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Diseases of the Endocrine System

C H A P T E R

Learning Objectives

After studying this chapter, you should be able to

■ Describe the functions of the endocrine glands

■ Identify the hormones secreted from each endocrine gland and their normal functions

■ Describe the consequences of hyposecretion and hypersecretion of endocrine hormones on various glands and organs

■ Identify the endocrine functions of the pancreas

■ Identify the etiology, signs and symptoms, diagnostic tests, and treatment for type 1 and type 2 diabetes

■ Compare and contrast the consequences of type 1 and type 2 diabetes

■ Describe the acute and chronic complications of diabetes

■ Identify age-related changes in endocrine function

12 The number of patients with type 2 diabetes is expected to increase dramatically and strain the healthcare system worldwide.

Fact:The worldwide prevalence of DM has risen dramatically over the past two decades. The prevalence of type 2 DM is ex- pected to rise more rapidly in the future because of increasing obesity and reduced activity lev- els. The number of diabetic pa- tients will reach 300 million in 2025. More than 97% of these patients will have type 2 dia- betes. The projected increase in the number of diabetic patients will strain the capabilities of healthcare providers worldwide. (International Diabetes Federa- tion, 2001)

Fact or Fiction?

Photomicrograph of a pituitary adenoma. (© O.J. Staats/ Custom Medical Stock Photo.)

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Human Diseases: A Systemic Approach, Seventh Edition, by Mark Zelman, Ph.D., Elaine Tompary, PharmD, Jill Raymond, Ph.D., Paul Holdaway, MA, and Mary Lou Mulvihill, Ph.D. Published by Prentice Hall. Copyright © 2010 by Pearson Education, Inc.

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Diabetes

A ncient Hindu writings record distinctive signs of diabetes thousands of years ago: large volumes of urine, to which ants and flies were attracted; intense thirst; and a wasting of the body. No treatment or cure existed for this mysterious

ailment, which killed children and whose complications crippled sur- vivors. It was not until the late nineteenth century, when diabetes was observed in dogs whose pancreas had been removed experimen- tally, that the disease could be linked to a specific organ. The key component of the pancreas was eventually isolated and identified as the protein hormone insulin. Today, instead of treating patients with insulin extracted from dog pancreas, human insulin is synthesized using recombinant DNA technology. Early diagnosis, treatment, and effective management have lengthened and greatly improved the lives of diabetics. However, no cure for diabetes exists.

Disease Chronicle

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304 ■ Chapter Twelve Diseases of the Endocrine System

Introduction

The endocrine system is responsible for the pro- duction, storage, and secretion of hormones, which are chemical messengers that regulate vital human functions. The major organs of the endocrine system include the pituitary, thyroid, and parathyroid glands; pancreatic islets; adrenal glands; and gonads (Figure 12–1 �). En- docrine glands communicate with other organs via complex networks involving the central and peripheral nervous system, hormones, cytokines

▼ (or regulators of immune response), and growth factors. Endocrine hormones affect many as- pects of body functions, including growth, de- velopment, energy metabolism, muscle and fat distribution, sexual development, fluid and electrolyte balance, inflammation, and immune responses. Endocrine functions can be affected by anomalies in the primary gland responsible for producing a particular hormone, defects in circulating concentrations of stimulating hor- mones or releasing hormones, or anomalies in both the primary gland and the target or receiv- ing organ. The result of endocrine abnormalities

Hypothalamus of brain

Pituitary

Thyroid and parathyroid

Ovary

Testis

Island of Langerhans

Adrenal

Thymus

Figure 12–1 � The endocrine glands.

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Chapter Twelve Diseases of the Endocrine System ■ 305

is either hypofunction or hyperfunction of a gland, hormone, or a target organ.

Impaired function of an endocrine gland can occur for a variety of reasons. Congenital de- fects can result in the absence of or impaired development of the endocrine gland or affect en- zymes needed for hormone synthesis. The gland may be destroyed by ischemia or a disruption in blood flow, infection, inflammation, autoim- mune diseases, or neoplastic growth. There may be a decline in function with age, or the gland may atrophy as the result of drug therapy or for unknown reasons. Some endocrine-deficient states are associated with receptor defect. Hor- mone receptors may be absent, receptor binding may be impaired, or cellular responsiveness to endocrine hormones may be impaired.

Hormones are released from endocrine glands into the bloodstream, where they affect activity in cells at distant sites. Some hormones affect the whole body, and others act only on target or distant organs. Most hormones are composed of proteins or chains of amino acids; others are steroids or fatty substances derived from cholesterol.

Most glandular activity is controlled by the pituitary, which is sometimes called the master gland. The pituitary itself is controlled by the hypothalamus.

The body is conservative and secretes hor- mones only as needed. For example, insulin is se- creted when the blood sugar level rises. Another hormone, glucagon, works antagonistically to in- sulin and is released when the blood sugar level falls below normal. Hormones are potent chemi- cals, so their circulating levels must be carefully controlled. When the level of a hormone is ade- quate, its further release is stopped. This type of control is called a negative-feedback mechanism. Its importance becomes clearer as specific dis- eases of the endocrine system are considered.

Overactivity or underactivity of a gland is the malfunction that most commonly causes en- docrine diseases. If a gland secretes an exces- sive amount of its hormone, it is hyperactive. This condition is sometimes caused by a hyper- trophied gland or by a glandular tumor.

A gland that fails to secrete its hormone or se- cretes an inadequate amount is hypoactive. This condition may be caused by disease or tumor, or

it may be caused by trauma, surgery, or radia- tion. A gland that has decreased in size and con- sequently is secreting inadequately is said to be atrophied. Each endocrine gland is discussed, with an emphasis on normal function and impor- tance. The diseases caused by hypoactivity and hyperactivity of each gland are then explained.

Structure and Function of the Pituitary Gland

The pituitary gland is a pea-sized organ located at the base of the brain. The gland has an anterior lobe called the adenohypophysis and a posterior lobe called the neurohypophysis. A stalk called the infundibulum connects the pituitary gland to the floor of the hypothalamus. The pituitary gland is regulated by the hypothalamus and feedback- control mechanisms in relation to blood concen- trations of circulating hormones (Figure 12–2 �).

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Thalamus

Hypothalamus

Stalk

Pituitary

Midbrain

Hypothalamus

Hormones traveling on nerve fibers

Releasing factors from hypothalamus

Bony depression of skull bone (sella turcica)

Anterior pituitary (adenohypophysis)Posterior pituitary

(neurohypophysis)

Figure 12–2 � The pituitary gland.

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Growth of bone and soft tissue–GH

Thyroid–TSH

Adrenal cortex–ACTH

Testis–FSH, LH

Breast–prolactin

Ovary–FSH, LH

Figure 12–3 � Anterior pituitary and its target organs.

The anterior pituitary produces six major hormones: prolactin, growth hormone, adreno- corticotropic hormone (ACTH), luteinizing hor- mone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone. Each of these pituitary hormones elicits a response in target organs (Figure 12–3 �). The hormones of the posterior pituitary or neurohypophysis are produced in the hypothalamus. The neurohy- pophysis stores and releases two important hormones: antidiuretic hormone (ADH), also known as vasopressin, and oxytocin. Vaso- pressin stimulates the elevation of blood pres- sure by regulating the reabsorption of water in the kidney tubules. The target organ of oxytocin is the smooth muscle of the uterus, where it stimulates uterine contractions, and the mam- mary glands, where it stimulates milk letdown.

Table 12–1 � lists the hormones of pituitary gland, target organs, and primary effects.

Hormones of the Anterior Pituitary

Growth Hormone Growth hormone (GH; also called somatotropin) affects all parts of the body by promoting growth and development of the tissues. Before puberty, it stimulates the growth of long bones, increasing the child’s height. Soft tissues—organs such as the liver, heart, and kidneys—also increase in size and develop under the influence of growth hor- mone. After adolescence, growth hormone is se- creted in lesser amounts but continues to func- tion in promoting tissue replacement and repair.

Growth hormone secretion is controlled by complex interactions between the hypothala- mus and peripheral organs. Growth hormone releasing hormone is a hypothalamic hormone that stimulates growth hormone synthesis and release. Somatotropin release inhibiting factor (SRIF) is also synthesized in the hypothalamus and inhibits growth hormone secretion. Periph- eral hormones that regulate growth hormone include insulin-like growth factors, glucocorti- coids, and estrogen. Insulin-like growth factors and glucocoridoids feed back to the hypothala- mus to inhibit growth hormone, whereas estro- gen induces growth hormone release.

Thyroid Stimulating Hormone The thyroid gland regulates metabolism, the rate at which the body produces and uses en- ergy. The anterior pituitary controls secretion of thyroid hormone by the thyroid gland. The pitu- itary hormone that stimulates the thyroid gland is thyroid stimulating hormone (TSH; also called thyrotropin). In the absence of TSH, the thyroid gland stops functioning.

Adrenocorticotropic Hormone The anterior pituitary also regulates the adrenal glands. The adrenal glands have an inner part, the adrenal medulla, and an outer portion, the

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Table 12–1 � Hormones of Pituitary Gland, Target Organs, and Primary Effects

Hormone Target Organ Physiological Effects

Anterior Lobe

Follicle stimulating hormone (FSH)

Ovary In females: stimulates the growth of graffian follicles of the ovary and secretion of estradiol

Testes In males: stimulates the epithelium of the seminiferous tubules and subsequent spermatogenesis

Leutinizing hormone (LH)

Corpus luteum In females: stimulates the production of the corpus luteum from the follicle; stimulates production of progesterone by the ovaries

Interstitial cells of the testes

In males: stimulates production of testosterone

Prolactin Female mammary gland Stimulates milk production after birth

Growth hormone (somatotropin)

All body tissues Increases the synthesis of protein and promotes the growth of bone and tissues

Adrenocorticotropic hormone (ACTH)

Adrenal cortex, skin, liver, and mammary gland

Stimulates the production of corticosteriods; increases me- tabolism and glycogen storage in the liver; responsible for darkening of the skin and nails

Thyroid stimulating hormone

Thyroid gland Stimulates the production of the thyroid hormone

Posterior Lobe

Vasopressin or antidiuretic hormone (ADH)

Smooth muscle of the arte- rioles and the kidney tubules

Constricts blood vessels, increases blood pressure; stimulates reabsorption of water by the kidney

Oxytocin Uterus and the mammary glands

Stimulates contration of the uterus; secrtion of milk or “milk letdown” by the mammary glands

adrenal cortex. The cortex is controlled by the anterior pituitary. The adrenal cortex is stimu- lated by the anterior pituitary hormone, adrenocorticotropic hormone (ACTH).

Gonadotropins The anterior pituitary regulates sexual develop- ment and function by means of hormones known as the gonadotropins. These are not sex hormones, but they affect the sex organs, the gonads. They are follicle stimulating hormone (FSH), luteinizing hormone (LH), and prolactin.

These gonadotropins regulate the menstrual cycle and secretion of male and female hor- mones.

Diagnostic Procedures for Endocrine Diseases

Indications of pituitary hyperactivity or hypoac- tivity can be confirmed by serum assays. Growth hormone (GH) levels can detect hyperpi- tuitarism (gigantism and/or acromegaly) and

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hypopituitarism (dwarfism). Thyroid stimulat- ing hormone (TSH) assay is useful in confirming primary hypothyroidism or hyperthyroidism. Activity of the posterior pituitary can be evalu- ated by the water deprivation and vasopressin test. A urine specimen is taken after controlled water deprivation, and a blood sample is drawn. Dilute urine and high osmotic pressure in the blood indicate that water is not being absorbed by the kidney tubules. If vasopressin injection corrects the massive polyuria, diabetes in- sipidus is confirmed.

Diseases of the thyroid gland are diagnosed on the basis of the levels of the serum thyroid hormones, tri-iodothyronine (T3) and thyroxine (T4) and by the serum level of TSH. An elevated TSH indicates low T4 function. A low TSH indi- cates an excess of T4 caused by a functioning adenoma or carcinoma. A thyroid scan provides visualization of the thyroid gland after adminis- tration of radioactive iodine. It is usually recom- mended after discovery of a mass, an enlarged gland, or an asymmetric goiter. Thyroid ultra- sonography evaluates characteristics of thyroid nodules and distinguishes between solid or cys- tic masses in the gland.

Diagnostic tests for parathyroid gland activity measure parathyroid hormone and calcium lev- els in the blood and can detect hyperparathy- roidism.

Adrenal gland activity can be evaluated by the level of plasma cortisol from the adrenal cor- tex. Abnormal levels indicate hypersecretion (Cushing’s syndrome) or hyposecretion (Addi- son’s disease). Urine tests measure steroid level and detect hyperactivity of the gland.

A fasting blood glucose test helps detect dia- betes mellitus and evaluate the clinical status of diabetic patients. An oral glucose tolerance test challenges the ability of the pancreas to secrete insulin in response to large doses of glucose. A glycated hemoglobin test, also called “hemoglobin A1c,” is an important blood test that is used to determine how well diabetes is controlled. The test provides an average of blood glucose measurements over a 6- to 12- week period and is used in conjunction with a patient’s home blood glucose monitoring devices.

Diseases of the Anterior Pituitary

Anterior Pituitary Insufficiency Inherited disorders, malignant tumors, inade- quate secretion of hormones, inflammation, and vascular changes of the pituitary gland can re- sult in hypofunction or insufficiency of the pitu- itary gland. The manifestations of hypopituitar- sim depend on which hormones are lost and the extent of the hormone deficiency. Growth hor- mone deficiency causes growth disorders in children and leads to abnormal body composi- tion in adults. FSH and LH deficiency causes menstrual disorders, infertility, and decreased sexual function in women, and loss of sec- ondary sexual characteristics in males. TSH de- ficiency causes growth retardation in children and features of hypothyroidism in both adults and children. ACTH deficiency leads to de- creased production adrenal cortical hormones.

Pituitary Dwarfism Pituitary dwarfism results from a growth hor- mone deficiency. Growth retardation may be- come evident in infancy and persists through- out childhood. The child’s growth curve, which is usually plotted on a standardized growth chart, may range from flat, indicating no growth, to shallow, indicating minimal growth. Normal puberty may or may not occur, depend- ing on the degree to which the pituitary gland can produce sufficient hormone levels other than growth hormone.

There are approximately 7000 to 10,000 cases of pituitary dwarfism in the United States. Many cases are due to a tumor known as a craniopharyngioma. A rare form of this disease may be caused by an inherited autosomal reces- sive gene. Similar to pituitary insufficiency, pi- tuitary dwarfism may also be associated with deficiencies in all pituitary hormones.

Symptoms of this disorder include slowed growth before the age of 5 years, absent or de- layed sexual development, and short stature and height for age. Confirmation of the diagnosis is made by evaluation of blood pituitary hormone levels. Hand x-rays help determine bone age,

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Chapter Twelve Diseases of the Endocrine System ■ 309

and cranial x-rays are useful for identifying any abnormalities of the skull that may contribute to this condition. MRI scans provide detailed im- ages of the pituitary and the hypothalamus.

Replacement therapy with injections of growth hormone is currently used to treat chil- dren with pituitary dwarfism who have isolated growth hormone deficiency. In cases of pituitary insufficiency, other associated hormone deficits should be corrected, especially glucocorticoids, thyroid hormone, and sex steroids. Treatment regimens that mimic physiologic hormone pro- duction allow for maintenance of satisfactory growth and metabolic homeostasis.

Adult Growth Hormone Deficiency Adult growth hormone deficiency (AGHD) is a rare condition that is usually caused by damage to the pituitary gland or the hypothalamus. Adults at risk for AGHD are those with a history of pi- tuitary surgery, a previous tumor of the pitu- itary or hypothalamus, history of radiation to the head, and previously documented growth hormone deficiency in childhood.

Clinical features of AGHD include changes to body composition such as increased body fat, reduced exercise capacity, impaired heart func- tion, reduced muscle mass, abnormal lipid pro- file, and atherosclerosis. Patients usually expe- rience decreased energy and drive and a decreased ability to concentrate.

Radiographic imaging studies are used to di- agnose masses or structural damage to the pi- tuitary gland. Blood serum hormone concentra- tions of growth hormones are suppressed, and concomitant gonadotropin, thyroid hormone, and ACTH deficits may be present.

Replacement of growth hormone in AGHD is associated with body composition changes such as increased muscle mass and lower body fat. Women generally require higher doses of syn- thetic growth hormone than men.

Hyperpituitarism Gigantism Gigantism is a rare condition of growth hormone excess that occurs during childhood. Prior to closure of the epiphyseal

growth plate, excess growth hormone stimulates excessive linear growth. The most common cause of this disorder is a benign tumor of the pituitary gland.

The appearance of gigantism is usually dra- matic, as all growth parameters are affected and accelerated linear growth occurs. Facial fea- tures may thicken, and the hands and feet may be disproportionately large.

Treatment of gigantism depends on the etiol- ogy of growth hormone excess. In cases of well-defined tumors, surgical resection may be curative. Radiation therapy may be used in con- junction with surgery or in cases where surgery is not possible. Medications that reduce growth hormone secretion are also used for cases where surgery is not possible.

Acromegaly Acromegaly is a condition that re- sults from excess growth hormone secretion after growth plate fusion has occurred. Worldwide, acromegaly occurs at a rate of 2.4 to 4 cases per one million. The mean age at the time of diagno- sis is between 40 and 45 years.

The most common cause of acromegaly is a pituitary tumor. Other etiologies are excess re- lease of growth hormone releasing hormone caused by hypothalamic tumors, or excess growth hormone releasing hormone secretion by nonendocrine malignant tumors.

Acromegaly has an insidious onset, and symptoms are usually present for a number of years before a diagnosis is made. The disease is characterized by weight gain, growth of the soft tissues, and enlargement of the small bones of the hands, feet, face, and skull. Prominent fa- cial features include development of a bulbous nose, a protruding jaw, and slanted forehead, and changes in bite with difficulty chewing. Bony changes to the spine lead to kyphosis, or hunchback. Bone overgrowth eventually results in degenerative arthritis to the hip, knees, and spine.

The metabolic effects of acromegaly are nu- merous and life threatening. Excess growth hor- mone stimulates release of free fatty acid from fat tissue. Glucose intolerance and diabetes mellitus ensues, with changes in carbohydrate metabolism.

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H2O

Na+

Hypothalamus

Na+ Na+

Na+

Posterior pituitary Blood

Distal convoluted tubule

Collecting duct

Sensors of osmotic pressure (blood concentration)

ADH influences H2O reabsorption from distal convoluted tubules and collecting ducts

The treatment for acromegaly focuses on cor- recting metabolic abnormalities, improving ad- verse clinical features, and correcting the un- derlying cause. Surgical resection of tumors of the pituitary or hypothalamus is the treatment of choice. Medications that decrease growth hormone secretion may be administered prior to surgery or in cases where surgery is not possi- ble to shrink the tumor. Radiation is also used to shrink the tumor and is used when medica- tion therapy fails and in cases where surgery is not an option.

Hypofunction of the Posterior Pituitary

Diabetes Insipidus Decreased secretion or action of ADH results in the syndrome of diabetes insipidus. The leading symptom of diabetes insipidus is the production of abnormally large amounts of urine, or polyuria. The polyuria produces symptoms of urinary frequency, disturbed sleep due to bed-

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Figure 12–4 � Normal action of antidiuretic hormone.

wetting, and daytime fatigue. Excessive uri- nation is accompanied by extreme thirst and a corresponding increase in fluid intake, or polydipsia.

The most common cause of diabetes in- sipidus is destruction of the neurohypophysis due to unknown causes. Diabetes insipidus can also occur when ADH levels are normal. This condition, nephrogenic diabetes in- sipidus, involves a defect in the kidney tubule that interferes with the reabsorption of water. The kidney fails to concentrate urine in re- sponse to the instructions of ADH. Figure 12–4 � illustrates the normal action of the an- tidiuretic hormone; Figure 12–5 � illustrates the effects of ADH deficiency.

The diagnosis of diabetes insipidus is based on the patient’s history, physical examination, and results of urine tests. An MRI of the pitu- itary gland or the hypothalamus assists in identifying the etiological basis of the diabetes insipidus.

Treatment of diabetes insipidus is aimed at removing the primary cause and treating the symptoms to prevent dehydration. Central dia-

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H2O

Na+

Hypothalamus

Na+ Na+

Na+

Diseased or nonfunctioning posterior pituitary

Blood

Distal convoluted tubule

Copious volume of dilute urine

Collecting duct

Sensors of osmotic pressure (blood concentration)

No ADH and no reabsorption of water from distal convoluted tubules or collecting ducts

Figure 12–5 � Effect of antidiuretic hormone deficiency.

betes insipidus may be controlled with vaso- pressin. Vasopressin is administered as either a nasal spray or tablets. Vasopressin is ineffective for nephrogenic diabetes insipidus. Treatment of nephrogenic diabetes insipidus requires com- pensatory fluid intake with effort to correct the underlying etiology.

Structure and Function of the Thyroid Gland

The activity of the thyroid gland affects the whole body. It regulates the metabolic rate, the rate at which calories are used. The thyroid gland, through its hormone thyroxine, governs cellular oxygen consumption and thus energy and heat production. The more oxygen that is used, the more calories are metabolized (“burned up”). Thyroxine assures that enough body heat is produced to maintain normal tem- perature even in a cold environment.

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Structure of the Thyroid Gland The thyroid gland is located in the neck region, one lobe on either side of the trachea. A con- necting strip, or isthmus, anterior to the tra- chea connects the two lobes. The thyroid gland lies just below the Adam’s apple, the protrusion formed by part of the larynx (Figure 12–6 �). In- ternally, the thyroid gland consists of follicles, or microscopic sacs. Within these protein-con- taining follicles, the thyroid hormones thyroxin and tri-iodothyronine are stored. Thin-walled capillaries run between the follicles in a position ideal for receiving the thyroid hormones.

Function of the Thyroid Gland The thyroid gland synthesizes, stores, and re- leases thyroid hormones, which contain iodine. Most of the iodide ions of the body are taken into the thyroid gland by a mechanism called the iodide trap. Iodine combines with an amino acid, and the thyroid hormones are formed.

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Thyroid cartilage of larynx (“Adam’s apple”)

Thyroid gland

Capillaries Colloidal material (storage of hormone)

Site of hormone synthesis (follicular cells)

Isthmus

Trachea

Follicle

Figure 12–6 � The thyroid gland.

The hormones are stored in the thyroid gland until needed and then released into the blood capillaries. Tests to determine the activity of the thyroid gland are based on tri-iodothyro- nine (T3) and thyroxine (T4) levels in the plasma. In the T3 and T4 tests, a sample of the patient’s serum is incubated with radioactive thyroid hormones and resin. The resin absorbs the hormones that are not bound to the blood proteins. Radioactivity counts of the serum and resin are made, and the percentage of thyroid hormones absorbed by the resin is calculated. A low percentage of absorption indicates a poorly functioning thyroid gland. A high per- centage of absorption indicates hyperactivity. In the latter case, the patient’s own thyroid hor- mones have saturated the plasma proteins, and the excess radioactive hormones are absorbed by the resin.

Effects of Thyroid Hormones Although there is more than one thyroid hor- mone, for clarity the thyroid hormones are re- ferred to here as thyroxine, or T4, the hormone that is secreted in the largest quantity. Thyrox- ine stimulates cellular metabolism by increas- ing the rate of oxygen use with subsequent en- ergy and heat production.

Secretion of thyroxine leads to a compen- satory increase in cardiac output. Faster cellu- lar metabolism increases the cell’s demand for oxygen, so more oxygen must be circulated to the cells. Nutrients are converted to energy in the presence of oxygen, and the waste products of metabolism, including carbon dioxide, are formed. These must be carried away from the cells. The circulatory system can meet these needs by increasing blood flow to the cells. In- creased blood flow is obtained by greater car- diac output, or more heart activity.

As cellular metabolism increases, respiration increases. The greater need for oxygen and a corresponding accumulation of carbon dioxide stimulate the respiratory center of the brain. Stimulation of the respiratory center results in a faster rate and greater depth of breathing.

Thyroxine increases body temperature. Heat is produced through cellular metabolism, and thyroxine stimulates this process. In a cold en- vironment, thyroxine secretion increases to as- sure adequate body heat. If excessive body heat is produced, it is dissipated in two ways. Blood vessels of the skin dilate, increasing blood flow at the body surface and giving the body a flushed appearance. As the blood flows through the skin’s blood vessels, excess heat escapes. The body is also cooled by the perspiration

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THYROXINE

Stimulates gastrointestinal

activity

Stimulates heart activity

Increases respiration

Increases body

temperature

Increases cellular

metabolism

Figure 12–7 � Effects of thyroxine.

Thyroid gland

Blood vessels

Thyroxine

Releasing factor (hormone)

Thyroid-stimulating hormone

Anterior pituitary

HypothalamusStimulation

L o w

t h yr

o xi

n e le

ve l

H ig

h t h yr

o xi

n e le

ve l

Inhibition

Figure 12–8 � Control of thyroxine secretion through nega- tive feedback.

mechanism. Body temperature is controlled by a regulatory center in the brain.

Thyroxine also has a stimulatory effect on the gastrointestinal system. It increases the secre- tion of digestive juices and the movement of ma- terial through the digestive tract. Absorption of carbohydrates from the intestine is also in- creased under the influence of thyroxine, assur- ing adequate fuel for cellular metabolism. The effects of thyroxin are illustrated in Figure 12–7 �. Many symptoms of thyroid diseases can be related to the effects of inadequate or exces- sive thyroxine secretion.

Control of Circulating Thyroxine Level The anterior pituitary gland stimulates the thy- roid by releasing TSH. The thyroid, in turn, re- leases thyroxine, which circulates in the blood to all cells and tissues. When the level of circu- lating thyroxine is high, the anterior pituitary is inhibited and stops releasing TSH. This is an example of a negative-feedback mechanism. An adequate level of thyroxine prevents further synthesis of the hormone. When the level of thy- roxine falls, the anterior pituitary is released from the inhibition and once again sends out TSH. This feedback mechanism is shown in Figure 12–8 �.

At times, this control mechanism fails, con- stituting one basis for a thyroid disease. The

thyroid gland also functions abnormally if the body’s iodine supply is inadequate, if the gland is overstimulated or understimulated by the an- terior pituitary, or if the thyroid gland itself be- comes diseased. Some of these conditions are discussed in the following section.

Diseases of the Thyroid Gland

Hypothyroidism Hypothyroid, or thyroid hormone deficiency, may affect almost all body functions. The sever- ity of hypothyroidism ranges from mild and un- recognized symptoms to striking symptoms such as mental status changes, extreme and prolonged fatigue, weight gain, swelling or com- plaints of cold in the hands and feet, menstrual irregularities, muscle aches, and hair thinning.

The etiology of hypothyroid disease may be due to a primary disease in the thyroid gland or a lack of pituitary TSH. Primary hypothyroidism is the most common form of this condition and is generally caused by autoimmune disease, use of radioactive iodine, destruction or removal of the thyroid gland, dietary iodide deficiency, overtreatment with thyroid medications, and medical treatment for bipolar disorder with the

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drug lithium. Secondary hypothyroidism is caused by inadequate secretion of TSH caused by a disease of the pituitary gland.

Hypothyroid disease occurs more frequently in women. The average annual rate of autoim- mune hypothyroidism is up to 4 per 1000 women, and 1 per 1000 men. The average age at onset of hypothyroid is around 60 years, and the prevalence continues to increase with age.

The most severe form of hypothyroidism is myxedema coma. Myxedema is a medical emer- gency with a high mortality rate. It is caused by hypothyroidism, but is usually precipitated by an acute illness or trauma. Physical signs may include severe hypotension, unresponsiveness, bradycardia (slow heart rate), shallow and slow breathing, convulsions, extremely low body temperature, and decreased oxygen delivery to vital organs such as the brain.

Thyroid hormone replacement therapy is often required for the duration of the patient’s life. Regular blood tests to measure circulating levels of thyroxine are required to regulate the dose of thyroid replacement medication. Treat- ment of myxedema requires hospitalization and intensive administration of intravenous fluids, intravenous administration of thyroid hor- mone, warming, mechanical ventilation, and cardiac support.

Congenital Hypothyroidism Hypothyroid of the newborn, also known as cretinism, is most often the result of hypoplasia (underdevelopment), aplasia (absence), and fail- ure of the thyroid gland to migrate to its normal anatomical position. Maternal factors such as excessive iodine intake and ingestion of an- tithyroid medications during pregnancy can cause hypothyroidism in both the mother and the fetus.

Most newborns with congenital hypothy- roidism generally appear normal at birth and gain weight normally for the first three to four months of life. Symptoms that follow include physical and mental sluggishness, constipation, poor muscle tone, umbilical hernia and a pro- truding abdomen, hypothermia, bradycardia, and growth retardation. Physical growth retar- dation includes short stature, preservation of

infantile facial features, and delayed dental eruption. Severe impairment of intellectual de- velopment with retardation of brain develop- ment is a severe consequence of untreated con- genital hypothyroidism.

Congenital hypothyroidism is diagnosed by neonatal screening techniques usually within the first 10 days of birth. Adequate treatment with thyroid hormone supplementation started as soon as possible improves the prognosis of intellectual development and function later in life.

Hyperthyroidism Hyperthyroidism is a hypermetabolic condition of thyroid hormone excess. The symptoms of hyperthyroid range from mild increases in metabolic rate to severe hyperactivity. The term thyrotoxicosis refers to the clinical manifesta- tions and etiologies associated with excess sys- temic thyroid hormone.

Graves’ disease is the most common etiology of thyrotoxicosis. It is an autoimmune disease that is more common in women than in men. The onset of Graves’ disease is between the ages of 20 and 40 years, and it is often associated with other autoimmune diseases, such as diabetes mellitus. Thyrotoxicosis is also caused by high levels of hormones secreted during pregnancy, pituitary tumors with excess secretion of TSH, and ingestion of excessive amounts of thyroid hormone medication.

Symptoms of thyrotoxicosis include nervous- ness, restlessness, heat intolerance, increased sweating, fatigue, weakness, muscle cramps, and weight loss. Women frequently report men- strual irregularities. Cardiac manifestations of thyrotoxicosis include a rapid pounding heart beat, cardiac arrhythmias, and heart failure, es- pecially in older individuals with long-standing mild hyperthyroidism.

Treatment of hyperthyroid disease depends on the severity, etiology, and presence of com- plications. The goal of treatment is to bring the metabolic rate to normal with minimal compli- cations. Medications, radioactive iodine, and surgery are used to treat hyperthyroidism. Drugs that inhibit the formation of thyroid hor- mone are administered until thyroid function

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Figure 12–9 � Thyroid goiter. (Newscom)

returns to normal. If thyroid levels cannot be maintained, radiation or surgery may be per- formed. Medications that control heart rate and blood pressure are administered to prevent complications of thyrotoxicosis.

Thyroiditis Thyroiditis, or swelling of the thyroid gland, is associated with viral or bacterial infections, autoimmune disease, and aging. Subacute thy- roiditis affects younger females and is usually associated with a viral infection. Hashimoto’s thy- roiditis is an autoimmune disease characterized by infiltration of leukocyte and progressive de- struction of the thyroid gland.

Subacute thyroiditis commonly occurs in younger women and may or may not be associ- ated with hyperthyroidism. Symptoms of pain, swelling, and thyroid tenderness last weeks or months and then disappear. Symptomatic man- agement includes the use of anti-inflammatory and pain medications, observation, and treat- ment for severe symptoms of hyperthyroid.

Hashimoto’s thyroiditis, or a firm enlarge- ment or goiter of the thyroid gland, most often occurs in women around 40 to 50 years of age (Figure 12–9 �). The goiter is painless, although local symptoms may develop due to compres- sion of the esophagus, trachea, neck veins, or laryngeal nerves. The goiter disrupts the func- tion of the thyroid gland. Treatment of

Hashimoto’s thyroiditis is directed toward relief of compression symptoms by surgical removal of the goiter. Thyroid hormone supplementation is used if hypothyroid develops.

Structure and Function of the Adrenal Glands

The adrenal glands are located on top of each kidney. Each of the glands consists of two dis- tinct parts: an outer part (the adrenal cortex) and an inner section (the adrenal medulla). The cortex and medulla secrete different hormones. The adrenal cortex is stimulated by ACTH from the anterior pituitary gland. The adrenal glands are shown in Figure 12–10 �.

The adrenal cortex secretes many steroid hor- mones, which can be classified into three groups. One group, the mineralocorticoids, regu- lates salt balance. The principal hormone of this group is aldosterone. Aldosterone causes sodium retention and potassium secretion by the kid- neys. Another group, the glucocorticoids, helps regulate carbohydrate, lipid, and protein metab- olism. The principal hormone of this group is cortisol or hydrocortisone. The third group of hor- mones is sex hormones: androgens, the male hormones, and estrogens, the female hormones.

The adrenal medulla secretes epinephrine and norepinephrine. These hormones are secreted in stress situations when additional energy and strength are needed. Epinephrine causes va- sodilatation and increases heart rate, blood pressure, and respiration. Norepinephrine brings about general vasoconstriction. Together, epinephrine and norepinephrine help shunt blood to vital organs when required.

Hyperactivity of the adrenal cortex is usu- ally caused by hyperplasia (enlargement of the glands), a tumor. Hyperactivity may also re- sult from overstimulation by the anterior pitu- itary gland.

Hypoactivity of the adrenal cortex sometimes results from a destructive disease, such as tu- berculosis. Some steroid hormones can cause the adrenal glands to atrophy by interfering with the normal control mechanism for corti- costeroid release.

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Adrenal glands

Adrenal gland

Right kidney

Inferior vena cava Aorta

Left kidney

Medulla

Cortex

Figure 12–10 � The adrenal glands.

Diseases of the Adrenal Cortex

Hypoadrenalism Primary adrenal insufficiency, or Addison’s disease, was first described in 1855 when Thomas Addi- son described symptoms associated with de- struction of the adrenal glands. Addison’s dis- ease can result from any disease process that damages the entire adrenal cortex; however, approximately 75% to 80% of all cases are due to an autoimmune process. Other common causes of adrenal insufficiency include infec- tious diseases such as tuberculosis, fungal dis- ease, opportunistic infections associated with AIDS, certain cancers, and hemorrhage of the

▼ adrenal gland secondary to anticoagulation medication.

The prevalence of Addison’s disease is rare, oc- curring in approximately 1 in every 1000 people in the United States. It is more common in females, with a female to male ration of 2 : 1, and is usually diagnosed in the third to fifth decades of life.

The lack of cortisol, aldosterone, and adrenal androgens contribute to the symptoms of Addi- son’s disease. Weight loss, fatigue, and anorexia occur with a deficiency in cortisol. The most dis- tinctive sign is hyperpigmentation found in non- sun-exposed areas of the body such as the gin- gival and in the creases of the palms of the hands. Gastrointestinal symptoms include anorexia or loss of appetite, abdominal discom-

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fort, vomiting, and diarrhea. Fluid loss from these symptoms may contribute to low blood pressure or hypotension. Hypotension is often associated with dizziness, lack of blood sodium, and syncope, or fainting.

Diagnostic tests for Addison’s disease in- clude a 24-hour urine test for cortisol or blood tests for serum cortisol level. An ACTH stimula- tion test measures adrenal gland response to an intravenous dose of ACTH. An abnormal re- sponse to ACTH stimulation establishes adrenal insufficiency.

Addison’s disease can result in a life-threat- ening condition known as acute adrenal insuffi- ciency. It may occur in patients with chronic adrenal insufficiency in the setting of another acute illness such as infections, trauma, or se- vere physical stress such as surgery. Symptoms develop rapidly and include nausea, vomiting, abdominal pain, and severe hypotension. Death can result from shock and cardiovascular col- lapse. Immediate rehydration with salt solution along with intravenous glucocoricoid replace- ment are essential to prevent death.

The treatment of chronic adrenal insuffi- ciency includes life-long replacement of both glucorticoids and mineralocorticoids. During stress, patients may require additional medica-

tion as these patients are not able to increase endogenous cortisol production.

Hyperadrenalism Hyperadrenalism, or Cushing’s syndrome, refers to the manifestations of excessive corticos- teroids. The prevalence of Cushing’s syndrome is approximately 1 in every 500,000 people in the United States. The etiology of Cushing’s syn- drome is most often due to benign pituitary ade- nomas causing hypersecretion of ACTH with ex- cess stimulation of the adrenal glands. Other causes include nonpituitary neoplasm, such as small cell lung carcinoma that produce exces- sive amounts of ACTH, and adrenal tumors that cause excessive secretion of cortisol.

Excess cortisol secretion results in a number of metabolic abnormalities, including hyper- glycemia, hyperlipidemia, fluid retention, weight gain, weakness, fatigue, and hyperten- sion. Clinical signs of cortisol excess include central obesity, “moon face,” fat accumulation behind the shoulders (also known as a buffalo hump), impaired wound healing, loss of elastic tissues, thinning of the skin, and emotional distress, including depression and psychosis (Figure 12–11 �). Untreated Cushing’s syndrome

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Figure 12–11 � A patient with Cushing’s syndrome (A) before and (B) after receiving treatment. (Sharmyn McGraw)

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Parathyroid glands

Lobe of thyroid gland (posterior view)

Trachea

Aorta

Figure 12–12 � Parathyroid glands.

can produce serious morbidity and even death. The patient may suffer from complications of hypertension or diabetes or from susceptibility to infections.

Laboratory test for Cushing’s syndrome in- clude blood tests for diabetes, electrolyte abnor- malities, and signs of infection. Urine tests pro- vide evidence for diabetes and excess cortisol. Radiographic tests, including MRI and CT scans, provide evidence for pituitary tumors or other tumors in the chest or abdomen that may be the source of excess ACTH.

The goal of treatment for Cushing’s syn- drome is to correct hypersecretion of adrenal hormones. Removal of pituitary tumors is ac- complished through microsurgery or radiation therapy. Medications are administered to treat symptoms of diabetes, hypertension, hyperlipi- demia, psychosis, and depression. Medications that block the synthesis of corticosteroids are useful in patients for whom surgery is not appropriate.

Diseases of the Adrenal Medulla

Pheochromocytoma Pheochromocytoma is a rare epinephrine- and norepinephrine-producing tumor that occurs equally in men and women in the fourth and fifth decades of life. Most pheochromocytomas (85% to 90%) are located in the adrenal medulla.

Excess release of epinephrine and norepi- nephrine is responsible for the signs and symp- toms of this disease. The most common clinical sign is hypertension. Headache, excessive sweating, and palpitations are the most com- mon symptoms. Some patients may also suffer from anxiety, constipation, low energy level, and exhaustion.

Pheochromocytomas are diagnosed by bio- chemical evidence in both blood and urine of overproduction of epinephrine and norepineph- rine. Imaging studies such as CT or MRI scan are essential for detection and localization of this tumor.

Surgery provides an effective cure by remov- ing the tumor. Medication therapy is used to

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stabilize blood pressure and to treat associated symptoms. Often various combinations of med- ications are necessary to stabilize the patient’s blood pressure.

Structure and Function of the Parathyroids

Structure of the Parathyroids The parathyroids are four tiny glands located on the posterior side of the thyroid gland. Before the function of the parathyroid glands was un- derstood, they were sometimes removed with a thyroidectomy. The hormone secreted by the parathyroids is parathormone, also called parathyroid hormone (Figure 12–12 �).

Function of the Parathyroids The parathyroid glands are extremely important in regulating the level of circulating calcium and phosphate. Ninety-nine percent of the body’s calcium is in bone, but the remaining 1% has many important functions. Calcium is essential to the blood-clotting mechanism. It increases the tone of heart muscle and plays a significant role in muscle contraction.

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There is a constant exchange of calcium and phosphate between bone and the blood. Two kinds of cells are at work within bone: osteo- blasts, which form bone tissue, and osteoclasts, which resorb salts out of bone, dissolving them. These salts are then released into the blood. The balance between these two processes, os- teoblastic and osteoclastic, is governed by the parathyroid hormone.

When the blood calcium level falls, parathor- mone is secreted. The hormone acts at three distinct sites to raise the blood level of calcium to normal. Parathormone increases the amount of calcium that is absorbed out of the digestive tract by interaction with ingested vit- amin D. It prevents a loss of calcium through the kidneys and releases calcium from bones by stimulating osteoclastic activity. When the proper level of circulating calcium is restored, parathormone is no longer released. An excess or a deficiency of calcium can have disastrous results. These conditions are usually the result of hyperactivity or hypoactivity of the parathy- roid glands.

Diseases of the Parathyroid Gland

Hyperparathyroidism Hyperparathyroidism, or excessive secretion of parathyroid hormone, is often caused by benign parathyroid tumors. The size of the tumor often correlates with the amount of parathyroid hor- mone secreted into the blood. Hyperparathy- roidism occurs most frequently in persons over the age of 50 years and is more common in women than in men.

Excessive parathormone raises the level of circulating calcium above normal, a condition called hypercalcemia. Much of the calcium comes from bone resorption mediated by parathor- mone. As the calcium level rises, the phosphate level falls.

With the loss of calcium, the bones are weak- ened. They tend to bend, become deformed, and fracture spontaneously. Giant cell tumors and cysts of the bone sometimes develop. Excessive

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calcium causes formation of kidney stones be- cause calcium forms insoluble compounds. Cal- cium deposited within the walls of the blood vessels makes them hard. Calcium may also be found in the stomach and lungs.

Hyperparathyroidism, with its concurrent ex- cess of calcium, causes generalized symptoms. There may be pain in the bones that is some- times confused with arthritis. The nervous sys- tem is depressed, and muscles lose their tone and weaken. Heart muscle is affected, and the pulse slows. Symptoms include gastrointestinal disturbances, abdominal pain, vomiting, and constipation. These symptoms result from de- posits of calcium in the mucosa of the gastroin- testinal tract. Deposits of calcium sometimes form in the eye, causing irritation and excessive tearing. Hyperparathyroidism usually results from a tumor. If the tumor is removed, para- thormone secretion returns to normal, and the level of circulating calcium is again properly controlled. See Box 12–1 � for complications of hyperparathyroidism.

The most common laboratory findings in pa- tients with hyperparathyroidism are elevated levels of blood serum calcium and excessive loss of phosphate in the urine. Imaging studies are used to locate the parathyroid tumor(s) and to guide surgical resection.

Medical treatment of hyperparathyroidism is aimed at lowering serum calcium level. This is accomplished through medication and intra- venous hydration therapy. Medications called biphosphanates are potent inhibitors of bone resorption and can temporarily treat the hy- percalcemia. Surgical resection is recom- mended for patients with severe chronic and recurrent symptoms.

Box 12–1 � Complications of Hyperparathyroidism: Hypercalcemia

• Kidney stone formation • Calcification of blood vessel walls • Calcification of organ walls • Spontaneous fractures

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Figure 12–13 � Tetany of the hand in hypoparathyroidism.

Hypoparathyroidism Hypoparathyroidism is mostly a transient con- dition that commonly occurs in patients follow- ing surgical resection of the thyroid gland. Parathyroid deficiency can also be the result of damage from heavy metals such as copper or iron, or it can result from immune disorders and infections.

The principal manifestation of hypoparathy- roidism is tetany, a sustained muscular con- traction. In hypoparathyroidism, the muscles of the hands and feet contract in a characteristic fashion. The typical tetanic contraction of the hand is seen in Figure 12–13 �. Symptoms of chronic disease include lethargy, personality changes, anxiety, blurred vision and trembling of the limbs.

Common laboratory findings include low serum calcium, high serum phosphate levels, and low urine calcium. Imaging studies may show excessive calcification of bone and in- creased bone mineral density.

Acute hypoparathyroid tetany is a medical emergency that occurs after surgery and re- quires immediate treatment. Emergency re- placement of calcium, magnesium, and vitamin

D is used to maintain blood calcium in the ap- propriate range.

Endocrine Function of the Pancreas

The pancreas is a long organ that lies across the middle of the abdominal cavity, below the stomach. It is divided into a head, body, and tail, with the head nearest to the duodenum and the opening of the pancreatic duct. (See page 221 in Chapter 9.) The pancreas carries out two types of functions: exocrine and en- docrine. Most of the pancreas is devoted to ex- ocrine secretion of digestive enzymes; the cells providing the endocrine function of the pan- creas make up a smaller part. The endocrine functions of the pancreas consist of synthesis, storage, and release of two hormones, insulin and glucagon.

Insulin is secreted by certain cells of the pan- creas called beta cells, located in patches of tis- sue named the islets of Langerhans or pancreatic islets. Glucagon is secreted by the alpha cells of the islets. Insulin and glucagon work antagonis- tically to each other. Insulin lowers the level of blood glucose, and glucagon elevates it. The combined effect of these hormones maintains the normal level of blood glucose.

Insulin is secreted when the blood glucose level rises. Insulin facilitates the entry of glu- cose into the cells, where it is primarily stored as glycogen and metabolized for energy. Glucose enters primarily skeletal muscle cells and fat cells.

As glucose enters cells and is converted to glycogen by the liver, the level of blood glucose falls. The normal level of glucose in the blood is about 90 mg/100 mL (or 90 mg/dL) of blood. This is also expressed as 90 mg percent.

When the level of blood glucose falls below normal, glucagon is released. Glucagon circu- lates to the liver and stimulates the release of glucose from its stored form, glycogen. This raises the level of blood glucose to normal. The control of glucose is illustrated in Figure 12–14 �.

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HIGH BLOOD GLUCOSE LOW BLOOD GLUCOSE

Alpha cells

Glucagon

Blood glucose raised

Liver releases glucose from glycogen

Beta cells

Insulin

Glucose enters cells

Blood glucose lowered

Hyposecretion of the Pancreas

Diabetes Mellitus (Hyperglycemia) Diabetes mellitus (DM) is an endocrine disease of impaired glucose regulation and hyper- glycemia caused by complex interactions of ge- netics, environmental factors, and lifestyle choices. Depending on the underlying etiology of DM, factors contributing to hyperglycemia may include an absolute insulin deficiency, re- duction in insulin secretion, decreased glucose utilization, and increased glucose production.

DM is classified on the basis of the underly- ing pathology that leads to hyperglycemia. The two broad categories of DM are designated as type 1 and type 2. Type 1 diabetes is character- ized by an absolute insulin deficiency and often results from autoimmune destruction of the in- sulin-producing beta cells of the pancreas. Type 2 diabetes often develops later in life and is associated with variable degrees of insulin re- sistance, impaired insulin secretion, and in- creased glucose production, and is associated with obesity. Diabetes may develop during pregnancy, a condition called gestational dia- betes. Resistance to the effects of insulin is re- lated to the metabolic changes of pregnancy

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Figure 12–14 � Control of blood glucose level.

associated with increased requirements for insulin.

Approximately 6.3% of the U.S. population, or 18.2 million people, is estimated to have dia- betes. Type 1 diabetes accounts for approxi- mately 5% to 10% of cases; type 2 diabetes ac- counts for 90% to 95% of diabetic cases. Gestational diabetes occurs in approximately 4% of pregnancies annually in the United States. Most women revert to normal glucose tolerance following pregnancy but continue to have a considerable risk for developing diabetes later in life.

Type 1 Diabetes Type 1 diabetes mellitus (T1DM) is characterized by total or near total absence of in- sulin production. This type of diabetes has also been referred to as “juvenile-onset diabetes,” as the peak incidence of this disease is between the ages of 10 to 14 years. Patients with T1DM re- quire continuous insulin supplementation and glucose monitoring to sustain life.

T1DM occurs when an autoimmune process develops in individuals who are genetically sus- ceptible and exposed to some unknown environ- mental trigger. In T1DM, the immune system at- tacks and destroys beta cells. This destruction typically occurs over several months, although it may be more rapid or last for years. Once 80% or more of beta cell function is destroyed, pa- tients no longer have sufficient insulin capacity to control blood glucose, so they develop the hy- perglycemia of diabetes. Eventually, patients lose the ability to produce insulin and depend on insulin injections to survive. Because type 1 diabetics cannot produce insulin, they are sus- ceptible to severe metabolic derangements such as diabetic ketoacidosis (DKA).

Symptoms of T1DM include polyuria, or ex- cessive urination, polydipsia, or excessive thirst; and polyphagia, or excessive hunger and weight loss. Because of water’s movement by concen- tration gradients, water is lost through the kid- neys as glucose concentrations rise. To compen- sate for fluid loss, patients develop extreme thirst. Although blood glucose levels are high, the body’s tissues are unable to take up the glu- cose and use it effectively as an energy source

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due to the lack of insulin. Patients develop ex- treme hunger in the presence of hyperglycemia, leading to excessive eating with a paradoxical weight loss. Patients experience rapid weight loss despite increased food intake.

As T1DM progresses without treatment, al- ternative metabolic pathways are stimulated, causing depletion of protein and fat stores. Me- tabolism of fat produces molecules called ketones. During starvation, ketones serve as an alternative energy source; however, in T1DM these molecules accumulate to dangerous lev- els due to excessive fat metabolism. Diabetic ketoacidosis results when ketone buildup is associated with blood glucose levels greater than 250 mg/dL. Diabetic ketoacidosis can lead to coma and death if not treated immedi- ately as a medical emergency. See the discus- sion of DKA in the section “Complications of Diabetes Mellitus.”

Type 2 Diabetes Unlike T1DM, type 2 diabetes (T2DM) is not associated with destruction of pan- creatic beta cells. T2DM results from defects in insulin secretion by the pancreas and insulin uti- lization in target tissues. Insulin resistance oc- curs when the tissues’ normal response to in- sulin is impaired. This insulin resistance leads to increased insulin secretion by the beta cells, with eventual insulin decline or insulin deficiency relative to blood glucose levels.

Insulin resistance can be induced by hor- mones such as cortisol, growth hormone, and epinephrine, or target tissue defects. Insulin re- ceptor defects include disruption of glucose transport by free fatty acid accumulation com- mon in obesity. Glucotoxicity, or high levels of blood glucose, results in structural and func- tional damage to the beta cells, reducing the ability of the beta cells to secrete sufficient in- sulin in response to glucose.

Type 2 diabetics retain some insulin-produc- ing capacity. The primary defects leading to T2DM are insulin resistance in liver, muscle, and fat cells and reduced insulin secretion by the pancreas, and increased glucose production by the liver. Obesity contributes to insulin resis- tance, and weight reduction may help improve insulin resistance and lower blood glucose in obese patients. As T2DM progresses, insulin

levels eventually decrease due to the inability of the pancreas to continue producing large amounts of insulin.

Risk factors for the development of T2DM in- clude a family history of diabetes, older age, obesity, history of gestational diabetes, seden- tary lifestyle, and history of high blood pressure and high cholesterol, or hyperlipidemia.

Treatment of T2DM includes diet and weight management and oral medications, and insulin for patients who cannot control their diabetes with diet and oral medications. Oral medica- tions increase insulin release from the beta cells, improve insulin utilization, and decrease insulin resistance. Patients often require more than one oral medication to control their dia- betes, and some progress to lifelong insulin injections.

Complications of Diabetes Mellitus Acute complications of diabetes are related to excessive hyperglycemia and include DKA and hyperosmolar hyperglycemic state (HHS). DKA occurs in patients with T1DM, whereas HHS is a rare complication of T2DM.

DKA can be the initial presenting problem in a newly diagnosed patient with T1DM. More commonly, DKA is caused by acute illnesses such as the flu or common cold or physical and emotional stress. During stress, the production of stress hormones such as epinephrine and norepinephrine inhibits insulin action and stim- ulates glucose production. Without adequate amounts of insulin, the body continues to break down all forms of stored energy to glucose. Eventually the liver uses fatty acids to produce ketone bodies. As ketone bodies accumulate, the blood becomes acidic. Symptoms of DKA in- clude nausea, vomiting, polyuria, polydipsia, dehydration, mental status changes, and rapid breathing. DKA treatment includes continuous intravenous infusions of fluids, electrolytes, and insulin until the ketosisis is reversed and the acidity is corrected.

Hyperosmolar hyperglycemic state typically occurs in older, debilitated type 2 diabetic pa- tients. Similar to DKA, HHS is associated with acute stress from infections, medical illnesses, or surgery. Because T2DM patients have some

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insulin function, ketone body formation is pre- vented; however, patients often present with hy- perglycemia in the range of 250 mg/dL to 400 mg/dL. Treatment of HHS is aimed at rehydra- tion and correction of hyperglycemia and elec- trolyte disturbances. Aggressive intravenous fluid and electrolyte replacement is necessary as patients can lose up to 10 liters, or 2.5 gal- lons, of fluid within a short period of time. Ad- ministration of intravenous insulin is essential to improve glucose utilization and correct the hyperglycemia.

Chronic complications of diabetes are due to chronic pathological insults to the microvascu- lature, or small blood vessels, and to the macrovasculature, or large vessels. Microvascu- lar disease occurs primarily in the eyes, kid- neys, and nerves. Hyperglycemia damages the endothelial cell lining of blood vessels, resulting in progressive narrowing and occlusion of large and small vessels. Cells die when vessel occlu- sion cuts off blood supply. Macrovascular dam- age leads to cardiovascular disease, the leading cause of death in patients with diabetes.

Microvascular disease of diabetes includes retinopathy, nephropathy, and neuropathy. Di- abetic retinopathy is the leading cause of blindness among adults aged 20 to 74 years. Diabetic nephropathy occurs in approximately 20% to 30% of patients with diabetes and is the leading cause of end-stage kidney disease. About 60% to 70% of patients with diabetes

have nerve damage or neuropathy. Typical symptoms of neuropathy include numbness or tingling in the hands and feet and or severe, burning muscle aches. The loss of sensation in the feet and poor circulation can lead to severe infections requiring amputations. More than 60% of nontraumatic limb amputations in the United States occur annually in people with diabetes.

Macrovascular disease includes the develop- ment of coronary vascular disease, peripheral vascular disease, and stroke. Death rates due to heart disease are two to four times higher for adults with diabetes compared to persons with- out diabetes; stroke is two to four times more likely. Approximately 75% to 80% of patients with diabetes die due to the complications of cardiovascular disease. Treatment of the under- lying factors that lead to cardiovascular disease is essential for the long-term health of patients with diabetes. The National Diabetes Education Program (NDEP) and the American Diabetes As- sociation have developed an education and treatment program called the ABCs of Diabetes Management. Research has shown that reduc- ing blood glucose as measured by blood levels of hemoglobin A1C (A), blood pressure (B), and cholesterol (C) levels reduces morbidity and mortality from cardiovascular disease in pa- tients with diabetes.

See Table 12–2 � for warning signs of type 1 and type 2 diabetes.

Table 12–2 � Warning Signs of Diabetes

Type 1 or Insulin-Dependent Diabetes Mellitus Type 2 or Non-Insulin-Dependent Diabetes Mellitus

Frequent urination Any of the Type 1 symptoms

Excessive thirst Frequent infections

Extreme hunger Recurring skin, gum, or bladder infections

Weight loss Blurred vision

Fatigue Cuts and bruises that heal slowly

Irritability Numbness or tingling sensations in the hands or feet

Source: American Diabetes Association website: www.diabetes.org/risk-test.jsp. Accessed August 25, 2008.

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Source: http://www.mypyramid.gov/kids/index.html

Obese Children and Type II Diabetes The number of overweight children is increasing in the United States. Obese children are at increased risk of developing Type 2 diabetes mellitus as young adults. They also have an increased lifetime risk for heart disease and cancer. These chronic diseases are largely preventable through proper diet, weight control, and adequate exercise appropriate for age; see the MyPyramid for Kids diagram below.

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Prevention PLUS!

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Tests for Diabetes Mellitus A simple urine test can show the presence or absence of glucose or ketones in the urine. Urine tests are helpful for initial screening and for those who are prone to ketoacidosis. Fasting blood glucose levels, glucose tolerance testing, and glycosylated hemoglobin testing are used to monitor and diagnose diabetes. For the fasting blood glucose level test, a sample of blood is taken after the person has fasted for 8 hours. The glucose tolerance test challenges the body’s ability to secrete and use insulin. The test is performed after a 10-hour fast. The patient drinks a standard glucose solution, and blood and urine sample are taken and analyzed for the next three hours. No glucose should appear in the urine, and the blood glucose levels should not exceed 170 mg/dL of blood if insulin is being produced and utilized. Glycosylated he- moglobin determination is a simple blood test that is used to monitor long-term control of dia- betes. It generally indicates the average blood glucose levels over the past 90 days. Normal val- ues should be below 6, and levels for diabetics should be less than 7.

Education of the Diabetic Patient The American Diabetes Association, physi- cians, nurses, and dieticians have made a great effort to assist the diabetic patient in leading a normal life. The diabetic who under- stands the disease knows the importance of weight control, diet, exercise, and either in- sulin or oral agents in leading a normal life. A safety precaution advised by the American Dia-

betes Association is that anyone who takes in- sulin carry an identification card explaining the emergency treatment required if an insulin reaction occurs.

Abnormalities in Secretion of Sex Hormones

The gonads (ovaries and testes) are endocrine glands as well as the source of the ova and sperm. They secrete the hormones estrogen and testosterone directly into the blood.

Hypergonadism (Hypersecretion) Abnormally increased functional activity of the gonads before puberty produces precocious sex- ual development in both sexes. In a male child, excessive production of testosterone may be caused by a tumor in the testes. This causes rapid growth of musculature and bones but pre- mature uniting of the epiphyses and shaft of long bones. Normal height, therefore, is not at- tained. Hypersecretion of ovarian hormones in the female is rare because negative-feedback stimulation of gonadotropic hormones stops ovarian hormone secretion.

Hypogonadism in the Male Several factors can cause hypogonadism, or de- creased functional activity of the gonads. A per- son may be born without functional testes, the testes may fail to descend and thus may atro- phy, or the testes may be lost through castration.

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Prevention PLUS! Diabetes Control Can control of blood sugar prevent complications of diabetes? Nearly three-fourths of adults with diabetes lack basic in- formation that can help control their disease. Studies have shown that better control of diabetes helps prevent serious complications that may develop over time.

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Testes fail to develop because of lack of go- nadotropic hormone.

Loss of the male gonads before puberty causes the condition of eunuchism, in which sexual characteristics do not develop. Develop- ment of male traits depends on testosterone se- creted by the testes. Castration after puberty causes some regression of secondary sexual characteristics, but masculinity is retained. Hormonal therapy, the administration of testos- terone, can be effective.

Hypogonadism in the Female Hyposecretion of hormones by the ovaries may be caused by poorly formed or missing ovaries. When ovaries are absent or fail to develop, fe- male eunichism results. Secondary sexual characteristics do not develop. A characteristic of this condition is excessive growth of long bones because the epiphyses do not seal with the shaft of the bone, as normally occurs at adolescence.

Age-Related Diseases

Some changes in endocrine function occur nor- mally with aging. Of these, none are significant causes of disease. However, some changes make the aging person more susceptible to disease.

Growth hormone level decreases with age. This is manifested in men after age 30 as a de- crease in lean body mass and decreases in thickness and strength of bone matrix. As the body fat level increases, the growth hormone level decreases further. Increased body fat is correlated with greater risk of diabetes, heart disease, and cancer. Decreased bone density makes bones more susceptible to fracture.

A slight decrease in T3 : T4 ratio is seen with age, resulting in decreased metabolic rate. The incidence of autoimmune disease of the thyroid among females increases with age.

Although aldosterone levels remain relatively steady, an age-related decline in the kidneys’

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sensitivity to aldosterone occurs, accompanied by a diminishing capacity of the kidneys to se- crete renin when needed. The body is less able to deal with the stress of changes in blood pressure, dehydration, and disease in general. There is an increased incidence of abnor- malities in blood pressure, sodium and potas- sium levels, acid-base balances, and osmotic pressure.

The pancreas retains the ability to secrete in- sulin at normal levels with age, but tissue re- sponsiveness to insulin decreases. Insulin re- sistance leads to a greater incidence of T2DM. It is estimated that T2DM occurs in 10% of those over age 56, 20% of those between 45 and 76, and 40% of people over age 85. Although T1DM

is somewhat less common than T2DM and its occurrence is unrelated to aging, it remains among the 10 leading causes of death among people over age 65.

Androgen and estrogen levels drop with age, although this is considered a normal process of aging.

R E S O U R C E S

American Diabetes Association, Diabetes Facts and Figures: www.diabetes.org/diabetes-statistics.jsp

National Diabetes Information Clearinghouse (NDIC): www.diabetes.niddk.nih.gov

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DISEASE AT A GLANCE Endocrine System

DISEASE ETIOLOGY SIGNS AND SYMPTOMS

Pituitary dwarfism GH hyposecretion beginning in childhood due to pituitary damage or ischemia

Normal mental development, slow growth, sexual development lacking

Adult growth hormone deficiency

Damage to the pituitary or hypothalamus Increased body fat, reduced exercise capacity, impaired heart function, reduced muscle mass and abnormal lipid profile

Gigantism GH hypersecretion beginning in childhood due to adenoma of anterior pituitary

Bone length increases rapidly, delayed sexual development

Acromegaly GH hypersecretion beginning in adulthood due to adenoma of anterior pituitary

Enlargement of feet, hands, face as bones grow in diameter; soft tissue growth; nose, lips, lower jaw protrude; tongue and skin thicken

Diabetes insipidus Central: hyposecretion of ADH by hypothalamic nuclei due to vascular lesion, neoplasm, trauma to base of skull, or inherited abnormality on chromosome 20 Nephrogenic: kidney insensitive to ADH due to X-linked gene or due to polycystic disease or pyelonephritis

Polyuria, polydipsia

Hyperprolactinemia Pregnancy, stress, infections, liver disease Hypogonadism, and reduced fertility

Hypothyroidism Primary disease of the thyroid gland, autoimmune disease, radioactive iodine, dietary iodine deficiency, lithium

Hypotension, weakness, fatigue, weight gain, complaints of cold in hands and feet

Congenital hypothyroidism Excessive maternal iodine intake during pregnanacy Physical and mental sluggishness, poor muscle tone, umbilical hernia, protruding abdomen, bradycardia, and growth retardation

Thyrotoxicosis Autoimmune, pituitary tumors, pregnancy Nervousness, restlessness, heat intolerance, increased sweating, fatigue, weakness, muscle cramps, and weight loss

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DIAGNOSIS TREATMENT PREVENTION LIFESPAN

Serum assay for GH Hormone replacement therapy

Unknown Diagnosed in childhood and persists though ones life

X-ray, serum assay for GH Hormone replacement therapy

Unknown Occurs in adults

Serum assay for GH None Unknown Diagnosed in childhood, persists for life

Serum assay for GH None Unknown Occurs in adults

Urinalysis in water deprivation vasopressin test

Administer ADH Unknown Can occur at any age

Serum assay for prolactin Treatment of the underlying cause

Unknown More common in women of child bearing years

Serum assay for thyroxine, and TSH

Thyroid hormone replacement

Prevention of iodine deficiency by consumption of iodized table salt

Can occur at any age

Serum assay for thyroxine and TSH

Thyroid hormone replacement

Unknown Diagnosed in infancy

Serum assay for thyroxine and TSH

Radioactive iodine, surgery to remove tumors, radiation

Unknown Usually diagnosed in adulthood, though can occur at any age

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DISEASES AT A GLANCE Endocrine System (continued)

DISEASE ETIOLOGY SIGNS AND SYMPTOMS

Thyroiditis Autoimmune, or viral infection Pain, swelling, thyroid tenderness, goiter

Addison’s disease Damage to the adrenal cortex, infections, opportunistic infections associated with AIDS, cancer, hemorrhage of the adrenal gland

Weight loss, fatigue, anorexia, abdominal discomfort, vomiting, diarrhea

Cushing’s syndrome Benign pituitary adenomas Hyperglycemia, hyperlipidemia, fluid retention, weight gain, weakness, fatigue, hypertension

Pheochromocytoma Tumor Hypertension

Hyperparathyroidism Neoplasm Weak bones deform and fracture easily, kidney stones, pain in bones, depressed nervous system, weak muscles, slow heart rate, abdominal pain, vomiting, constipation

Hypoparathyroidism Complication of thyroidectomy; also rare X-linked syndrome

Overexcited muscular and nervous system, characteristic tetany in hands, laryngeal spasm

Type 1 diabetes mellitus Autoimmune destruction of the beta cells of the pancreas

Polyuria, polydipsia, polyphagia, weight loss

Type 2 diabetes mellitus Obesity, hypertension, hyperlipidemia Polyuria, polydipsia,

Hypergonadism Hypersecretion of sex hormones caused by tumors Precocious sexual development

Hypogonadism Hyposecretion of sex hormones caused by undeveloped gonads

Lack of sexual development, eunuchism

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DIAGNOSIS TREATMENT PREVENTION LIFESPAN

Swelling and pain in neck region of thyroid gland

Anti-inflammatory medications, pain medications

Unknown Can occur at any age

24-hour urine assay for cortisol

Replacement of glucocorticoids and mineralocorticoids

Unknown Can occur at any age, though more common in adults

Serum assay for diabetes, electrolyte disturbance, x-rays to diagnose tumor

Surgery, radiation, medications to treat hypertension, diabetes, and hyperlipidemia

Unknown Occurs in adults

X-ray, CT scan, MRI Antihypertensive medication Unknown Occurs mostly in adults

High serum calcium, patient history, kidney stones

Surgical removal of tumor, medication to lower calcium

Unknown Can occur at any age, though mostly diagnosed in adults

Low serum calcium, patient history

Administer vitamin D and calcium

Unknown Can occur at any age, though mostly diagnosed in adults

Serum assay for glucose, hemoglobin A1C

Insulin Unknown Can occur at any age, though mostly diagnosed prior to the age of 20 years

Serum assay for glucose, hemoglobin A1C

Weight loss, exercise, oral antidiabetic medication, insulin

Control of weight, healthy eating, exercise

Diagnosed in adulthood

Serum sex hormones Administration of sex hormones

Unknown Can occur at any age

Serum sex hormones Administration of sex hormones

Unknown Can occur at any age

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7. Which gland secretes epinephrine and norepinephrine?

a. pancreas b. parathyroid c. testes d. adrenal

8. A deficiency in corticosteroids is associated with ____________________.

a. Addison’s disease b. Conn’s disease c. diabetes insipidus d. pheochromocytoma

9. An absolute insulin deficiency is characteristic of ____________________.

a. type 1 diabetes b. gestational diabetes c. type 2 diabetes d. all of the above

10. Iodine is required for the body to make ____________________.

a. bone b. insulin c. thyroxine d. glucose

1. Acromegaly results from hyperactivity of the ____________________.

a. thyroid b. parathyroid c. anterior pituitary d. posterior pituitary

2. Which hormone increases the blood calcium level?

a. glucagon b. parathormone c. androgen d. insulin

3. Hypoglycemia is a sign in ____________________.

a. Cushing’s disease b. Addison’s disease c. diabetes d. Graves’ disease

4. The trunk is obese in ____________________.

a. Graves’ disease b. Cushing’s disease c. Addison’s disease d. Conn’s disease

5. A deficiency of ADH is the cause of ____________________.

a. IDDM b. NIDDM c. diabetes insipidus d. ketoacidosis

6. Which of these is associated with hypersecretion of thyroxine?

a. Graves’ disease b. gigantism c. cretinism d. myxedema

1. A mother brings her 5-year-old son to the pediatrician with complaints that her son has been wetting the bed consis- tently. The child has a good appetite, drinks a lot of water, and has a high metabolism, according to the mother. On ex- amination, the doctor notes that the child has lost 10 pounds since his last physical 6 months ago. What diseases should be ruled out?

2. A 59-year-old woman reports to the doctor’s office with a chief complaint of terrible headaches, especially between her eyes. Her blood pressure, blood sugar, and cholesterol

332 ■ Chapter Twelve Diseases of the Endocrine System

level are high. The doctor also notes a terrible bruise on her leg that was there since her last examination 2 months ago. What diseases should be ruled out?

3. A 45-year-old man reports to the emergency room with ter- rible dehydration. He has a yellowish appearance and can hardly stand without assistance. His blood level of potas- sium is extremely high and his legs feel tingly. His heartbeat is very rapid, and his breathing is shallow. What diseases might this man have?

Interactive Exercises

Cases for Critical Thinking

Multiple Choice

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True or False

_______ 1. Kidney stones are likely to form in hypoparathyroidism.

_______ 2. Hypercalcemia causes tetany.

_______ 3. Glucagon prevents hyperglycemia.

_______ 4. Steroids that suppress the inflammatory response, as in arthritis, are produced by the thyroid.

_______ 5. Hypertension accompanies Addison’s disease.

_______ 6. Myxedema results from thyrotoxicosis.

_______ 7. A person with Graves’ disease is very sensitive to cold.

_______ 8. Dehydration can develop in diabetes mellitus.

_______ 9. Cushing’s syndrome results from an excess of glucocorticoids.

_______ 10. Glucagon elevates blood glucose level.

Fill-Ins

1. Overproduction of growth hormone before puberty is called ____________________.

2. An overproduction of growth hormone after puberty is called ____________________.

3. The posterior pituitary secretes ____________________ and ____________________.

4. Microvascular disease is a chronic complication of ____________________.

5. A tumor of the adrenal medulla, or ____________________, causes overproduction of epinephrine and norepinephrine.

6. Insulin is secreted by cells of the pancreas called ____________________ ____________________.

7. Elevated blood levels of calcium are associated with excess ____________________ hormone.

8. Tropic hormones are secreted by the ____________________ ____________________.

9. Dwarfism is associated with hyposecretion of ____________________ ____________________.

10. Sexual characteristics do not develop in the rare condition called ____________________ ____________________.

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334 ■ Chapter Twelve Diseases of the Endocrine System

Labeling Exercise

Use the blank lines below to label the following image.

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Multimedia Preview

Additional interactive resources and activities for this chapter can be found on the Companion Web- site. For videos, audio glossary, and review, access the accompanying DVD-ROM in this book.

DVD-ROM Highlights▼

Strikeout Click on the alphabet tiles to fill in the empty squares in the word or phrase to complete the sentence. This game quizzes your vocabulary and spelling. But choose your letters carefully because three strikes means you’re out!

Labeling Exercise A picture is worth a thousand words, but only if it’s labeled correctly. Review anatomy by clicking and dragging the terms that cor- relate to a figure from this chapter. The cor- rect labels will lock into place beside the picture.

Audio Glossary Take advantage of the free-access online study guide that accompanies your textbook. You’ll find an audio glossary with definitions and audio pronunciations for every term in the book. By clicking on this URL you’ll also access a variety of quizzes with instant feedback and links to current news articles.

Website Highlights—www.pearsonhighered.com/zelman▼

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