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Thyroid GlandNormal ThyroidThe thyroid gland develops from an evagination of the tongue anlage, termed foramen cecum, and then descends to the neck. May descend into thorax in abnormal conditions. If the canal formed by the evagination doesn't close, then thyroglossal cysts persist. Aberrant thyroid tissue is usually found in the midline, anterior triangle of neck. Normally the thyroid weighs 20-25gm. HistologyFig. 1a Normal Thyroid Microscopic Spheroidal Follicles are formed by acini lined by cuboidal epithelium. The cells possess microvilli that project into the colloid. The colloid material in follicles contains thyroglobulin, which is the carrier molecule for T3 and T4. The microvilli are believed to participate in the mobilization of thyroid hormones from Thyroglobulin, by the enzymatic cleavage of T3/T4 from Thyroglobulin. Thyroid hormone affects cellular oxidative processes throughout the body. Hormone Synthesis.
Feedback mechanisms:If TBG increases there is less T3/T4 then TSH increases, then stimulation of thyroid tissue growth occurs. T4 binds to alpha globulin (T4 is the most commonly synthesized hormone in thyroid). T3 binds less tightly. TBG increases with pregnancy. Decreases with advanced liver damage.
Control of Thyroid Function:Pituitary Thyroid AxisTSH regulates the synthesis and secretion of thyroxine (T4) and triiodothyronine (T3). TSH is a 28 kDa glycoprotein secreted by pituitary thyrotrophs and is composed of two subunits. Its alpha-subunit is identical to the alpha-subunit of LH and FSH and is devoid of biologic activity. The beta-subunit determines the biologic actions and immunologic characteristics of TSH. TSH circulates unbound in blood and has a half-life of approximately 50 minutes. It is secreted in a pulsatile fashion with the highest levels found between 0200 and 0400 hours. The major regulator of TSH secretion is negative feedback control on thyrotrophs by thyroxine (T4) and triiodothyronine (T3). However, hypothalamic TRH is necessary for the normal maintenance of TSH secretion. TSH secretion in response to TRH stimulation is enhanced when thyroid hor-mone levels are low and blunted when thyroid hormone levels are high. T4 and T3 circulate primarily in the protein bound state -- thyroxine-binding globulin (TBG), thyroxine-binding prealbumin circulated unbound -- it is this free fraction that is biologically active. T3 has a 3-fold greater biologic activity than T4. These hormones have many target tissues and increase metabolic ac-tivity and protein synthesis. Conditions which affect TBG levels affect the levels of total T4. For example, estrogens (oral contraceptives, pregnancy), genetically determined, and acute hepatitis may increase levels of TBG. Whereas, in the settings of glucocorticoid therapy, severe illness, or nephrotic syndrome TBG levels may be low. Click here for more information on the Pituitary Thyroid Axis
Clinical SyndromesHypothyroidism.When thyroid hormone concentrations are low many metabolic processes slow down. Typical presenting symptoms in-clude: fatigue, slowing of physical and mental performance, hoarseness, cold intolerance, con-stipation, dry skin, coarse hair. Endocrine DisordersSecondary and tertiary hypothyroidism are defined as pituitary TSH deficiency and hypothalamic TRH deficiency, respectively. Secondary hypothyroidism is likely, in the setting of low T4, with inappropriately low serum TSH levels that do not increase after TRH administra-tion. This usually is associated with deficiencies of other anterior pituitary hormones; however, isolated thyrotroph failure has also been reported. Tertiary hypothyroidism is suggested by inappropriately low plasma TSH levels, normal or exaggerated response to exogenous TRH, and imaging evidence of hypothalamic or pituitary stalk disease. Secondary and tertiary hypothyroidism are very rare compared to primary hypothyroidism. Primary hypothyroidismlow concentration of serum T4 and increased level of TSH -- is common. Chronic lymphocytic thyroiditis (Hashimoto's) is the most common form (affecting approximately 2% to 4% of the population in the 5th decade) and frequently serum antibodies toward thyroglobulin or thyroid microsomal an-tigen can be found. When diagnosed, most patients with Hashimoto's thyroiditis are clinically and biochemically euthyroid -- a firm bosselated goiter usually leads to the biochemical confirmation. Stimulation testing is usually not needed in the evaluation of hypothyroidism. Hyperthyroidism.This clinical syndrome is due to excessive circulating thyroid hormone levels. The signs and symptoms are associated with increased tissue metabolic activity and ap-parent increased tissue sensitivity to catecholamines. The clinical presentation in-cludes: nervousness, heat intolerance, weight loss despite increased appetite, warm moist skin, increased perspiration, palpitations, systolic hypertension, and onycholysis. The most common spontaneous form of hyperthyroidism is Graves' disease. It is 6-fold more common in women than men and occurs with a frequency of 0.4% in the general population. This is an autoimmune of disorder associated with the generation thyroid-stimulating Immunoglobulins (TSIS) that act as agonists at the TSH receptor. Two other components of Graves' disease are an infiltrative ophthalmopathy and dermopathy -- also presumably on an autoimmune basis. Other causes of hyperthyroidism include: hyperfunctioning solitary thyroid adenoma, toxic mul-tinodular goiter, lymphocytic thyroiditis with low thyroid radioactive iodine uptake, TSH-producing pituitary tumor, trophoblastic tumor (e.g., hydatidiform mole), and struma ovarii (ovarian teratoma with follicular thyroid tissue). The diagnosis of hyperthyroidism is usually straight forward: elevated serum T4 concentra-tion and suppressed serum STSH concentration. The most common subtype, Graves' disease, can be confirmed with finding an elevated plasma TSI and high thyroid radioactive iodine uptake. The thyroiditis forms of hyperthyroidism are uni-que in that the hyperthyroxinemia is partly due to damage to the thyroid gland and release of stored thyroid hormone -- thyroid radioactive iodine uptake in this circumstance is very low. Inappropriate secretion of TSH.-- Inappropriate secretion of TSH is defined as TSH hypersecretion in the presence of high circulating levels of T4 or T3 or both. TSH levels may be inappropriately high in several clinical settings including resistance to thyroid hormone and pituitary adenomas that secrete TSH. TSH-producing pituitary tumors are very uncommon: only 2 cases were identified among 1,000 pituitary tumor patients in a large neurosurgical series (Wilson, 1984), and a total of approximately 70 cases have been reported in the literature. Despite this low incidence it is important to recognize this condition and to avoid inappropriate management.
Dynamic Function TestsRH-stimulation testThe recent development of ultra-sensitive immunoassays has limited the need for TIM stimulation testing for TSH. TM, a synthetic tripeptide, is administered following a four-hour fast and the patient is at bed rest during the test (Jackson, 1982). TRH 400 mcg [pediatric dose 7 mcg/4 (maximum. dose = 400 mcg)] is administered as an intravenous bolus at time zero after obtaining a blood specimen for baseline TSH. Blood specimens for TSH are obtained at 30 and 60 minutes following TRH administration. Side effects include: transient hypertension or hypotension, headache, dizziness, metallic taste, sensation of warmth urge to micturate, nausea (vomiting rare), and abdominal cramps. These side effects are usually mild and transient. The increase in TSH should be at least 6 MIUAL in all females and in males under 40 years of age and at least 2 MIU/L in males over 40 years. Peak values should occur at 30 minutes. An aggregated rise in TSH is consistent with primary hypothyroidism --however, no strict criteria exist to distinguish the response of patients with primary hypothyroidism from the response of normal subjects. The incremental TSH response to TRH is significantly greater in hyper-prolactinemic women and obese women than in normal women. A blunted TSH response is consistent with secondary hypothyroidism when clinical and chemical evidence of hypothyroidism exists. In addition, a blunted TSH response is consistent with autonomous thyroid function even in some patients who are clinically euthyroid (e.g., euthyroid Graves'). A normal response to TRH excludes the diagnosis of hyperthyroidism. A blunted TSH response can occur with: elderly patients, psychiatric disorders, acute medical illness, chronic renal failure, glucocorticoid excess, dopamine agonists, and salicylates.
TSH CONTROLS1. Hypothalamic and hypophyseal. 2. Feedback inhibition of TSH. TSH stimulates hormone production and protein synthesis, through activation of adenylate cyclase. TSH increases exocytosis as well as increased pseudopod formation on thyroid gland epithelial cells. TSH, LH and FSH have identical alpha chains, beta chain critical for receptor interaction on thyroid epithelial cell membrane. Half life of TSH is less than 1 hr. Only free hormone regulates the hypophysis. 3. T3/T4 act to suppress production of TSH in hypothalamus- hypophyseal circuit. 4. Auto-regulation of thyroid gland also exists and is gaining recognition as a control mechanism.
Thyroid Hormone Transport:
Conditions Influencing TBG:Increased:
Decreased:
Hormone Inactivation Via deiodinase, that break up the thyroid hormone rings. Thyroid Hormone Action:Thyroid hormone interacts with nuclei of cells by binding to nuclear receptors and mitochondrial receptors with resulting increase of ATP. Actions:
Since the thyroid is in a constant state of adaptation, i.e. during puberty and pregnancy, as well as during stress, it is not surprising to observe manifestation of thyroid gland pathology during these conditions. Certain substances affect thyroid gland hormone synthesis. Thiourea and Mercaptoimidazole inhibit oxidation of iodide with resulting decrements of circulating T3/T4. This results in TSH-mediated hypercellular follicles. Conversely, an increment of iodides results in increased colloid, but lower thyroid function. Increased iodide intake results in thyroid block (Wolff-Chaikoff Block).
Main Thyroid Function Tests:
Pathologic Conditions:
Hyperthyroidism:Thyrotoxicosis:T3/T4 levels are increased, radioiodine uptake elevated, failure of T3 suppression, there is a hypermetabolic state. Clinical: Nervousness, increased pulse, weight loss, heat intolerance, tremor. Warm, flushed, moist skin. Wide eyed gaze, upper lid retraction. Supraventricular arrhythmias. There may be myocardial lymphocytic and eosinophilic infiltration. Thyrotoxic cardiomyopathy. New myosin with increased ATPase activity.
Hypothyroidism:
Causes:
Cretinism:Signs:Mental retardation, macroglossia. Delayed fontanel closure, pot-belly delayed epiphyseal closure. Lab : low T3/T4. Myxedema:Signs:Fatigue, lethargy, cold intolerance, periorbital edema. Thick, dry skin. Enlargement of the tongue. Decreased cardiac output. Lab: Low T3/T4. Primary type-High TSH . Hypothalamic failure-low TSH. High cholesterol, macrocytic anemia, stippling of epiphyses. Thyroiditis:Etiology:
Hashimoto's Thyroiditis (Struma Lymphomatosa).Deficiency in suppressor T-cells. Increment in cytotoxic T-cells and activated B-cells. HLADr5. Autoantibodies bind to TSH receptor activating cells as TSH would. Pathology:Intense interstitial infiltrate with lymphocytes and plasma cells as well as lymphocyte follicle formation. Characteristics:
Types of Antibodies:
It is possible that a viral infection stimulates the production of interferon-gamma inducing the expression of HLA Dr antigens, leading to the triggering of the autoimmune process. Morphological Variants:
Clinical: Goitrous enlargement, TSH increment may be mild at the onset. T3/T4 may be Nl then low. Increased incidence of lymphoma in these patients. De Quervain's Granulomatous ThyroiditisGenerally secondary to a viral infection by:
Transient hyperthyroidism. The disease is not autoimmune. Pathology:Granulomas with giant cells, macrophages, lymphocytes and destroyed thyroid follicles.
Clinically: The disease has an acute, febrile onset, with acute enlargement of the gland. Increased Sed rate. Transient increase of T3/T4 and decreased TSH.
Subacute Lymphocytic Thyroiditis Responsible for 15% of cases of thyroiditis. T3/T4 levels are increased. More common in postpartum. Riedel's ThyroiditisFemale to male ratio 3:1. Fibrosing, sclerosing process of stroma. Stony hard thyroid. May resemble Carcinoma. Graves Disease:Hyperthyroidism caused by a diffuse enlargement of the thyroid gland. There is ophthalmopathy with lid lag. Female to male ratio 5:1. The disease is autoimmune, with production of an IgG antibody against the TSH receptor. There are immune response genes of the HLADr3 type. It appears mostly in the third decade. Auto reactive B-cells are not held in check because of a genetic defect of T-suppressor cells. TSI's thyroid stimulating Ig's. TGI's thyroid growth Ig's. Clinically-Ophthalmopathy is also of autoimmune origin. Monoclonal antibodies to eye muscle antigen cross react with thyroid microsomes. There is diffuse hyperplasia of the acini with increased height of epithelium (tall columnar cells). Hypertrophic Golgi. Increased vascularity of the gland. Exophthalmos is at the expense of increased mucopolysaccharides with fibrosis and contracture of eye muscles. Graves presents with thyrotoxicosis with increased T3/T4. Corneal lacerations may occur due to exposure. No increment in cancer observed. Diffuse nontoxic goiter.May become nodular. Diffuse nontoxic simple goiter.
Female to male ratio: 8:1. Mechanism:Low iodide causes release of TSH with production of Adenylcyclase with resulting gland growth. Increased demand in puberty and pregnancy. Other causes: hereditary:
Pathological stages:
Clinical:Euthyroid--asymptomatic, cosmetic. Early iodide ingestion may decrease the formation of goiter. Colloid goiter is a forerunner of nodular goiter. There is a heterogeneity in both iodination and response to TSH. Then there is a generation of nodules, bleeding, with subsequent scarring, and further formation of nodules. Pathology:Nodules, hemosiderin, hemorrhage, calcification. Multinodular goiter: Increased size and location of gland. Abnormal function. Must be differentiated from neoplasm. Symptoms:Nodular enlargement of long duration with sensation of choking, superior vena cava syndrome, less than 50% of cases result in toxic nodular goiter. Resembles thyrotoxicosis of Graves disease but without exophthalmos or dermatopathy. May present with cardiac symptoms. T3/T4 may be elevated slightly. Radioiodine accumulated in patchy pattern.
TumorsClinically palpable nodules are present in 4 to 7% of adults in the US. Children 1%. More than 5-fold in individuals exposed to ionizing radiation. 25 to 35 cases per million have cancer of the thyroid. 1 to 2% percent of palpable masses in the thyroid are cancerous. Thyroid cancer is uncommon. 50% of palpable nodules are tumors. 70% of these are benign adenomas. Most cancers and adenomas do not uptake iodine 125 (cold nodules). Only 20% of cold nodules are carcinomas. Rarely adenomas or carcinomas may be hot nodules. Thyroglobulin levels are significant in patients with surgical or radioactive ablation, because they indicate the possibility of recurrence. Fine needle aspiration is useful, 5% are positive for carcinoma. Nodules in younger patients have a higher risk of being carcinomas. Adenomas:
All follicular papillary lesions are considered carcinomas. Benign adenomas rarely exceed 3 cm in diameter. Pathology of adenomas:Fig . 5 Gross Image of Solitary Thyroid Adenoma Fig. 6 Benign Thyroid Adenoma Microscopic Image
Clinical course:Most are cold nodules, slow increase in size, sudden enlargement may occur with hemorrhage, if they become hyperactive they may become radioactively hot. Other benign lesions (various types of cysts). Malignant tumors:Thyroid carcinoma causes 7000 deaths per year in the US. Female to male ratio 3:1. Spectrum of disease: Range from relatively benign papillary carcinomas to undifferentiated carcinomas. 4 to 9% of children irradiated for acne or thymic enlargement have developed thyroid carcinomas 20 years after the event. Types of carcinomas:
Clinical Staging:
Papillary carcinomas:Fig. 7 Gross Image Papillary Carcinoma Fig. 8 Microscopic figure of papillary Ca. FNA Papillary Carcinoma Fig. 9 Good prognosis even when follicular areas are seen. 10 to 20% of cases appear clinically as positive neck nodes. Fig. 10 ( positive Lymph Node invaded by Papillary Carcinoma of Thyroid. More prominent in third to seventh decade. 80% of thyroid carcinomas of patients under 40 years old. Sometimes appear as an incidental painless mass. 10% of autopsies may show papillary carcinomas. Pathology:Papillary fronds with vessels. Nuclei have a typical "Orphan Annie" or"ground glass" appearance. Psammoma bodies frequently seen positive for thyroglobulin. E.M. shows increased mitochondria, increased RER, increased apical microvilli. Papillary carcinomas have an indolent growth. 40% of cases spread out of capsule. 10% go to distant metastases. 20% of children show lung mets. Prognosis:
Follicular carcinoma:25% of all carcinomas of thyroid. More frequent in females. More aggressive than papillary carcinoma. 70% mortality in 5 years. Pathology:No "ground glass" nuclei, no papillary fronds, no psammoma bodies. Many areas of hemorrhage, vascular infiltration, necrosis. Fig. 11 Gross Image of Follicular Carcinoma of Thyroid Fig. 12 Microscopic image of follicular Carcinoma of the thyroid Microscopic Image shows :Small follicles with prominent nucleoli. Types:
Clinical: Stages III and IV can be controlled with TSH followed by radiation if they are well-differentiated. Medullary Carcinoma:In addition to the cuboidal cells of the acini , another endocrine cell is present in the thyroid, the c-cell, which synthesizes calcitonin. Medullary carcinomas arise from c-cells. These are neuroendocrine neoplasms. Characteristics: amyloid stroma
90% appear in adults, the rest in children. 80 to 90% secrete calcitonin. Somatostatin, gastrin or bombesin, histaminase, prostaglandins (causative of diarrhea in 30% of cases) and rarely ACTH. May be solitary with subsequent extension or multicentric. Gross pathology: white or tan yellow nodules. 50% have distant mets at time of diagnosis. Microscopic pathology: round neuroid cells with an organoid pattern. Calcitonin secretory granules, amyloid stroma, c-cell hyperplasia, calcium and pentagastrin secretion. Mets to lung, liver and bones. Fig. 13 Medullary Carcinoma of the Thyroid Fig14 Anti-Calcitonin for Medullary Ca of the thyroid Fig15 FNA of Medullary carcinoma
Undifferentiated carcinoma:10 to 15% of cases. Most in seventh-eighth decade. May be small or giant cell types. Follicular and papillary patterns may be seen. These tumors usually appear in the seventh decade but may be seen in children. Because they are diagnosed earlier , they now have a better prognosis than formerly. Agressive chemotherapy and radiation are used to treat these neoplasms. Fig. 16 Anaplastic Carcinoma of the thyroid Fig. 17 FNA of anaplastic thyroid Ca.
Other tumors:Hodgkin's disease and non-Hodgkin's lymphomas may accompany Hashimoto's. Sarcomas may be seen. Thyroid Sarcoma Fig. 18
Other anomalies of thyroid: Fig. 19 Thyroglossal duct cyst these are midline lesions. The tract is lined by squamous epithelium with dense lymphocytic infiltrate adjacent to epithelium. Ectopic thyroidfound most commonly at the base of the tongue. Athyrotic cretinism may result from removal of glossal thyroid. Secondary thyroid atrophy:
Clinical SyndromesHypothyroidism.-- When thyroid hormone concentrations are low many metabolic proces-ses slow down. Typical presenting symptoms in-clude: fatigue, slowing of physical and mental performance, hoarseness, cold intolerance, con-stipation, dry skin, and coarse hair. Secondary and tertiary hypothyroidism are defined as pituitary TSH deficiency and hypothalamic TRH deficiency, respectively. Secondary hypothyroidism is likely, in the setting of low T4, with inappropriately low serum TSH levels that do not increase after TRH administra-tion. This usually is associated with deficiencies of other anterior pituitary hormones; however, isolated thyrotroph failure has also been reported. Tertiary hypothyroidism is suggested by inappropriately low plasma TSH levels, nor-mal or exaggerated response to exogenous TRH, and imaging evidence of hypothalamic or pituitary stalk disease. Secondary and tertiary hypothyroidism are very rare compared to primary hypothyroidism. Primary hypothyroidismlow concentration of serum T4 and increased level of TSH -- is com-mon. Chronic lymphocytic thyroiditis (Hashimoto's) is the most common form (affect-ing approximately 2% to 4% of the population in the 5th decade) and frequently serum antibodies toward thyroglobulin or thyroid microsomal an-tigen can be found. When diagnosed, most patients with Hashimoto's thyroiditis are clini-cally and biochemically euthyroid -- a firm bos-selated goiter usually leads to the biochemical confirmation. Stimulation testing is usually not needed in the evaluation of hypothyroidism. Hyperthyroidism.This clinical syndrome is due to excessive circulating thyroid hormone levels. The signs and symptoms are associated with increased tissue metabolic activity and ap-parent increased tissue sensitivity to catecholamines. The clinical presentation in-cludes: nervousness, heat intolerance, weight loss despite increased appetite, warm moist skin, increased perspiration, palpitations, systolic hypertension, and onycholysis. The most common spontaneous form of hyperthyroidism is Graves' disease. It is 6-fold more common in women than men and occurs with a frequency of 0.4% in the general population. This is an autoimmune of disorder associated with the generation of thyroid-stimulating Immunoglobulins (TSIS) that act as agonists at the TSH receptor. Two other components of Graves' disease are an infiltrative ophthalmopathy and dermopathy -- also presumably on an autoimmune basis. Other causes of hyperthyroidism include: hyper-functioning solitary thyroid adenoma, toxic mul-tinodular goiter, lymphocytic thyroiditis with low thyroid radioactive iodine uptake, TSH-produc-ing pituitary tumor, trophoblastic tumor (e.g., hydatidiform mole), and struma ovarii (ovarian teratoma with follicular thyroid tissue). The diagnosis of hyperthyroidism is usually straight forward: elevated serum T4 concentra-tion and suppressed serum STSH concentration. The most common subtype, Graves' disease, can be confirmed with finding an elevated plasma TSI and high thyroid radioactive iodine uptake. The thyroiditis forms of hyperthyroidism are uni-que in that the hyperthyroxinemia is due to damage to the thyroid gland and release of stored thyroid hormone -- thyroid radioactive iodine uptake in this circumstance is very low.
Inappropriate secretion of TSH.-- Inap-propriate secretion of TSH is defined as TSH hypersecretion in the presence of high circulating levels of T4 or T3 or both. TSH levels may be inappropriately high in several clinical settings including resistance to thyroid hormone and pituitary adenomas that secrete TSH. TSH--producing pituitary tumors are very uncommon: only 2 cases were identified among 1,000 pituitary tumor patients in a large neurosurgical series (Wilson, 1984), and a total of approximate-ly 70 cases have been reported in the literature. Despite this low incidence it is important to recognize this condition and to avoid inap-propriate management. Updated June 13, 2005
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