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  • 1. 1155Chapter 24 - The Endocrine System Anirban Maitra MBBS Abul K. Abbas MBBS Chapter 24 - The Endocrine System Pituitary Gland Normal Pathology Clinical Manifestations of Pituitary Disease Pituitary Adenomas and Hyperpituitarism Morphology. Clinical Course. PROLACTINOMAS GROWTH HORMONE (SOMATOTROPH CELL) ADENOMAS CORTICOTROPH CELL ADENOMAS OTHER ANTERIOR PITUITARY ADENOMAS Hypopituitarism Posterior Pituitary Syndromes Hypothalamic Suprasellar Tumors Morphology. Thyroid Gland Normal Pathology Hyperthyroidism Clinical Course. Hypothyroidism CRETINISM MYXEDEMA Thyroiditis HASHIMOTO THYROIDITIS Pathogenesis. Morphology. Clinical Course. SUBACUTE (GRANULOMATOUS) THYROIDITIS Pathogenesis. Morphology. Clinical Course. SUBACUTE LYMPHOCYTIC (PAINLESS) THYROIDITIS Morphology. Clinical Course.

2. Graves Disease Pathogenesis. Morphology. Clinical Course. Diffuse and Multinodular Goiters DIFFUSE NONTOXIC (SIMPLE) GOITER Morphology. Clinical Course. MULTINODULAR GOITER Morphology. Clinical Course. Neoplasms of the Thyroid ADENOMAS Pathogenesis. Morphology. Clinical Features. OTHER BENIGN TUMORS CARCINOMAS Pathogenesis Genetic Factors. Follicular Thyroid Carcinomas. Papillary Thyroid Carcinomas. Medullary Thyroid Carcinomas. Anaplastic Carcinomas. Environmental Factors. Papillary Carcinoma Morphology. Clinical Course. Follicular Carcinoma Morphology. Clinical Course. Medullary Carcinoma Morphology. Clinical Course. Anaplastic Carcinoma Morphology. Clinical Course. Congenital Anomalies Parathyroid Glands Normal Pathology Hyperparathyroidism PRIMARY HYPERPARATHYROIDISM Morphology. Clinical Course. Asymptomatic Hyperparathyroidism. 3. Symptomatic Primary Hyperparathyroidism. SECONDARY HYPERPARATHYROIDISM Morphology. Clinical Course. Hypoparathyroidism Pseudohypoparathyroidism The Endocrine Pancreas Normal Pathology Diabetes Mellitus DIAGNOSIS CLASSIFICATION NORMAL INSULIN PHYSIOLOGY Regulation of Insulin Release Insulin Action and Insulin Signaling Pathways PATHOGENESIS OF TYPE 1 DIABETES MELLITUS Mechanisms of Cell Destruction Genetic Susceptibility The MHC Locus. Non-MHC Genes. Environmental Factors PATHOGENESIS OF TYPE 2 DIABETES MELLITUS Insulin Resistance Genetic Defects of the Insulin Receptor and Insulin Signaling Pathway. Obesity and Insulin Resistance. -Cell Dysfunction MONOGENIC FORMS OF DIABETES Maturity-Onset Diabetes of the Young (MODY). Mitochondrial Diabetes. Diabetes Associated with Insulin Gene or Insulin Receptor Mutations. PATHOGENESIS OF THE COMPLICATIONS OF DIABETES Formation of Advanced Glycation End Products. Activation of Protein Kinase C. Intracellular Hyperglycemia with Disturbances in Polyol Pathways. MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS Morphology. 4. Pancreas. Diabetic Macrovascular Disease. Diabetic Microangiopathy. Diabetic Nephropathy. Diabetic Ocular Complications. Diabetic Neuropathy. CLINICAL FEATURES OF DIABETES Pancreatic Endocrine Neoplasms HYPERINSULINISM (INSULINOMA) Morphology. ZOLLINGER-ELLISON SYNDROME(GASTRINOMAS) Morphology. OTHER RARE PANCREATIC ENDOCRINENEOPLASMS Adrenal Glands Adrenal Cortex Normal Pathology ADRENOCORTICAL HYPERFUNCTION(HYPERADRENALISM) Hypercortisolism (Cushing Syndrome) Pathogenesis. Morphology. Clinical Course. Primary Hyperaldosteronism Morphology. Clinical Course. Adrenogenital Syndromes 21-Hydroxylase Deficiency. Morphology. Clinical Course. ADRENAL INSUFFICIENCY Primary Acute Adrenocortical Insufficiency Waterhouse-Friderichsen Syndrome Primary Chronic Adrenocortical Insufficiency (Addison Disease) Pathogenesis. Morphology. Clinical Course. Secondary Adrenocortical Insufficiency Morphology. ADRENOCORTICAL NEOPLASMS Morphology. OTHER LESIONS OF THE ADRENAL Adrenal Medulla 5. Normal Pathology PHEOCHROMOCYTOMA Morphology. Clinical Course. TUMORS OF EXTRA-ADRENALPARAGANGLIA NEUROBLASTOMA Multiple Endocrine Neoplasia Syndromes MULTIPLE ENDOCRINE NEOPLASIA, TYPE 1 MULTIPLE ENDOCRINE NEOPLASIA, TYPE 2 Pineal Gland Normal Pathology PINEALOMAS Morphology. 1156 The endocrine system contains a highly integrated and widely distributed group of organs that orchestrates a state of metabolic equilibrium, or homeostasis, among the various organs of the body. Signaling by extracellular secreted molecules can be classified into three typesautocrine, paracrine, or endocrineon the basis of the distance over which the signal acts. In endocrine signaling, the secreted molecules, which are frequently called hormones, act on target cells that are distant from their site of synthesis. An endocrine hormone is frequently carried by the blood from its site of release to its target. Increased activity of the target tissue often down-regulates the activity of the gland that secretes the stimulating hormone, a process known as feedback inhibition.Hormones can be classified into several broad categories on the basis of the nature of their receptors. Cellular receptors and signaling pathways were discussed in Chapter 3 , and only a few comments about signaling by hormone receptors follow: Hormones that trigger biochemical signals upon interacting with cell-surfacereceptors: This large class of compounds is composed of two groups: (1) peptidehormones, such as growth hormone and insulin, and (2) small molecules, such asepinephrine. Binding of these hormones to cell-surface receptors leads to anincrease in intracellular signaling molecules, termed second messengers, such ascyclic adenosine monophosphate (cAMP); production of mediators frommembrane phospholipids, such as inositol 1,4,5-trisphosphate or IP3 ; and shifts inthe intracellular levels of ionized calcium. The elevated levels of one or more ofthese can control proliferation, differentiation, survival, and functional activity ofcells, mainly by regulating the expression of specific genes. Hormones that diffuse across the plasma membrane and interact withintracellular receptors: Many lipid-soluble hormones diffuse across the plasma 6. membrane and interact with receptors in the cytosol or the nucleus. The resulting hormone-receptor complexes bind specifically to recognition elements in DNA, thereby affecting the expression of specific target genes. Hormones of this type include the steroids (e.g., estrogen, progesterone, and glucocorticoids), and thyroxine.A number of processes can disturb the normal activity of the endocrine system, including impaired synthesis or release of hormones, abnormal interactions between hormones and their target tissues, and abnormal responses of target organs. Endocrine diseases can be generally classified as (1) diseases of underproduction or overproduction of hormones and their resulting biochemical and clinical consequences and (2) diseases associated with the development of mass lesions. Such lesions might be nonfunctional, or they might be associated with overproduction or underproduction of hormones. The study of endocrine diseases requires integration of morphologic findings with biochemical measurements of the levels of hormones, their regulators, and other metabolites.Pituitary GlandNormalThe pituitary is a small bean-shaped organ that measures about 1 cm in greatest diameter and weighs about 0.5 gm, although it enlarges during pregnancy. Its small size belies its great functional significance. It is located at the base of the brain, where it lies nestled within the confines of the sella turcica in close proximity to the optic chiasm and the cavernous sinuses. The pituitary is attached to the hypothalamus by the pituitary stalk, which passes out of the sella through an opening in the dura mater surrounding the brain. Along with the hypothalamus, the pituitary gland plays a critical role in1157 Figure 24-1 Hormones released by the anterior pituitary. The adenohypophysis (anterior pituitary) releases five hormones that are in turn under the control of various stimulatory and inhibitory hypothalamic releasing factors. TSH, thyroid-stimulating hormone (thyrotropin); PRL, prolactin; ACTH, adrenocorticotrophic hormone (corticotropin); GH, growth hormone (somatotropin); FSH, follicle- 7. stimulating hormone; LH, luteinizing hormone. The stimulatory releasing factors are TRH (thyrotropin- releasing factor), CRH (corticotropin-releasing factor), GHRH (growth hormone-releasing factor), GnRH (gonadotropin-releasing factor). The inhibitory hypothalamic influences are comprised of PIF (prolactin inhibitory factor or dopamine) and growth hormone inhibitory factor (GIH or somatostatin).the regulation of most of the other endocrine glands. The pituitary is composed of two morphologically and functionally distinct components: The anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis).The anterior pituitary, or adenohypophysis, constitutes about 80% of the gland. It is derived embryologically from Rathke pouch, which is an extension of the developing oral cavity. It is eventually cut off from its origins by the growth of the sphenoid bone, which creates a saddle-like depression, the sella turcica. The anterior pituitary has a portal vascular system that is the conduit for the transport of hypothalamic releasing hormones from the hypothalamus to the pituitary. Hypothalamic neurons have terminals in the median eminence where the hormones are released into the portal system, from where they traverse the pituitary stalk and enter the anterior pituitary gland. The production of most pituitary hormones is controlled predominantly by positive-acting releasing factors from the hypothalamus ( Fig. 24-1 ). Prolactin is the major exception, since its primary hypothalamic control is inhibitory, through the action of dopamine, while pituitary Figure 24-2 A, Photomicrograph of normal pituitary. The gland is populated by several distinct cell populations containing a variety of stimulating (trophic) hormones. B, Each of the hormones has different staining characteristics, resulting in a mixture of cell types in routine histologic preparations. Immunostain for human growth hormone.growth hormone receives both stimulatory and inhibitory influences via the hypothalamus. In routine histologic sections of the anterior pituitary, a colorful array of cells is present that contain eosinophilic cytoplasm (acidophil), basophilic cytoplasm (basophil), or poorly staining cytoplasm (chromophobe) cells ( Fig. 24-2 ). Specific antibodies against the pituitary hormones identify five cell types: 8. 1. Somatotrophs, producing growth hormone (GH): These acidophilic cells constitute half of all the hormone-producing cells in the anterior pituitary.2. Lactotrophs (mammotrophs), producing prolactin: These acidophilic cells secrete prolactin, which is essential for lactation.3. Corticotrophs: These basophilic cells produce adrenocorticotropic hormone (ACTH), pro-opiomelanocortin (POMC), melanocyte-stimulating hormone (MSH), endorphins, and lipotropin.4. Thyrotrophs: These pale basophilic cells produce thyroid-stimulating hormone (TSH). 11585. Gonadotrophs: These basophilic cells produce both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates the formation of graafian follicles in the ovary, and LH induces ovulation and the formation of corpora lutea in the ovary.The posterior pituitary, or neurohypophysis, consists of modified glial cells (termed pituicytes) and axonal processes extending from nerve cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus, through the pituitary stalk to the posterior lobe. These neurons produce two peptide hormones, anti-diuretic hormone (ADH, also called vasopressin) and oxytocin. The hormones are stored in axon terminals in the posterior pituitary and are released into the circulation in response to appropriate stimuli. Oxytocin stimulates contraction of the smooth muscle cells in the gravid uterus and cells surrounding the lactiferous ducts of the mammary glands. ADH is a nonapeptide hormone synthesized predominantly in the supraoptic nucleus. In response to a number of different stimuli, including increased plasma osmotic pressure, left atrial distention, exercise, and certain emotional states, ADH is released from the axon terminals in the neurohypophysis into the general circulation. The posterior pituitary is derived embryologically from an outpouching of the floor of the third ventricle, which grows downward alongside the anterior lobe. In contrast to the anterior lobe, the posterior lobe of the pituitary is supplied by an artery and drains into a vein, where its hormones are released directly into the systemic circulation. Thus, the pituitary has a dual circulation, composed of arteries and veins and a portal venous system linking the hypothalamus and the anterior lobe. Pathology Clinical Manifestations of Pituitary DiseaseThe manifestations of pituitary disorders are as follows: 9. Hyperpituitarism: Arising from excess secretion of trophic hormones. Thecauses of hyperpituitarism include pituitary adenoma, hyperplasia and carcinomasof the anterior pituitary, secretion of hormones by nonpituitary tumors, andcertain hypothalamic disorders. The symptoms of hyperpituitarism are discussedin the context of individual tumors below. Hypopituitarism: Arising from deficiency of trophic hormones. This may becaused by destructive processes, including ischemic injury, surgery or radiation,and inflammatory reactions. In addition, nonfunctional pituitary adenomas mayencroach upon and destroy adjacent normal anterior pituitary parenchyma andcause hypopituitarism. Local mass effects: Among the earliest changes referable to mass effect areradiographic abnormalities of the sella turcica, including sellar expansion, bonyerosion, and disruption of the diaphragma sella. Because of the close proximity ofthe optic nerves and chiasm to the sella, expanding pituitary lesions oftencompress decussating fibers in the optic chiasm. This gives rise to visual fieldabnormalities, classically in the form of defects in the lateral (temporal) visualfields, so-called bitemporal hemianopsia. In addition, a variety of other visualfield abnormalities may be caused by asymmetric growth of many tumors. Likeany expanding intracranial mass, pituitary adenomas can produce signs andsymptoms of elevated intracranial pressure, including headache, nausea, andvomiting. On occasion, acute hemorrhage into an adenoma is associated withclinical evidence of rapid enlargement of the lesion, a situation appropriatelytermed pituitary apoplexy. Acute pituitary apoplexy is a neurosurgical emergency,since it can cause sudden death (see below). Diseases of the posterior pituitary often come to clinical attention because ofincreased or decreased secretion of one of its products, ADH. Pituitary Adenomas and HyperpituitarismThe most common cause of hyperpituitarism is an adenoma arising in the anterior lobe. Other, less common, causes include hyperplasia and carcinomas of the anterior pituitary, secretion of hormones by some extrapituitary tumors, and certain hypothalamic disorders. Pituitary adenomas can be functional (i.e., associated with hormone excess and clinical manifestations thereof) or silent (i.e., immunohistochemical and/or ultrastructural demonstration of hormone production at the tissue level only, without clinical symptoms of hormone excess). Both functional and silent pituitary adenomas are usually composed of a single cell type and produce a single predominant hormone, although exceptions are known to occur. Pituitary adenomas are classified on the basis of hormone(s) produced by the neoplastic cells detected by immunohistochemical stains performed on tissue sections ( Table 24-1 ). Some pituitary adenomas can secrete two hormones (GH and prolactin being the most common combination), and rarely, pituitary adenomas are plurihormonal. Finally, pituitary adenomas may be hormone-negative, based on absence of immunohistochemical reactivity and ultrastructural TABLE 24-1 -- Classification of Pituitary Adenomas 10. Prolactin cell (lactotroph) adenoma Growth hormone cell (somatotroph) adenoma Densely granulated GH cell adenoma Sparsely granulated GH cell adenoma with fibrous bodies Thyroid-stimulating hormone cell (thyrotroph) adenomas ACTH cell (corticotroph) adenomas Gonadotroph cell adenomas Silent gonadotroph adenomas include most so-called null cell and oncocytic adenomas Mixed growth hormone-prolactin cell (mammosomatotroph) adenomas Other plurihormonal adenomas Hormone-negative adenomas ACTH, adrenocorticotropic hormone.1159 demonstration of lineage-specific differentiation. Both silent and hormone-negative pituitary adenomas may cause hypopituitarism as they encroach on and destroy adjacent anterior pituitary parenchyma.Clinically diagnosed pituitary adenomas are responsible for about 10% of intracranial neoplasms; they are discovered incidentally in up to 25% of routine autopsies. In fact, using high-resolution computed tomography or magnetic resonance imaging suggest that approximately 20% of "normal" adult pituitary glands harbor an incidental lesion measuring 3 mm or more in diameter, usually a silent adenoma. Pituitary adenomas are [1] usually found in adults, with a peak incidence from the thirties to the fifties. Most pituitary adenomas occur as isolated lesions. In about 3% of cases, however, adenomas are associated with multiple endocrine neoplasia (MEN) type 1 (discussed later). Pituitary adenomas are designated, somewhat arbitrarily, microadenomas if they are less than 1 cm in diameter and macroadenomas if they exceed 1 cm in diameter. Silent and hormone- negative adenomas are likely to come to clinical attention at a later stage than those associated with endocrine abnormalities and are therefore more likely to be macroadenomas.With recent advances in molecular techniques, substantial insight has been gained into the genetic abnormalities associated with pituitary adenomas: [2] 11. The great majority of pituitary adenomas are monoclonal in origin, even those that are plurihormonal, suggesting that most arise from a single somatic cell. Some plurihormonal tumors may arise from clonal expansion of primitive stem cells, which then differentiate in several directions simultaneously. G-protein mutations are possibly the best-characterized molecular abnormalities in pituitary adenomas. G-proteins are described in Chapter 3 ; here we will review their function in the context of endocrine neoplasms. G-proteins play a critical role in signal transduction, transmitting signals from cell-surface receptors (e.g., GHRH receptor) to intracellular effectors (e.g., adenyl cyclase), which then generate second messengers (e.g., cyclic AMP, cAMP). These are heterotrimeric proteins, composed of a specific -subunit that binds guanine nucleotide and interacts with both cell surface receptors and intracellular effectors ( Fig. 24-3 ); the - and -subunits are noncovalently bound to the specific -subunit. Gs is a stimulatory G-protein that has a pivotal role in signal transduction in several endocrine organs, including the pituitary. The -subunit of Gs (Gs ) is encoded by the GNAS1 gene, located on chromosome 20q13. In the basal state, Gs exists as an inactive protein, with GDP bound to the guanine nucleotide-binding site of the - subunit of Gs . On interaction with the ligand-bound cell-surface receptor, GDP dissociates, and GTP binds to Gs , activating the G-protein. The activation of Gs results in the generation of cAMP, which acts as a potent mitogenic stimulus for a variety of endocrine cell types (such as pituitary somatotrophs and corticotrophs, thyroid follicular cells, parathyroid cells), promoting cellular proliferation and hormone synthesis and secretion. The activation of Gs , and resultant generation of cAMP, are transient because of an intrinsic GTPase activity in the -subunit, which hydrolyzes GTP into GDP. A mutation in the - subunit that interferes with its intrinsic GTPase activity will therefore result in constitutive activation of Gs , persistent generation of cAMP, and unchecked cellular proliferation ( Fig. 24-3 ). Approximately 40% of somatotroph cell adenomas bear GNAS1 mutations that abrogate the GTPase activity of Gs . The mutant form of GNAS1 is also known as the gsp oncogene because of its effects on tumorigenesis. In addition, GNAS1 mutations have also been described in a minority of corticotroph adenomas; in contrast, GNAS1 mutations are absent in thyrotroph, lactotroph, and gonadotroph adenomas, since their respective hypothalamic release hormones do not mediate their action via cAMP-dependent pathways. Multiple endocrine neoplasia (MEN) syndrome (discussed in detail below) is a familial disorder associated with tumors and hyperplasias of multiple endocrine organs, including the pituitary. A subtype of MEN syndrome, known as MEN-1, is caused by germ line mutations of the gene MEN1, on chromosome 11q13. While MEN1 mutations are, by definition, present in pituitary adenomas arising in context of the MEN-1 syndrome, they are uncommon in sporadic pituitary adenomas. Additional molecular abnormalities present in aggressive or advanced pituitary adenomas include activating mutations of the RAS oncogene and overexpression of the c-MYC oncogene, suggesting that these genetic events are linked to disease progression.[3] 12. Figure 24-3 The mechanism of G-protein mutations in endocrine neoplasia. Mutations in the G-protein- signaling pathway are seen in a variety of endocrine neoplasms, including pituitary, thyroid, and parathyroid adenomas. G-proteins play a critical role in signal transduction, transmitting signals from cell- surface receptors (GHRH, TSH, or PTH receptor) to intracellular effectors (e.g., adenyl cyclase), which then generate second messengers (cAMP).1160 Morphology. The common pituitary adenoma is a soft, well-circumscribed lesion that may be confined to the sella turcica. Larger lesions typically extend superiorly through the diaphragm sella into the suprasellar region, where they often compress the optic chiasm and adjacent structures, such as some of the cranial nerves ( Fig. 24-4 ). As these adenomas expand, they frequently erode the sella turcica and anterior clinoid processes. They may also extend locally into the cavernous and sphenoid sinuses. In up to 30% of cases, the adenomas are not grossly encapsulated and infiltrate adjacent bone, dura, and (rarely) brain, but they do not demonstrate the ability for distant metastasis. Such lesions are 13. termed invasive adenomas. Foci of hemorrhage and necrosis are common in larger adenomas.Histologically, pituitary adenomas are composed of relatively uniform, polygonal cells arrayed in sheets or cords. Supporting connective tissue, or reticulin, is sparse, accounting for the soft, gelatinous consistency of many of these lesions. The nuclei of the neoplastic cells may be uniform or pleomorphic. Mitotic activity is usually modest. The cytoplasm of the constituent cells may be acidophilic, basophilic, or chromophobic, depending on the type and amount of secretory product within the cells, but it is generally uniform throughout the cytoplasm. This cellular monomorphism and the absence of a significant reticulin network distinguish pituitary adenomas from nonneoplastic anterior pituitary parenchyma ( Fig. 24-5 ). The functional status of the adenoma cannot be reliably predicted from its histologic appearance. Clinical Course. The signs and symptoms of pituitary adenomas include endocrine abnormalities and mass effects. The abnormalities associated with the secretion of excessive quantities of anterior pituitary hormones are mentioned below, when we describe the specific types of pituitary adenoma. Local mass effects may be encountered in any type of pituitary tumor and have been discussed previously under clinical manifestations of pituitary disease. Briefly, these include radiographic abnormalities of the sella turcica, visual Figure 24-4 Pituitary adenoma. This massive, nonfunctional adenoma has grown far beyond the confines of the sella turcica and has distorted the overlying brain. Nonfunctional adenomas tend to be larger at the time of diagnosis than those that secrete a hormone. 14. Figure 24-5 Pituitary adenoma. The monomorphism of these cells contrasts markedly with the mixture of cells seen in the normal anterior pituitary. Note also the absence of reticulin network.field abnormalities, signs and symptoms of elevated intracranial pressure, and occasionally hypopituitarism. Acute hemorrhage into an adenoma is sometimes associated with pituitary apoplexy, as was noted previously.With this general introduction to pituitary adenomas, we proceed to a discussion of the individual types of tumors. PROLACTINOMAS Prolactinomas (lactotroph adenomas) are the most frequent type of hyperfunctioning pituitary adenoma, accounting for about 30% of all clinically recognized pituitary adenomas. These lesions range from small microadenomas to large, expansile tumors associated with substantial mass effect. Microscopically, the overwhelming majority of prolactinomas are composed of weakly acidophilic or chromophobic cells (sparsely granulated prolactinoma); rare prolactinomas are strongly acidophilic (densely granulated prolactinoma) ( Fig. 24-6 ). Prolactin can be demonstrated within the secretory granules in the cytoplasm of the cells using immunohistochemical approaches. Prolactinomas have a propensity to undergo dystrophic calcification, ranging from isolated psammoma bodies to extensive calcification of virtually the entire tumor mass ("pituitary stone"). Prolactin secretion by functioning adenomas is characterized by its efficiencyeven microadenomas secrete sufficient prolactin to cause hyperprolactinemia and by its proportionality, in that serum prolactin concentrations tend to correlate with the size of the adenoma.Increased serum levels of prolactin, or prolactinemia, cause amenorrhea, galactorrhea, loss of libido, and infertility. The diagnosis of an adenoma is made more readily in women than in men, especially between the ages of 20 and 40 years, presumably because of the sensitivity of menses to disruption by hyperprolactinemia. This tumor underlies almost a quarter of cases of amenorrhea. In contrast, in men and older women, the 15. hormonal manifestations may be subtle, allowing the tumors to reach considerable size (macroadenomas) before being detected clinically.Hyperprolactinemia may result from causes other than prolactin-secreting pituitary adenomas. Physiologic hyperprolactinemia occurs in pregnancy; serum prolactin levels1161 Figure 24-6 Ultrastructural features of prolactinomas. A, Electron micrograph of a sparsely granulated prolactinoma. The tumor cells contain abundant granular endoplasmic reticulum (indicative of active protein synthesis) and small numbers of secretory granules (6000X). B, Electron micrograph of densely granulated growth hormone-secreting adenoma. The tumor cells are filled with large, membrane-bound secretory granules (6000X). (Courtesy of Dr. Eva Horvath, St. Michael's Hospital, Toronto, Ontario, Canada.)increase throughout pregnancy, reaching a peak at delivery. Prolactin levels are also elevated by nipple stimulation, as occurs during suckling in lactating women, and as a response to many types of stress. Pathologic hyperprolactinemia can also result from lactotroph hyperplasia, such as when there is interference with normal dopamine inhibition of prolactin secretion. This may occur as a result of damage to the dopaminergic neurons of the hypothalamus, pituitary stalk section (e.g., owing to head trauma), or drugs that block dopamine receptors on lactotroph cells. Any mass in the suprasellar compartment may disturb the normal inhibitory influence of the hypothalamus on prolactin secretion, resulting in hyperprolactinemia, a phenomenon called the stalk effect. Therefore, a mild elevation in serum prolactin in a patient with a pituitary adenoma does not necessarily indicate a prolactin-secreting tumor. Several classes of drugs can cause hyperprolactinemia, including dopamine receptor antagonists such as the neuroleptic drugs (phenothiazines, haloperidol) and older antihypertensive drugs, such as reserpine, which inhibit dopamine storage. Other causes of hyperprolactinemia include estrogens, renal failure, and hypothyroidism. Prolactinomas are treated by surgery or, more commonly, with bromocriptine, a dopamine receptor agonist, which causes the lesions to diminish in size. 16. GROWTH HORMONE (SOMATOTROPH CELL) ADENOMAS GH-secreting tumors are the second most common type of functioning pituitary adenoma. As we have mentioned, 40% of somatotroph cell adenomas express a mutant GTPase- deficient -subunit of the G-protein, Gs . Somatotroph cell adenomas may be quite large by the time they come to clinical attention because the manifestations of excessive GH may be subtle. Histologically, GH-containing adenomas are also classified into two subtypes: densely granulated and sparsely granulated. The densely granulated adenomas are composed of cells that are monomorphic and acidophilic in routine sections, retain strong cytoplasmic GH reactivity on immunohistochemistry, and demonstrate cytokeratin staining in a perinuclear distribution. In contrast, the sparsely granulated variants are composed of chromophobe cells with considerable nuclear and cytologic pleomorphism, and retain focal and weak GH reactivity. Bihormonal mammosomatotroph adenomas[4] that are reactive for both GH and prolactin are being increasingly recognized with the availability of better reagents for immunohistochemical analysis; morphologically, most bihormonal adenomas resemble the densely granulated pure somatotroph adenomas.Persistent hypersecretion of GH stimulates the hepatic secretion of insulin-like growth factor I (IGF-I or somatomedin C), which causes many of the clinical manifestations. If a somatotrophic adenoma appears in children before the epiphyses have closed, the elevated levels of GH (and IGF-1) result in gigantism. This is characterized by a generalized increase in body size with disproportionately long arms and legs. If the increased levels of GH are present after closure of the epiphyses, patients develop acromegaly. In this condition, growth is most conspicuous in skin and soft tissues; viscera (thyroid, heart, liver, and adrenals); and bones of the face, hands, and feet. Bone density may be increased (hyperostosis) in both the spine and the hips. Enlargement of the jaw results in protrusion (prognathism) with broadening of the lower face. The hands and feet are enlarged with broad, sausage-like fingers. In most instances, gigantism is also accompanied by evidence of acromegaly. These changes develop for decades before being recognized, hence the opportunity for the adenomas to reach substantial size. GH excess is also correlated with a variety of other disturbances, including gonadal dysfunction, diabetes mellitus, generalized muscle weakness, hypertension, arthritis, congestive heart failure, and an increased risk of gastrointestinal cancers.The diagnosis of pituitary GH excess relies on documentation of elevated serum GH and IGF-1 levels. In addition, failure to suppress GH production in response to an oral load of glucose is one of the most sensitive tests for acromegaly. The goals of treatment are to restore GH levels to normal and to decrease symptoms referable to a pituitary mass lesion while not causing hypopituitarism. To achieve these goals, the tumor can be removed surgically or destroyed by radiation therapy,1162 or GH secretion can be reduced by drug therapy. When effective control of GH hypersecretion is achieved, the characteristic tissue overgrowth and related symptoms gradually recede, and the metabolic abnormalities improve. 17. CORTICOTROPH CELL ADENOMAS Corticotroph adenomas are usually small microadenomas at the time of diagnosis. These tumors are most often basophilic (densely granulated) and occasionally chromophobic (sparsely granulated). Both variants stain positively with periodic acid-Schiff (PAS) because of the presence of carbohydrate in pre-opiomelanocorticotropin (POMC), the ACTH precursor molecule; in addition, they demonstrate variable immunoreactivity for POMC and its derivatives, including ACTH and -endorphin.Excess production of ACTH by the corticotroph adenoma leads to adrenal hypersecretion of cortisol and the development of hypercortisolism (also known as Cushing syndrome). This syndrome is discussed in more detail later with the diseases of the adrenal gland. It can be caused by a wide variety of conditions in addition to ACTH-producing pituitary tumors. When the hypercortisolism is due to excessive production of ACTH by the pituitary, the process is designated Cushing disease. Large destructive adenomas can develop in patients after surgical removal of the adrenal glands for treatment of Cushing syndrome. This condition, known as Nelson syndrome, occurs most often because of a loss of the inhibitory effect of adrenal corticosteroids on a pre-existing corticotroph microadenoma. Because the adrenals are absent in patients with this disorder, hypercortisolism does not develop. In contrast, patients present with mass effects of the pituitary tumor. In addition, there can be hyperpigmentation because of the stimulatory effect of other products of the ACTH precursor molecule on melanocytes. OTHER ANTERIOR PITUITARY ADENOMAS Pituitary adenomas may elaborate more than one hormone. For example, prolactin may be demonstrable by immunolabeling of somatotroph adenomas. In other cases, unusual plurihormonal adenomas are capable of secreting multiple hormones; these tumors are usually aggressive. A few comments are made about several of the less frequent functioning tumors.Gonadotroph (LH-producing and FSH-producing) adenomas can be difficult to recognize because they secrete hormones inefficiently and variably, and the secretory products usually do not cause a recognizable clinical syndrome. Gonadotroph adenomas are most frequently found in middle-aged men and women when they become large enough to cause neurologic symptoms, such as impaired vision, headaches, diplopia, or pituitary apoplexy. Pituitary hormone deficiencies can also be found, most commonly impaired secretion of LH. This causes decreased energy and libido in men (due to reduced testosterone) and amenorrhea in premenopausal women. Thus, gonadotroph adenomas are paradoxically associated with secondary gonadal hypofunction. Most gonadotroph adenomas are large and composed of chromophobic cells. The neoplastic cells usually demonstrate immunoreactivity for the common gonadotropin -subunit and the specific -FSH and -LH subunits; FSH is usually the predominant secreted hormone. The availability of reliable immunoassays for the gonadotropin -subunit and the recognition of gonadotroph-specific transcription factors has led to the reclassification of many previously hormone-negative adenomas ("null cell adenomas") as silent gonadotroph adenomas (see below). [5] 18. Thyrotroph (TSH-producing) adenomas are rare, accounting for approximately 1% of all pituitary adenomas. Thyrotroph adenomas are chromophobic or basophilic and are a rare cause of hyperthyroidism.Nonfunctioning pituitary adenomas comprise both clinically silent counterparts of the functioning adenomas described above (for example, a silent somatotroph adenoma) and true hormone-negative adenomas. Nonfunctioning adenomas constitute approximately 25% of all pituitary tumors. In the past, the majority of nonfunctioning adenomas were classified as "null cell adenomas" because of the inability to demonstrate markers of differentiation. It is now known that most null cell adenomas have biochemical and ultrastructural features that allow their characterization as silent tumors of gonadotrophic lineage. True hormone-negative adenomas are therefore unusual. Not [5] surprisingly, the typical presentation of nonfunctioning adenomas is mass effects. These lesions may also compromise the residual anterior pituitary sufficiently to cause hypopituitarism. This may occur as a result of gradual enlargement of the adenoma or after abrupt enlargement of the tumor because of acute hemorrhage (pituitary apoplexy).Pituitary carcinomas are quite rare, and most are not functional. These malignant tumors range from well differentiated, resembling somewhat atypical adenomas, to poorly differentiated, with variable degrees of pleomorphism and the features that are characteristic of carcinomas in other locations. The diagnosis of carcinoma requires the demonstration of metastases, usually to lymph nodes, bone, liver, and sometimes elsewhere.HypopituitarismHypopituitarism refers to decreased secretion of pituitary hormones, which can result from diseases of the hypothalamus or of the pituitary. Hypofunction of the anterior pituitary occurs when approximately 75% of the parenchyma is lost or absent. This may be congenital or the result of a variety of acquired abnormalities that are intrinsic to the pituitary. Hypopituitarism accompanied by evidence of posterior pituitary dysfunction in the form of diabetes insipidus (see below) is almost always of hypothalamic origin. Most cases of hypofunction arise from destructive processes directly involving the anterior pituitary, although other mechanisms have been identified: Tumors and other mass lesions: Pituitary adenomas, other benign tumors arisingwithin the sella, primary and metastatic malignancies, and cysts can causehypopituitarism. Any mass lesion in the sella can cause damage by exertingpressure on adjacent pituitary cells. Pituitary surgery or radiation: Surgical excision of a pituitary adenoma mayinadvertently extend to the nonadenomatous pituitary. Radiation of the pituitary,used to prevent1163regrowth of residual tumor after surgery, can damage the nonadenomatouspituitary. 19. Pituitary apoplexy: As has been mentioned, this is a sudden hemorrhage into thepituitary gland, often occurring into a pituitary adenoma. In its most dramaticpresentation, apoplexy causes the sudden onset of excruciating headache, diplopiaowing to pressure on the oculomotor nerves, and hypopituitarism. In severe cases,it can cause cardiovascular collapse, loss of consciousness, and even suddendeath. Thus, pituitary apoplexy is a true neurosurgical emergency. Ischemic necrosis of the pituitary and Sheehan syndrome: Ischemic necrosis ofthe anterior pituitary is an important cause of pituitary insufficiency. Sheehansyndrome, or postpartum necrosis of the anterior pituitary, is the most commonform of clinically significant ischemic necrosis of the anterior pituitary. During[6]pregnancy, the anterior pituitary enlarges to almost twice its normal size. Thisphysiologic expansion of the gland is not accompanied by an increase in bloodsupply from the low-pressure venous system; hence, there is relative anoxia of thepituitary. Further reduction in blood supply caused by obstetric hemorrhage orshock may precipitate infarction of the anterior lobe. The posterior pituitary,because it receives its blood directly from arterial branches, is much lesssusceptible to ischemic injury in this setting and is therefore usually not affected.Pituitary necrosis may also be encountered in other conditions, such asdisseminated intravascular coagulation and (more rarely) sickle cell anemia,elevated intracranial pressure, traumatic injury, and shock of any origin. Whateverthe pathogenesis, the ischemic area is resorbed and replaced by a nubbin offibrous tissue attached to the wall of an empty sella. Rathke cleft cyst: These cysts, lined by ciliated cuboidal epithelium withoccasional goblet cells and anterior pituitary cells, can accumulate proteinaceousfluid and expand, compromising the normal gland. Empty sella syndrome: Any condition that destroys part or all of the pituitarygland, such as ablation of the pituitary by surgery or radiation, can result in anempty sella. The empty sella syndrome refers to the presence of an enlarged,empty sella turcica that is not filled with pituitary tissue. There are two types: (1)In a primary empty sella, there is a defect in the diaphragma sella that allows thearachnoid mater and cerebrospinal fluid to herniate into the sella, resulting inexpansion of the sella and compression of the pituitary. Classically, affectedpatients are obese women with a history of multiple pregnancies. The empty sellasyndrome may be associated with visual field defects and occasionally withendocrine anomalies, such as hyperprolactinemia, owing to interruption ofinhibitory hypothalamic effects. Loss of functioning parenchyma can be severeenough to result in hypopituitarism. (2) In a secondary empty sella, a mass, suchas a pituitary adenoma, enlarges the sella, but then it is either surgically removedor undergoes spontaneous necrosis, leading to loss of pituitary function.Hypopituitarism can result from the treatment or spontaneous infarction. Genetic defects: Rare congenital deficiencies of one or more pituitary hormoneshave been recognized in children. For example, mutations in pit-1, a pituitarytranscription factor, result in combined deficiency of GH, prolactin, and TSH. [7] Less frequently, disorders that interfere with the delivery of pituitary hormone-releasing factors from the hypothalamus, such as hypothalamic tumors, may also cause 20. hypofunction of the anterior pituitary. Any disease involving the hypothalamus can alter secretion of one or more of the hypothalamic hormones that influence secretion of the corresponding pituitary hormones. In contrast to diseases that involve the pituitary directly, any of these conditions can also diminish the secretion of ADH, resulting in diabetes insipidus (discussed later). Hypothalamic lesions that cause hypopituitarism include: Tumors, including benign lesions that arise in the hypothalamus, such ascraniopharyngiomas, and malignant tumors that metastasize to that site, such asbreast and lung carcinomas. Hypothalamic hormone deficiency can ensue whenbrain or nasopharyngeal tumors are treated with radiation. Inflammatory disorders and infections, such as sarcoidosis or tuberculousmeningitis, can cause deficiencies of anterior pituitary hormones and diabetesinsipidus.The clinical manifestations of anterior pituitary hypofunction depend on the specific hormone(s) that are lacking. Children can develop growth failure (pituitary dwarfism) due to growth hormone deficiency. Gonadotropin (GnRH) deficiency leads to amenorrhea and infertility in women and decreased libido, impotence, and loss of pubic and axillary hair in men. TSH and ACTH deficiencies result in symptoms of hypothyroidism and hypoadrenalism, respectively, and are discussed later in the chapter. Prolactin deficiency results in failure of postpartum lactation. The anterior pituitary is also a rich source of melanocyte-stimulating hormone (MSH), synthesized from the same precursor molecule that produces ACTH; therefore, one of the manifestations of hypopituitarism includes pallor due to a loss of stimulatory effects of MSH on melanocytes. Posterior Pituitary SyndromesThe clinically relevant posterior pituitary syndromes involve ADH and include diabetes insipidus and secretion of inappropriately high levels of ADH. Diabetes insipidus. ADH deficiency causes diabetes insipidus, a conditioncharacterized by excessive urination (polyuria) owing to an inability of the kidneyto resorb water properly from the urine. It can result from a variety of processes,including head trauma, tumors, and inflammatory disorders of the hypothalamusand pituitary as well as surgical procedures involving these organs. The conditioncan also arise spontaneously, in the absence of an underlying disorder. Diabetesinsipidus from ADH deficiency is designated as central to differentiate it fromnephrogenic diabetes insipidus, which is a result of renal tubularunresponsiveness to circulating ADH. The clinical manifestations of the twodiseases are similar and include the excretion of large volumes of dilute urine 21. with an inappropriately low specific gravity. Serum sodium and osmolality areincreased owing to excessive renal loss of free1164water, resulting in thirst and polydipsia. Patients who can drink water cangenerally compensate for urinary losses; patients who are obtunded, bedridden, orotherwise limited in their ability to obtain water may develop life-threateningdehydration. Syndrome of inappropriate ADH (SIADH) secretion. ADH excess causesresorption of excessive amounts of free water, resulting in hyponatremia. Themost frequent causes of SIADH include the secretion of ectopic ADH bymalignant neoplasms (particularly small cell carcinomas of the lung), non-neoplastic diseases of the lung, and local injury to the hypothalamus or posteriorpituitary (or both). The clinical manifestations of SIADH are dominated byhyponatremia, cerebral edema, and resultant neurologic dysfunction. Althoughtotal body water is increased, blood volume remains normal, and peripheraledema does not develop. Hypothalamic Suprasellar TumorsNeoplasms in this location may induce hypofunction or hyperfunction of the anterior pituitary, diabetes insipidus, or combinations of these manifestations. The most commonly implicated lesions are gliomas (sometimes arising in the chiasm; see Chapter 28 ) and craniopharyngiomas. The craniopharyngioma is thought to be derived from vestigial remnants of Rathke pouch. These slow-growing tumors account for 1% to 5% of intracranial tumors; a small minority of these lesions arise within the sella, but most are suprasellar, with or without an intrasellar extension. A bimodal age distribution is observed, with one peak in childhood (5 to 15 years) and a second peak in adults in the sixth decade or older. Children usually come to clinical attention because of endocrine deficiencies such as growth retardation, whereas adults usually present with visual disturbances. Pituitary hormonal deficiencies, including diabetes insipidus, are common. Morphology. Craniopharyngiomas average 3 to 4 cm in diameter; they may be encapsulated and solid, but more commonly, they are cystic and sometimes multiloculated. In their strategic location, they often encroach on the optic chiasm or cranial nerves, and not infrequently, they bulge into the floor of the third ventricle and base of the brain. Two distinct pathologic variants are recognized: adamantinomatous craniopharyngioma and papillary craniopharyngioma. The adamantinomatous type frequently contains radiologically demonstrable calcifications; the papillary variant is calcified only rarely. 22. Adamantinomatous craniopharyngioma consists of nests or cords of stratified squamous epithelium embedded in a spongy "reticulum" that becomes more prominent in the internal layers. Peripherally, the nests of squamous cells gradually merge into a layer of columnar cells, forming a palisade resting on a basement membrane. Compact, lamellar keratin formation ("wet keratin") is a diagnostic feature of this tumor. As was previously mentioned, dystrophic calcification is a frequent finding. Additional features include cyst formation, fibrosis, and chronic inflammatory reaction. The cysts of adamantinomatous craniopharyngiomas often contain a cholesterol-rich, thick brownish yellow fluid that has been compared to "machinery oil." These tumors extend fingerlets of epithelium into adjacent brain, where they elicit a brisk glial reaction.Papillary craniopahryngiomas contain both solid sheets and papillae lined by well- differentiated squamous epithelium. These tumors usually lack keratin, calcification, and cysts. The squamous cells of the solid sections of the tumor do not have the peripheral palisading and do not typically generate a spongy reticulum in the internal layers.Patients with craniopharyngiomas have an excellent recurrence-free and overall survival. Tumors greater than 5 cm in diameter are associated with a significantly higher recurrence rate. Adamantinomatous tumors are associated with a higher frequency of brain invasion, but this does not necessarily correlate with an adverse prognosis. Malignant transformation of craniopharyngiomas into squamous carcinomas is exceptionally rare and usually occurs postradiation. Thyroid GlandNormalThe thyroid gland consists of two bulky lateral lobes connected by a relatively thin isthmus, usually located below and anterior to the larynx. Normal variations in the structure of the thyroid gland include the presence of a pyramidal lobe, a remnant of the thyroglossal duct above the isthmus.The thyroid gland develops from an evagination of the developing pharyngeal epithelium that descends as part of the thyroglossal duct from the foramen cecum at the base of the tongue to its normal position in the anterior neck. This pattern of descent explains the occasional presence of ectopic thyroid tissue, most commonly located at the base of the tongue (lingual thyroid) or at other sites abnormally high in the neck. Excessive descent leads to substernal thyroid glands. The clinical significance of these lesions lies in distinguishing 1165 23. them from metastatic thyroid carcinomas and the extremely rare occasions on which these ectopic sites can develop a primary thyroid malignancy. Patients with lingual [8] thyroids present an additional problem in that the ectopic thyroid tissue is sometimes the only thyroid tissue (total migration failure), and removal of the lingual thyroid results in symptomatic hypothyroidism. Malformations of branchial pouch differentiation may result in intrathyroidal sites of the thymus or parathyroid glands. The implication of these deviations becomes evident in the patient who has a total thyroidectomy and subsequently develops hypoparathyroidism.The weight of the normal adult thyroid is approximately 15 to 25 gm. The thyroid has a rich intraglandular capillary network that is supplied by the superior and inferior thyroidal arteries. Nerve fibers from the cervical sympathetic ganglia indirectly influence thyroid secretion by acting on the blood vessels. The thyroid is divided by thin fibrous septae into lobules composed of about 20 to 40 evenly dispersed follicles. Normal follicles range from 50 to 500 m in size, are lined by cuboidal to low columnar epithelium, and are filled with periodic acid Schiff (PAS)-positive thyroglobulin.In response to trophic factors from the hypothalamus, TSH (thyrotropin) is released by thyrotrophs in the anterior pituitary into the circulation. The binding of TSH to its receptor on the thyroid follicular epithelium results in activation and conformational change in the receptor, allowing it to associate with a stimulatory G-protein ( Fig. 24-7 ). Activation of the G-protein eventually results in an increase in intracellular cAMP levels, which stimulates thyroid growth, and hormone synthesis and release via cAMP- dependent protein kinases. The dissociation of thyroid hormone synthesis and release from the controlled influence of TSH-signaling pathways results in so-called thyroid autonomy and hyperfunction (see below).Thyroid follicular epithelial cells convert thyroglobulin into thyroxine (T4 ) and lesser amounts of triiodothyronine (T3 ). T4 and T3 are released into the systemic circulation, where most of these peptides are reversibly bound to circulating plasma proteins, such as thyroxine-binding globulin (TBG) and transthyretin, for transport to peripheral tissues. The binding proteins serve to maintain the serum unbound ("free") T3 and T4 concentrations within narrow limits yet ensure that the hormones are readily available to the tissues. In the periphery, the majority of free T4 is deiodinated to T3 ; the latter binds to thyroid hormone nuclear receptors in target cells with tenfold greater affinity than does T4 and has proportionately greater activity. The interaction of thyroid hormone with its nuclear thyroid hormone receptor (TR) results in the formation of a multi-protein hormone-receptor complex that binds to thyroid hormone response elements (TREs) in target genes, regulating their transcription (see Fig. 24-7 ). Thyroid hormone has [9] diverse cellular effects, including up-regulation of carbohydrate and lipid catabolism and stimulation of protein synthesis in a wide range of cells. The net result of these processes is an increase in the basal metabolic rate. One of the most important functions of thyroid hormone is its critical role in brain development, since absence of thyroid hormone during the fetal and neonatal periods may profoundly interfere with intellectual growth (see below). 24. The thyroid gland is one of the most responsive organs in the body and contains the largest store of hormones of any endocrine gland. The gland responds to many stimuli and is Figure 24-7 Homeostasis in the hypothalamus-pituitary-thyroid axis and mechanism of action of thyroid hormones. Secretion of thyroid hormones (T3 and T4 ) is controlled by trophic factors secreted by both the hypothalamus and the anterior pituitary. Decreased levels of T3 and T4 stimulate the release of thyrotropin- releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormone (TSH) from the anterior pituitary, causing T3 and T4 levels to rise. Elevated T3 and T4 levels, in turn, suppress the secretion of both TRH and TSH. This relationship is termed a negative-feedback loop. TSH binds to the TSH receptor on the thyroid follicular epithelium, which causes activation of G proteins, and cyclic AMP (cAMP)-mediated synthesis and release of thyroid hormones (T3 and T4). In the periphery, T3 and T4 interact with the thyroid hormone receptor (TR) to form a hormone-receptor complex that translocates to the nucleus and binds to so-called thyroid response elements (TREs) on target genes initiating a constant state of adaptation. During puberty, pregnancy, and physiologic stress from any source, the gland increases in size and becomes more active. This functional lability 25. is reflected in transient hyperplasia of the thyroidal epithelium. At this time, thyroglobulin is resorbed, and the follicular cells become tall and more columnar, sometimes forming small, infolded buds or papillae. When the stress abates, involution occurs; that is, the height of the epithelium falls, colloid accumulates, and the follicular cells resume their normal size and architecture. Failure of this normal balance between hyperplasia and involution can produce major or minor deviations from the usual histologic pattern.The function of the thyroid gland can be inhibited by a variety of chemical agents, collectively referred to as goitrogens. Because they suppress T3 and T4 synthesis, the level of TSH increases, and subsequent hyperplastic enlargement of the gland (goiter) follows. The antithyroid agent propylthiouracil inhibits the oxidation of iodide and blocks production1166 of the thyroid hormones; parenthetically, propylthiouracil also inhibits the peripheral deiodination of circulating T4 into T3 , thus ameliorating symptoms of thyroid hormone excess (see below). Iodide, when given to patients with thyroid hyperfunction, also blocks the release of thyroid hormones but through different mechanisms. Iodides in large doses inhibit proteolysis of thyroglobulin. Thus, thyroid hormone is synthesized and incorporated within increasing amounts of colloid, but it is not released into the blood.The thyroid gland follicles also contain a population of parafollicular cells, or C cells, which synthesize and secrete the hormone calcitonin. This hormone promotes the absorption of calcium by the skeletal system and inhibits the resorption of bone by osteoclasts.PathologyDiseases of the thyroid are of great importance because most are amenable to medical or surgical management. They include conditions associated with excessive release of thyroid hormones (hyperthyroidism), those associated with thyroid hormone deficiency (hypothyroidism), and mass lesions of the thyroid. We first consider the clinical consequences of disturbed thyroid function, then focus on the disorders that generate these problems.HyperthyroidismThyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T3 and T4 . Because it is caused most commonly by hyperfunction of the thyroid gland, it is often referred to as hyperthyroidism. However, in certain conditions the oversupply is related to either excessive release of preformed thyroid hormone (e.g., in thyroiditis) or to an extrathyroidal source, rather than hyperfunction of the gland ( Table 24-2 ). Thus, strictly speaking, hyperthyroidism is only 26. TABLE 24-2 -- Disorders Associated with Thyrotoxicosis Associated with Hyperthyroidism Primary Diffuse toxic hyperplasia (Graves disease) Hyperfunctioning ("toxic") multinodular goiter Hyperfunctioning ("toxic") adenoma Hyperfunctioning thyroid carcinoma Iodine-induced hyperthyroidism Neonatal thyrotoxicosis associated with maternal Graves disease Secondary TSH-secreting pituitary adenoma (rare)* Not Associated with Hyperthyroidism Subacute granulomatous thyroiditis (painful) Subacute lymphocytic thyroiditis (painless) Struma ovarii (ovarian teratoma with ectopic thyroid) Factitious thyrotoxicosis (exogenous thyroxine intake)*Associated with increased TSH; all other causes of thyrotoxicosis associated with decreased TSH. one (albeit the most common) cause of thyrotoxicosis. The terms primary and secondary hyperthyroidism are sometimes used to designate hyperthyroidism arising from an intrinsic thyroid abnormality and that arising from processes outside of the thyroid, such as a TSH-secreting pituitary tumor. With this disclaimer, we will follow the common practice of using the terms thyrotoxicosis and hyperthyroidism interchangeably. The three most common causes of thyrotoxicosis are also associated with hyperfunction of the gland and include the following: Diffuse hyperplasia of the thyroid associated with Graves disease (accounts for 85% of cases) Hyperfunctional multinodular goiter Hyperfunctional adenoma of the thyroid Clinical Course. 27. The clinical manifestations of hyperthyroidism are protean and include changes referable to the hypermetabolic state induced by excess thyroid hormone as well as those related to overactivity of the sympathetic nervous system (i.e., an increase in the -adrenergic "tone").Excessive levels of thyroid hormone result in an increase in the basal metabolic rate. The skin of thyrotoxic patients tends to be soft, warm, and flushed because of increased blood flow and peripheral vasodilation to increase heat loss. Heat intolerance is common. Sweating is increased because of higher levels of calorigenesis. Increased basal metabolic rate also results in characteristic weight loss despite increased appetite.Cardiac manifestations are among the earliest and most consistent features of hyperthyroidism. Patients with hyperthyroidism can have an increase in cardiac output, owing to both increased cardiac contractility and increased peripheral oxygen requirements. Tachycardia, palpitations, and cardiomegaly are common. Arrhythmias, particularly atrial fibrillation, occur frequently and are more common in older patients. Congestive heart failure may develop, particularly in elderly patients with pre-existing cardiac disease. Myocardial changes, such as foci of lymphocytic and eosinophilic infiltration, mild fibrosis in the interstitium, fatty changes in myofibers, and an increase in size and number of mitochondria, have been described. Some patients with thyrotoxicosis develop a reversible diastolic dysfunction and a "low-output" failure, so- called thyrotoxic dilated cardiomyopathy.In the neuromuscular system, overactivity of the sympathetic nervous system produces tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, and insomnia. Proximal muscle weakness is common with decreased muscle mass (thyroid myopathy).Ocular changes often call attention to hyperthyroidism. A wide, staring gaze and lid lag are present because of sympathetic overstimulation of the levator palpebrae superioris ( Fig. 24-8 ). However, true thyroid ophthalmopathy associated with proptosis is a feature seen only in Graves disease (see below).In the gastrointestinal system, sympathetic hyperstimulation of the gut results in hypermotility, malabsorption, and diarrhea.The skeletal system is also affected in hyperthyroidism. Thyroid hormone stimulates bone resorption, resulting in increased porosity of cortical bone and reduced volume of trabecular bone. The net effect is osteoporosis and an increased risk of fractures in patients with chronic hyperthyroidism.1167 28. Figure 24-8 A patient with hyperthyroidism. A wide-eyed, staring gaze, caused by overactivity of the sympathetic nervous system, is one of the features of this disorder. In Graves disease, one of the most important causes of hyperthyroidism, accumulation of loose connective tissue behind the eyeballs also adds to the protuberant appearance of the eyes.Other findings throughout the body include atrophy of skeletal muscle, with fatty infiltration and focal interstitial lymphocytic infiltrates; minimal liver enlargement due to fatty changes in the hepatocytes; and generalized lymphoid hyperplasia with lymphadenopathy in patients with Graves disease.Thyroid storm is used to designate the abrupt onset of severe hyperthyroidism. This condition occurs most commonly in patients with underlying Graves disease and probably results from an acute elevation in catecholamine levels, as might be encountered during infection, surgery, cessation of antithyroid medication, or any form of stress. Patients are often febrile and present with tachycardia out of proportion to the fever. Thyroid storm is a medical emergency: A significant number of untreated patients die of cardiac arrhythmias.Apathetic hyperthyroidism refers to thyrotoxicosis occurring in the elderly, in whom old age and various comorbidities may blunt the typical features of thyroid hormone excess seen in younger patients. The diagnosis of thyrotoxicosis in these patients is often made during laboratory work-up for unexplained weight loss or worsening cardiovascular disease.A diagnosis of hyperthyroidism is made using both clinical and laboratory findings. The measurement of serum TSH concentration using sensitive TSH (sTSH) assays provides the most useful single screening test for hyperthyroidism, as its levels are decreased even at the earliest stages, when the disease may still be subclinical. A low TSH value is [10] usually confirmed with measurement of free T4 , which is expectedly increased. In an occasional patient, hyperthyroidism results predominantly from increased circulating levels of T3 ("T3 toxicosis"). In these cases, free T4 levels may be decreased, and direct 29. measurement of serum T3 may be useful. In rare cases of pituitary-associated (secondary) hyperthyroidism, TSH levels are either normal or raised. Determining TSH levels after the injection of TRH (TRH stimulation test) is used in the evaluation of cases of suspected hyperthyroidism with equivocal changes in the baseline serum TSH level. A normal rise in TSH after administration of TRH excludes secondary hyperthyroidism. Once the diagnosis of thyrotoxicosis has been confirmed by a combination of sTSH assays and free thyroid hormone levels, measurement of radioactive iodine uptake by the thyroid gland may be valuable in determining the etiology. For example, there may be diffusely increased uptake in the whole gland (Graves disease), increased uptake in a solitary nodule (toxic adenoma), or decreased uptake (thyroiditis). The therapeutic options for hyperthyroidism include multiple medications, each of which has a different mechanism of action. Typically, these include a -blocker to control symptoms induced by increased adrenergic tone, a thionamide to block new hormone synthesis, an iodine solution to block the release of thyroid hormone, and agents that inhibit peripheral conversion of T4 to T3 . Radioiodine, which is incorporated into thyroid tissues, resulting in ablation of thyroid function over a period of 6 to 18 weeks, may also be used. HypothyroidismHypothyroidism is caused by any structural or functional derangement that interferes with the production of adequate levels of thyroid hormone. It can result from a defect anywhere in the hypothalamic-pituitary-thyroid axis. As in the case of hyperthyroidism, this disorder is divided into primary and secondary categories, depending on whether the hypothyroidism arises from an intrinsic abnormality in the thyroid or occurs as a result of pituitary disease; rarely, hypothalamic failure is a cause of tertiary hypothyroidism ( Table 24-3 ). Primary hypothyroidism accounts for the vast majority of cases of hypothyroidism. Primary hypothyroidism can be thyroprivic (due to absence or loss of thyroid parenchyma) or goitrous (due to enlargement of the thyroid gland under the influence of TSH). The causes of primary hypothyroidism include the following.Surgical or radiation-induced ablation of thyroid parenchyma can cause hypothyroidism. A large resection of the gland (total thyroidectomy) for the treatment of hyperthyroidism of a primary neoplasm can lead to hypothyroidism. The gland may also be ablated by radiation, whether in the form of radioiodine administered for the treatment of hyperthyroidism, or TABLE 24-3 -- Causes of Hypothyroidism Primary Developmental (thyroid dysgenesis: PAX-8, TTF-2, TSH-receptor mutations) Thyroid hormone resistance syndrome (TR mutations) 30. Postablative Surgery, radioiodine therapy, or external radiation Autoimmune hypothyroidism Hashimoto thyroiditis* Iodine deficiency * Drugs (lithium, iodides, p-aminosalicylic acid)* Congenital biosynthetic defect (dyshormonogenetic goiter) * Secondary Pituitary failure Tertiary Hypothalamic failure (rare)*Associated with enlargement of thyroid ("goitrous hypothyroidism"). Hashimoto thyroiditis and postablative hypothroidism account for the majority of cases. 1168 exogenous irradiation, such as external radiation therapy to the neck.Autoimmune hypothyroidism is the most common cause of goitrous hypothyroidism in iodine-sufficient areas of the world. The vast majority of cases of autoimmune hypothyroidism are due to Hashimoto thyroiditis. Circulating autoantibodies, including anti-TSH receptor autoantibodies, are commonly found in Hashimoto thyroiditis. Some patients with hypothyroidism have circulating anti-TSH antibodies, but they usually do not have the goitrous enlargement or lymphocytic infiltrate characteristic of Hashimoto thyroiditis. In the past, many of these patients were classified as having primary "idiopathic" hypothyroidism, but the disease is now recognized as a type of autoimmune disorder of the thyroid, occurring either in isolation or in conjunction with other autoimmune endocrine manifestations.Drugs given intentionally to decrease thyroid secretion (e.g., methimazole and propylthiouracil) can cause hypothyroidism, as can agents used to treat nonthyroid conditions (e.g., lithium, p-aminosalicylic acid).Inborn errors of thyroid metabolism are an uncommon cause of goitrous hypothyroidism (dyshormonogenetic goiter). Any one of the multiple steps leading to thyroid hormone synthesis may be deficient: (1) iodide transport defect, (2) organification defect, (3) 31. dehalogenase defect, and (4) iodotyrosine coupling defect. Organification of iodine involves binding of oxidized iodide with tyrosyl residues in thyroglobulin, and this process is deficient in patients with Pendred syndrome, wherein goitrous hypothyroidism is accompanied by sensorineural deafness.Thyroid hormone resistance syndrome is a rare autosomal-dominant disorder caused by inherited mutations in the thyroid hormone receptor (TR), which abolish the ability of the receptor to bind thyroid hormones. Patients demonstrate a generalized resistance to [11] thyroid hormone, despite high circulating levels of T3 and T4 . Since the pituitary is also resistant to feedback from thyroid hormones, TSH levels tend to be high as well. In rare instances, there may be complete absence of thyroid parenchyma (thyroid agenesis), or the gland may be greatly reduced in size (thyroid hypoplasia). Mutations in the TSH receptor are a newly recognized cause of congenital hypothyroidism associated with a hypoplastic thyroid gland. Recently, mutations in two transcription factors that are [12] expressed in the developing thyroid and regulate follicular differentiationthyroid transcription factor-2 (TTF-2) and Paired Homeobox-8 (PAX-8) have been[13] [14] reported in patients with thyroid agenesis. Thyroid agenesis caused by TTF-2 mutations is usually associated with a cleft palate.Secondary hypothyroidism is caused by TSH deficiency, and tertiary (central) hypothyroidism is caused by TRH deficiency. Secondary hypothyroidism can result from any of the causes of hypopituitarism. Frequently, the cause is a pituitary tumor; other causes include postpartum pituitary necrosis, trauma, and nonpituitary tumors, as was previously discussed. Tertiary (central) hypothyroidism can be caused by any disorder that damages the hypothalamus or interferes with hypothalamic-pituitary portal blood flow, thereby preventing delivery of TRH to the pituitary. This can result from hypothalamic damage from tumors, trauma, radiation therapy, or infiltrative diseases. Classic clinical manifestations of hypothyroidism include cretinism and myxedema. CRETINISM Cretinism refers to hypothyroidism that develops in infancy or early childhood. The term cretin was derived from the French chrtien, meaning Christian or Christlike, and was applied to these unfortunates because they were considered to be so mentally retarded as to be incapable of sinning. In the past, this disorder occurred fairly commonly in areas of the world where dietary iodine deficiency is endemic, such as the Himalayas, inland China, Africa, and other mountainous areas. It has become much less frequent in recent years, owing to the widespread supplementation of foods with iodine. On rare occasions, cretinism may also result from inborn errors in metabolism (e.g., enzyme deficiencies) that interfere with the biosynthesis of normal levels of thyroid hormone (sporadic cretinism).Clinical features of cretinism include impaired development of the skeletal system and central nervous system, manifested by severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia. The severity of the mental impairment in cretinism appears to be related to the time at which thyroid deficiency occurs in utero. Normally, maternal hormones, including T3 and T4 , cross the placenta 32. and are critical to fetal brain development. If there is maternal thyroid deficiency before the development of the fetal thyroid gland, mental retardation is severe. In contrast, reduction in maternal thyroid hormones later in pregnancy, after the fetal thyroid has developed, allows normal brain development. MYXEDEMA The term myxedema is applied to hypothyroidism developing in the older child or adult. Myxedema, or Gull disease, was first linked with thyroid dysfunction in 1873 by Sir William Gull in a paper addressing the development of a "cretinoid state" in adults. The clinical manifestations vary with the age of onset of the deficiency. The older child shows signs and symptoms intermediate between those of the cretin and those of the adult with hypothyroidism. In the adult, the condition appears insidiously and may take years to reach the level of clinical suspicion.Clinical features of myxedema are characterized by a slowing of physical and mental activity. The initial symptoms include generalized fatigue, apathy, and mental sluggishness, which may mimic depression in the early stages of the disease. Speech and intellectual functions become slowed. Patients with myxedema are listless, cold- intolerant, and frequently overweight. Reduced cardiac output probably contributes to shortness of breath and decreased exercise capacity, two frequent complaints in patients with hypothyroidism. Decreased sympathetic activity results in constipation and decreased sweating. The skin in these patients is cool and pale because of decreased blood flow. Histologically, there is an accumulation of matrix substances, such as glycosaminoglycans and hyaluronic acid, in skin, subcutaneous tissue, and a number of visceral sites. This results in edema, a broadening and coarsening of facial features, enlargement of the tongue, and deepening of the voice.Laboratory evaluation plays a vital role in the diagnosis of suspected hypothyroidism because of the nonspecific nature 1169 of symptoms. Measurement of the serum TSH level is the most sensitive screening test for this disorder. The TSH level is increased in primary hypothyroidism due to a loss of feedback inhibition of TRH and TSH production by the hypothalamus and pituitary, respectively. The TSH level is not increased in patients with hypothyroidism due to primary hypothalamic or pituitary disease. T4 levels are decreased in patients with hypothyroidism of any origin. ThyroiditisThyroiditis, or inflammation of the thyroid gland, encompasses a diverse group of disorders characterized by some form of thyroid inflammation. These diseases include conditions that result in acute illness with severe thyroid pain (e.g., infectious thyroiditis, 33. subacute granulomatous thyroiditis) and disorders in which there is relatively little inflammation and the illness is manifested primarily by thyroid dysfunction (subacute lymphocytic thyroiditis and fibrous [Reidel] thyroiditis).Infectious thyroiditis may be either acute or chronic. Acute infections can reach the thyroid via hematogenous spread or through direct seeding of the gland, such as via a fistula from the piriform sinus adjacent to the larynx. Other infections of the thyroid, including mycobacterial, fungal, and Pneumocystis infections, are more chronic and frequently occur in immunocompromised patients. Whatever the cause, the inflammatory involvement may cause sudden onset of neck pain and tenderness in the area of the gland and is accompanied by fever, chills, and other signs of infection. Infectious thyroiditis can be self-limited or can be controlled with appropriate therapy. Thyroid function is usually not significantly affected, and there are few residual effects except for possible small foci of scarring. This section focuses on the more common and clinically significant types of thyroiditis: (1) Hashimoto thyroiditis (or chronic lymphocytic thyroiditis), (2) subacute granulomatous thyroiditis, and (3) subacute lymphocytic thyroiditis. HASHIMOTO THYROIDITIS Hashimoto thyroiditis (or chronic lymphocytic thyroiditis) is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient. It is characterized by gradual thyroid failure because of autoimmune destruction of the thyroid gland. The name Hashimoto thyroiditis is derived from the 1912 report by Hashimoto describing patients with goiter and intense lymphocytic infiltration of the thyroid (struma lymphomatosa). This disorder is most prevalent between 45 and 65 years of age and is more common in women than in men, with a female predominance of 10:1 to 20:1. Although it is primarily a disease of older women, it can occur in children and is a major cause of nonendemic goiter in children.Epidemiologic studies have demonstrated a significant genetic component to Hashimoto thyroiditis, although, as in most other autoimmune disorders, the pattern of inheritance is non-Mendelian and likely to be influenced by subtle variations in the functions of multiple genes. The concordance rate in monozygotic twins is 30% to 60%, and up to 50% of asymptomatic first-degree relatives of Hashimoto patients demonstrate circulating antithyroid antibodies. Several chromosomal abnormalities have been [15] associated with thyroid autoimmunity. For example, adults with Turner syndrome (see Chapter 5 ) have a high prevalence of circulating antithyroid antibodies, and a substantial minority (20%) develops subclinical or clinical hypothyroidism that is indistinguishable from Hashimoto thyroiditis. Similarly, adults with trisomy 21 (Down syndrome, see Chapter 5 ) are also at an increased risk for developing Hashimoto thyroiditis and hypothyroidism. There are reports that polymorphisms in the HLA locus, specifically the HLA-DR3 and HLA-DR5 alleles, are linked to Hashimoto thyroiditis, but the association is weak. Finally, genomewide linkage analyses in families with Hashimoto thyroiditis have provided evidence for several susceptibility loci, such as on chromosomes 6p and 12q, that may harbor genes predisposing to this disorder. [16] 34. Pathogenesis. Hashimoto thyroiditis is an autoimmune disease in which the immune system reacts against a variety of thyroid antigens. The overriding feature of Hashimoto thyroiditis is progressive depletion of thyroid epithelial cells (thyrocytes), which are gradually replaced by mononuclear cell infiltration and fibrosis. Multiple immunologic mechanisms may contribute to the death of thyrocytes ( Fig. 24-9 ). Sensitization of autoreactive[17] [18] CD4+ T-helper cells to thyroid antigens appears to be the initiating event. The effector mechanisms for thyrocyte death include the following: CD8+ cytotoxic T cell-mediated cell death: CD8+ cytotoxic T cells may cause thyrocyte destruction by one of two pathways: exocytosis of perforin/granzyme granules or engagement of death receptors, specifically CD95 (also known as Fas) on the target cell ( Chapter 6 ). Cytokine-mediated cell death: CD4+ T cells produce inflammatory cytokines such as IFN- in the immediate thyrocyte milieu, with resultant recruitment and activation of macrophages and damage to follicles. Binding of antithyroid antibodies (anti-TSH receptor antibodies, antithyroglobulin, and antithyroid peroxidase antibodies) followed by antibody- dependent cell-mediated cytotoxicity (ADCC) ( Chapter 6 ). Morphology. The thyroid is often diffusely enlarged, although more localized enlargement may be seen in some cases. The capsule is intact, and the gland is well demarcated from adjacent structures. The cut surface is pale, yellow-tan, firm, and somewhat nodular. Microscopic examination reveals extensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centers ( Fig. 24-10 ). The thyroid follicles are atrophic and are lined in many areas by epithelial cells distinguished by the presence of abundant eosinophilic, granular cytoplasm, termed Hrthle cells. This is a metaplastic response of the normally low cuboidal follicular epithelium to ongoing injury. In fine-needle aspiration biopsies, the presence of Hrthle cells in conjunction with a heterogeneous population of lymphocytes is characteristic of Hashimoto thyroiditis. In "classic" Hashimoto thyroiditis, interstitial connective tissue is increased and may be abundant. A fibrous variant is 1170 35. Figure 24-9 Pathogenesis of Hashimoto thyroiditis. Three proposed models for mechanism of thyrocyte destruction in Hashimoto disease. Sensitization of autoreactive CD4+ T cells to thyroid antigens appears to be the initiating event for all three mechanisms of thyroid cell death. See the text for details.characterized by severe thyroid follicular atrophy and dense "keloid-like" fibrosis, with broad bands of acellular collagen encompassing residual thyroid tissue. Unlike Reidel thyroiditis (see below), the fibrosis does not extend beyond the capsule of the gland. The remnant thyroid parenchyma demonstrates features of chronic lymphocytic thyroiditis. Clinical Course. Hashimoto thyroiditis comes to clinical attention as painless enlargement of the thyroid, usually associated with some degree of hypothyroidism, in a middle-aged woman. The enlargement of the gland is usually symmetric and diffuse, but in some cases, it may be sufficiently localized to raise a suspicion of neoplasm. In the usual clinical course, 36. Figure 24-10 Hashimoto thyroiditis. The thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic Hrthle cells are also seen.hypothyroidism develops gradually. In some cases, however, it may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, with secondary release of thyroid hormones ("hashitoxicosis"). During this phase, free T4 and T3 levels are elevated, TSH is diminished, and radioactive iodine uptake is decreased. As hypothyroidism supervenes, T4 and T3 levels progressively fall, accompanied by a compensatory increase in TSH. Patients with Hashimoto thyroiditis are at increased risk for developing other concomitant autoimmune diseases, both endocrine (type 1 diabetes, autoimmune adrenalitis), and nonendocrine (systemic lupus erythematosus, myasthenia gravis, and Sjgren syndrome; see Chapter 6 ), and also at increased risk for the development of B-cell non-Hodgkin lymphomas. However, there is no established risk for developing thyroid epithelial neoplasms. SUBACUTE (GRANULOMATOUS) THYROIDITIS Subacute thyroiditis, which is also referred to as granulomatous thyroiditis or De Quervain thyroiditis, occurs much less frequently than does Hashimoto disease. The disorder is most common between the ages of 30 and 50 and, like other forms of thyroiditis, affects women considerably more often than men (3:1 to 5:1). Pathogenesis. Subacute thyroiditis is believed to be caused by a viral infection or a postviral inflammatory process. The majority of patients have a history of an upper respiratory infection just before the onset of thyroiditis. The disease has a seasonal incidence, with occurrences peaking in the summer, and clusters of cases have been reported in association with coxsackievirus, mumps, measles, adenovirus, and other viral illnesses. Although the pathogenesis of the disease is unclear, one model suggests that it results from a viral infection that provides an antigen, either viral or a thyroid antigen that is 37. 1171 released secondary to virus-induced host tissue damage. This antigen stimulates cytotoxic T lymphocytes, which then damage thyroid follicular cells. In contrast to autoimmune thyroid disease, the immune response is virus-initiated and not self-perpetuating, so the process is limited. Morphology. The gland may be unilaterally or bilaterally enlarged and firm, with an intact capsule. It may be slightly adherent to surrounding structures. On cut section, the involved areas are firm and yellow-white and stand out from the more rubbery, normal brown thyroid substance. Histologically, the changes are patchy and depend on the stage of the disease. Early in the active inflammatory phase, scattered follicles may be entirely disrupted and replaced by neutrophils forming microabscesses. Later, the more characteristic features appear in the form of aggregations of lymphocytes, histiocytes, and plasma cells about collapsed and damaged thyroid follicles. Multinucleate giant cells enclose naked pools or fragments of colloid ( Fig. 24-11 ), hence the designation granulomatous thyroiditis. In later stages of the disease, a chronic inflammatory infiltrate and fibrosis may replace the foci of injury. Different histologic stages are sometimes found in the same gland, suggesting waves of destruction over a period of time. Clinical Course. The presentation of subacute thyroiditis may be sudden or gradual. It is characterized by pain in the neck, which may radiate to the upper neck, jaw, throat, or ears, particularly when swallowing. Fever, fatigue, malaise, anorexia, and myalgia accompany a variable enlargement of the thyroid. The resultant thyroid inflammation and hyperthyroidism are transient, usually diminishing in 2 to 6 weeks, even if the patient is not treated. It may be followed by a period of transient, usually asymptomatic hypothyroidism lasting from 2 to 8 weeks, but recovery is virtually always complete.The transient hyperthyroidism, as in other cases of thyroiditis, is due to disruption of thyroid follicles and release of excessive thyroid hormone. Nearly all patients have high serum T4 and T3 levels and low serum TSH levels. Radioactive 38. Figure 24-11 Subacute thyroiditis. The thyroid parenchyma contains a chronic inflammatory infiltrate with a multinucleate giant cell (above left) and a colloid follicle (bottom right).iodine uptake is low because of suppression of TSH. The serum T4 and T3 levels are only modestly elevated. However, unlike in hyperthyroid states such as Graves disease, radioactive iodine uptake is diminished. After recovery, generally in 6 to 8 weeks, normal thyroid function returns. SUBACUTE LYMPHOCYTIC (PAINLESS) THYROIDITIS Subacute lymphocytic thyroiditis, which is also referred to as painless thyroiditis or silent thyroiditis, is an uncommon cause of hyperthyroidism. It usually comes to clinical attention because of mild hyperthyroidism, goitrous enlargement of the gland, or both. Although it can occur at any age, it is most often seen in middle-aged adults and is more common in women, especially during the postpartum period (postpartum thyroiditis), than in men. Depending on the study, the frequency of this form of thyroiditis varies[19] considerably, from 1% to about 10% of cases of hyperthyroid patients. The pathogenesis of this disorder is unknown. An autoimmune basis has been suggested because some patients have elevated levels of antibodies to thyroglobulin and thyroid peroxidase or a family history of thyroid autoimmune disease, and occasionally the disease evolves into overt chronic autoimmune thyroiditis several years later. There is no evidence that points toward a particular viral or other agent. Morphology. Except for possible mild symmetric enlargement, the thyroid appears normal on gross inspection. The most specific histologic features consist of lymphocytic infiltration with hyperplastic germinal centers within the thyroid parenchyma and patch disruption and collapse of thyroid follicles. Unlike in Hashimoto thyroiditis, fibrosis and Hrthle cell metaplasia are not commonly seen. Clinical Course. 39. The principal clinical manifestation of painless thyroiditis is hyperthyroidism. Symptoms usually develop over 1 to 2 weeks and last from 2 to 8 weeks before subsiding. The patient may have any of the common findings of hyperthyroidism (e.g., palpitations, tachycardia, tremor, weakness, and fatigue). The thyroid gland is not usually tender but is minimally and diffusely enlarged. Infiltrative ophthalmopathy and other manifestations of Graves disease (see below) are not present. Patients with one episode of postpartum thyroiditis are at an increased risk of recurrence following subsequent pregnancies. A minority of affected individuals eventually progress to hypothyroidism. Some patients have no signs or symptoms, and the disorder is detected incidentally during routine thyroid testing.Laboratory findings during periods of thyrotoxicosis include elevated levels of T4 and T3 and depressed levels of TSH.Other, less common forms of thyroiditis include Riedel thyroiditis, a rare disorder of unknown etiology characterized by extensive fibrosis involving the thyroid and contiguous neck structures. The presence of a hard and fixed thyroid mass clinically simulates a thyroid carcinoma. It may be associated with idiopathic fibrosis in other sites in the body, such as the retroperitoneum. The presence of circulating antithyroid antibodies in most patients suggests an autoimmune etiology. Palpation 1172 thyroiditis, caused by vigorous clinical palpation of the thyroid gland, results in multifocal follicular disruption associated with chronic inflammatory cells and occasional giant cell formation. Unlike De Quervain thyroiditis, abnormalities of thyroid function are not present, and this is usually an incidental finding in specimens resected for other reasons. Graves DiseaseGraves reported in 1835 his observations of a disease characterized by "violent and long continued palpitations in females" associated with enlargement of the thyroid gland. Graves disease is the most common cause of endogenous hyperthyroidism. It is characterized by a triad of clinical findings: 1. Hyperthyroidism owing to hyperfunctional, diffuse enlargement of the thyroid2. Infiltrative ophthalmopathy with resultant exophthalmos3. Localized, infiltrative dermopathy, sometimes called pretibial myxedema, which is present in a minority of patientsGraves disease has a peak incidence between the ages of 20 and 40, women being affected up to seven times more frequently than men. This disorder is said to be present in 1.5% to 2.0% of women in the United States. Genetic factors are important in the etiology of Graves disease. An increased incidence of Graves disease occurs among 40. family members of affected patients, and the concordance rate in monozygotic twins is as high as 60%. A recurring theme, as with other autoimmune disorders, is a genetic susceptibility to Graves disease associated with the presence of certain major histocompatibility haplotypes, specifically HLA-B8 and -DR3. Polymorphisms in the cytotoxic T-lymphocyte-associated-4 (CTLA-4) gene are also linked to Graves disease. [20] Recall that the HLA proteins are a critical component of antigen presentation to T cells, [21] while CTLA-4 is an inhibitory receptor th