diabetes was controlled or the smoking eliminated. If the periodontal disease worsened after another bout of uncontrolled diabetes or resumption of smoking, the circumstantial evidence link may reasonably be established as corroborative evidence.
Both the scientific community and the courts accept circumstantial evidence as proof of a postu- late.61 For example, a classic periodontal study demonstrated that dental students developed gin- givitis with failure to maintain oral hygiene and that the condition was reversed when oral hygiene measures were restored.63
A patient-plaintiff need not prove in a lawsuit that the practitioner’s negligence was the sole cause of the patient’s disease but, rather, that such negli- gence was a substantial factor in causing injury.64
For instance, an expert may testify that defective restorations predispose to bacterial plaque accumu- lation and resulting periodontal disease.65 If peri- odontal disease is confined to the offending plaque retentive restorations, rather than being generalized, such evidence constitutes circumstantial evidence which supports the expert’s opinion that the defec- tive plaque-accumulating restoration substantially increased the risk for localized periodontal disease. This opinion is particularly apt if it is clear that the patient’s natural host resistance prevented periodon- tal disease elsewhere in the mouth where the patient had similar types of restorations that were not defec- tive. Such comparative evidence constitutes strong circumstantial evidence that restorative deficiencies caused the localized periodontal disease.
RESEARCH EVIDENCE
Scientific research is the basis for evidence-based parameters of care. Traditionally, most dental clin- ical decisions were based on the clinician’s experi- ence. In an evidence-based approach, however, all scientific evidence is not accorded the same weight. The stronger the scientific supporting evidence,
284 Periodontal Medicine
the stronger is the supporting recommendation.66
An evidence-based approach places greater weight on analytic methods that determine both statistical and clinical significance as well as measure both risks and benefits. Scientific standards include (1) double-blind, placebo-controlled clinical trial to reduce potential bias, and (2) longitudinal studies to evaluate the long-term effects of treatment alter- ing the natural history of a disease.
Under federal law, scientific evidence concern- ing health care has to meet scientific standards of proof before being admitted into evidence for the jury’s consideration. Four factors that must be eval- uated to determine if a scientific theory or tech- nique is reliable are:
• whether it has been, or can be, tested; • whether it has been subjected to peer review or
publication; • its known or potential rate of error; and • whether it is generally accepted by the relevant
scientific community.67,68
Emerging and changing technologies offer great benefit to patient care but challenge the pru- dent practitioner to carefully evaluate manufactur- er-supported studies for biased interpretation or inadequate research. Due to political pressures, governmental agencies have shortened the review time as well as the review process for approval. Manufacturers frequently argue that governmental approval delays are due to governmental bureau- cracy rather than the adequacy of research data. However, it is important to realize that the pres- sures to rush a new product to market may also bring about conclusions that have not stood the test of time with long-term clinical studies.
Manufacturer-subsidized researchers use gov- ernmental agency approval (such as FDA approval) in their claim for efficacy or superiority. Instead of blindly accepting all advertising claims, prudent practitioners must independently assess the validi- ty of the research claims as biased research or disin- genuous data create untrustworthy research con- clusions and interpretations.
Governmental approval has not always proven efficacious in the disclosure of risk assessment. The burden of assessing advertised claims has increas- ingly shifted to the prudent practitioner, who must carefully evaluate the foundation of research con- clusions of claimed product efficacy or superiority before wholesale adoption of new devices or thera- pies and abandonment of the time-tested methods.
Multicenter research studies do not always guarantee statistically valid research conclusions. For
instance, the recent FDA approvals of local delivery drugs were based on a 9-month study.69 The sup- porting research studies to obtain FDA approval evaluated the therapeutic efficacy of local drug ther- apy on chronic periodontal disease. Periodontal dis- ease progresses episodically over years, with periods of remission or exacerbation. Yet, the FDA approved for marketing these local delivery drugs with a study that lasted only three-quarters of a year.
The manufacturer also made claims that pocket reduction and clinical attachment levels, when combined with scaling and root planing, were superior to or at least equalled scaling and root planing alone. Reading the study’s research proto- col reveals that the so-called combined therapy group of the experimental drug, when combined with scaling and root planing, only existed at base- line. Thereafter, scaling and root planing were not repeated at 3 months, 6 months, or at the conclusion of the 9-month period studied. Patients with moder- ate periodontal disease consisting of 5- to 6-mm pockets with bleeding on probing who were stud- ied in the research group should have been gener- ally maintained with periodontal procedures on a quarterly basis. General practitioners would likely have performed subgingival débridement at (mini- mal) 6-month intervals. Consequently, the study evaluated what occurred in those that may be regarded as poorly maintained patients, ie, who were maintained solely on the locally delivered drug rather than with quarterly subgingival débridement as is common practice. This is but one of many examples where a prudent practition- er should carefully evaluate advertised conclusions before blindly adopting them.
Drug manufacturers are liable if their sales per- sonnel promote an FDA-approved drug with mis- leading statements, if the manufacturer is aware of such marketing abuses.70 The individual practi- tioner need not abide by FDA-approved uses only and may prescribe a drug for uses unapproved by the FDA but the practitioner who strays beyond the FDA-approved line risks engaging in experi- mental medicine. Prescribing a drug for unap- proved use may be based only on empirical anec- dotal evidence rather than controlled careful research studies.
Diet drugs, such as Pondimin and Redux, are a case in point. Although the FDA approved each drug individually by specific labelled use, the FDA never approved the combination of fenfluramine and Phentermine for birth control. Consequently, risks of heart valve damage, which would likely have manifested with long-term clinical testing in
Medicolegal Issues 285
a research controlled environment with sufficient numbers of patients, were undetected before mass prescription of the potentially dangerous drug combination occurred.*
Long-term clinical trials with vast numbers of studied patients are often regarded as the ideal valid- ity test group for clinical research. Different patient population groups need to be evaluated to avoid erroneous diagnoses. Nevertheless, such platinum- standard protocols may be tarnished if control groups are not matched with the studied groups for similar variables. Data inaccuracy results when there is misclassification between subgroups, which may affect the research trial outcome.71
In order to have predictably valid results, elim- ination of heterogeneity between trial groups is necessary. Discrepancies occur within clinical research trial groups so that the concept of com- parison of similar homogeneous groups is often a myth, considering the variable treatment responses of different persons, populations, and protocols. If the different groups studied have different risks, a fair comparison cannot be established. This may explain the reason for inconsistent results among various studies. Although a greater number of patients provides greater statistical power, size alone does not compensate for research method- ologic flaws. As one research team concluded:
Periodontal research often confuses lack of sig- nificance in a clinical trial designed for superi- ority for equivalence between different thera- pies. Acceptable mean differences in equiva- lency trials should be determined based not only on statistical considerations, but also on clinical relevance of the proposed differences.
Equivalency trial has some concepts that are very different from those in a superiority design. It can be difficult distinguishing between the items that are similar between the two designs and those that are different. Equivalency designs require larger sample sizes than their superiority counterparts.
Scientific research continues to guide the pru- dent practitioner through the ever burgeoning world of science. The long history of randomized,
but controlled, trials, has resulted in improved pre- ventive measures, such as vaccines and disease screening, as well as more efficacious therapies.
In applying diagnostic algorithms, objective probability estimates should be grounded in data from well-designed studies to minimize the effect of numerous biases that potentially cloud diagnostic analysis. Studies that compare patients with severe disease with normal, healthy volunteers, may over- estimate the usefulness of diagnostic testing.72
Statistical validity is a critical issue to measure quality that explains a substantial variation in research results, including tentative or uncertain results.
Case reports describe a single case with clear benefits. The degree of benefit derived from the new treatment is often greater in single case reports than in large cohort studies of patients entered into a trial study.
To obtain FDA approval, two well-controlled clinical trials are needed. Before prudent practi- tioners accept evidence for a new drug therapy, they must ensure that it is based on a high propor- tion of double-blind, randomized, placebo-con- trolled clinical trials rather than on empirical con- clusions. The standard-of-care, evidence-based approach can then integrate scientific research into clinical practice. When scientific evidence is dis- puted, the court can appoint its own independent expert or panel of experts. For instance, a federal judge in Alabama established a scientific panel to help the court evaluate evidence in 8,600 nation- wide breast implant cases.73 The scientific panel set up under the Federal Rules of Evidence concluded that there was “no evidence that silicone breast implants precipitate novel immune responses or induce systemic inflammation.” The independent panel also criticized other studies as “methodolog- ically inadequate,” including flawed comparison subjects, “unorthodox data analyses,” and other problems. Also, “inconsistent results in studies purporting to evaluate the same immunologic parameters are common.”
COMPARATIVE NEGLIGENCE
The U.S. legal system is based in part on the maxim, “No one can take advantage of his own wrong.” (California Civil Code section 3517) Regardless of how negligent the practitioner may have been, a patient’s own negligence (termed con- tributory negligence) may partially offset, or elim- inate, any liability.
*A Texas class action against American Home Products, seller of the diet drugs fenfluramine and dexfenflu- ramine, seeks medical screening for all Texans who took the drugs for 60 days or more at a cost of around $500 for each test. Class action certification of a Washington state case is expected soon.
286 Periodontal Medicine
In those states that recognize pure comparative negligence, the patient’s negligence, if any, is com- pared with the practitioner’s negligence, and any recovery by the patient is offset by the proportion of the patient’s negligence. For example, if the patient is held to have been 25% negligent, any recovery for the patient is reduced by 25%. In other states, if the patient’s negligence exceeds 51% of the total negligent conduct of both plaintiff and defendant, the plaintiff-patient may be completely denied from any recovery.
Comparative negligence should be distin- guished from failure to mitigate (minimize) dam- ages. Comparative negligence assumes that the patient contributed to the cause or aggravation of the injury by the offending practitioner. If, after the injury occurred, the patient fails to obtain rec- ommended treatment from subsequent practition- ers, the patient is held responsible for failing to minimize further damages. For example, in a case alleging failure to diagnose and treat periodontal disease, the patient’s failure to maintain adequate oral hygiene and attend recommended quarterly periodontal maintenance procedure appointments while under the care of the defendant-practitioner may constitute comparative negligence. The patient’s failure to also do so under the care of a subsequent practitioner may constitute a failure to mitigate or reduce further damages.
Patients advised to curtail or quit smoking but who fail to do so may arguably be held to be com- paratively negligent. However, if the patient is advised to restrict smoking after he or she has become addicted to smoking, the volitional element is substantially reduced or eliminated since the suc- cess of smoking cessation programs frequently does not exceed 6%.74 Conversely, the reasonably prudent patient may argue that the majority of patients in a similar situation cannot overcome smoking addic- tion. Accordingly, it is not the patient’s fault but, rather, the cigarette manufacturer whose advertise- ments led to the addictive incurable smoking habit before the patient realized the pernicious effects of smoking. Smokers > age 25 years only constitute 5% of addicted smokers.83 A practitioner’s advice to quit smoking is likely given to an addicted patient. The frustratingly small success rates of smoking ces- sation programs are therefore not surprising.
CONCLUSION
The guiding principle of the ancient Hippocratic Oath for medical practitioners is “primum non
nocere,” meaning “First, do no harm.” This prin- ciple remains the bedrock foundation on which modern medicine provides optimum patient care.
Dentists are ethically obligated to adhere to the patient’s best dental health interest. The Hippocratic Oath principles are embodied in the following:
“. . . I understand and accept that my primary responsibility is to my patients, and I shall ded- icate myself to render, to the best of my abili- ty, the highest standard of oral health care and to maintain a relationship of respect and con- fidence. Therefore, let all come to me safe in the knowledge that their total health and well- being are my first considerations. . . .” [empha- sis added.] (ADA Dentist’s Pledge, 1991)
Dentists are legally obligated to protect and preserve the patient’s health interests as foremost since the dentist-patient relationship is fiduciary.
In the new millennium, periodontics recognizes the obligation to protect and preserve the patient’s total health care. Dentists and physicians are now able to see more clearly in the light of evidence- based periodontics. This new insight illuminates the inter-relationship between oral and systemic health rather than the tunnel vision of earlier views which separated the periodontium from the body’s general health system.
REFERENCES
1. California Book of Approved Civil Jury Instruc- tions (BAJI), BAJI No. 6.00.1. 1999.
2. California Dental Association Peer Review Manu- al, page 1 (1995).
3. American Dental Association Statement on Dental Unit Waterlines (1995).
4. Simpson vs. Davis, 219 Kansas 584, 549 P.2d 950 (1976).
5. American Academy of Periodontology. Parameters of Comprehensive Periodontal Examination (1995).
6. American Academy of Periodontology. Parameters of Comprehensive Periodontal Examination (1995).
7. Jury Award (120 Million) Against HMO is Biggest Ever. Pittsburgh Post Gazette; January 22, 1999. p. A17.
8. Brown R, Hadley JN, Chambers DW. An evalua- tion of ektaspeed film versus ultraspeed film for endodontic working length determination. J Endo 1988;24:(1):54–6.
9. Hadley J. Dental radiology quality of care: the den- tist makes the difference. J Calif Dent Assoc 1995;23(5):17–20.
Medicolegal Issues 287
10. Kolstead RA. How well does the chemiclave steril- ize handpieces? JADA 1998;129(7):985–91.
11. Burke FJI, Coulter WA, Cheung SW, Pallemk MS. Autoclave performance and practitioner knowl- edge of autoclave use. A survey of selected UK practices. Quintessence Intl 1998;29(4):231–8.
12. California Book of Approved Civil Jury Instruc- tions (BAJI), BAJI Nos. 6.01, 6.04. 1999.
13. Fry RJ, Grosovsky A, Hanawalt PC, et al. The impact of biology on risk assessment. Workshop of the National Research Council’s Board on Radiation Effects Research. July 21–22, 1997. Radiation Research 1998;150(6):695–705.
14. Carlin vs. Superior Court. 13 Cal. 4th 1004, 920 P.2d 1347, citing Restatement Second of Torts section 402A (1996).
15. California Book of Approved Civil Jury Instruc- tions (BAJI), BAJI No. 6.11. 1999.
16. Sfikas PM. Informed consent and the law. JADA 1998;129:1613–4.
17. Waller vs. Aggarwal. 116 Ohio App.3d 355, 688 N.E. 2d 274 (1996).
18. Hales vs. Pittman 118 Ariz. 305, 576 P.2d 493 (1978).
19. Shelter vs. Rochelle. 2 Ariz. App. 370, 409 P.2d 86 (1965).
20. Quan vs. Truck Insurance Exchange. 67 Cal. App.4th 583, 79 Cal. Rptr.2d 134 (1998).
21. Abbott vs. Bragdon. (1st Cir) 118 S. Ct. 2196 (1998).
22. State vs. Clausen. (Minn. Ct. App.) 491 N.W.2d 662 (1992).
23. Newman M. Genetic, environmental and behav- ioral influence on periodontal infections. Com- pendium 1998;19:25–31.
24. Ehrmann EH. Focal infection: the endodontic point of view. Oral Surg 1977;44:628.
25. Anonymous. Dental amalgam: update on safety concerns. JADA 1998;129(4):494–503.
26. Remington DN, Joondeph AJ. Long term evalua- tion of root resorption occurring during ortho- dontic treatment. Am J Orth Dent Fac Ortho P 1989;96:43–6.
27. Kornman KS, Crane A, Wong H-Y, et al. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997;24:72.
28. Piper S. Gary Armitage searches for new ways to diagnose and treat periodontal disease. UCSF Oracal 1998;12:11. Armitage G. Submitted for publication J. Perio.
29. Armitage G, Wu Y, Wang HY, et al. Low preva- lence of a periodontitis associated interleukin 1 composite genotype in individuals of Chinese heritage. J Periodontol 1999. [Forthcoming]
30. Norman-Bloodshaw vs. Lawrence Berkeley Labora- tory. 9th Cir. 135 F.3d 1260 (1998).
31. Aldridge JP, Lester V, Watts TLP, et al. Single-blind studies on the effects of improved periodontal health on metabolic control in type 2 diabetes mellitus. J Periodontol 1996;67:166–76.
32. Cohen DW, Rose LF. The periodontal-medical risk relationship. Compendium 1998;19:11–24.
33. Severson HH, Andrews JH, Lichtenstein E, et al. Using the hygiene visit to deliver a tobacco ces- sation program: results of a randomized clinical trial. JADA 1998;129:993–9.
34. Ramjford SP. Maintenance care and supportive periodontal therapy. Quintessence Int 1993;24: 465–71.
35. Haffajee AD, Socransky SS, Dzink JL, et al. Clini- cal, microbiological and immunological features of subjects with destructive periodontal diseases. J Clin Periodontol 1988;15:240–6.
36. Grossi SG, Genco RJ, Machtel EE. Assessment of risk for periodontal disease. II: Risk indicators for alveolar bone loss. J Periodontol 1995;66:23–9.
37. Grossi SG, Zambon JJ, Jo AW. Assessment of risk for periodontal disease. I: Risk indicators for alveolar bone loss. J Periodontol 1994;65:260–7.
38. Moss ME, Beck JD, Kaplan BH, et al. Exploratory case-control analysis of psychosocial factors and adult periodontitis. J Periodontol 1996;67: 1060–9.
39. Klokkevold PR. Periodontal medicine: assessment of risk factors for disease. Calif Dent Assoc J 1999; 27:135.
40. Offenbacker S, Beck J. Periodontitis: a potential risk factor for spontaneous preterm birth. Com- pendium 1998;19:32.
41. Gibbs RS, Ronero R, Hiller SL, et al. A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992;166:1515.
42. Iams J. Prevention of Preterm Birth. New Engl J Med 1998;338(1):54–6.
43. Dajani AS, Taubert KA, Wilson W, et al. Preven- tion of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1997;277:1794–1801.
44. Larson PE. The effect of a chlorhexidine rinse on the incidence of alveolar osteitis following the surgical removal of impacted mandibular third molars. J Oral Maxillofac Surg 1991; 49:932–7.
45. Ragno JR Jr, Szkutnkik AJ. Evaluation of 0.12% chlorhexidine rinse on the prevention of alveo- lar osteitis. Oral Surg Oral Med Oral Pathol 1991;72:524–6.
46. Bonine FI. Effect of chlorhexidine rinse on the incidence of dry socket in impacted mandibular
288 Periodontal Medicine
third molar extraction sites. Oral Surg Oral Med Oral Pathol 1995;79:154.
47. American Association of Oral and Maxillofacial Surgeons. Report of a workshop on the man- agement of patients with third molar teeth. J Oral Maxillofac Surg 1994;52:1102–12.
48. Rechmann P, Seewald M, Strassburg M, Naumann P. Incidence of bacteremia following extrac- tions—a double blind study on local disinfec- tion using chlorhexidine. Dtsch Zahnarztl A 1989;44:622–4.
49. Rahn R, Schneider S, Diehl O, et al. Preventing post-treatment bacteremia: comparing topical povidone-iodine and chlorhexidine [comment]. J Am Dent Assoc 1995;126:1474.
50. Albandar JM, Gjermo P, Preus HR. Chlorhexidine use after two decades of over-the-counter avail- ability. J Periodontol 1994;65:109.
51. Morlino vs. Medical Ctr. of Orange County. 706 A.2d 721 (1998).
52. Shen EC, Maddalozzo D, Robinson PJ, Geivelis M. Root planing following short term pocket distension. J Periodontol 1997;68:632–5.
53. LeLorier J, Grègoire G, Benhaddad A, et al. Dis- crepancies between meta-analysis and subse- quent large randomized controlled trials. N Engl J Med 1997;337:536–42.
54. Capelleri JC, Ioannidis JP, Schmid CH, et al. Large trials vs. meta-analysis of smaller trials: how do their results compare? JAMA 1996;276: 1332–8.
55. Villar J, Carroli G, Belizan JM. Predictive ability of meta-analyses of randomised controlled trials. Lancet 1995;345:772–6.
56. Ioannidis JP, Cappelleri JC, Sacks HS, Lau J. The relationship between study design, results and reporting of randomized clinical trials of HIV infection. Control Clin Trials 1997;18:431–44.
57. Horowitz RI, Singer BH, Makuch RW, Viscoli CM. Can treatment that is helpful on average be harmful to some patients? A study of the conflicting information needs of clinical inquiry and drug regulation. J Clin Epidemiol 1996;49: 395–400.
58. Monmaney T. AMA fires editor over publishing sex survey. Los Angeles Times, p. A16 (16 January 1999).
59. Reilly J. Tobacco use assessment is a new vital sign in dentistry. J Mass Dent Soc 1997;46:25–32.
60. Page RC, Beck JD. Risk assessment for periodontal diseases. Int Dent J 1997;47:61.
61. California Book of Approved Civil Jury Instruc- tions (BAJI), BAJI No. 2.0.
62. Williams RC. Periodontal disease: the emergence of a new paradigm. Compendium 1998;19:4.
63. Loe H, Theilade E, Jensen SB. Experimental gin- givitis in man. J Periodontol 1965;36:177.
64. California Book of Approved Civil Jury Instruc- tions (BAJI), BAJI No. 3.76.
65. Peumans M, Van Meerbeek B, Lambrechts P, et al. The influence of direct composite additions for the correction of the tooth form and/or position on periodontal health. A retrospective study. J Periodontol 1998;69:422–7.
66. Jeffcoat MK, McGuire M, Newman MG. Evi- dence-based periodontal treatment. Highlights from the 1996 World Workshop in Periodon- tics. JADA 1997;128:713–24.
67. Daubert vs. Merrell Dow Pharmaceuticals, Inc. 509 U.S. 579 (1993).
68. Kumho Tire Co. vs. Carmichael. 119 S.Ct. 1167 (1999).
69. Jeffcoat MK, Bray KS, Ciancio SG. Adjunctive use of a subgingival controlled-release chlorhexidine chip reduces probing depth and improves attach- ment level compared with scaling and root plan- ing alone. J Periodontol 1998;69:989–97.
70. Toole vs. Richardson-Merrill Inc. 251 Cal. App.3d 689; 60 Cal.Rptr. 398 (1967). 21 Code of Fed- eral Regulations, section 801.4 (intended use may be shown by oral statements of manufac- turer’s representatives).
71. Woods KL. Mega-trials and management of acute myocardial infarction. Lancet 1995;346:611–4.
72. Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med 1978;299:926.
73. Fewer implant cases seen on wake of scientific find- ings. San Francisco Daily Journal 1998 Dec 2; Sect. C:1.
74. Severson HH, Andrews JH, Lichtenstein E, et al. Using the hygiene visit to deliver a tobacco ces- sation program: results of a randomized clinical trial. JADA 1998;129:993–9.
INDEX
Acatalasia, 18 Acetaminophen, acute renal failure
and, 208 Acidosis, 123
hyperosmolar nonketotic, 125 Acquired immune deficiency
syndrome (AIDS), 17, 18, 64 Acute myeloid leukemia, 18 Acyclovir, acute renal failure and, 208 Adhesion receptors, 91 Adult periodontitis, 21, 45–49,
51–56 in HIV patients, 190–191
Advanced glycosylation end-products (AGEs), 128–129, 133–134
Age, as risk factor, 14, 25, 132 Agranulocytosis, 15, 18 Alendronate, 19, 179 Alpha-1 antitrypsin, 18, 2, 85 Alport’s syndrome, 206 Alprazolam, 153, 262 Alveolar bone, 2, 5
medications and, 264 Alveolar bone height, genetics and, 22 Alveolar bone loss
in diabetes, 16 estrogen and, 176 as predictor of stroke, 77 as risk factor for COPD, 90 tobacco smoke and, 101, 176
Alveolar crestal heights, 74, 172 Alveolar mucosa, 2 Alveolar process, 4–5 Alveolar ridge resorption, 18 American Heart Association (AHA)
recommendations, 68–69 Aminoglycosides, acute renal failure
and, 208 Amoxicillin/penicillin, 68, 248–249
adverse effects, 249 in breast milk, 249 metronidazole with, 11, 250
Amphotericin B, 92 Ampicillin, with contraceptives, 244 Androgens, 168 Angiotensin-converting enzyme
(ACE) inhibitors, 206 Anorexia nervosa, 64, 65 Antacids, 153 Antibiotics, 243–266. See also
individual antibiotics activity of, 245
antagonism, 244 cross-resistance, 243 in diabetics, 142 dosages, 245 infective endocarditis and, 67–69,
214 irrigation with, 251–253 liver disease and, 214 local delivery, 253–256, 281 in meat, 266 nephrotoxic, 211, 213 in neutropenia, 199 oral contraceptives and, 244–245 patient instruction, 266 in periodontal therapy, 250–251 post-transplant, 205–217 during pregnancy, 160 reduced effectiveness, 244 resistance, 243–244, 266 risk, 67 selective pressure, 244 spectrum, 244 superinfection, 244 synergism, 244 topical oropharyngeal, 92
Anticoagulants, 236–238 contraindications for, 237 INR, 70 oral, 42, 70–71
Anticoagulated patients, 70–71 Anticoagulation, 231–232
antifibrinolysis, 239–240 monitoring, 42, 70–71 severe factor deficiencies, 239
Antineoplastic chemotherapy, 230 Antioxidants, 72 Antiseptic rinses, 68, 251 Antiseptics, 256 Antivirals, 200 Aphthous ulcers, 152 Arthralgias, 64 Ascites, 214 Aspirin, 70–71
risk, 71 Atheroma formation, 71, 78, 128, 134 Atherosclerosis
atheroma formation, 78, 134 in diabetes, 127 genetic predisposition, 79 infections in, 71 mechanisms of, 72 patient management, 79
periodontal infection and, 78–79 Ross response, 71 triggers, 78
Attachment apparatus, 4–6 Attachment loss, 15, 50
in diabetes, 17 improving, 258 in myocardial infarction, 73 in psychological disorders, 20
Azathioprine, liver disease, and 210 Azithromycin/clarithromycin, 68
Baby-bottle tooth decay, 158 Bacteremia, transient, 67
risk, 68 Bacteria as opportunists, 2 Bacterial endocarditis, 280 Bacterial pneumonia, 83–86
nosocomial, 83–84, 85, 86, 92 prevention of, 92
Bacteroides forsythus, 73 heat-shock protein, 78 pocket depth and, 24 as risk factor, 11, 23, 25
Basic multicellular unit (BMU), 167 Berger’s disease, 206 Biofilms, 2, 87 Bismuth line, 23 Bleeding, 233–236
applying pressure, 234 fibrin sealants, 240 post-extraction, 231–232 on probing, 24 spontaneous, 232 suturing, 235 topical agents, 234–236, 237 treatment, 234
Bleeding disorders, 229–241 Bleeding time, 41, 233
normal range, 41 Blood urea nitrogen (BUN), 41
normal range, 41 Bone loss, 54 Bone marrow transplantation,
196–200, 216–217 Bone mass, 169 Bone metabolism, 167
fluoride and, 177 smoking and, 176
Bone mineral density, 169 estrogen and, 175 loss of, 18
290 Index
mandibular, 171–172, 175 Bone remodeling, 167–169
imbalance, 171 peak bone mass, 168–169, 178
Bone resorption, 174 Bronchitis, 89 Bronchopneumonia, 84 Bruxism, as risk factor, 25 Bupropion HCl (Zyban), 110
contraindication for, 110 Burden of proof, 282–283
Calan, 23 Calcitonin, 168 Calcium, dietary, 19, 177, 178
as risk indicator, 15, 25 Calcium, serum, normal range, 41 Calculus, as risk factor, 24 Cancer, head and neck, 195–196
oropharyngeal, 200 Candida albicans, 259
as risk factor, 11 Candidiasis, oral, in HIV patients, 17 Capoten, 262 Captopril, 262 Carbamazepine, 23 Cardia valve prostheses, 64 Cardiac conditions and dental
treatment, 65 Cardiac valve prosthesis, target INR,
42 Cardiovascular diseases, 63–82
as risk factor, 279 CD4 cells, 17, 183, 186, 190 Cementum, 2–6 Cephalexin/cefadroxil, 68 Cephalosporins, 68 Cerebral infarction, 76
TDI in, 76 Cerebral ischemia, 76 Chédiak-Higashi syndrome, 18 Chemotherapy, 196–200 Cherubism, 20 Chlamydia pneumoniae, heart disease
and, 73 Chlorhexidine, 210
delivery system (PerioChip), 256–258
irrigation with, 253 plaque formation and, 199
Chlorhexidine gluconate, 68, 187 nosocomial reduction, 93
Chronic bronchitis, 84 Chronic obstructive pulmonary
disease (COPD), 84–90 Chronic renal failure, 206–297 Ciprofloxacin, 249 Circular fibers, 3 Circumstantial evidence, 283 Clefts, 21
Dentoalveolar unit, 4 Dentures, 199 Depression, 20, 65
nicotine dependency and, 105 Dermal gangrene, 64 Desmopressin, 238 Diabetes mellitus, 121–150
acidosis, 123 autoantigens in, 123 causes, 122 characteristics of, 123 classifications, 121–125 complications of, 125–129, 137 dental implants and, 136 dental management, 140–145 diagnosis, 129 diarrhea, 127 emergencies, 144 gestational, 121, 125 histocompatibility complex antigens, 123 insulin-dependent, 121 insulin therapy, 138–140 “juvenile,” 123 ketoacidosis, 123–125 laboratory diagnosis, 130 macrovascular disease in, 125 management of, 136–145 markers for, 122 medical history, 36 monitoring, 129 myocardial infarction in, 127 non–insulin-dependent, 121 obesity in, 124, 136 onset of, 123 oral agents used, 138 oral complications, 130–135 other types, 121 pathophysiology, 124 periodontal infection in, 135–136 presentation, 129 renal failure, 126 as risk factor, 16–17, 25, 278 risk factors for, 124 self-monitoring, 130 susceptibility to, 123 treatment, 131 type 1, 121, 122–124, 136–137 type 2, 124–125, 131–132,
136–137 viral infections and, 123
Dialysis, 64, 208–209 Diet
osteoporosis and, 177 during pregnancy, 158 as risk indicator, 15, 19
Dihydropyridines, 23 Distress, as risk indicator, 15, 20, 25 Dose response, 14 Down syndrome, 18, 21, 46, 65
Cleidocranial dysplasia, 21 Clindamycin 249, 68 Clonidine, 111 Clot formation, 228 Clotrimazole (Lotrimin, Mycelex), 260
adverse effects, 260 Coagulation cascade, 227–229 Coagulation disorders, 230–231 Colgate Total, 261 Collagen, 128, 134–135
tetracycline and, 135 Complete blood count (CBC), 38 Congenital chromosomal disorders,
46 Congenital neutropenia, as risk
indicator, 15 Consultations, 276 Contraceptives, oral, 161–162
antibiotic interference, 162, 244–245
Coping, as risk indicator, 15, 20, 25, 174, 278, 279
Coronary artery disease, 71 C-reactive protein, 78 in diabetics, 127 fibrinogen, 78 incidence of, 75 oral infections and, 73–76 TDI as predictor, 74–75
Coronary atheromatosis, 73 Cortical bone loss, 18 Corticosteroid resistance, 206 Corticosteroids, post-transplant, 209 Cortisol, 122, 123, 142 Cotinine, 15, 101 Coumadin
action of, 70, 231–232, 236 medications affecting, 239 monitoring, 70 vitamin K administration, 70
Craniofacial dysostosis, 21 C-Reactive protein, 78 Crohn’s disease, 18 Cryptitopes, 93 Cyclosporine therapy, 23, 206, 210 Cytokines, 87
bone cells and, 168 in diabetes, 129, 134 production of, 12, 51–55, 91–92 protease cascade, 72 release of, 91 in respiratory disease, 91–92
Cytomegalovirus heart disease and, 73 post-transplant, 200
Data analysis, 13, 14 Dentifrices, 260–261 Dentin, 6, 5 Dento-peristeal fibers, 4
Index 291
Doxycycline, 254–255 amoxicillin with, 251 in diabetes, 17, 135, 136 metronidazole with, 250 Periostat, 258, 281 subgingival delivery (Atridox), 254
Drug packet inserts, 281 Drug side effects, 280 Due care, 273
Eating disorders, 152 Ehlers-Danlos syndrome, 18, 21, 65,
171 as risk indicator, 15
Emphysema, 84–85, 89 Enalapril maleate, 262 End-stage renal disease, 205 Endothelial injury, 72–73 Epidemiologic research, 282 Epinephrine, 122, 123, 142 Epithelial cells, 91 Epstein-Barr virus, 17 Erythema, 184–187 Estrogen, 15, 152, 156, 175
deficiency, 173, 174–175 and periodontal disease, 174, 175 in skeletal development, 168, 174
Estrogen replacement therapy, 174, 175–177, 178 smoking and, 176
Extracellular matrix, 12, 72
Failure-to-inform, 275 Fatigability, 64 Fcg receptor, 49, 51
polymorphism, 22 Febrile infections, stroke and, 77 Fenfluramine/phentermine, 65 Fever, 64, 69 Fibrillary glomerulonephritis, 206 Fibrinogen, as risk factor, 78 Fibrinolysis, 228 Fibronectin, 90 Fibrosis, 23 Fluoxetine, 153, 262 Fragile X syndrome, 21 Fraud, 276 Fructosamine tests, 130 Fungal infections, 259–262
anti-fungal agents, 259 Furcation, 55, 102
Gastroesophageal reflux disease (GERD), 152–153
Gender, as risk factor, 15, 25 Genetic counseling, 58 Genetic disorders, types of, 46–47 Genetic factors, 20–22
orofacial abnormalities, 20–21 Genetic information issues, 58, 59
Glucometer, 130, 131, 143 Gluconeogenesis, 122 Glucose, blood, 41, 125
normal range, 41 Glyburide, 138 Glycemia, 122 Glycemic control, 17, 132
bone loss and, 132 periodontal infection and, 135
Glycosylated hemoglobin (HbA1c), 129–130 normal values, 130, 142
Glycosylation, 128 Gold salts, 206 Goodpasture’s syndrome, 206 Governmental agency standards, 275
manufacture compliance with, 275 Growth hormone, 168
Hairy leukoplakia, oral, 210 in HIV patients, 17
Heart disease, 11 Heart-lung transplants, 215 Heart surgery, 69 Heart transplantation, 215–217 Heat-shock protein, 78 Helicobacter pylori, heart disease and,
73 Hematocrit, 38
normal range, 41 Hemifacial hypertrophy, 21 Hemoglobin, 38
normal range, 41 Hemophilias, 230–231
liver clot, 231 Hemophilus influenza
and COPD, 85 Hemostasis, 227–229
platelet phase, 227, 232 questionnaire, 234
Heparin, 232, 237–238 Hepatitis, 212 Hereditary nephritis, 206 Hippocratic Oath, 286 Histocompatibility complex, 48, 49 History-taking, 36–38 HIV periodontitis, 17 HIV-gingivitis, 17, 184 Human immunodeficiency virus
(HIV), 183–193 oral lesions in, 17, 184 resistance to, 48, 49
Human leukocyte antigen (HLA), 21, 21–22, 48
Hypercholesterolemia, 47 Hyperglycemia, 122, 127
sustained, 129 Hyperhomocystinemia, 72 Hyperimmunoglobulin-E recurrent
infection syndrome, 18
Genetic paradigm, 6–8 Genetic polymorphisms, 22 Genetic susceptibility, 48–49, 51
resistance, 48 test requirements, 59 types of, 48
Genetic testing, 59–61 patient selection for, 60 potential benefit(s) of, 60
Genetics, 45–62 autosomal dominant disorders,
46, 47 autosomal recessive disorders, 47 carriers, 47 in clinical practice, 56–57 environmental factors and, 47–49 ethics, 57–58 heterozygotes, 47 homozygotes, 47 phenotype, 48 pleiotropism, 46, 47 polymorphisms, 48 predisposition, 277–278 utility of, 57 variable expression, 46, 47
Gingiva, 2 blood supply of, 4 enlargement, 264 healthy, 4, 7 medications and, 263–264
Gingival banding, 186 Gingival bleeding, 196 Gingival crevicular fluid, 264–266
antibiotic resistance, 265 change in content, 265 cytokines in, 92 IL-1 in, 52, 53 medications and, 264–266 pneumonia and, 87
Gingival grafts, 69, 102 Gingival hyperplasia, 155
pretransplant, 210 Gingival infiltration, 196, 197 Gingival overgrowth, 22, 23, 210 Gingival sulcus fluid, 3 Gingival sulcus, 2–3, 90, 92 Gingival ulceration, 196 Gingivectomy, 69 Gingivitis, 3, 4, 56
bleeding disorders and, 227 in diabetes, 132 HIV-associated, 184 in leukemia, 198 irrigation and, 251
Glimepiride, 138 Glipizide, 138 Glomerulonephritis, 205 Glucagon, 123
injection, 144 Glucocorticoids, 168
292 Index
Hyperresponsiveness, 12 Hypertension, 72
stroke and, 77 Hypertriglyceridemia, stroke and, 77 Hypocomplementemia, 206 Hypoglycemia, 122, 140, 144–145
emergency treatment of, 144 severe, 140 signs of, 144 unawareness, 145
Hypophosphatasia, as risk indicator, 15
IgG2, 16 Immune response, 49 Immunocompromised patients, 200,
205 Immunoglobulin A (IgA)
nephropathy, 206 Immunosuppression, 64
as risk factor, 190 risks, 1
Infective endocarditis, 63–64 antibiotic administration, 67–69 dental considerations, 67–69 prevention, 64, 68
Inflammatory bowel disease, 18 Informed consent/misrepresentation,
275 Insulin, 137–140
action of, 122 control of glucose, 122 production of, 122 secretion, 124, 137
Insulin deficiency, 122 Insulin infusion pump, 137, 138–139 Insulin-like growth factor (IGF), 129,
168 Insulin resistance, 124, 125
gestational diabetes and, 125 infection and, 136
Insulin therapy, 137–140 Intensive care units, 87–89 Inter-radicular fibers, 6 Interdental craters, 187 Interleukin 1 (IL-1), 12, 45, 91
in adult periodontitis, 51–55 bone cells and, 168 in diabetes, 129 genetic variations, 52–56 genetics of, 22, 51 polymorphisms, 25, 52, 53 production of, 53 response to treatment, 54–55
International normalized ratio (INR), 42, 70, 213–214, 236, 237 management using, 238
International sensitivity index (ISI), 42, 236
Intraligamental analgesia, 67
female patients, 162 forms, 39–40 medications, 36 social history, 37
Medications and periodontium, 262–263 over-the-counter, 263
Medications, effects of, 22–23 Membranoproliferative
glomerulonephritis, 206 Membranous nephropathy, 206 Mendelian disorders, 46–47 Menses, 152–153 Mercury line, 23 Metals, heavy, 23 Metformin, 138, 143 Methysergide, 65 Metronidazole, 248
contraindications, 248 in neutropenic patients, 199 subgingival delivery, 256
Miconazole (Monistat), 260 adverse effects, 260
Microalbuminuria, 126 Microflora, local, as risk factor, 23–25 Minocycline, 255–256
in diabetes, 135 Misfeasance, 275 Misrepresentation, 275–276 Mitral regurgitation, 66 Mitral valve prolapse, 47, 64, 65 Molecular medicine, 6 Moniliasis, 259 Monocytes, 38 Mouthrinse, 260–262 Mucositis, 18 Multiple myeloma, 170 Myalgias, 64 Myelodysplastic syndrome, 197 Myocardial infarction, 73
studies, 74
Necrotizing periodontal diseases, 187–189
Necrotizing stomatis, 187, 189 Necrotizing ulcerative lesions
in AIDS patients, 17 Necrotizing ulcerative gingivitis,
19–20 Necrotizing ulcerative periodontitis
in HIV patients, 17 Negligence, comparative, 285–286 Negligent custom, 273–274 Nephropathy, 125, 127 Nephrosis, 208 Nephrotic syndrome, 206 Neuropathy, 125–126 Neutropenia, 18, 199 Neutrophil disorders, 18, 21, 134
as risk indicators, 18, 25
Irrigation, 251–253
Job’s syndrome, 18 Juvenile periodontitis, 21, 24
Kaposi’s sarcoma, in AIDS patients, 17
Kawasaki disease, 65 Ketoacidosis, 123–124 Ketoconazole, 213, 259–260
adverse effects, 260 Kidney transplantation, 205,
209–212
Laboratory studies, 38–42 normal ranges, 41
Lead poisoning, 23 Lesions, HIV-associated, 184–191 Leukemia, 196–200
latent herpes simplex in, 199–200 Leukocyte adhesion deficiency, 18 Liebman Sacks verrucae, 66 Linear gingival erythema, 184–187
in AIDS patients, 17 Lipid
accumulation of, 71 altered metabolism, 129 in diabetics, 129
Listerine, 251, 260 Liver cirrhosis, 212 Liver disease, 212
abnormal hemostasis in, 232 bleeding disorders in, 213 hemmorrhage in, 232
Liver transplant, 213–214 complications of, 213 dental management, 213–214
Low-density lipoproteins (LDL), 71–72 elevated, 133 oxidation of, 128, 129
Lung cancer, 99–100 Lung infection, 85–86
risk factors, 86 Lung, normal, 85 Lung transplantation, 214 Lymphocytes, 38
Macrophages, 71 Malaise, 64 Mandibulofacial dysostosis, 21 Marfan’s syndrome, 21, 47, 65, 171 Matrix metalloproteinases, 12, 51,
72, 134 Medical history, 36–38
allergies, 36 body systems, 37 dental history, 43 diabetes, 36 family history, 37
Index 293
Neutrophils, 38 Nicotine, 101
action of, 103 addiction, 104 cardiovascular system and, 104 effects on fibroblasts, 101 nonpharmacologic agents, 111 replacement agents, 109 withdrawal, 104, 109
Nicotine dependency, 103–114 Nicotine gum, 107, 109–110
contraindications for, 110 with patch, 111
Nicotine nasal spray, 110 contraindications for, 110
Nicotine patches, 109 contraindications for, 110 with gum, 111
Nifedipine (Procardia), 23 Night sweats, 64 Nitrendipine, 23 Non-Hodgkin’s lymphoma, in AIDS
patients, 17 Non-Mendelian disorders, 47 Nonfeasance, 275 Nonsteroidal anti-inflammatories,
206 Nystatin, 259
Occlusion, as risk factor, 25 Optimum treatment, 57 Oral hygiene, and risk, 24 Oral lichen planus, 186 Oropharyngeal cancer, 7–8
risk factors for, 8 Osler’s nodes, 64 Osteoclasts, activation of, 12 Osteogenesis imperfecta, 20 Osteopenia, 167–182
oral bone and, 171–173 as risk factor, 18–19 as risk indicator, 15
Osteoporosis, 169–182, 278 causes, 171 classification, 170 definition, 169 diet, 177 future research, 179 genetics, 177 high turnover, 174 involutional, 170 in liver disease, 213 pathophysiology, 171 and periodontal disease, 172–179 postmenopausal, 170 as risk indicator, 15, 25 as risk factor, 18–19 risk factors for, 173 secondary, 170 smoking and, 175–177
Pharmacogenomics, 57 Phenytoin (sodium
5,5-phenylhydantoin), 22–23, 213, 263–264 side effects, 22, 263
Physician Desk Reference, 281 Pierre-Robin syndrome, 21 Pigmentation, 23 Plaque, 56
accumulation, 45 composition, 262–263 during pregnancy, 155, 156, 157 medications and, 262–263 respiratory disease and, 87–89 as risk factor, 24, 280 types of, 45–46
Plasminogen, 72 Plasminogen activator inhibitor, 155 Platelet count, 41 Platelet disorders, 229–230
aspirin and, 230 Platelet dysfunction, 196 Platelet transfusions, 240 Platelet-derived growth factor, 129,
133, 263 Pneumonia, 83–89
prevention, 92–93 Pocket, 3, 6 Polymyxin B, 92 Porphyromonas gingivalis, 9, 73
heat-shock protein, 78 as risk factor, 23, 25
Povidone iodine, 68, 187 Pregnancy, 153–161
antibiotics, 160, 162 breast feeding, 161, 162 dental treatment, 158–161 diet, 158 emergency treatments, 158–159 fetal risk, 159, 279 gingivitis, 153 immunoresponse, 155, 156 local anesthetics/analgesics, 160,
162 management, 157–158 medications, 159 nicotine replacement during, 110 nutrition, 157 perimylolysis, 157 plaque composition, 155, 156 prenatal fluoride, 158 preterm low-birth-weight births,
156–157, 279 radiography, 159 sedatives, 160, 162 supine hypotensive syndrome, 158
Pregnancy tumors, 154–155, 157, 158
Preleukemic syndrome, 18 Premenstrual syndrome, 153
treatment, 178–179 Oxidant stress, 133
Pancreatic transplantation, 214 Panic disorder, 65 Pantomographic index, 73 Papillon-Lefèvre syndrome, 18
as risk indicator, 15 Partial thromboplastin time (PTT),
42, 232, 237 normal range, 41
Patient evaluation, 35–38 reasons for, 35
Patient monitoring, 276 Penicillin, 68. See also Amoxicillin
allergy, 68 with contraceptives, 244 resistance, 68
Periapical lesions, as risk factor, 25 Periapical pathosis, 199 PerioChip, 256–258 Periodontal disease, 1–9, 279
background factors, 14–15 diabetes and, 132–136 etiology of, 11 genetics of, 46, 49–62 glycemic control and, 135–136 heart disease and, 11 pathogenesis of, 12 pre-existing, 24–25 pregnancy and, 153–155 presentation, 46 risk assessment, 12–15, 60, 173,
283 as risk factor for COPD, 90 second-hand smoke, 99 smoking-associated, 100, 101 stroke and, 76–78 systemic disease and, 1–9, 15–22 untreated, 91
Periodontal ligament, 2, 4, 5–6, 7 Periodontitis, 45
bleeding disorders and, 227 diabetes and, 135–136 in diabetics, 132 early-onset, 46, 49 etiology of, 56 HIV associated, 184–191 in leukemia, 198 measurement of, 13 rapidly progressive, 190–191 recurrence of, 12 stroke and, 77, 78
Periodontium, 2–6 diabetic influence on, 133–135 medications and, 262–263 smoking and, 100
Peritonitis, 209 Peroxetine, 153 Petechiae, oral, 64
294 Index
Principal fibers, 4 Probing, 24
improving depths, 258 Progesterone, 152–153, 156 Prognosis, 55 Prostaglandin E2, 51 Prosthetic valve endocarditis, 69
contraindications for dental treatment, 69–70
Protease, 91 Protease cascade, 72, 73 Protein metabolism, abnormal, 214 Prothrombin (PT) test, 41–42, 232
INR, 42, 70, 213, 236 Pseudomembranous colitis, 250
antibiotics and, 250 Psychological disorders
as risk indicators, 19–20 Puberty, 151–152 Pulpal infection, as risk factor, 25 Pyogenic granulomas, 154
Race, as risk factor, 15 Radiation therapy, 195–196 Re-evaluation, 276 Red blood cell (RBC) count, 38, 41 Referral to specialists, 274 Refractory periodontitis, 52, 102 Refusal to treat, 276 Renal failure, 205–208 Renal transplantation, 209–212
immunosuppressive therapy, 209–210
nephrotoxic antibiotics, 211 Repaglinide, 138 Research evidence, 283–285 Respiratory diseases, 83–97 Retinopathy, 125–126 Rhabdomyolysis, 206 Rheumatic fever, 65, 244
and infective endocarditis, 64 and mitral valve stenosis, 65
Rheumatic heart disease, 69 Risk analysis, 25, 26 Risk categories, 42 Risk factor, 12 Risk factors, 11, 277–280 Risk indicator, 12
Saliva, 262–263 in diabetes, 130–131 enzyme activity in, 90 pneumonia and, 87, 90
Salivary dysfunction, 19, 152 Salivary pellicles, 90 Sanguinaria, 254, 260 Scorbutic gingivitis, 19
Thrombocytopenia, 229–230 Thromboembolism, risk, 237 Thrush, 259 Tissue plasmin activator, 72 Tobacco toxicity, 100–101, 110 Tobacco use, 99–119. See also
Smoking “4 A’s,” 107–112 biohazards, 110 cost, 99–103 reduced response, 103 as risk factor, 15–16
Tobramycin, 92 Tooth loss, 53–56, 179
coronary heart disease and, 76 and osteoporosis, 172
Topical clotting agents, 70 Total dental index, 73–74, 75, 76 Tranexamic acid, 239–240
in oral rinses, 214 Trans-septal fibers, 3 Transplantation
dental management in, 210–212 treatment planning for, 210
Triclosan, 261–262 Trimethoprim, 217 Trisomy 21, 21, 46 Troglitazone, 143 Tumor necrosis factor (TNF)-a, 12,
45, 51, 91 bone cells and, 168 in diabetes, 129, 134 genetics of, 22, 49
Twin studies, 22, 46, 50–51
Ulcerative mucositis, 197
Valvar heart disease, 63–69 Valvar prostheses, 66 Ventilated patients, 93 Verapamil hydrochloride, 23 Vitamin C, 15, 177
in smokers, 19 Vitamin D, 167, 177 Vitamin E, 72 Vitamin K administration, 70 Vitamin K supplementation, 214 Von Willebrand disease, 231, 239
Warfarin, 42, 231, 236 Wellbutrin, 110 White blood cell (WBC) count, 38 Wilson’s disease, 212 Women’s Health Initiative (WHI), 172
Xerostomia, 130–131, 157 medications causing, 263
Selective digestive decontamination, 92–93
Serotonin, 153 Serotonin agonists, 65 Sertraline, 153 Sharpey’s fibers, 5, 7 Skill/learning updates, 274 Smokeless tobacco, 16 Smoking, 99–119. See also Tobacco
use bone density and, 175–177 IgG2 and, 16 IL-1 and, 53–54, 278 as risk factor, 15–16, 25, 54, 85,
99, 175–177 second-hand smoke, 99 stroke and, 77
Sodium valproate, 23 Soft tissue necrosis, 197 Solid tumors, 198–199 Spiramycin, 249 Spirochetes, as risk factor, 11 Spongiosa, 5 Standard of care, 273, 275
risk factors, 277–280 Streptococcus pneumonia
and COPD, 85 Stress, 19–20
diabetes and, 122, 123 as risk indicator, 15, 25, 174, 278 with financial strain, 20
Stroke, 76–78 Study designs, 12–14, 13 Substance dependency, 104 Sulfamethoxazole, 217 Sulfonamides, 208 Sulfonylurea, 138, 143 Supra-alveolar connective tissue, 3–4 Susceptibility, 48, 50 Syndrome X, 124, 125 Syphilis, tests for, 41 Systemic lupus erythematosus (SLE),
66
Teledyne Water Pik, 251–253 Temporomandibular disorders, 19 Tetracycline, 69, 136, 245–248
with contraceptives, 244, 281 contraindications for, 70, 246 dairy products and, 245 diabetics and, 26, 135 fibers (Actisite), 253–254, 281 in nephrosis, 208 photosensitivity, 281 prothrombin activity and, 281 side effects, 247 toxicities, 247
- Half Title Page
- Title Page
- Copyright Page
- Contributors
- Dedication
- Preface
- Contents
- Chapter 1: Periodontal Disease and Systemic Disease
- Chapter 2: Risk Factors for Periodontal Disease
- Chapter 3: Clinical History and Laboratory Tests
- Chapter 4: Role of Genetics in Assessment, Risk, and Management of Adult Periodontitis
- Chapter 5: Cardiovascular Diseases and Oral Infections
- Chapter 6: Relationships between Periodontal and Respiratory Diseases
- Chapter 7: Tobacco Use and Intervention
- Chapter 8: Diabetes Mellitus
- Chapter 9: Periodontal Medicine and the Female Patient
- Chapter 10: Osteopenia, Osteoporosis and Oral Disease
- Chapter 11: HIV Infection and Periodontal Diseases
- Chapter 12: Periodontal Disease and Periodontal Management in Patients with Cancer
- Chapter 13: Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants
- Chapter 14: Bleeding Disorders
- Chapter 15: Pharmacotherapy
- Chapter 16: Medicolegal Issues
- Index
