Thyroid Gland Disorders: Causes, Symptoms & Treatment | PDF

Thyroid gland 1075 Thyroid Gland The thyroid gland consists of two lateral lobes connected protein triggers downstream events that increase intracellular by a thin isthmus, usually located below and anterior to cAMP levels, which, in turn, s...

Thyroid gland 1075 Thyroid Gland The thyroid gland consists of two lateral lobes connected protein triggers downstream events that increase intracellular by a thin isthmus, usually located below and anterior to cAMP levels, which, in turn, stimulates thyroid growth and the larynx. It develops embryologically from an evagination thyroid hormone synthesis and release via cAMP-dependent of the pharyngeal epithelium that descends from the foramen protein kinases. cecum at the base of the tongue to its normal position in Thyroid follicular epithelial cells convert thyroglobulin the anterior neck. This pattern of descent explains the into thyroxine (T4) and lesser amounts of triiodothyronine occasional presence of ectopic thyroid tissue at the base of (T3). T4 and T3 are released into the systemic circulation, the tongue (lingual thyroid) or at other sites high in the where most of these peptide hormones are reversibly bound neck. The thyroid is divided by thin fibrous septae into to circulating plasma proteins, such as thyroxine-binding lobules composed of 20 to 40 follicles, lined by a cuboidal globulin and transthyretin. The binding proteins act as a to low columnar epithelium and filled with PAS-positive buffer that maintains the serum unbound (“free”) T3 and thyroglobulin. T4 concentrations within narrow limits, while ensuring that In response to hypothalamic factors, TSH (thyrotropin) adequate amounts of the hormones are readily available to is released by thyrotrophs in the anterior pituitary into the the tissues. In the periphery, the majority of free T4 is circulation. The binding of TSH to its receptor on thyroid deiodinated to T3; the latter binds to thyroid hormone nuclear follicular epithelial cells activates the receptor, which then receptors in target cells with tenfold greater affinity than associates with a Gs protein (Fig. 24.8). Activation of the G does T4 and has proportionately greater activity. Binding of thyroid hormone to its nuclear thyroid hormone receptor (TR) results in the assembly of a multiprotein hormone- receptor complex on thyroid hormone response elements (TREs) near target genes, increasing their transcription (see Fig. 24.8). Thyroid hormone has diverse cellular effects, including the stimulation of carbohydrate and lipid catabo- lism and protein synthesis in a wide range of cells. The net result is an increase in the basal metabolic rate. In addition, TRH thyroid hormone has a critical role in brain development in the fetus and neonate (see later). The function of the thyroid gland can be inhibited by a T3, T4 variety of chemical agents, collectively referred to as goitro- TSH gens. Because they suppress T3 and T4 synthesis, the level Pituitary of TSH increases, causing subsequent hyperplastic enlarge- ment of the gland (goiter). The antithyroid agent propyl- thiouracil inhibits the oxidation of iodide and thus blocks TSH receptor the production of thyroid hormones; propylthiouracil also Thyroid hormone inhibits the peripheral deiodination of circulating T4 into G G-protein T3, thus ameliorating symptoms of thyroid hormone excess receptor (see later). Iodide, when given in large doses to individuals GTP GDP T3, T4 with thyroid hyperfunction, blocks the release of thyroid hormones by inhibiting the proteolysis of thyroglobulin. Thyroid Target Thus, thyroid hormone is synthesized and incorporated into cAMP gene 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 absorp- Gene expression on tion of calcium by the skeletal system and inhibits the resorption of bone by osteoclasts. Figure 24.8 Homeostasis in the hypothalamus-pituitary-thyroid axis and Diseases of the thyroid include conditions associated with mechanism of action of thyroid hormones. Secretion of thyroid hormones excessive release of thyroid hormones (hyperthyroidism), (T3 and T4) is controlled by trophic factors secreted by both the hypothalamus and the anterior pituitary. Decreased levels of T3 and T4 thyroid hormone deficiency (hypothyroidism), and mass stimulate the release of thyrotropin-releasing hormone (TRH) from the lesions of the thyroid. We will first consider the clinical hypothalamus and thyroid-stimulating hormone (TSH) from the anterior consequences of disturbed thyroid function, and then turn pituitary, causing T3 and T4 levels to rise. Elevated T3 and T4 levels, in turn, to the disorders that generate these problems. feed back to suppress the secretion of both TRH and TSH. TSH binds to the TSH receptor on the thyroid follicular epithelium, which causes activation of G-proteins, and cAMP-mediated synthesis and release of thyroid hormones (T3 and T4). In the periphery, T3 and T4 interact with the HYPERTHYROIDISM thyroid hormone receptor to form a hormone-receptor complex that translocates to the nucleus and binds to so-called thyroid response Thyrotoxicosis is a hypermetabolic state caused by elevated elements on target genes to initiate transcription. circulating levels of free T3 and T4. Because it is caused 1076 C H A P T E R 24 The Endocrine System Table 24.3 Disorders Associated With Thyrotoxicosis Associated With Hyperthyroidism Primary Diffuse hyperplasia (Graves disease) Hyperfunctioning (“toxic”) multinodular goiter Hyperfunctioning (“toxic”) adenoma Iodine-induced hyperthyroidism Neonatal thyrotoxicosis associated with maternal Graves disease Secondary TSH-secreting pituitary adenoma (rare)a Not Associated With Hyperthyroidism Granulomatous (de Quervain) thyroiditis (painful) Subacute lymphocytic thyroiditis (painless) Struma ovarii (ovarian teratoma with ectopic thyroid) Factitious thyrotoxicosis (exogenous thyroxine intake) a Associated with increased thyroid-stimulating hormone (TSH); all other causes of thyrotoxicosis associated with decreased TSH. Figure 24.9 A person with hyperthyroidism. A wide-eyed, staring gaze, caused by overactivity of the sympathetic nervous system, is one feature of this disorder. In Graves disease, an important cause of hyperthyroidism, accumulation of loose connective tissue behind the orbit also adds to the most commonly by hyperfunction of the thyroid gland, it protuberant appearance of the eyes. 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 may develop, especially in older adults with preexisting an extrathyroidal source, rather than hyperfunction of the cardiac disease. Myocardial changes, including focal gland (Table 24.3). Thus, strictly speaking, hyperthyroidism lymphocytic and eosinophilic infiltrates, mild fibrosis, is only one (albeit the most common) cause of thyrotoxicosis. myofibril fatty change, and an increase in size and number The terms primary and secondary hyperthyroidism are some- of mitochondria, have been described. Some individuals times used to designate hyperthyroidism arising from an with thyrotoxicosis develop reversible left ventricular intrinsic thyroid abnormality and that arising from processes dysfunction and “low-output” heart failure, so-called outside of the thyroid, such as a TSH-secreting pituitary thyrotoxic or hyperthyroid cardiomyopathy. tumor. With this caveat, we follow the common practice Overactivity of the sympathetic nervous system produces of using the terms thyrotoxicosis and hyperthyroidism tremor, hyperactivity, emotional lability, anxiety, inability interchangeably. to concentrate, and insomnia. Proximal muscle weak- The most common causes of thyrotoxicosis are associated ness and decreased muscle mass are common (thyroid with hyperfunction of the gland and include the following: myopathy). In the gastrointestinal system, hypermotility Diffuse hyperplasia of the thyroid associated with Graves and reduced transit times lead to hyperdefecation (not to disease (approximately 85% of cases) be confused with diarrhea), which typically responds to Hyperfunctional multinodular goiter beta-blockers, suggesting sympathetic hyperstimulation Hyperfunctional thyroid adenoma is the likely underlying pathophysiology. Most patients also develop some degree of fat malabsorption. Clinical Features Ocular changes often call attention to hyperthyroidism. The manifestations of hyperthyroidism are protean and A wide, staring gaze and lid lag are present because of include changes referable to the hypermetabolic state sympathetic overstimulation of the superior tarsal muscle induced by excess thyroid hormone and to overactivity (also known as Müller’s muscle), which functions along- of the sympathetic nervous system (i.e., an increase in the side the levator palpebrae superioris muscle to raise the β-adrenergic “tone”). upper eyelid (Fig. 24.9). However, true thyroid ophthal- Excessive levels of thyroid hormone result in an increase mopathy associated with proptosis occurs only in Graves in the basal metabolic rate. The skin of thyrotoxic patients disease (see later). tends to be soft, warm, and flushed because of increased The skeletal system is also affected. Thyroid hormone blood flow and peripheral vasodilation, adaptations that stimulates bone resorption, increasing cortical bone serve to increase heat loss. Heat intolerance is common. porosity and reducing trabecular bone volume. The net Sweating is increased because of higher levels of calori- effect is osteoporosis and an increased risk of fractures. genesis. Heightened catabolic metabolism results in weight Other findings include atrophy of skeletal muscle, with loss despite increased appetite. fatty infiltration and focal interstitial lymphocytic infil- Cardiac manifestations are among the earliest and most trates; hepatic fatty change (steatosis) leading to mild consistent features. Individuals with hyperthyroidism hepatomegaly; and generalized lymphoid hyperplasia can have elevated cardiac contractility and output, a and lymphadenopathy in patients with Graves disease. response to increased peripheral oxygen requirements. Thyroid storm refers to the abrupt onset of severe hyper- Tachycardia, palpitations, and cardiomegaly are common. thyroidism. This condition occurs most commonly in Arrhythmias such as atrial fibrillation occur frequently, patients with Graves disease and probably results from particularly in older patients. Congestive heart failure an acute elevation in catecholamine levels, as might be  Thyroid gland 1077 encountered during infection, surgery, cessation of Table 24.4 Causes of Hypothyroidism antithyroid medication, or any form of stress. Patients Primary are often febrile and present with tachycardia out of Genetic defects in thyroid development (PAX8, FOXE1, TSH receptor proportion to the fever. Thyroid storm is a medical mutations; rare) emergency. A significant number of untreated patients Thyroid hormone resistance syndrome (THRB mutations; rare) die of cardiac arrhythmias. Postablative Apathetic hyperthyroidism refers to thyrotoxicosis occurring Surgery, radioiodine therapy, or external irradiation in older adults, in whom advanced age and various Autoimmune hypothyroidism Hashimoto thyroiditisa comorbidities blunt the typical features of thyroid Iodine deficiencya hormone excess. The diagnosis in these individuals is Drugs (lithium, iodides, p-aminosalicylic acid)a often made during laboratory workup for unexplained Congenital biosynthetic defect (dyshormonogenetic goiter; rare)a weight loss or worsening cardiovascular disease. Secondary (“Central Hypothyroidism”) Laboratory findings that support the diagnosis of hyper- Pituitary failure (rare) Hypothalamic failure (rare) thyroidism include a low TSH value accompanied by an a increase in free T4. The measurement of serum TSH concentra- Associated with enlargement of thyroid (“goitrous hypothyroidism”). Hashimoto thyroiditis and postablative hypothyroidism account for the majority of cases of tion is the most useful single screening test for hyperthyroid- hypothyroidism in high-income countries. FOXE1, Forkhead box E1; PAX8, paired ism, because its levels are decreased even at the earliest box 8; THRB, thyroid hormone receptor β. stages, when the disease may still be subclinical. In occasional patients, hyperthyroidism results predominantly from increased circulating levels of T3 (“T3 toxicosis”). In these or as a result of pituitary and hypothalamic disease (Table cases, free T4 levels may be decreased, and direct measure- 24.4). Primary hypothyroidism accounts for the vast majority ment of serum T3 is useful. In rare cases of pituitary-associated of cases and may be accompanied by enlargement of the (secondary) hyperthyroidism, TSH levels are either normal thyroid gland (goiter). or raised. Determining TSH levels after the injection of Primary hypothyroidism can be congenital, autoimmune, thyrotropin-releasing hormone (TRH stimulation test) is or iatrogenic. used in the evaluation of cases of suspected hyperthyroidism Congenital hypothyroidism. Worldwide, congenital hypo- with equivocal changes in the baseline serum TSH level. A thyroidism is most often the result of endemic iodine normal rise in TSH after administration of TRH excludes deficiency in the diet (see later). Other rare forms of secondary hyperthyroidism. Once the diagnosis of thyro- congenital hypothyroidism include inborn errors of toxicosis has been confirmed by a combination of TSH assays thyroid metabolism (dyshormonogenetic goiter), wherein and free thyroid hormone levels, measurement of radioactive one of the several steps leading to thyroid hormone iodine uptake by the thyroid gland can help determine the synthesis is defective, such as (1) iodide transport into etiology. For example, there may be diffusely increased thyrocytes, (2) “organification” of iodine (covalent binding uptake in the gland (Graves disease), increased uptake in of iodine to tyrosine residues in thyroglobulin), and (3) a solitary nodule (toxic adenoma), or decreased uptake further processing to form hormonally active T3 and T4. (thyroiditis). In rare instances, there may be complete absence of thyroid The therapeutic options for hyperthyroidism include parenchyma (thyroid agenesis), or the gland may be greatly several medications, each with a different mechanism of reduced in size (thyroid hypoplasia) due to germline muta- action. Typically, these include a β-blocker to control tions in genes responsible for thyroid development (see symptoms induced by increased adrenergic tone, a thion- Table 24.4). amide (e.g., methimazole or propylthiouracil) to block new Autoimmune hypothyroidism. Autoimmune hypothyroidism hormone synthesis, an iodine solution to block the release is the most common cause of hypothyroidism in iodine- of thyroid hormone, and agents that inhibit peripheral sufficient areas of the world. The vast majority of cases conversion of T4 to T3. Radioactive iodine, which is incor- of autoimmune hypothyroidism are due to Hashimoto porated into thyroid tissues, resulting in ablation of thyroid thyroiditis. Circulating autoantibodies, including anti- function over a period of 6 to 18 weeks, may also be used. microsomal, antithyroid peroxidase, and antithyroglobulin antibodies, are found in this disorder, and the thyroid is typically enlarged (goitrous). Autoimmune hypothy- HYPOTHYROIDISM roidism can occur in isolation or in conjunction with autoimmune polyendocrine syndrome types 1 and 2 Hypothyroidism is a condition caused by a structural or (APS-1 and APS-2; see discussion in the Adrenal Glands functional derangement that interferes with the production section later in this chapter). of thyroid hormone. Hypothyroidism is a common disorder. Iatrogenic hypothyroidism. This can be caused by either By some estimates, the prevalence of overt hypothyroid- surgical or radiation-induced ablation. Resection of a large ism is 0.3%, while that of subclinical hypothyroidism is portion of the gland for the treatment of hyperthyroidism greater than 4%. The prevalence increases with age, and or a primary neoplasm can lead to hypothyroidism. The it is nearly 10-fold more common in women than in men. gland may also be ablated by radiation, whether in the Hypothyroidism can result from a defect anywhere in the form of radioiodine administered for the treatment of hypothalamic-pituitary-thyroid axis. Like hyperthyroidism, it hyperthyroidism, or exogenous irradiation, such as external can be divided into primary and secondary forms, depending radiation therapy to the neck. Drugs given to decrease on whether it arises from an intrinsic thyroid abnormality thyroid secretion (e.g., thionamides like methimazole and 1078 C H A P T E R 24 The Endocrine System propylthiouracil) can also cause acquired hypothyroidism, diminished expression of these genes results in a decrease as can agents used to treat nonthyroid conditions (e.g., in cardiac output. In addition, changes in lipid metabolism lithium, p-aminosalicylic acid). produce an increase in total cholesterol and low-density lipoprotein (LDL) levels that is pro-atherogenic, contributing Secondary (or central) hypothyroidism is caused by to increased cardiovascular mortality. Histologically, there deficiencies of TSH or, far more uncommonly, TRH. Any is an accumulation of matrix substances, such as glycos- of the causes of hypopituitarism (e.g., pituitary tumor, aminoglycans and hyaluronic acid, in skin, subcutaneous postpartum pituitary necrosis, trauma, and nonpituitary tissue, and visceral sites. This results in nonpitting edema, tumors) or hypothalamic damage (e.g., tumors, trauma, a broadening and coarsening of facial features, enlargement radiation therapy, or infiltrative diseases) can cause central of the tongue, and deepening of the voice. hypothyroidism. Laboratory evaluation plays a vital role in the diagnosis of suspected hypothyroidism because of the nonspecific Cretinism nature of symptoms. Patients with unexplained increases in body weight or hypercholesterolemia should be assessed Cretinism refers to hypothyroidism that develops in infancy for potential hypothyroidism. Measurement of the serum or early childhood. The term cretin was derived from the TSH level is the most sensitive screening test for this French chrétien, meaning “Christian” or “Christlike,” and disorder. The TSH level is increased in primary hypothyroid- was applied to those affected because they were felt to be ism as a result of a loss of feedback inhibition of TRH and too mentally challenged to be capable of sinning. In the TSH production by the hypothalamus and pituitary, past, this disorder occurred fairly commonly in regions of respectively. The TSH level is not increased in persons with the world where dietary iodine deficiency is endemic, such hypothyroidism due to primary hypothalamic or pituitary as the Himalayas, inland China, Africa, and other mountain- disease. T4 levels are decreased in individuals with hypo- ous areas. It is now much less prevalent as a result of the thyroidism of any origin. widespread supplementation of foods with iodine. On rare occasions, cretinism results from genetic defects that interfere with the biosynthesis of thyroid hormone (dyshormonoge- THYROIDITIS netic goiter). Clinical features of cretinism include severe intellectual Thyroiditis encompasses a diverse group of disorders disability, short stature, coarse facial features, a protruding characterized by some form of thyroid inflammation. tongue, and umbilical hernia. The severity of the mental This discussion focuses on the three most common and impairment seems to be related to the time at which thyroid clinically significant subtypes: (1) Hashimoto thyroiditis, (2) deficiency occurs in utero. Normally, maternal T3 and T4 granulomatous (de Quervain) thyroiditis, and (3) subacute cross the placenta and are critical for fetal brain development. lymphocytic thyroiditis. If there is maternal thyroid deficiency before the development of the fetal thyroid gland, intellectual disability is severe. Hashimoto Thyroiditis In contrast, maternal thyroid hormone deficiency later in pregnancy, after the fetal thyroid has become functional, Hashimoto thyroiditis is an autoimmune disease that does not affect normal brain development. results in destruction of the thyroid gland and gradual and progressive thyroid failure. It is the most common Myxedema cause of hypothyroidism in areas of the world where iodine levels are sufficient. The name is derived from the 1912 The term myxedema is applied to hypothyroidism develop- report by Hashimoto describing patients with goiter and ing in the older child or adult. Myxedema was first linked lymphocytic infiltration of the thyroid (struma lymphomatosa). with thyroid dysfunction in 1873 by Sir William Gull in an It is most prevalent between 45 and 65 years of age and article addressing the development of a “cretinoid state” is more common in women than in men, with a female in adults. The clinical findings vary with age of onset. Older predominance of 10 : 1 to 20 : 1. It can also occur in children children show signs and symptoms intermediate between and is a major cause of nonendemic goiter in the pediatric those of the cretin and those of the adult with hypothyroid- population. ism. In the adult, the condition appears insidiously and may take years before arousing clinical suspicion. Pathogenesis Myxedema is marked by a slowing of physical and mental Hashimoto thyroiditis is caused by a breakdown in activity. Early symptoms include generalized fatigue, apathy, self-tolerance to thyroid autoantigens. This is exempli- and mental sluggishness, which may mimic depression. fied by the presence of circulating autoantibodies against Speech and intellectual functions are slowed, and patients thyroglobulin and thyroid peroxidase in the vast majority are listless, cold intolerant, and frequently overweight. of patients. The inciting events have not been elucidated, Decreased sympathetic activity results in constipation and but possibilities include abnormalities of regulatory T decreased sweating. The skin is cool and pale because of cells (Tregs), or exposure of normally sequestered thyroid decreased blood flow. Reduced cardiac output probably antigens (Chapter 6). Similar to other autoimmune diseases, contributes to shortness of breath and decreased exercise Hashimoto thyroiditis predisposition has a strong genetic capacity, two frequent complaints. Thyroid hormones regu- component. Increased susceptibility is associated with late the transcription of several sarcolemmal genes, such as polymorphisms in several immune regulation–associated calcium ATPases and the β-adrenergic receptor, and genes, such as cytotoxic T lymphocyte–associated antigen-4  Thyroid gland 1079 Thyroid epithelium Breakdown in self tolerance and induction of thyroid autoimmunity Plasma cell CD4+ CD8+ Th1 cell cytotoxic Anti-thyroid T-cell antibodies IFN-γ MHC Activated macrophages T-cell–mediated Fc receptor cytotoxicity NK cell Antibody-dependent Thyrocyte injury cell-mediated cytotoxicity Figure 24.10 Pathogenesis of Hashimoto thyroiditis. Breakdown of peripheral tolerance to thyroid autoantigens results in progressive autoimmune destruction of thyroid cells by infiltrating cytotoxic T cells, locally released cytokines, or antibody-dependent cytotoxicity. (CTLA4), protein tyrosine phosphatase-22 (PTPN22), and interleukin-2 receptor α chain (IL2RA), all of which encode regulators of T-cell responses. Not surprisingly, genome-wide association studies (GWAS) have found similar associations between CTLA4, PTPN22, and IL2RA polymorphisms and Graves disease, another type of autoimmune thyroid disease (discussed later), as well as with other systemic autoimmune diseases such as type 1 diabetes (T1D). The genetic associa- tions support the idea that breakdown in immune tolerance is a common pathophysiologic theme for many autoimmune diseases, more than one of which can coexist in the same individual. Induction of thyroid autoimmunity is accompanied by a progressive depletion of thyroid epithelial cells and replacement of the thyroid parenchyma by lymphocytic infiltrates and fibrosis. Multiple immunologic mechanisms Figure 24.11 Hashimoto thyroiditis. The thyroid parenchyma contains a may contribute to thyroid cell death, including (Fig. 24.10): dense lymphocytic infiltrate with germinal centers. Residual thyroid CD8+ cytotoxic T cell–mediated cell death: CD8+ cytotoxic follicles lined by deeply eosinophilic Hürthle cells are also seen. T cells may destroy thyroid follicular cells. Cytokine-mediated cell death: Activation of CD4+ Th1 cells leads to the production of inflammatory cytokines such as interferon-γ in the thyroid gland, with resultant recruit- extensive infiltration of the parenchyma by a mononuclear ment and activation of macrophages and damage to inflammatory infiltrate containing small lymphocytes, plasma follicles. cells, and well-developed germinal centers (Fig. 24.11). The A less likely mechanism involves binding of antithyroid thyroid follicles are atrophic and are lined in many areas by epithelial antibodies (antithyroglobulin, and antithyroid peroxidase cells with abundant eosinophilic, granular cytoplasm, termed antibodies) followed by antibody-dependent cell-mediated Hürthle cells, which represent a metaplastic response of the cytotoxicity (Chapter 6). normally low cuboidal follicular epithelium to chronic injury. In fine-needle aspiration biopsy samples, the presence of Hürthle MORPHOLOGY cells in conjunction with a heterogeneous population of lympho- cytes is characteristic of Hashimoto thyroiditis. In “classic” The thyroid is usually diffusely enlarged. The capsule is intact, and Hashimoto thyroiditis, interstitial connective tissue is increased the gland is well demarcated from adjacent structures. The cut and may be abundant. Unlike Reidel thyroiditis (see later), the surface is pale, yellow-tan, firm, and somewhat nodular. There is fibrosis does not extend beyond the capsule of the gland. 1080 C H A P T E R 24 The Endocrine System age and, like other forms of thyroiditis, affects women more Clinical Features often than men (4 : 1). Hashimoto thyroiditis most often comes to attention as painless enlargement of the thyroid, usually associated with Pathogenesis some degree of hypothyroidism, in a middle-aged woman. Granulomatous thyroiditis is believed to be triggered by a The enlargement of the gland is generally symmetric and viral infection. The majority of patients have a history of diffuse, but in some cases it may be sufficiently localized an upper respiratory infection just before the onset of to raise the suspicion of a neoplasm. In the typical case, thyroiditis. The disease is seasonal, with occurrences peaking hypothyroidism develops gradually. In some patients, in the summer, and clusters of cases have been reported in however, it may be preceded by transient thyrotoxicosis association with coxsackievirus, mumps, measles, adenovirus, caused by disruption of thyroid follicles and release of and other viral infections. Although the pathogenesis of the thyroid hormones (hashitoxicosis). During this phase, free disease is unclear, one model suggests that it results from T4 and T3 levels are elevated, TSH is diminished, and radioac- virus-induced host tissue damage that stimulates a cytotoxic tive iodine uptake is decreased. As hypothyroidism super- T-lymphocyte response to one or more thyroid antigens venes, T4 and T3 levels fall, accompanied by a compensatory that damages thyroid follicle cells. In contrast to autoimmune increase in TSH. thyroid disease, the immune response is virus-initiated and Individuals with Hashimoto thyroiditis are at increased not self-perpetuating, so the process is limited. risk for developing other autoimmune diseases, both endocrine (type 1 diabetes, autoimmune adrenalitis) and MORPHOLOGY non-endocrine (systemic lupus erythematosus, myasthenia gravis, and Sjögren syndrome; Chapter 6). They are also at The gland may be unilaterally or bilaterally enlarged and firm, increased risk for development of extranodal marginal zone with an intact capsule that may adhere to surrounding structures. B-cell lymphoma within the thyroid gland (Chapter 13). On cut section, the involved areas are firm and yellow-white and The relationship between Hashimoto disease and thyroid stand out from adjacent normal rubbery, brown thyroid gland. epithelial cancers remains controversial, with some mor- Histologic changes are patchy and depend on the stage of the phologic and molecular studies suggesting a predisposition disease. Early in the active inflammatory phase, scattered follicles to papillary carcinoma. may be disrupted and replaced by neutrophils forming microab- scesses. Later, more characteristic features appear in the form of Subacute Lymphocytic (Painless) Thyroiditis aggregates of lymphocytes, activated macrophages, and plasma cells associated with collapsed and damaged thyroid follicles. Subacute lymphocytic thyroiditis, which is also referred to as Multinucleate giant cells enclose pools of colloid (Fig. 24.12), painless thyroiditis, is a presumed autoimmune disease. Most hence the designation granulomatous thyroiditis. In later stages patients have circulating antithyroid peroxidase antibodies of the disease, a chronic inflammatory infiltrate and fibrosis may or a family history of other autoimmune disorders. A similar replace the foci of injury. Different histologic stages are sometimes disease process can occur during the postpartum period in found in the same gland, suggesting waves of destruction over a up to 5% of women (postpartum thyroiditis). period of time. MORPHOLOGY Clinical Features Except for possible mild symmetric enlargement, the thyroid Granulomatous thyroiditis is the most common cause of appears grossly normal. Microscopic examination reveals lympho- thyroid pain. There is variable enlargement of the gland. cytic infiltration with large germinal centers within the thyroid Inflammation of the thyroid and hyperthyroidism are parenchyma and patchy disruption and collapse of thyroid follicles. Unlike Hashimoto thyroiditis, however, fibrosis and Hürthle cell metaplasia are not prominent. Clinical Features Painless thyroiditis usually comes to attention because of mild, transient hyperthyroidism, painless goiter, or both. Although it can occur at any age, it is most often seen in middle-aged adults and is more common in women. Some patients transition from hyperthyroidism to hypothyroidism before recovery. As many as one-third of cases evolve into overt hypothyroidism over a 10-year period, with pathogic features that resemble Hashimoto thyroiditis. Granulomatous Thyroiditis Granulomatous thyroiditis (also called De Quervain thyroiditis) Figure 24.12 Granulomatous thyroiditis. The thyroid parenchyma occurs much less frequently than does Hashimoto thyroiditis. contains a chronic inflammatory infiltrate with a multinucleate giant cell The disorder is most common between 40 and 50 years of (top left) and a colloid follicle (bottom right).  Thyroid gland 1081 transient, usually diminishing in 2 to 6 weeks, even if the antibody subtype, known as thyroid-stimulating immuno- patient is not treated. Nearly all patients have high serum globulin (TSI), is observed in approximately 90% of patients. T4 and T3 levels and low serum TSH levels during this In contrast to antibodies against thyroglobulin and thyroid phase. However, unlike in hyperthyroid states such as peroxidase, TSI is almost never observed in other autoimmune Graves disease, radioactive iodine uptake is diminished. diseases of the thyroid. TSI binds to the TSH receptor and After recovery, generally in 6 to 8 weeks, normal thyroid mimics its actions, stimulating adenyl cyclase and increasing function returns. the release of thyroid hormones. As stated earlier, TSH Other, less common forms of thyroiditis include Riedel receptor blocking antibodies may also be present, and in a thyroiditis, a rare disorder characterized by extensive fibrosis minority of patients these lead to hypothyroidism. involving the thyroid and contiguous neck structures. The Perhaps unsurprisingly, factors that predispose to Graves presence of a hard and fixed thyroid mass clinically simulates disease overlap with risk factors for Hashimoto thyroiditis, a thyroid carcinoma. It may be associated with fibrosis in the other major form of autoimmune thyroid disease. The other sites in the body, such as the retroperitoneum, and concordance rate in monozygotic twins is 30% to 40%, appears to be another manifestation of IgG4-related disease, compared with less than 5% among dizygotic twins, and which is associated with fibrosis and tissue infiltration by similar to Hashimoto thyroiditis, genetic susceptibility is plasma cells producing IgG4 (Chapter 6). associated with polymorphisms in immune-function genes like CTLA4, PTPN22, and IL2RA. In addition, GWAS data has also implicated variants in the TSH receptor (TSHR) KEY CONCEPTS gene locus in susceptibility to Graves disease. Autoimmunity also plays a role in the development of THYROIDITIS the infiltrative ophthalmopathy that is characteristic of Graves Hashimoto thyroiditis is the most common cause of hypothyroid- disease. Activated CD4+ helper T cells secrete cytokines that ism in regions where dietary iodine levels are sufficient. stimulate fibroblast proliferation and synthesis of extracellular Hashimoto thyroiditis is an autoimmune thyroiditis characterized matrix proteins (glycosaminoglycans), leading to progressive by progressive destruction of thyroid parenchyma, Hürthle cell infiltration of the retro-orbital space and ophthalmopathy. change, and mononuclear (lymphoplasmacytic) infiltrates, with The protrusion of the eyeball (exopthalmos) is caused by an germinal centers and variable degrees of fibrosis. increase in the volume of the retro-orbital connective tissues Subacute lymphocytic thyroiditis often occurs after pregnancy and extraocular muscles, which occurs for several reasons: (1) (postpartum thyroiditis), typically is painless, and is characterized marked infiltration of connective tissue by mononuclear cells, by lymphocytic inflammation in the thyroid. It is another type predominantly T cells; (2) inflammation, edema, and swelling of autoimmune thyroiditis. of extraocular muscles; (3) accumulation of extracellular Granulomatous (de Quervain) thyroiditis is a self-limited disease, matrix components, specifically hydrophilic glycosamino- probably secondary to a viral infection, and is characterized by glycans such as hyaluronic acid and chondroitin sulfate; pain and granulomatous inflammation of the thyroid. and (4) increased numbers of adipocytes (fatty infiltration). These changes not only displace the eyeball but also may interfere with the function of the extraocular muscles. GRAVES DISEASE MORPHOLOGY Graves disease is the most common cause of endogenous The thyroid gland is usually symmetrically enlarged due to diffuse hyperthyroidism. Graves reported in 1835 his observations hypertrophy and hyperplasia of thyroid follicular epithelial cells of a disease characterized by “violent and long continued (Fig. 24.13A). Increases in weight to over 80 g are not uncommon. palpitations in females” associated with enlargement of the On cut section, the parenchyma has a soft, meaty appearance resem- thyroid gland. The disease is characterized by a triad of bling muscle. Histologically, the follicle epithelial cells in untreated clinical findings: cases are tall and more crowded than usual. This crowding often Hyperthyroidism associated with diffuse enlargement of results in the formation of small papillae that project into the follicle the gland lumen and encroach on the colloid, sometimes filling the follicles Infiltrative ophthalmopathy and resultant exophthalmos (Fig. 24.13B). Such papillae lack fibrovascular cores, in contrast to Localized, infiltrative dermopathy, sometimes called pretibial those of papillary carcinoma (see later). The colloid within the myxedema, which is present in a minority of patients follicle lumen is pale, with scalloped margins. Lymphoid infiltrates, consisting predominantly of T cells, along with scattered B cells Graves disease has a peak incidence between 20 and 40 and mature plasma cells, are present throughout the interstitium. years of age. Women are affected as much as 10 times more Germinal centers are common. frequently than men. This disorder is said to affect 1.5% to Preoperative therapy alters the morphology of the thyroid in 2% of women in the United States. Graves disease. Administration of iodine causes involution of the Pathogenesis epithelium and the accumulation of colloid by blocking thyroglobulin secretion. Treatment with the antithyroid drug propylthiouracil Graves disease is an autoimmune disorder characterized exaggerates the epithelial hypertrophy and hyperplasia by stimulat- by the production of autoantibodies against multiple ing TSH secretion. thyroid proteins, most importantly the TSH receptor. A Changes in extrathyroidal tissue include lymphoid hyperplasia, variety of antibodies that either stimulate or block the TSH especially enlargement of the thymus in younger patients. The receptor are detected in the circulation. The most common 1082 C H A P T E R 24 The Endocrine System A B Figure 24.13 Graves disease. (A) There is diffuse symmetric enlargement of the gland and a beefy deep red parenchyma. Compare with gross photograph of multinodular goiter in Fig. 24.15. (B) Diffusely hyperplastic thyroid in a case of Graves disease. The follicles are lined by tall, columnar epithelium. The crowded, enlarged epithelial cells project into the lumens of the follicles. These cells actively resorb the colloid in the centers of the follicles, resulting in the scalloped appearance of the edges of the colloid. (A, Reproduced with permission from Lloyd RV, Douglas BR, Young WF Jr, editors: Atlas of Nontumor Pathology: Endocrine Diseases, Washington, DC, 2002, American Registry of Pathology.) Graves disease is treated with β-blockers, which dampen heart may be hypertrophied, and ischemic changes may be present, symptoms related to increased sympathetic nervous system particularly in patients with preexisting coronary artery disease. activity (e.g., tachycardia, palpitations, tremulousness, and In patients with ophthalmopathy, the tissues of the orbit are anxiety), and by measures that decrease thyroid hormone edematous because of the presence of hydrophilic mucopolysac- synthesis, such as the administration of thionamides (e.g., charides. In addition, there is infiltration by lymphocytes and fibrosis. propylthiouracil), radioiodine ablation, and thyroidectomy. Orbital muscles are edematous initially but may undergo fibrosis Surgery is used mostly in patients who have large goiters late in the course of the disease. The dermopathy, if present, is characterized by thickening of the dermis due to deposition of that are compressing surrounding structures. glycosaminoglycans and lymphocyte infiltration. KEY CONCEPTS Clinical Features GRAVES DISEASE The findings in Graves disease include changes associ- Graves disease, the most common cause of endogenous ated with thyrotoxicosis and others associated uniquely hyperthyroidism, is characterized by the triad of thyrotoxicosis, with Graves disease, such as diffuse hyperplasia of the ophthalmopathy, and dermopathy. thyroid, ophthalmopathy, and dermopathy. The degree of Graves disease is an autoimmune disorder caused by activation thyrotoxicosis varies from case to case and is sometimes of thyroid epithelial cells by autoantibodies to the TSH receptor less conspicuous than other manifestations of the disease. that mimic TSH action (thyroid-stimulating immunoglobulins). Diffuse enlargement of the thyroid is present in all cases. The thyroid in Graves disease shows diffuse hypertrophy and The thyroid enlargement may be accompanied by increased hyperplasia of follicles and lymphoid infiltrates; glycosaminoglycan flow of blood through the hyperactive gland, often produc- deposition and lymphoid infiltrates are responsible for the ing an audible “bruit.” Sympathetic overactivity produces ophthalmopathy and dermopathy. a characteristic wide, staring gaze and lid lag, while the Laboratory features include elevations in serum free T3 and T4 ophthalmopathy causes exophthalmos. The exophthalmos and decreased serum TSH. may persist or progress despite successful treatment of the thyrotoxicosis, sometimes resulting in corneal injury. The extraocular muscles are often weak. The infiltrative dermopathy (pretibial myxedema) is most common in the skin DIFFUSE AND MULTINODULAR overlying the shins, where it presents as scaly thickening GOITER and induration. The basis of such localization is not clear, and it is present only in a minority of patients. Sometimes Enlargement of the thyroid, or goiter, is caused by individuals spontaneously develop thyroid hypofunction. impaired synthesis of thyroid hormone, which is most Patients are at increased risk for other autoimmune diseases, often the result of dietary iodine deficiency. Reduced such as systemic lupus erythematosus, pernicious anemia, thyroid hormone production leads to a compensatory rise type 1 diabetes, and Addison disease. in the serum TSH level, which, in turn, causes hypertrophy Laboratory findings in Graves disease include elevated and hyperplasia of thyroid follicular cells and, ultimately, free T4 and T3 levels and depressed TSH levels. Because of enlargement of the thyroid gland. This increase in func- ongoing stimulation by thyroid-stimulating immunoglobu- tional mass of the gland usually overcomes the hormone lins, radioiodine scans show a diffusely increased uptake deficiency, ensuring a euthyroid metabolic state in most of iodine in the thyroid gland. individuals. If the underlying disorder is sufficiently severe  Thyroid gland 1083 (e.g., a congenital biosynthetic defect or endemic iodine by crowded columnar cells, which may pile up and form projections deficiency, discussed later), the compensatory responses similar to those seen in Graves disease. The accumulation is not may be inadequate, resulting in goitrous hypothyroidism. uniform throughout the gland, and some follicles are hugely The degree of thyroid enlargement is proportional to the distended, whereas others remain small. If dietary iodine subse- level and duration of thyroid hormone deficiency. Goiters quently increases or if the demand for thyroid hormone decreases, can broadly be divided into two types: diffuse nontoxic and the stimulated follicle epithelium involutes to form an enlarged, multinodular. colloid-rich gland (colloid goiter). In these cases, the cut surface of the thyroid is usually brown, somewhat glassy, and translucent. Diffuse Nontoxic (Simple) Goiter Histologically the follicle epithelium is flattened and cuboidal, and colloid is abundant during periods of involution. Diffuse nontoxic (simple) goiter causes enlargement of the entire gland without producing nodularity. Because the enlarged follicles are filled with colloid, the term colloid goiter has been applied to this condition. This disorder occurs Clinical Features in both an endemic and a sporadic distribution. As stated earlier, most persons with simple goiters are clini- Endemic goiter occurs in geographic areas where the soil, cally euthyroid. Therefore, the clinical manifestations are water, and food supply contain low levels of iodine. The primarily related to mass effects from the enlarged thyroid term endemic is used when goiters are present in more gland (Fig. 24.14). Although serum T3 and T4 levels are than 10% of the population in a given region. Such condi- normal, the serum TSH is usually elevated or at the upper tions are particularly common in mountainous areas of range of normal, as is expected in marginally euthyroid the world, including the Andes and Himalayas, where individuals. In children, dyshormonogenetic goiter, caused iodine deficiency is widespread. The lack of iodine by a congenital biosynthetic defect, may induce cretinism. leads to decreased synthesis of thyroid hormone and a compensatory increase in TSH, leading to follicular cell Multinodular Goiter hypertrophy and hyperplasia and goitrous enlargement. With increasing dietary iodine supplementation, the With time, recurrent episodes of hyperplasia and involution frequency and severity of endemic goiter have declined combine to produce a more irregular enlargement of the significantly, although as many as 200 million people thyroid, termed multinodular goiter. Virtually all long-standing worldwide continue to be at risk for severe iodine simple goiters convert into multinodular goiters. Multi- deficiency. nodular goiters produce the most extreme thyroid enlarge- Variations in the prevalence of endemic goiter in ments and are more frequently mistaken for neoplasms regions with similar levels of iodine deficiency point to than any other form of thyroid disease. Because they derive the existence of other causative influences, particularly from simple goiter, they occur in both sporadic and endemic dietary substances, referred to as goitrogens. The inges- tion of substances that interfere with thyroid hormone synthesis at some level, such as vegetables belonging to the Brassicaceae (Cruciferae) family (e.g., cabbage, cauliflower, Brussels sprouts, turnips, and cassava), has been documented to be goitrogenic. Native populations subsisting on cassava root are particularly at risk. Cassava contains a thiocyanate that inhibits iodide transport within the thyroid, worsening any concurrent iodine deficiency. Sporadic goiter occurs less frequently than does endemic goiter. There is a striking female preponderance and a peak incidence at puberty or in young adult life. Sporadic goiter can be caused by several conditions, including the ingestion of substances that interfere with thyroid hormone synthesis. In other instances, goiter may result from hereditary enzymatic defects that interfere with thyroid hormone synthesis, all transmitted as autosomal recessive conditions (dyshormonogenetic goiter; see earlier). In most cases, however, the cause of sporadic goiter is not apparent. MORPHOLOGY Two phases can be identified in the evolution of diffuse nontoxic goiter: the hyperplastic phase and the phase of colloid involu- tion. In the hyperplastic phase, the thyroid gland is diffusely and Figure 24.14 A 52-year-old woman with a huge colloid goiter who symmetrically enlarged, although the increase is usually modest, developed compressive symptoms. (Reproduced with permission from and the gland rarely exceeds 100 to 150 g. The follicles are lined Lloyd RV, Douglas BR, Young WF Jr, editors: Atlas of Nontumor Pathology: Endocrine Diseases, Washington, DC, 2002, American Registry of Pathology.) 1084 C H A P T E R 24 The Endocrine System forms, having the same female-to-male distribution and presumably the same origins but affecting older individuals Clinical Features because they are late complications. The dominant clinical features of multinodular goiter are those caused by mass effects. In addition to their cosmetic Pathogenesis effects, goiters may cause airway obstruction, dysphagia, It is believed that multinodular goiters arise because of and compression of large vessels in the neck and upper variations among follicular cells in their response to external thorax (superior vena cava syndrome). Most patients are stimuli, such as trophic hormones. If some cells in a follicle euthyroid or have subclinical hyperthyroidism (identified have a growth advantage, perhaps because of acquired genetic by reduced TSH levels), but about 10% of patients over a abnormalities similar to those that give rise to adenomas, they 10-year period develop an autonomous nodule within a may begin to proliferate autonomously, producing a nodule. long-standing goiter that produces hyperthyroidism (toxic Consistent with this model, both polyclonal and monoclonal multinodular goiter), also known as Plummer syndrome. The nodules coexist within the same multinodular goiter, the incidence of malignancy in long-standing multinodular latter presumably having arisen because of the acquisition goiters is low (