Chapter 4. Thyroid Gland

• Identify the steps and control factors of thyroid hormone biosynthesis, storage, and release.
• Describe the distribution of iodine and the metabolic pathway involved in thyroid hormone synthesis.
• Explain the importance of thyroid hormone binding in blood for free and total thyroid hormone levels.
• Understand the significance of the conversion of tetraiodothyronine (T4) to triiodothyronine (T3) and reverse T3 (rT3) in extrathyroidal tissues.
• Understand how thyroid hormones produce their cellular effects.
• Describe their effects on development and metabolism.
• Understand the causes and consequences of excess and deficiency of thyroid hormones.

Thyroid hormones play important roles in maintaining energy homeostasis and regulating energy expenditure. Their physiologic effects, mediated at multiple target organs, are primarily to stimulate cell metabolism and activity. The vital roles of these hormones, particularly in development, differentiation, and maturation, are underscored by the severe mental retardation observed in infants with deficient thyroid hormone function during gestation. Thyroid hormones are derived from the amino acid tyrosine and are produced by the thyroid gland in response to stimulation by thyroid-stimulating hormone (TSH) produced by the anterior pituitary. TSH, in turn, is regulated by the hypophysiotropic peptide thyrotropin-releasing hormone (TRH) (Figure 4–1). Thyroid hormone production is also under regulation by dietary iodine.

The thyroid gland is a highly vascular, ductless alveolar (acinar) gland located in the anterior neck in front of the trachea. The gland weighs 10–25 g and consists of a right and left lobe connected by the isthmus. The cellular composition of the thyroid gland is diverse, including the following:

• Follicular (epithelial) cells, involved in thyroid hormone synthesis
• Endothelial cells lining the capillaries that provide the blood supply to the follicles
• Parafollicular or C cells, involved in the production of calcitonin, a hormone involved in calcium metabolism
• Fibroblasts, lymphocytes, and adipocytes

Thyroid Follicle

The main function of the thyroid gland is the synthesis and storage of thyroid hormone. The secretory or functional unit of the thyroid gland is the thyroid follicle, consisting of a layer of thyroid epithelial cells arranged around a large central cavity filled with colloid. Colloid makes up approximately 30% of the thyroid gland mass and contains a protein called thyroglobulin (Tg). Tg plays a central role in the synthesis and storage of thyroid hormone, as discussed later. The thyroid epithelial cells are morphologically and functionally polarized. That is, each side or compartment of the cell has specific functions pertaining to the synthesis of thyroid hormones and their release. The apical surface of the follicular cell faces the follicular lumen, where colloid is stored. The basolateral surface faces the interstitium and is therefore exposed to the bloodstream.

The polarity of the thyroid follicular cells is important in the overall function of the cell. Thyroid hormone synthesis requires the iodination of tyrosine residues on the protein Tg, which is stored in the colloid. This process occurs in the colloid at the apical plasma membrane, yet iodine is obtained from the circulation. Whereas thyroid hormone synthesis occurs on the apical side of the thyroid epithelial cell, hormone release occurs at the basolateral side of the cell. Thus, the polarity of the thyroid epithelial cells is critical for maintaining basolaterally located iodide uptake and T4 (tetraiodothyronine) deiodination, and apically located iodide efflux and iodination mechanisms.

The parafollicular cells surrounding the follicles synthesize and secrete the hormone calcitonin, and therefore they are frequently referred to as C cells. They are preferentially located in central regions of the thyroid gland lobes, where follicular cell activity is the greatest. Parafollicular cells secrete regulatory factors other than calcitonin that modulate follicular cell activity in a paracrine fashion.

Blood and Nerve Supply

The thyroid gland is highly vascularized with arterial blood derived from the superior and inferior thyroid arteries. The veins draining the thyroid gland form a plexus on the surface of the gland and on the front of the trachea and give rise to the superior, middle, and inferior thyroid veins, which drain into the internal jugular and innominate veins. The lymphatic vessels end in the thoracic and right lymphatic trunks. Innervation to the thyroid gland is provided through the middle and inferior cervical ganglia of the sympathetic nervous system.

Hypothalamic Regulation of Thyroid-Stimulating Hormone Release

TSH is transported in the bloodstream to the thyroid gland, where it binds to the TSH receptor located on the basolateral membrane of thyroid follicular epithelial cells. The TSH receptor is a cell membrane G protein–coupled receptor. Adequate function of the TSH receptor is critical in the development, growth, and function of the thyroid gland. Binding of TSH to its receptor initiates signaling through cyclic 3′,5′-adenosine monophosphate (cAMP), phospholipase C, and the protein kinase A signal transduction systems. Activation of adenylate cyclase, formation of cAMP, and activation of protein kinase A regulate iodide uptake and transcription of Tg, thyroid peroxidase (TPO), and the activity of the sodium-iodide (Na+/I−) symporter. Signaling through phospholipase C and intracellular Ca2+ regulate iodide efflux, H2O2 production, and Tg iodination. The TSH receptor is an important antigenic site involved in thyroid autoimmune disease. Autoantibodies to the receptor may act as agonists mimicking the actions of TSH in the case of Graves disease; or antagonists in the case of autoimmune hypothyroidism (Hashimoto thyroiditis).

TSH receptor activation results in stimulation of all of the steps involved in thyroid hormone synthesis, including iodine uptake and organification, production and release of iodothyronines from the gland, and promotion of thyroid growth. As part of this process, TSH regulates thyroidal uptake of nutrients as well as intracellular transport of specific proteins involved in thyroid hormone synthesis, storage, and release. These cellular events involve regulation of cellular metabolic processes, morphologic differentiation, cell proliferation, and protection from apoptosis. Specifically, the biologic effects of TSH include stimulation of gene transcription of the following:

• Na+/I− symporter, the protein involved in transporting and concentrating iodide in the thyroid epithelial cell
• Tg, the glycoprotein that serves as a scaffold for tyrosine iodination and thyroid hormone synthesis, as well as storage of thyroid hormone
• TPO, the enzyme involved in catalyzing the oxidation of iodide and its incorporation into tyrosine residues of Tg
• Thyroid hormones T4 and T3 (triiodothyronine)

As mentioned earlier, both growth and function of the thyroid are stimulated by the rise in cAMP produced by TSH stimulation. Therefore, continued stimulation of the cAMP pathway by binding to the TSH receptor causes hyperthyroidism and thyroid hyperplasia.

Thyroid Hormone Regulation of Thyroid-Stimulating Hormone Release

The production and release of thyroid hormones are under negative feedback regulation by the hypothalamic-pituitary-thyroid axis. The release of TSH is inhibited mainly by T3, produced by conversion of T4 to T3 in the hypothalamus, and in the anterior pituitary by type II deiodinase. The contribution of this intracellularly derived T3 in producing the negative feedback inhibition of TSH release is greater than that of T3 derived from the circulation. Other neuroendocrine mediators that inhibit TSH release include dopamine, somatostatin, and glucocorticoids at high levels, which produce partial suppression of TSH release (see Chapter 10).

Thyroid Hormone Synthesis

Thyroglobulin, plays an important role in the synthesis and storage of thyroid hormone (Figure 4–2). Tg is a glycoprotein containing multiple tyrosine residues. It is synthesized in the thyroid follicular epithelial cells and secreted through the apical membrane into the follicular lumen, where it is stored in the colloid. A small amount of noniodinated Tg is also secreted through the basolateral membrane into the circulation. Although circulating levels of Tg can be detected under normal conditions, levels are elevated in diseases such as thyroiditis and Graves disease.

Tg can be considered a scaffold upon which thyroid hormone synthesis takes place. Once Tg is secreted into the follicular lumen, it undergoes major post-translational modification during the production of thyroid hormones. At the apical surface of the thyroid follicular epithelial cells, multiple tyrosine residues of Tg are iodinated, followed by coupling of some of the iodotyrosine residues to form T3 and T4.

Regulation of Iodine Metabolism in the Thyroid Follicular Cell

The iodination of Tg residues is a process that occurs at the apical membrane. Thus, once inside the cell, iodide must leave the follicular cell through apical efflux by an iodide-permeating mechanism consisting of a chloride-iodide transporting protein (iodide channel) located in the apical membrane of the thyroid follicular cell. The uptake, concentration, and efflux of iodide through the iodide channel are all a function of TSH-stimulated transepithelial transport of iodide. As already mentioned, this transcellular transport of iodide is possible because of the morphologic and functional polarization of the thyroid epithelial cell.

The transport of iodine through the Na+/I− symporter can be substituted by other substances including perchlorate and pertechnetate. Radiolabeled pertechnetate (99mTcO4) can be used for imaging of the thyroid gland. Moreover, the ability of the thyroid gland to accumulate iodine allows therapeutic administration of radioactive iodine leading to ablation of thyroid tissue, which is important in the treatment of thyroid malignancies. In the follicular lumen, tyrosine residues of Tg are iodinated by iodine (I+; formed by oxidation of I−by TPO) (see Figure 4–2). This reaction requires hydrogen peroxide, which is generated by a flavoprotein Ca++-dependent reduced nicotinamide adenine dinucleotide phosphate oxidase at the apical cell surface and serves as an electron acceptor in the reaction process. As shown in the figure, iodine bonds to carbon 3 or to carbon 5 of the tyrosine residues on Tg in a process referred to as the organification of iodine. This iodination of specific tyrosines located on Tg yields monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT) residues that are enzymatically coupled to form triiodothyronine (T3) or tetraiodothyronine (T4). The coupling of iodinated tyrosine residues, either of 2 DIT residues or of 1 MIT and 1 DIT residue, is catalyzed by the enzyme thyroid peroxidase. Because not all of the iodinated tyrosine residues undergo coupling, Tg stored in the follicular lumen contains MIT and DIT residues as well as formed T3 and T4 (Figure 4–4).

As mentioned previously, TSH controls the energy-dependent uptake and concentration of iodide by the thyroid gland and its transcellular transport through the follicular epithelial cell. However, iodine metabolism within the thyroid can also be regulated independently of TSH. This mechanism is important when plasma iodide levels are elevated (15–20-fold above normal) because this elevation inhibits the organic binding of iodine within the thyroid. This autoregulatory phenomenon consisting of inhibition of the organification of iodine by elevated circulating levels of iodide is known as the Wolff-Chaikoff effect. This effect lasts for a few days and is followed by the so-called escape phenomenon, at which point the organification of intra-thyroidal iodine resumes and the normal synthesis of T4 and T3 returns. The escape phenomenon results from a decrease in the inorganic iodine concentration inside the thyroid gland from downregulation of the Na+/I− symporter. This relative decrease in intra-thyroidal inorganic iodine allows the TPO–H2O2 system to resume normal activity. The mechanisms responsible for the acute Wolff-Chaikoff effect have not been elucidated but may be caused by the formation of organic iodocompounds within the thyroid.

Regulation of Thyroid Hormone Release

The preceding sections have described the steps involved in the synthesis of thyroid hormone, TSH regulation of the iodination of tyrosine residues on Tg, and coupling of the iodinated residues for the formation of thyroid hormones (see Figure 4–4). TSH also regulates the release of thyroid hormones from the thyroid gland. The synthesis of thyroid hormone takes place in the colloid space. As mentioned previously, the apical surface of the follicular epithelial cell faces the colloid and not the interstitial space, and thus has no access to the bloodstream. Therefore, thyroid hormone release involves endocytosis of vesicles containing Tg from the apical surface of the follicular cell. The vesicles fuse with follicular epithelial phagolysosomes, leading to proteolytic digestion and cleavage of Tg. In addition to the thyroid hormones T4 and T3, the products of this reaction include iodinated tyrosine residues (MIT and DIT). MIT and DIT are deiodinated intracellularly, and iodide is transported by apical efflux into the follicular colloid space, where it is reused in thyroid hormone synthesis. T4 and T3 are released from the basolateral membrane into the circulation. The thyroid gland releases greater amounts of T4 than T3, so plasma concentrations of T4 are 40-fold higher than those of T3 (90 vs 2 nM). Most of the circulating T3 is formed peripherally by deiodination of T4, a process that involves the removal of iodine from carbon 5 on the outer ring of T4. Thus, T4 acts as a prohormone for T3. Although this deiodination occurs predominantly in the liver, some occurs in the thyroid follicular epithelial cell itself. This intrathyroidal deiodination of T4 is the result of TSH stimulation of the type I deiodinase.

Transport and Tissue Delivery of Thyroid Hormones

Once thyroid hormones are released into the circulation, most of them circulate bound to protein. Approximately 70% of T4 and T3 is bound to thyroid-binding globulin. Other proteins involved in thyroid binding include transthyretin, which binds 10% of T4, and albumin, which binds 15% of T4 and 25% of T3. A small fraction of each hormone (0.03% of T4 and 0.3% of T3) circulates in its free form. This fraction of the circulating hormone pool is bioavailable and can enter the cell to bind to the thyroid receptor. Of the 2 thyroid hormones, T4 binds more tightly to binding proteins than T3 and thus has a lower metabolic clearance rate and a longer half-life (7 days) than T3 (1 day). The kidneys readily excrete free T4 and T3. Binding of thyroid hormones to plasma proteins ensures a circulating reserve and delays their clearance.

The release of hormone from its protein-bound form is in a dynamic equilibrium. Although the role of binding proteins in delivery of hormone to specific tissues remains to be fully understood, it is known that drugs such as salicylate may affect thyroid hormone binding to plasma proteins. The binding-hormone capacity of the individual can also be altered by disease or hormonal changes. For example, liver disease is associated with a decrease in the synthesis of binding proteins, whereas high estrogen levels (eg, during pregnancy) increase binding-protein synthesis. These changes in the total amount of plasma proteins available to bind thyroid hormone will impact the total amount of circulating thyroid hormone because of a constant homeostatic adjustment to changes in free hormone levels. As in a classic feedback system, the hypothalamic-pituitary-thyroid axis is controlled by the amount of free hormone available. Thus, a decrease in free thyroid hormone because of an increase in plasma-binding proteins will stimulate the release of TSH from the anterior pituitary, which will in turn stimulate the synthesis and release of thyroid hormone from the thyroid gland. In contrast, a decrease in binding-protein levels, with a resulting rise in free thyroid hormone levels, will suppress TSH release and decrease thyroid hormone synthesis and release. These dynamic changes occur throughout the life of the individual, whether in health or disease. Disruption in these feedback mechanisms will result in manifestations of excess or deficient thyroid hormone function.

Thyroid Hormone Metabolism

This extrathyroidal progressive deiodination of thyroid hormones catalyzed by deiodinases plays a significant role in thyroid hormone metabolism and requires the trace element selenocysteine for optimal enzymatic activity. Three types of deiodinases have been identified, which differ in their tissue distribution, catalytic profiles, substrate specificities, physiologic functions, and regulation.

Type I Deiodinase

Type I deiodinase catalyzes outer- and inner-ring deiodination of T4 and rT3. It is found predominantly in the liver, kidney, and thyroid. It is considered the primary deiodinase responsible for T4 to T3 conversion in hyperthyroid patients in the periphery. This enzyme also converts T3 to T2. The activity of type I deiodinase expressed in the thyroid gland is increased by TSH-stimulated cAMP production and has a significant influence on the amount of T3 released by the thyroid. Propylthiouracil and iodinated x-ray contrast agents such as iopanoic acid inhibit the activity of this enzyme and consequently the thyroidal production of T3.

Type II Deiodinase

Type II deiodinase is expressed in the brain, pituitary gland, brown adipose tissue, thyroid, placenta, and skeletal and cardiac muscle. Type II deiodinase has only outer-ring activity and converts T4 to T3. This enzyme is thought to be the major source of T3 in the euthyroid state. This enzyme plays an important role in tissues that produce a relatively high proportion of the receptor-bound T3 themselves, rather than deriving T3 from plasma. In these tissues, type II deiodinases are an important source of intracellular T3 and provide more than 50% of the nuclear receptor-bound T3. The critical role of the type II deiodinases is underscored by the fact that T3 formed in the anterior pituitary is necessary for negative feedback inhibition of TSH secretion.

Type III Deiodinase

Type III deiodinase is expressed in the brain, placenta, and skin. Type III deiodinase has inner-ring activity and converts T4 to rT3, and T3 to T2, thus inactivating T4 and T3. This process is an important feature in placental protection of the fetus. The placental conversion of T4 to rT3 and of T3 to T2 reduces the flow of T3 (the most active thyroid hormone) from mother to fetus. Small amounts of maternal T4 are transferred to the fetus and converted to T3, which increases the T3 concentration in the fetal brain, preventing hypothyroidism. In the adult brain, the expression of type III deiodinases is enhanced by thyroid hormone excess, serving as a protective mechanism against high thyroid hormone concentrations.

Biologic Effects of Thyroid Hormones

Thyroid hormone receptors are expressed in virtually all tissues and affect multiple cellular events. Their effects are mediated primarily by the transcriptional regulation of target genes, and are thus known as genomic effects. Recently, it has become evident that thyroid hormones also exert nongenomic effects, which do not require modification of gene transcription. Some of these effects include stimulation of activity of Ca2+-adenosine triphosphatase (ATPase) at the plasma membrane and sarcoplasmic reticulum, rapid stimulation of the Na+/H+ antiporter, and increases in oxygen consumption (see Chapter 10). The nature of the receptors that mediate these effects and the signaling pathways involved are not yet completely elucidated. However, T3 exerts rapid effects on ion fluxes and electrophysiologic events, predominantly in the cardiovascular system.

Thyroid Hormone Receptors

The cellular actions of thyroid hormones are mediated by multiple thyroid hormone receptor isoforms derived from 2 distinct genes (α and β) encoding thyroid hormone receptors. The functional significance of the different isoforms has not yet been elucidated. Thyroid hormone receptors are nuclear receptors intimately associated with chromatin (see Figure 4–6). Thyroid hormone receptors are DNA-binding transcription factors that function as molecular switches in response to hormone binding. The hormone receptor can activate or repress gene transcription, depending on the promoter context and ligand-binding status. Unoccupied thyroid hormone receptors are bound to DNA thyroid hormone response elements and are associated with a complex of proteins containing corepressor proteins. Hormone binding to the receptor promotes corepressor dissociation and binding of a coactivator, leading to modulation of gene transcription. Thyroid hormone receptors bind the hormone with high affinity and specificity. They have low capacity but high affinity for T3. The majority (85%) of nuclear-bound thyroid hormone is T3, and approximately 15% is T4.

Because thyroid hormone receptors are present in virtually all tissues, thyroid hormones play a vital role in cellular metabolism. The cellular events that they mediate include the following:

• Transcription of cell membrane Na+/K+-ATPase, leading to an increase in oxygen consumption
• Transcription of uncoupling protein, enhancing fatty acid oxidation and heat generation without production of adenosine triphosphate
• Protein synthesis and degradation, contributing to growth and differentiation
• Epinephrine-induced glycogenolysis, and insulin-induced glycogen synthesis and glucose utilization
• Cholesterol synthesis and low-density lipoprotein receptor regulation

Organ-Specific Effects of Thyroid Hormone

Bone

Thyroid hormone is essential for bone growth and development through activation of osteoclast and osteoblast activities. Deficiency during childhood affects growth. In adults, excess thyroid hormone levels are associated with increased risk of osteoporosis.

Cardiovascular System

Thyroid hormone has cardiac inotropic and chronotropic effects, increases cardiac output and blood volume, and decreases systemic vascular resistance. These responses are mediated through thyroid hormone changes in gene transcription of several proteins including Ca2+-ATPase, phospholamban, myosin, β-adrenergic receptors, adenylyl cyclase, guanine-nucleotide–binding proteins, Na+/Ca2+ exchanger, Na+/K+-ATPase, and voltage-gated potassium channels.

Fat

Thyroid hormone induces white adipose tissue differentiation, lipogenic enzymes, and intracellular lipid accumulation; stimulates adipocyte cell proliferation; stimulates uncoupling proteins; and uncouples oxidative phosphorylation. Hyperthyroidism enhances and hypothyroidism decreases lipolysis through different mechanisms. The induction of catecholamine-mediated lipolysis by thyroid hormones results from an increased β-adrenoceptor number and a decrease in phosphodiesterase activity resulting in an increase in cAMP level and hormone-sensitive lipase activity.

Liver

Thyroid hormone regulates triglyceride and cholesterol metabolism, as well as lipoprotein homeostasis. Thyroid hormone also modulates cell proliferation and mitochondrial respiration.

Pituitary

Thyroid hormone regulates the synthesis of pituitary hormones, stimulates growth hormone production, and inhibits TSH.

Brain

Thyroid hormone controls expression of genes involved in myelination, cell differentiation, migration, and signaling. Thyroid hormone is necessary for axonal growth and development.

The widespread distribution of thyroid hormone receptors and the multitude of physiologic effects that they exert are highlighted in cases of abnormal thyroid function (Table 4–2). Dysfunction can result from 3 factors: (1) alterations in the circulating levels of thyroid hormones, (2) impaired metabolism of thyroid hormones in the periphery, and (3) resistance to thyroid hormone actions at the tissue level.

An individual whose thyroid function is normal is said to be in a euthyroid state. The clinical state resulting from an alteration in thyroid function is classified as either hypothyroidism (low thyroid function) or hyperthyroidism (excessive thyroid function). As with most endocrine abnormalities, altered thyroid function may be genetic or acquired, and its duration may be transient or permanent. Autoimmune diseases play an important role in thyroid disease. Abnormal immune responses directed to thyroid-related proteins result in 2 opposite pathogenic processes: thyroid enlargement (hyperplasia) in Graves disease and thyroid destruction in Hashimoto thyroiditis.

The most common presentations of thyroid hormone abnormalities are summarized as follows (see Table 4–2).

Hypothyroidism

Hypothyroidism is the condition resulting from insufficient thyroid hormone action. It has an incidence of 2% in adult women and is less common in men. Two main types are distinguished, primary and secondary hypothyroidism, with primary being the most common. Alternatively, patients may present with signs and symptoms of hypothyroidism but without a decrease in circulating thyroid hormone levels. This condition, known as thyroid hormone resistance, is a rare dominant inherited condition in which the responsiveness of target tissues to thyroid hormone is reduced. It occurs in 1 per 50,000 live births. The low incidence is probably caused by the reduced survival of these embryos. The thyroid-resistant state associated with mutations in the thyroid receptor gene is characterized by elevated circulating levels of free thyroid hormone and normal or elevated levels of TSH. Patients usually present with enlargement of the thyroid gland (goiter) and either normal (euthyroid) or mildly decreased (hypothyroid) metabolic state. The T3, T4, and TSH levels may be high in what appears to be a compensatory mechanism to ensure maintenance of euthyroid and eumetabolic states.

Primary Hypothyroidism

The most frequent cause of hypothyroidism (95% of cases) is disease of the thyroid gland. When the decrease in thyroid function occurs in utero, the result is severe mental retardation or cretinism, underscoring the vital role that thyroid hormone plays in development and growth. Hypothyroidism in adult patients may be associated with either a decrease or an increase in thyroid gland size. The decrease in thyroid tissue is usually caused by autoimmune disease, leading to the destruction of thyroid parenchyma, but it can also be the result of surgery or radioactive iodine treatment. Hypothyroidism may also be associated with thyroid enlargement (goiter), resulting from lymphocytic infiltration as in Hashimoto disease or dietary iodine deficiency.

Secondary Hypothyroidism

Secondary hypothyroidism is characterized by decreased TSH secretion and subsequently decreased thyroid hormone release. It is the result of disorders of the anterior pituitary or hypothalamus and can sometimes occur in association with other abnormalities of anterior pituitary hormones. Secondary hypothyroidism is not because of alterations at the level of the thyroid gland itself and is strictly caused by a lack of stimulation of the TSH receptor because of impaired TSH release.

Hyperthyroidism

Hyperthyroidism is excessive functional activity of the thyroid gland, characterized by increased basal metabolism and disturbances in the autonomic nervous system as a result of excess thyroid hormone production. The incidence is higher in women (2%) than in men (0.02%). Several conditions can lead to hyperthyroidism: diffuse toxic goiter or Graves disease, toxic nodular goiter, toxic adenoma, therapy-induced hyperthyroidism (eg, excess T4 or T3 substitution), excess iodine intake, thyroiditis, follicular carcinoma, and TSH-producing tumor of the pituitary. However, the most common cause of hyperthyroidism in adults is diffuse toxic goiter or Graves disease.

Graves Disease

Graves disease is an autoimmune condition leading to autonomous excess thyroid hormone secretion because of TSH receptor stimulation by immunoglobulin G. The continuous stimulation of TSH receptor by TSH-like antibodies results in excess T4 and T3 production. The incidence of Graves disease peaks in the third to fourth decades and is 8 times more common in women than in men.

Clinically, approximately 40%–50% of patients with hyperthyroidism present with protruding eyes (exophthalmos) as a result of lymphocyte and fibroblast infiltration of the extraocular tissues and muscles, and accumulation of hyaluronate, a glycosaminoglycan produced by fibroblasts in the tissues and muscles. The expression of TSH receptors in the periocular fibroblasts contributes to the pathogenesis of exophthalmos. The majority (90%) of patients with thyroid ophthalmopathy have Graves hyperthyroidism.

Thyroid-Stimulating Hormone–Secreting Adenomas

Secondary hyperthyroidism is caused by increased thyroid hormone release by the thyroid gland in response to elevated TSH levels derived from TSH-secreting pituitary adenomas. TSH-secreting adenomas represent a small fraction (1%–2%) of all pituitary adenomas and result in a syndrome of excess secretion of TSH. The hormonal profile is characterized by the inability to suppress TSH despite elevated levels of free thyroid hormones (T3 and T4).

Euthyroid Sick Syndrome

Euthyroid sick syndrome is a clinical condition in which patients suffering from nonthyroid diseases show biochemical evidence of altered thyroid function, but appear euthyroid when examined clinically. These patients present with normal or decreased T4 concentration, decreased T4 binding to thyroid-binding globulin, decreased T3 concentration, increased rT3 concentration, normal TSH, and normal scintigraphic imaging. This condition can be precipitated by stresses such as fasting, starvation, anorexia nervosa, protein malnutrition, surgical trauma, myocardial infarction, chronic renal failure, diabetic ketosis, cirrhosis, sepsis, and hyperthermia (see Chapter 10). The alteration in thyroid hormone profile is because of an increase in type III deiodinase activity. Euthyroid sick syndrome may also be because of impaired conversion of T4 to T3, as occurs with pharmacologic agents such as propranolol and amiodarone.

Abnormalities in Iodine Metabolism

Iodine is an essential component of thyroid hormone, but both low and high iodine intake may lead to disease. The daily requirement of iodine for thyroid hormone synthesis is 150 μg. As already described, the thyroid gland has intrinsic mechanisms that maintain normal thyroid function even in the presence of iodine excess. The thyroid also tries to compensate when dietary sources of iodine are limited. Several drugs can interfere with the ability of the thyroid gland to concentrate iodide. Perchlorate is a contaminant that can be found in drinking and ground water, and occasionally in cow’s milk. Ingestion of high levels, as with consumption of well water can lead to inhibition of iodine transport into the follicular cells. Methimazole, the active form of carbimazole, inhibits iodide uptake and organification of iodine. Thiouracil and propylthiouracil inhibit iodine organification; the latter also inhibits the peripheral conversion of T4 to T3.

Abnormalities in the metabolism or supply of iodine have particular importance in fetal development. Severe iodine deficiency of the mother may lead to insufficient thyroid hormone synthesis in both mother and fetus, resulting in developmental brain injury. Iodine deficiency is the leading cause of preventable mental retardation. Conversely, excess iodine given to the mother (eg, use of amiodarone or excess iodine supplementation) may inhibit fetal thyroid function, leading to hypothyroidism and goiter, or may precipitate hyperthyroidism (iodine toxicity).

A rare familial disorder may lead to a defect in iodide transport. This defect is caused by the genetic absence or derangement of the Na+/I− symporter protein, which is involved in the active transport and concentration of iodide in the thyroid follicular cells. This condition can present in neonates as goiter with or without cretinism. In these individuals, T3 and T4 levels tend to be low and the TSH level is high. The diagnosis is confirmed by demonstrating poor thyroid uptake of radiolabeled iodine (I131) or sodium pertechnetate (Na99mTcO4).

Thyroiditis

Thyroiditis, or inflammation of the thyroid gland, may lead to abnormalities in thyroid hormone state. This condition may be acute, subacute, or chronic.

Acute Thyroiditis

Patients with acute thyroiditis present with a painful thyroid; chills and fever; a hot, enlarged, and palpable gland; and initially with hyperthyroidism. This condition is rare and infectious. Levels of T3, T4, and TSH are usually normal, and rT3 is increased.

Chronic Thyroiditis

Chronic thyroiditis (Hashimoto thyroiditis, chronic lymphocytic thyroiditis, autoimmune thyroiditis) is an autoimmune disease of the thyroid gland characterized by lymphocyte infiltration and circulating autoimmune antibodies. These antibodies inhibit the Na+/I− symporter, preventing iodide uptake and consequently thyroid hormone synthesis. Hashimoto thyroiditis is the most common cause of adult hypothyroidism. It is more prevalent in women than in men (ratio 8:1) and peaks at the age of 30–50 years. Individuals presenting with Hashimoto thyroiditis frequently have a family history of thyroid disorders. Hashimoto thyroiditis is also more common in persons with chromosomal disorders, such as Turner, Down, or Klinefelter syndromes, and in some cases is associated with autoimmune conditions such as Addison disease, hypoparathyroidism, and diabetes. Hashimoto thyroiditis may present early on with variable T4, T3, and TSH concentrations and antibody titers to TPO and Tg. As the disease progresses, some patients develop hypothyroidism with low T4 and T3 levels; high TSH levels and specific antibodies are usually no longer detectable.

The previous section provided a brief description of some of the diseases resulting from abnormalities in thyroid function. Tests of thyroid function allow the clinician to diagnose the disease and provide the follow-up necessary once therapy has been instituted. Although the most important keys to diagnosis are a thorough interview and physical examination of the patient, an understanding of the normal physiology of thyroid function allows proper interpretation of the diverse laboratory approaches for measuring function. Some of the most useful approaches are described as follows.

Thyroid-Stimulating Hormone and Thyroid Hormone Levels

Normal TSH values average 0.4–4.5 μU/mL and can be measured in plasma by immunometric assays. TSH levels are useful in evaluation of the patient because small changes in free thyroid hormone levels lead to greater changes in TSH levels. Serum TSH concentrations are considered the single most reliable test to diagnose all common forms of hypothyroidism and hyperthyroidism, particularly in the ambulatory setting. Overt hyperthyroidism is accompanied by low serum TSH concentrations, typically less than 0.1 mIU/L. Interpretation of TSH levels is best done with simultaneous measures of thyroid hormone levels.

Total T4 and T3 levels are measured by competitive immunoassay methods, and normal ranges are 5–12 μg/dL and 60–180 ng/dL, respectively. Total T4 includes both bound and free hormone. As described earlier, only the free hormone (0.05% of the total) is biologically active; thus, changes in the levels of thyroid-binding globulin, albumin, or thyroid-binding prealbumin will affect total T4 but not the free hormone. The same applies for measures of total T3. T3 levels are increased in almost all cases of hyperthyroidism, usually earlier than T4, making it a more sensitive indicator of hyperthyroidism than total T4. In hypothyroidism, T3 is often normal even when T4 is low. T3 is decreased during acute illness and starvation and is affected by several medications, including propranolol, steroids, and amiodarone.

Free Triiodothyronine and Tetraiodothyronine

The amount of free hormone depends on how much is bound to proteins. Estrogens and acute liver disease increase thyroid hormone-binding protein synthesis, whereas androgens, steroids, chronic liver disease, and severe illness can decrease it.

Reverse Triiodothyronine

Critical illness is associated with reduced TSH and thyroid hormone secretion, and with changes in peripheral thyroid hormone metabolism, resulting in low serum T3 and high rT3. As a result of altered peripheral thyroid hormone metabolism, decreased serum levels of T3 are associated with increased concentrations of rT3, an inactive form of thyroid hormone.

Antibody Levels

Determination of antithyroid antibodies is important in establishing the cause of thyroid disease. The antibodies of greatest clinical importance are the antithyroid microsomal (antiperoxidase) antibodies, the anti-Tg antibodies, and the thyroid-stimulating immunoglobulins (TSIs). In general, the antithyroid microsomal antibodies are usually elevated in patients with autoimmune thyroiditis (Hashimoto thyroiditis). Less frequently and to a lesser degree, the anti-Tg antibodies may be elevated in patients with autoimmune thyroiditis. Elevation of TSI is associated with Graves disease and is the likely cause of the hyperthyroidism seen in this condition.

Thyroid Nodule

The management of patients with thyroid masses or nodules involves utilization of several diagnostic techniques, which are briefly presented here.

Thyroid Ultrasound

Ultrasonography of a thyroid mass allows determination of size, composition (solid, cystic, mixed, or complex), calcifications, and presence of additional nodules.

Fine Needle Aspiration

Performed by palpation or guided by an ultrasound, this technique allows for cytologic analysis of the fluid and cells obtained through percutaneous needle aspiration of thyroid nodules.

Thyroid Scan

The Na+/I− symporter of the thyroid follicular epithelial cell does not discriminate between dietary iodide and radioactive isotopes such as iodine-123 or technetium-99. Therefore, these isotopes are used to visualize the functional anatomy of the thyroid. Regions of the thyroid that are functioning and actively incorporating the isotope are detected with a counter. The image of the thyroid reflects the ability of specific regions of the thyroid to take up the isotope and therefore to function normally (Figure 4–7). Areas that do not take up the radiolabeled iodine are referred to as nonfunctional or “cold.” Because most malignant tumors do not express the Na+/I−symporter, they often present as cold nodules. Areas that accumulate iodide in excess of that of the surrounding tissues are referred to as “hot nodules.”

• The thyroid gland is regulated by the hypothalamic-pituitary-thyroid axis.
• Dietary iodine is required for thyroid hormone synthesis.
• The thyroid gland produces thyroid hormones by a process of concentration of iodine in the thyroid, iodination of tyrosine residues of Tg in the colloid space of the follicle, and endocytosis of colloid followed by proteolytic release of thyroid hormones (T4 and T3).
• Thyroid hormones undergo metabolism in peripheral tissues, leading to the production of the more active T3 and deactivation of thyroid hormones.
• The presence of deiodinases and their substrate specificity play a central role in thyroid hormone function in target tissues.
• Thyroid hormones are transported into the cell where they bind to hormone receptors that bind DNA and alter gene transcription.
• Thyroid hormone actions are systemic and vital for development, growth, and metabolism.