Chapter 39: Thyroid and Anti-Thyroid Drugs

History. The thyroid is named for the Greek word for "shield shaped," from the shape of the nearby tracheal cartilage. It was first recognized as an organ of importance when thyroid enlargement was observed to be associated with changes in the eyes and the heart in the condition we now call hyperthyroidism. Parry saw his first patient in 1786 but did not publish his findings until 1825. Graves reported the disorder in 1835 and Basedow in 1840. Hypothyroidism was described later, in 1874, when Gull associated atrophy of the gland with the symptoms characteristic of hypothyroidism. The term myxedema was applied to the clinical syndrome in 1878 by Ord in the belief that the characteristic thickening of the subcutaneous tissues was due to excessive formation of mucus. In 1891, Murray first treated a case of hypothyroidism by injecting an extract of sheep thyroid gland, later shown to be fully effective when given by mouth. The successful treatment of thyroid deficiency by administering thyroid extract was an important step toward modern endocrinology.

Extirpation experiments to elucidate the function of the thyroid were at first misinterpreted because of the simultaneous removal of the parathyroids. However, Gley's research on the parathyroid glands in the late 19th century allowed the functional differentiation of these two endocrine glands. The structure of parathyroid hormone, however, was not reported until the early 1970s. Calcitonin was discovered in 1961, demonstrating that the thyroid gland produced a hormone in addition to thyroxine.

Chemistry of Thyroid Hormones. The principal hormones of the thyroid gland are the iodine-containing amino acid derivatives of thyronine (T₄ and T₃; Figure 39–1). Following the isolation and the chemical identification of thyroxine, it was generally thought that all the hormonal activity of thyroid tissue could be accounted for by its content of thyroxine. However, careful studies revealed that crude thyroid preparations possessed greater calorigenic activity than could be accounted for by their thyroxine content. The presence of a "second" thyroid hormone was debated, but triiodothyronine was finally detected, isolated, and synthesized by Gross and Pitt-Rivers (1952). Triiodothyronine has a much higher affinity for the nuclear thyroid hormone receptor compared with thyroxine and is much more potent biologically on a molar basis. The subsequent demonstration of T₃ production from T₄ in athyreotic humans led to the practice of effective replacement in hypothyroidism with levothyroxine only (Braverman et al., 1970).

Structure–Activity Relationships. The structural requirements for a significant degree of thyroid hormone activity have been defined (Baxter and Webb, 2009; Yoshihara et al., 2003). The 3′-monosubstituted compounds are more active than the 3′,5′-disubstituted molecules. Thus, triiodothyronine is five times more potent than thyroxine, and 3′-isopropyl-3,5-diiodothyronine has seven times the activity. Substitutions at the 3,5,3′, and 5′ sites influence the conformation of the molecule. In thyronine, the two rings are angulated at ∼120° at the ether oxygen and are free to rotate on their axes. As depicted schematically in Figure 39–2, the 3,5 iodines restrict rotation of the two rings, which tend to take up positions perpendicular to one another. In general, the affinity of iodothyronines for the thyroid hormone receptors (TRs) parallels their biological potency (Yen, 2001), but additional factors can affect therapeutic potency, including affinity for plasma proteins, rate of metabolism, and rate of entry into cell nuclei. Specific thyroid hormone transporters, such as MCT8, are likely to be important in specific tissues.

The stereochemical nature of the thyroid hormones plays an important role in defining hormone activity. Many structural analogs of thyroxine have been synthesized to define the structure–activity relationship, to detect antagonists of thyroid hormones, and to find compounds exhibiting a desirable activity while not showing unwanted effects. Introduction of specific arylmethyl groups at the 3′ position of triiodothyronine results in analogs that are liver-selective, cardiac-sparing thyromimetics (Brenta et al., 2007). Solving the x-ray crystallographic structure of the ligand binding domains of the nuclear thyroid hormone receptors α and β has resulted in the rapid development of a range of TR isoform-selective compounds. The difference in the ligand binding domain pocket between TRα and TRβ is only a single amino acid (Ser 277 in TRα and Asn 331 in TRβ). GC-1, a TRβ-specific agonist, stabilizes the ligand binding domain by promoting hydrogen bonding between Asn331 and Arg282. GC-1 has a 10-fold greater affinity for TRβ, the predominant TR isoform in the liver, than TRα, the predominant TR isoform in the heart, and lowers cholesterol without stimulating the heart. Cholesterol lowering with cardiac sparing by GC-1 and other TRβ-selective agonists, however, is also the result of much higher distribution in the liver and less in the heart compared with T₃. Similar compounds, such as KB-141, lower cholesterol in clinical studies (Baxter and Webb, 2009). Interestingly, none of these newer thyroid hormone analogs contains iodine or any halogen.

NIS has been identified in many other tissues, including the salivary glands, gastric mucosa, midportion of the small intestine, choroid plexus, skin, mammary gland, and perhaps the placenta, all of which maintain a concentration of iodide greater than that of the blood. Iodide accumulation by the placenta and mammary gland may provide adequate supplies for the fetus and infant. Iodine accumulation throughout the body is mediated by a single NIS gene. Individuals with congenital NIS gene mutations have absent or defective iodine concentration in all tissues known to concentrate iodine.

The oxidation of iodide to its active form is accomplished by thyroid peroxidase, a heme-containing enzyme that uses hydrogen peroxide (H₂O₂) as the oxidant (Dunn and Dunn, 2001). The peroxidase is membrane bound and appears to be concentrated at or near the apical surface of the thyroid cell. The reaction results in the formation of monoiodotyrosyl and diiodotyrosyl residues in thyroglobulin just prior to its extracellular storage in the lumen of the thyroid follicle. The formation of the H₂O₂ that serves as a substrate for the peroxidase probably occurs near its site of utilization and is stimulated by a rise in cytosolic Ca²⁺ (Takasu et al., 1987). The TSH receptor is notably promiscuous in its coupling, stimulating members of four G protein families including G_q, which couples to the PLC-IP₃-Ca²⁺ pathway (Laugwitz et al., 1996); thus, a Ca²⁺-dependent effect on H₂O₂ production may be a means by which TSH stimulates the organification of iodide in thyroid cells (Figure 39–3).

Although many other proteins can serve as substrates for the peroxidase, none is as efficient as thyroglobulin in yielding thyroxine. Presumably, conformation of thyroglobulin facilitates this coupling reaction. Thyroxine formation primarily occurs near the amino terminus of the protein, whereas most of the triiodotyrosine is synthesized near the carboxy terminus (Dunn and Dunn, 2001). The relative rates of synthetic activity at the various sites depend on the concentration of TSH and the availability of iodide. Iodine deficiency is associated with an increase in thyroidal T₃ relative to T₄ content (Zimmerman, 2009). Because triiodothyronine is the transcriptionally active iodothyronine and contains only three-fourths as much iodine, a decrease in the quantity of available iodine need have little impact on the effective amount of thyroid hormone elaborated by the gland. Although a decrease in the availability of iodide and the associated increase in the proportion of monoiodotyrosine favor the formation of triiodothyronine over thyroxine, a deficiency in diiodotyrosine ultimately can impair the formation of both compounds. Intrathyroidal and secreted T₃ are also generated by the 5′-deiodination of thyroxine.

TSH enhances the degradation of thyroglobulin by increasing the activity of several thiol endopeptidases of the lysosomes. Endopeptidases selectively cleave thyroglobulin, yielding hormone-containing intermediates that subsequently are processed by exopeptidases (Dunn and Dunn, 2001). The liberated hormones then exit the cell, presumably at its basal membrane. When thyroglobulin is hydrolyzed, monoiodotyrosine and diiodotyrosine also are liberated but usually do not leave the thyroid; rather, they are selectively metabolized and the iodine, liberated as I⁻, is reincorporated into protein. The iodotyrosine deiodinase enzyme, DHAL1, is essential for conserving iodine and mutations of this gene identified in several kindreds are associated with goitrous hypothyroidism and cognitive deficit (Moreno et al., 2008). Normally, all this iodide is reused; however, when proteolysis is activated intensely by TSH, some of the iodide reaches the circulation, at times accompanied by trace amounts of the iodotyrosines.

Key properties of the three iodothyronine deiodinases are summarized in Table 39–1. The types 1 and 2 deiodinases (D1, D2) convert thyroxine to triiodothyronine (St. Germain et al., 2009). These enzymes contribute approximately equally to the plasma T₃ in rats, but it has not been possible to determine their relative contributions in humans. D1 is expressed primarily in the liver and kidney, and also in the thyroid and pituitary (Figure 39–5). It is upregulated in hyperthyroidism and downregulated in hypothyroidism. A clinically important feature of D1 is its inhibition by the anti-thyroid drug propylthiouracil. D1 is localized to the plasma membrane, and the T₃ it produces equilibrates rapidly with the plasma. D2 is expressed primarily in the CNS (including the pituitary and hypothalamus) and brown adipose tissue, also in the thyroid, and at very low levels in other organs such as skeletal muscle. The activity of D2 is unaffected by propylthiouracil. D2 localizes to the endoplasmic reticulum, which facilitates access of D2-generated T₃ to the nucleus. Hence organs that express D2 tend to use the locally generated T₃ to increase the occupancy of nuclear T₃ receptors, and D2-generated T₃ equilibrates slowly with the plasma. D2 is dynamically regulated by its substrate, thyroxine, such that elevated levels of the enzyme are found in hypothyroidism and suppressed levels are found in hyperthyroidism. Thus, D2 autoregulates the intracellular supply of triiodothyronine in organs in which it is expressed.

Inner ring- or 5-deiodination, the main inactivating pathway of T₃ metabolism, is catalyzed mainly by the type 3 deiodinase (D3), and to some extent also by D1. D3 is found at highest levels in the CNS and placenta, and it also is expressed in skin and uterus (St. Germain et al., 2009). It is highly expressed in hemangiomas. D3 can be induced at sites of inflammation, and at least in an animal model this can result in local hypothyroidism (Peeters et al., 2003; Simonides et al., 2008).

D2 and D3 also play important roles in regulating local T3 levels during development, during which thyroid hormone tends to promote differentiation and decrease proliferation. Examples include chondrocyte development and bone differentiation, and auditory (cochlea) development. In the brain, D2 is expressed in glial cells and D3 in neurons. Because T₃ receptors are enriched in neurons, the current model is that glial cells convert T₄ to T₃, which is then exported and taken up by neurons where it activates T₃ receptors, with subsequent degradation by D3 and termination of the T₃ effect. There is a growing recognition of circumstances where D2 and D3 regulate local thyroid hormone levels independent of the plasma T₄ and T₃ concentrations.

The three deiodinases contain the rare amino acid selenocysteine in their active sites. Incorporation of selenocysteine into the growing peptide chain is a complex process involving multiple proteins. Mutations in one such protein, SECIS binding protein 2, are associated with abnormal circulating thyroid hormone levels (Dumitrescu et al., 2005).

Thyroxine-binding globulin (TBG) is the major carrier of thyroid hormones. It is an acidic glycoprotein with a molecular mass of ∼63,000 Da that binds one molecule of T₄ per molecule of protein with a very high affinity (the equilibration dissociation constant, K_d, is ∼10^–10 M). T₃ is bound less avidly. Thyroxine, but not triiodothyronine, also is bound by transthyretin (thyroxine-binding prealbumin), a retinol-binding protein. This protein is present in higher concentration than is TBG and primarily binds thyroxine with an equilibrium dissociation constant ∼10^–7 M. Transthyretin has four apparently identical subunits but only a single high-affinity binding site. Albumin also can bind thyroxine when the more avid carriers are saturated, but it is difficult to estimate its quantitative or physiological importance except in familial dysalbuminemic hyperthyroxinemia. This syndrome is an autosomal dominant disorder characterized by the increased affinity of albumin for thyroxine due to a point mutation in the albumin gene. There are a number of genetic defects of thyroid-binding globulin (Refetoff, 1989), but these individuals generally have normal circulating free thyroid hormones and serum TSH, and they are euthyroid.

The liver is the major site of non-deiodinative degradation of thyroid hormones; T₄ and T₃ are conjugated with glucuronic and sulfuric acids through the phenolic hydroxyl group and excreted in the bile. Some thyroid hormone is liberated by hydrolysis of the conjugates in the intestine and reabsorbed. A portion of the conjugated material reaches the colon unchanged, where it is hydrolyzed and eliminated in feces as the free compounds.

As discussed earlier, the major route of metabolism of T₄ is deiodination to either T₃ or reverse T₃. Triiodothyronine and reverse T₃ are deiodinated to three different diiodothyronines, which are further deiodinated to two monoiodothyronines (Figure 39–4), inactive metabolites that are normal constituents of human plasma. Additional metabolites (monoiodotyrosine and diiodotyrosine) in which the diphenyl ether linkage is cleaved have been detected both in vitro and in vivo.

TRH also has been localized in the CNS in the cerebral cortex, circumventricular structures, neurohypophysis, pineal gland, and spinal cord. These findings, as well as its localization in nerve endings, suggest that TRH may act as a neurotransmitter or neuromodulator outside of the hypothalamus. Administration of TRH to animals produces CNS-mediated effects on behavior, thermoregulation, autonomic tone, and cardiovascular function, including increases in blood pressure and heart rate. TRH also has been identified in pancreatic islets, heart, testis, and parts of the gastrointestinal tract. Its physiological role in these sites is not known. Two TRH receptors have now been identified, TRH-R1 and TRH-R2, as well as selective analogs for these receptors (Monga et al., 2008). TRH analogs with CNS activity, but without other hormonal actions, are being developed for therapeutic applications. TRH is no longer available in the U.S.

Multiple mutations of the TSH receptor result in clinical thyroid dysfunction (Latif et al., 2009). Germline mutations can present as congenital, nonautoimmune hypothyroidism or as autosomal dominant toxic thyroid hyperplasia. Germline mutations of the TSH receptor can cause gestational hyperthyroidism due to a hypersensitivity of the receptor to HCG (Rodien et al., 1998). Somatic mutations that result in constitutive activation of the receptor are associated with hyperfunctioning thyroid adenomas (Krohn and Paschke, 2001). Finally, resistance to TSH has been described, both in families with mutant TSH receptors (Sunthornthepvarakul et al., 1995) and in those with no apparent mutations in either the TSH receptor or in TSH itself (Xie et al., 1997).

Iodine has been used empirically for the treatment of iodine-deficiency goiter for 150 years; however, its modern use evolved from extensive studies using iodine to prevent goiter in school children in Akron, Ohio, where endemic iodine-deficiency goiter was prevalent. The success of these experiments led to the adoption of iodine prophylaxis and therapy in many regions throughout the world where iodine-deficiency goiter was endemic.

The most practical method for providing small supplements of iodine for large segments of the population is the addition of iodide or iodate to table salt; iodate is now preferred. The use of iodized salt is required by law in some countries, but in others such as the U.S., the use is optional. In the U.S., iodized salt provides 100 μg of iodine per gram. Although the U.S. population remains iodine sufficient, iodine intake has steadily decreased over the last 20 years (Hollowell et al., 1998). The most recent data indicate that iodine intake has stabilized, although pregnant women remain a susceptible population for iodine insufficiency (Haddow et al., 2007; Hollowell and Haddow, 2007). Other vehicles for supplying iodine to large populations who are iodine deficient include oral or intramuscular injection of iodized oil (Elnagar et al., 1995), iodized drinking water supplies, iodized irrigation systems, and iodized animal feed.

The TRs are the cellular homologs of the avian retroviral oncoprotein c-erbA. There are two genes that encode TRs, THRA and THRB. THRA encodes the receptor TRα1. The biological function of TRα1 is inferred largely through studies of genetically modified mice and cell culture experiments because human mutations in THRA have not been described. Although TRα1 is expressed in most cell types, studies in knockout mice demonstrate that the major specific roles for this isoform are in the regulation of heart rate, body temperature, skeletal muscle function, and the development of bone and small intestine (O'Shea and Williams, 2002). Alternative splicing of the TRα primary transcript results in the production of TRα2, which does not bind T₃ because it lacks part of the ligand-binding domain (LBD). TRα2 is expressed ubiquitously and its function is unknown, although there is some evidence that it may inhibit T₃ action. A cryptic promoter within intron 7 of THRA drives the production of small proteins that contain only a portion of the TRα LBD. These non-hormone-binding proteins appear to play a role, along with TRα1, in GI development.

The THRB gene has two promoters that lead to the production of TRβ1 and TRβ2. These receptors have unique amino terminal domains but otherwise are identical. TRβ1 is ubiquitous, whereas TRβ2 has a highly restricted pattern of expression. Mutations in THRB cause the syndrome of resistance to thyroid hormone (Refetoff and Dumitrescu, 2007). Studies in these patients, as well as in genetically modified mice and in cell culture, demonstrate a specific role for TRβ1 in liver metabolism (including the hypocholesterolemic effect of T₃), and for TRβ2 in the negative feedback by T₃ on hypothalamic TRH and pituitary TSH (O'Shea and Williams, 2002). TRβ2 also is important in the development of cones in the retina and in inner ear development.

There also is evidence for non-genomic actions of thyroid hormone via a plasma membrane receptor within integrin αVβ3 (Davis et al., 2008). This putative receptor binds extracellular T₄ in preference to T₃, resulting in activation of MAP kinase. However, the importance of non-genomic actions in thyroid hormone physiology and pathophysiology remains uncertain.

Effects of Thyroid Hormone Metabolites. 3-Iodothyronamine and thyronamine, naturally occurring metabolites of T₄, are ligands for the GPCR trace amine-associated receptor 1 (TAAR1) (Scanlan et al., 2004). Administration of 3-iodothyronamine or thyronamine to mice causes hypothermia and bradycardia, presumably through activation of TAAR1 and G_s. 3-Iodothyronamine activation of TAAR1 also induces insulin secretion in the MIN6 cell line (Regard et al., 2007). Interestingly, 3-iodothyronamine also binds to the α_2A adrenergic receptor, leading to decreased insulin secretion from mouse islets via a G_i protein-coupled mechanism (Regard et al., 2007). The importance of these effects in human physiology and disease remains to be determined.

The mechanisms by which thyroid hormone promotes brain development are incompletely understood. Surprisingly, mice with genetic deletions of TRα, TRβ, or both have essentially normal brain development (Gothe et al., 1999). Equally surprisingly, genetic deletion of TRα1 protects mice from the toxic effects of hypothyroidism on brain development (Morte et al., 2002). Perhaps it is the effects of unliganded TRs that result in impaired brain development, such that either T₃ or the absence of TRs is protective. T₃ induces the expression of a number of genes that could plausibly be important in normal brain development, but the exact roles of these specific gene inductions are not known (Anderson et al., 2003). The T₃-dependent expression of many proteins appears to be merely delayed in the hypothyroid animal; normal levels are eventually achieved. Myelin basic protein, a major component of myelin, is induced by T₃ during development. Decreased expression of myelin basic protein in the hypothyroid brain impairs myelinization. RC3/neurogranin, a protein involved in synaptic plasticity, also is induced by T₃. Through its induction of the transcription factor BTEB (basic transcription element binding protein), T3 expands a network of secondary genes in brain development.

Cretinism is usually classified as endemic or sporadic. Endemic cretinism occurs in regions of endemic goiter and usually is caused by extreme iodine deficiency. Goiter may or may not be present. Sporadic cretinism is a consequence of failure of the thyroid to develop normally or the result of a defect in the synthesis of thyroid hormone. Goiter is present if a synthetic defect is at fault. While detectable at birth, cretinism often is not recognized until 3-5 months of age. When untreated, the condition eventually leads to such gross changes as to be unmistakable: The child is dwarfed, with short extremities, mentally retarded, inactive, uncomplaining, and listless. The face is puffy and expressionless, and the enlarged tongue may protrude through the thickened lips of the half-opened mouth. The skin may have a yellowish hue and feel doughy, dry, and cool to the touch. The heart rate is slow, the body temperature may be low, closure of the fontanels is delayed, and the teeth erupt late. Appetite is poor, feeding is slow and interrupted by choking, constipation is frequent, and there may be an umbilical hernia.

For treatment to be fully effective, the diagnosis must be made long before these changes are obvious. In regions of endemic cretinism due to iodine deficiency, iodine replacement is best instituted before pregnancy. However, iodine replacement given to pregnant women up to the end of the second trimester has been shown to enhance the neurological and psychological development of the children (Cao et al., 1994). Screening of newborn infants for deficient thyroid function is carried out in the U.S. and in most industrialized countries. Concentrations of TSH and thyroxine are measured in blood from the umbilical cord or from a heel stick. The incidence of congenital dysfunction of the thyroid is ∼1 per 4000 births.

Triiodothyronine directly regulates myocardial gene expression primarily through TRα1, which is expressed at a higher level in cardiomyocytes than TRβ. T₃ shortens diastolic relaxation (lusitropic effect) by inducing expression of the sarcoplasmic reticulum ATPase SERCa2 and decreasing phospholamban, a SERCa2 inhibitor. T₃ increases the force of myocardial contraction (inotropic effect) in part by inducing expression of the ryanodine channel, the calcium channel of the sarcoplasmic reticulum. T₃ induces the gene encoding the myosin heavy chain (MHC) α isoform and decreases expression of the MHC β gene. Because MHCα endows the myosin holoenzyme with greater ATPase activity, this is one mechanism by which T₃ enhances the velocity of contraction. The chronotropic effect of T₃ is mediated by increases in the pacemaker ion current I_f in the sinoatrial node. Several proteins that comprise the I_f channel are induced by T₃, including HCN2 and HCN4. Interestingly, T₃ also appears to have a direct non-genomic vasodilating effect on vascular smooth muscle (Hiroi et al., 2006), which may contribute to the decreased systemic vascular resistance and increased cardiac output of hyperthyroidism.

Common symptoms of hypothyroidism include fatigue, lethargy, cold intolerance, mental slowness, depression, dry skin, constipation, mild weight gain, fluid retention, muscle aches and stiffness, irregular menses, and infertility. Common signs include goiter (primary hypothyroidism only), bradycardia, delayed relaxation phase of the deep tendon reflexes, cool and dry skin, hypertension, nonpitting edema, and facial puffiness. Deficiency of thyroid hormone during the first few months of life causes feeding problems, failure to thrive, constipation, and sleepiness. Retardation of mental development is irreversible if not treated promptly. Childhood hypothyroidism impairs linear growth and bone maturation. Because the signs and symptoms of hypothyroidism are nonspecific, diagnosis requires the finding of an elevated serum TSH or, in cases of central hypothyroidism, a decreased serum free T₄. Because physicians maintain a high index of suspicion, the diagnosis usually is made at a relatively early stage. Thus, severe hypothyroidism and myxedema coma are uncommon, except in hypothyroid patients who are noncompliant with their thyroid hormone replacement therapy or individuals without access to medical care.

The characteristic exophthalmos associated with Graves' disease is an infiltrative ophthalmopathy and is considered an autoimmune-mediated inflammation of the periorbital connective tissue and extraocular muscles. This disorder is clinically evident with various degrees of severity in ∼50% of patients with Graves' disease, but it is present on radiological studies, such as ultrasound or CT scan, in almost all patients. The pathogenesis of Graves' ophthalmopathy, including the role of the TSH receptor present in retro-orbital tissues, and the management of this disorder, remain controversial (Khoo and Bahn, 2007).

Toxic uninodular/multinodular goiter accounts for 10-40% of cases of hyperthyroidism and is more common in older patients. Infiltrative ophthalmopathy is absent.

A low RAIU is seen in the destructive thyroiditides and in thyrotoxicosis resulting from exogenous thyroid hormone ingestion. Low RAIU thyrotoxicosis caused by subacute (painful) and silent (painless or lymphocytic) thyroiditis represents ∼5-20% of all cases. Silent thyroiditis occurs in 7-10% of postpartum women in the U.S. (Abalovich et al., 2007). Other causes of thyrotoxicosis are much less common.

Most of the signs and symptoms of thyrotoxicosis stem from the excessive production of heat, increased motor activity, and increased sensitivity to catecholamines produced by the sympathetic nervous system. The skin is flushed, warm, and moist; the muscles are weak and tremulous; the heart rate is rapid, the heartbeat is forceful, and the arterial pulses are prominent and bounding. Increased expenditure of energy gives rise to increased appetite and, if intake is insufficient, to loss of weight. There also may be insomnia, difficulty in remaining still, anxiety and apprehension, intolerance to heat, and increased frequency of bowel movements. Angina, arrhythmias, and heart failure may be present in older patients. Older patients may experience less manifestations of sympathetic nervous system stimulation, so called apathetic hyperthyroidism. Some individuals may show extensive muscular wasting as a result of thyroid myopathy. Patients with long-standing undiagnosed or undertreated thyrotoxicosis may develop osteoporosis due to increased bone turnover (Murphy and Williams, 2004).

Thyroid Function Tests. The development of radioimmunoassays and, more recently, chemiluminescent and enzyme-linked immunoassays for T₄, T₃, and TSH have greatly improved the laboratory diagnosis of thyroid disorders (Demers and Spencer, 2003). However, measurement of the total hormone concentration in plasma may not give an accurate picture of the activity of the thyroid gland. The total hormone concentration changes with alterations in either the amount of TBG in plasma or the binding affinity of TBG for hormones. Although equilibrium dialysis of undiluted serum and radioimmunoassay for free thyroxine (FT₄) in the dialysate represent the gold standard for determining FT₄ concentrations, this assay is typically not available in routine clinical laboratories. The FT₄ index is an estimation of the FT₄ concentration and is calculated by multiplying the total thyroxine concentration by the thyroid hormone binding ratio, which estimates the degree of saturation of TBG. The most common assays used for estimating the free T₄ and free T₃ concentrations employ labeled analogs of these iodothyronines in chemiluminescence and enzyme-linked immunoassays. These assays correlate well with free T₄ concentrations measured by the more cumbersome equilibrium dialysis method and are easily adaptable to routine clinical laboratory use. However, the analog assays are affected by extremes of serum binding proteins as well as a wide variety of non-thyroidal disease states, including acute illness, and by certain drugs to a greater degree than are the free T₄ index and free T₄ determined by equilibrium dialysis.

In individuals with normal pituitary function, serum measurement of TSH is the thyroid function test of choice because pituitary secretion of TSH is sensitively regulated in response to circulating concentrations of thyroid hormones.

A major use of the TSH assay is to differentiate between normal and thyrotoxic patients, who should exhibit suppressed TSH values. Indeed, the sensitive TSH assay has replaced evaluation of the response of TSH to injection of synthetic TRH (TRH stimulation test) in the thyrotoxic patient. Although the serum TSH assay is extremely useful in determining the euthyroid state and titrating the replacement dose of thyroid hormone in patients with primary hypothyroidism, abnormal serum TSH concentrations may not always indicate thyroid dysfunction. In such patients, assessment of the circulating thyroid hormone levels will further determine whether or not thyroid dysfunction is truly present. Synthetic preparations of TRH (protirelin) are no longer available in the U.S. for the evaluation of pituitary or hypothalamic failure as a cause of secondary hypothyroidism.

Recombinant human TSH (thyrotropin alfa, thyrogen) is available as an injectable preparation to test the ability of thyroid tissue, both normal and malignant, to take up radioactive iodine and release thyroglobulin (Duntas and Cooper, 2008; Haugen et al., 1999; Pacini and Castangna, 2008).

The potency standards of levothyroxine have been narrowed from the previous standard of 90-110% to 95-105%, and the content must be stable at this level for the designated shelf life. Absorption of thyroxine occurs in the stomach and small intestine and is incomplete (∼80% of the dose is absorbed). Absorption is slightly increased when the hormone is taken on an empty stomach, and it is associated with less variability in the TSH when taken this way regularly (Bach-Huynh et al., 2009). The serum T₄ peaks 2-4 hours after oral ingestion, but changes are barely discernable with once-daily dosing due to the 7-day plasma t_1/2 of the T₄. Given this long t_1/2, omission of one day's dose does not materially affect the serum TSH or FT₄, but to maintain consistent dosing the patient should be instructed to take a double dose the next day. For any given serum TSH, the serum T₄/T₃ ratio is higher in patients taking levothyroxine than in patients with endogenous thyroid function, due to the fact that ∼20% of circulating T₃ normally is supplied by direct thyroidal secretion (Jonklaas et al., 2008). Occasionally this may result in a levothyroxine-treated patient having a marginally elevated free T₄ and a normal TSH, which is acceptable. Follow-up blood tests typically are done ∼6 weeks after any dosage change due to the 1-week plasma t_1/2 of T₄. Dosages are discussed subsequently under specific indications.

In situations where patients cannot take oral medications or where intestinal absorption is in question, levothyroxine may be given intravenously once a day at a dose ∼80% of the patient's daily oral requirement.

Liothyronine absorption is nearly 100% with peak serum levels 2-4 hours following oral ingestion. Liothyronine may be used occasionally when a more rapid onset of action is desired such as in the rare presentation of myxedema coma or if rapid termination of action is desired such as when preparing a thyroid cancer patient for ¹³¹I therapy. Liothyronine is less desirable for chronic replacement therapy due to the requirement for more frequent dosing (plasma t_1/2 = 0.75 days), higher cost, and transient elevations of serum T₃ concentrations above the normal range. In addition, organs that express the type 2 deiodinase use the locally generated T₃ in addition to plasma T₃, and hence there is theoretical concern that these organs will not maintain physiological intracellular T₃ levels in the absence of plasma T₄. Ten to 15 μg of liothyronine sodium three times per day typically yields a normal serum free T₃ in an athyreotic individual. However, normalization of circulating TSH may require higher levels of free T₃, perhaps because negative feedback normally relies in part on the local generation of T₃ from circulating T₄ (Koutras et al., 1981, Saberi and Utiger, 1974).

Other Preparations.

A mixture of thyroxine and triiodothyronine 4:1 by weight is marketed as liotrix (thyrolar). Desiccated thyroid preparations such as (armour thyroid, others), with a similar T₄:T₃ ratio, also are available. A 60-mg (1 grain) desiccated thyroid tablet is approximately equivalent in activity to 80 μg of thyroxine. This conversion can be used when changing a patient from replacement therapy with desiccated thyroid to levothyroxine, but typically such patients can be dosed with levothyroxine using dosing guidelines based on age and weight.

The average daily adult replacement dose of levothyroxine sodium is 1.7 μg/kg body weight (0.8 μg/lb), although the variation about this average is substantial. Dosing should generally be based on lean body mass (Santini et al., 2005). Although not ideal, once-a-week dosing can be used in situations where compliance is otherwise not possible (Grebe et al., 1997). The goal of therapy is to normalize the serum TSH (in primary hypothyroidism) or free T₄ (in secondary or tertiary hypothyroidism) and to relieve symptoms of hypothyroidism. In primary hypothyroidism, generally it is sufficient to follow TSH without free T₄. A patient with mild primary hypothyroidism will achieve a normal TSH with substantially less than a full replacement dose, but as the endogenous thyroid function declines, the dose will need to be increased. Thus, especially in young healthy patients, it can be simpler to begin with nearly a full replacement dose. In individuals >60 years of age and those with known or suspected cardiac disease or with areas of autonomous thyroid function, institution of therapy at a lower daily dose of levothyroxine sodium (12.5-50 μg per day) is appropriate. The dose can be increased at a rate of 25 μg per day every 6-8 weeks until the TSH is normalized.

An elevated TSH, especially common among elderly patients and among centenarians, may even be associated with longevity (Atzmon et al., 2009). Patients with subclinical hypothyroidism who may benefit from levothyroxine therapy include those with goiter, autoimmune thyroid disease, hypercholesterolemia, cognitive dysfunction, or pregnancy, and those patients who have nonspecific symptoms that could be due to hypothyroidism (Biondi and Cooper, 2008).

The increased levothyroxine requirement averages 30-50% and can become apparent as early as the fifth week of gestation. The magnitude of thyroxine dose adjustment is greatest for women who are athyreotic from surgical thyroidectomy or radioiodine ablation (Loh et al., 2009). The optimal way to anticipate this increased dosage need and hence to avoid an elevated TSH is not known. Some experts recommend that women increase their levothyroxine dosage by ∼30% as soon as pregnancy is confirmed, which can be accomplished by taking two extra pills per week. Most measure a serum TSH in the first trimester and then adjust the thyroxine dose based on this result. Subsequent dosage adjustments would be based on serum TSH, measured 4-6 weeks after each adjustment. For nonpregnant women of reproductive age not using contraception, maintaining the TSH in the lower portion of the reference range (∼0.3-2.0 mIU/L) will allow room to move within the reference range during the early part of pregnancy. For similar reasons, dosage adjustments during pregnancy should be made to bring the TSH into the lower portion of the reference range. The increased dosage requirement plateaus at about gestation week 16-20, and dosage needs fall back to prepregnancy levels immediately after delivery.

Cardinal features of myxedema coma are:

• hypothermia, which may be profound

• respiratory depression

• decreased consciousness

Other clinical features include bradycardia, macroglossia, delayed reflexes, and dry, rough skin. Dilutional hyponatremia is common and may be severe. Elevated plasma creatine kinase (CK) and lactate dehydrogenase (LDH) concentrations, acidosis, and anemia are common findings. Lumbar puncture reveals increased opening pressure and high protein content. Hypothyroidism is confirmed by measuring the serum FT₄ and TSH. Ultimately, myxedema coma is a clinical diagnosis.

There are no randomized controlled clinical trials to evaluate the optimal form of thyroid hormone therapy in myxedema coma. Intravenous administration of thyroid hormone is advised due to uncertain absorption through the gut. Therapy with levothyroxine is commonly begun with a loading dose of 250-500 μg followed by a daily full replacement dose, although some clinicians omit the loading dose. Some clinicians recommend adding liothyronine (10 μg intravenously every 8 hours) with the initial dose of levothyroxine, until the patient is stable and conscious. The limited studies that are available suggest that excessive treatment with either levothyroxine (>500 μg per day) or liothyronine (>75 μg) may be associated with an increased mortality rate.

To rapidly normalize the serum thyroxine concentration in the congenitally hypothyroid infant, an initial daily dose of levothyroxine of 10-15 μg/kg is recommended. This dose will increase the serum FT₄ concentration to the upper half of the normal range in most infants within 1-2 weeks. A dose of up to 17 μg/kg has been suggested for the most severely hypothyroid infants, which can normalize the serum T₄ in 3 days (LaFranchi and Austin, 2007). Laboratory evaluations of TSH and FT₄ are performed 2 and 4 weeks after treatment is initiated, every 1-2 months in the first 6 months, every 3-4 months between 6 months and 3 years of age, and every 6-12 months from age 3 years until the end of growth. The goal is to maintain serum FT₄ in the upper half of the reference range and the TSH in the lower normal range during the first 3 years of life. Assessments that are important guides for appropriate hormone replacement include physical growth, motor development, bone maturation, and developmental progress.

Management of premature infants with hypothyroxinemia (∼50% of those born at <30 weeks of gestation) remains a therapeutic dilemma. Despite impaired psychomotor development in these patients (Reuss et al., 1996), it is not clear whether levothyroxine therapy may be beneficial, and in some settings it may be detrimental (van Wassenaer et al., 2005).

The evaluation of the patient with nodular thyroid disease includes a careful physical examination, biochemical analysis of thyroid function, and assessment of the malignant potential of the nodule (Cooper et al., 2006). Thyroid nodules usually are asymptomatic, although they can cause neck discomfort, dysphagia, and a choking sensation. Most patients with thyroid nodules are euthyroid, which should be confirmed by TSH measurement. The most useful diagnostic procedures generally are ultrasound imaging and a fine-needle aspiration biopsy.

TSH suppressive therapy with levothyroxine sometimes is prescribed for the patient with a benign thyroid nodule and a normal serum TSH. The rationale is that a benign nodule will either stop growing or decrease in size after TSH stimulation of the thyroid gland has been suppressed. However, a meta-analysis of randomized trials reveals the shortcomings of this approach (Sdano et al., 2005). Only 22% of nodules decrease in volume by >50% with levothyroxine versus 10% with placebo. Eight patients need to be treated to have one response, and limited data suggest that the nodule will regrow if the levothyroxine is stopped. Furthermore, a 50% decrease in volume represents only about a 20% decrease in linear dimension, a very modest change. The minimum level of TSH suppression needed to achieve this modest response is not known, and long-term exposure to excess thyroid hormone carries risks such as osteoporosis and atrial fibrillation. Thus the use of levothyroxine to suppress TSH in euthyroid individuals with thyroid nodules cannot be recommended as a general practice. However, if the TSH is elevated, it is appropriate to administer levothyroxine to bring the TSH into the lower portion of the reference range.

Given the generally excellent prognosis of well-differentiated thyroid cancer, a prospective randomized controlled trial to assess which patients benefit from suppressive therapy, how low the TSH should be, or how long the suppression should be maintained has not been done. For most low-risk patients with stage 1 or 2 disease, maintaining the TSH just below the reference range for not more than 5 years is one reasonable approach. A greater degree of TSH suppression for a longer duration is recommended for higher risk patients and those with metastatic disease (Cooper et al., 2006).

Non-thyroidal Illness (Sick Euthyroid) Syndrome. Although the circulating free T₃ is low in the non-thyroidal illness syndrome, the current standard of care is not to treat with thyroid hormone because there is no convincing evidence that the low T₃ state contributes to the patient's prognosis or that thyroid hormone therapy would alter the course of the illness. However, there have been very few randomized controlled trials, and these generally involve small numbers of patients and hence have little statistical power. Two trials suggest possible benefit of T₃ therapy in cardiac surgery patients (Klemperer et al., 1995, 1996; Mullis-Jansson et al., 1999).

Depression. Data from several small double-blind placebo-controlled studies suggest potential efficacy of thyroid hormone therapy in euthyroid individuals with major depression, when added to tricyclic antidepressants (Carvalho et al., 2007). It is unclear whether T₃ supplementation of specific serotonin reuptake inhibitor (SSRI) therapy is beneficial (Papakostas et al., 2009). One study suggests that a beneficial effect of T3 added to the SSRI sertraline is seen primarily in subjects with a C785T polymorphism in the type 1 deiodinase gene (Cooper-Kazaz et al., 2009). The mechanism of the T₃ effect (if any) is not known.

TRβ Agonists. Thyroid hormone has long been known to reduce serum cholesterol via effects on hepatic metabolism, but T₄ and T₃ are not useful hypocholesterolemic drugs due to the adverse effects of thyrotoxicosis on the heart and other organs. However, the liver primarily expresses TRβ, whereas the heart primarily expresses TRα. T₃ analogs that have a higher affinity for TRβ than TRα and that accumulate preferentially in the liver have been shown to lower serum cholesterol without causing tachycardia in humans and animals (Erion et al., 2007). These analogs also can induce weight loss in mice with diet-induced obesity. Thyromimetics with preferential action on TRβ also might be useful in the management of thyroid hormone resistance, which in most cases is caused by mutations in TRβ that lower the binding affinity for T₃ (Refetoff and Dumitrescu, 2007).

Thyroid Hormone Receptor α Agonists. Because TRα1 is expressed preferentially in the heart, specific agonists might find use in the management of heart failure or bradycardia. The design of specific agonists for TRα, however, has proven much more difficult than for TRβ (Ocasio and Scanlan, 2008).

Thyromimetics with Altered Entry into Cells. Monocarboxylate transporter 8 (MCT8) transports T₃ into cells and is highly expressed in the brain. Patients with MCT8 mutations have the Allan-Herndon-Dudley syndrome with severe neurological impairment, presumably due to intracellular thyroid hormone deficiency. A thyromimetic that can enter the brain in an MCT8-independent manner could be valuable in treating these patients. The thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) has this property in mice (Di Cosmo et al., 2009).

Thyroid Hormone Receptor Antagonists. In principle, thyroid hormone receptor antagonists could be useful therapeutics in the medical management of thyrotoxicosis, and possibly even in the management of cardiac arrhythmias. A thyroid hormone analog denoted NH3 antagonizes the cholesterol lowering, TSH lowering, and tachycardic actions of T₃ in rats, but at high doses this drug functions as a T₃ agonist (Grover et al., 2007).

Thyronamines. 3-Iodothyronamine and thyronamine are endogenous thyroid hormone metabolites that functions as agonists for the GRCR Trace Amine Associated Receptor 1 (TAAR1) and the α_2A adrenergic receptor. These compounds appear to have broad metabolic effects in experimental animals, such as inducing hypothermia and bradycardia (Scanlan et al., 2004), and conferring protection against brain ischemia (Doyle et al., 2007). The therapeutic potential of these agents or their analogs requires further investigation.

History. Studies on the mechanism of the development of goiter began with the observation that rabbits fed a diet composed largely of cabbage often developed goiters. This result was probably due to the presence of precursors of the thiocyanate ion in cabbage leaves. Later, two pure compounds were shown to produce goiter: sulfaguanidine, a sulfanilamide antimicrobial used to treat enteric infections, and phenylthiourea.

Investigation of the effects of thiourea derivatives revealed that rats became hypothyroid despite hyperplastic changes in their thyroid glands that were characteristic of intense thyrotropic stimulation. After treatment was begun, no new hormone was made, and the goitrogen had no visible effect on the thyroid gland following hypophysectomy or the administration of thyroid hormone. This suggested that the goiter was a compensatory change resulting from the induced state of hypothyroidism and that the primary action of the compounds was to inhibit the formation of thyroid hormone. The therapeutic possibilities of such agents in hyperthyroidism were evident, and the substances so used became known as anti-thyroid drugs (Astwood, 1945).

Thiourea and its simpler aliphatic derivatives and heterocyclic compounds containing a thioureylene group make up most of the known anti-thyroid agents that are effective in humans. Although most of them incorporate the entire thioureylene group, in some a nitrogen atom is replaced by oxygen or sulfur so that only the thioamide group is common to all. Among the heterocyclic compounds, active representatives are the sulfur derivatives of imidazole, oxazole, hydantoin, thiazole, thiadiazole, uracil, and barbituric acid.

l-5-Vinyl-2-thiooxazolidone (goitrin) is responsible for the goiter that results from consuming turnips or the seeds or green parts of cruciferous plants. These plants are eaten by cows, and the compound is found in cow's milk in areas of endemic goiter in Finland; it is about as active as propylthiouracil in humans.

As the result of industrial exposure, toxicological studies, or clinical trials for various purposes, several other compounds have been noted to possess anti-thyroid activity (Miller et al., 2009). Thiopental and oral hypoglycemic drugs of the sulfonylurea class have weak anti-thyroid action in experimental animals. This is not significant at usual doses in humans. However, anti-thyroid effects in humans have been observed from dimercaprol and lithium salts. Polychlorinated biphenyls bear a striking structural resemblance to the thyroid hormones and may function as either agonists or antagonists of thyroid hormone action (Zoeller et al., 2000). Amiodarone, the iodine-rich drug used in the management of cardiac arrhythmias, has complex effects on thyroid function (Basaria and Cooper, 2005). In areas of iodine sufficiency, amiodarone-induced hypothyroidism due to the excess iodine is not uncommon, whereas in iodine-deficient regions, amiodarone-induced thyrotoxicosis predominates, whether because of the excess iodine or the thyroiditis induced by the drug. Amiodarone and its major metabolite, desethylamiodarone, are potent inhibitors of iodothyronine deiodination, resulting in decreased conversion of thyroxine to triiodothyronine. In addition, desethylamiodarone decreases binding of triiodothyronine to its nuclear receptors. Recommendations have been made as to screening methods to identify chemicals that may alter thyroid hormone action or homeostasis (Diamanti-Kandarakis et al., 2009).

Measurements of the course of organification of radioactive iodine by the thyroid show that absorption of effective amounts of propylthiouracil follows within 20-30 minutes of an oral dose and that the duration of action of the compounds used clinically is brief. The effect of a dose of 100 mg of propylthiouracil begins to wane in 2-3 hours, and even a 500-mg dose is completely inhibitory for only 6-8 hours. As little as 0.5 mg of methimazole similarly decreases the organification of radioactive iodine in the thyroid gland, but a single dose of 10-25 mg is needed to extend the inhibition to 24 hours.

The t_1/2 of propylthiouracil in plasma is ∼75 minutes, whereas that of methimazole is 4-6 hours. The drugs are concentrated in the thyroid, and methimazole, derived from the metabolism of carbimazole, accumulates after carbimazole is administered. Drugs and metabolites appear largely in the urine.

Propylthiouracil and methimazole cross the placenta equally (Mortimer et al., 1997) and also can be found in milk. The use of these drugs during pregnancy is discussed later.

Agranulocytosis usually occurs during the first few weeks or months of therapy but may occur later. Because agranulocytosis can develop rapidly, periodic white cell counts usually are of little help, although a baseline white blood cell count and differential should be obtained before anti-thyroid drug treatment is initiated. Patients should be instructed to immediately report the development of sore throat or fever, which are often signs of the presence of leukopenia. If these signs or symptoms occur, patients should discontinue their anti-thyroid drug and obtain a granuloctye count. Agranulocytosis is reversible upon discontinuation of the offending drug, and the administration of recombinant human granulocyte colony-stimulating factor may hasten recovery (Magner and Snyder, 1994). Mild granulocytopenia, if noted, may be due to thyrotoxicosis or may be the first sign of this dangerous drug reaction. Caution and frequent leukocyte counts are then required.

The most common reaction is a mild, occasionally purpuric, urticarial papular rash. It often subsides spontaneously without interrupting treatment, but it sometimes calls for the administration of an antihistamine, corticosteroids, and changing to another drug (cross-sensitivity between propylthiouracil and methimazole is uncommon). Other less frequent complications are pain and stiffness in the joints, paresthesias, headache, nausea, skin pigmentation, and loss of hair. Drug fever, hepatitis, and nephritis are rare, although abnormal liver function tests are not infrequent with higher doses of propylthiouracil. Although vasculitis was previously thought to be a rare complication, antineutrophilic cytoplasmic antibodies (ANCAs) have been reported to occur in ∼50% of patients receiving propylthiouracil and rarely with methimazole (Sato et al., 2000; Sera et al., 2000).

Propylthiouracil-associated hepatic failure has been increasingly recognized, especially in children and pregnant women (Cooper and Rivkees, 2009). There are 47 published reports of propylthiouracil-associated liver failure in adults and children, and 23 liver transplants between 1990 and 2007 due to propylthiouracil-associated liver failure. Methimazole may cause cholestatic dysfunction, but it is not associated with hepatocellular necrosis, and there are no reports of liver transplants due to methimazole-associated liver toxicity. There is increasing concern about using propylthiouracil as a first-line treatment, except in severe thyrotoxicosis when the inhibition of T₄ to T₃ is desired, and possibly in the first trimester of pregnancy. The FDA has added a "black box" warning to propylthiouracil because of liver failure, recommending close monitoring of liver function during its use. Propylthiouracil should not be used in children except in the case of methimazole allergy.

Methimazole is the drug of choice for Graves' disease; it is effective when given as a single daily dose, has improved adherence, and is less toxic than propylthiouracil. Methimazole has a relatively long plasma and intrathyroidal t_1/2, as well as a long duration of action. The usual starting dose for methimazole is 15–40 mg per day. The usual starting dose of propylthiouracil is 100 mg every 8 hours. When doses >300 mg daily are needed, further subdivision of the time of administration to every 4-6 hours is occasionally helpful. Failures of response to daily treatment with 300-400 mg of propylthiouracil or 30-40 mg of methimazole are most commonly due to nonadherence but can be seen with very severe disease. Delayed responses also are noted in patients with very large goiters or those in whom iodine in any form has been given beforehand. Once euthyroidism is achieved, usually within 12 weeks, the dose of anti-thyroid drug can be reduced, but not stopped, lest an exacerbation of Graves' disease occur (see later section on remissions).

After treatment is initiated, patients should be examined and thyroid function tests (serum FT₄ and total or free triiodothyronine concentrations) measured every 2-4 months. Serum TSH will often remain suppressed for several months after a patient has been hyperthyroid, so the circulating thyroxine and triiodothyronine concentrations are the most reliable assessment of thyroid status (Uy et al., 1995). Once euthyroidism is established, follow-up every 4-6 months is reasonable.

Control of the hyperthyroidism usually is associated with a decrease in goiter size. When this occurs, the dose of the anti-thyroid drug should be significantly decreased and/or levothyroxine can be added once hypothyroidism is confirmed by laboratory testing.

Many investigators consider coexisting ophthalmopathy to be a relative contraindication for radioactive iodine therapy because worsening of ophthalmopathy has been reported after radioactive iodine (Bartalena et al., 1998a), although this remains controversial. Others suggest that development of hypothyroidism, regardless of the treatment, is the strongest risk factor for progression of ophthalmopathy. Smoking is a risk factor for worsening ophthalmopathy (Bartelena et al., 1998b). In older patients, depleting the thyroid gland of preformed hormone by treatment with anti-thyroid drugs is advisable before therapy with radioactive iodine, thus preventing a severe exacerbation of the hyperthyroid state during the subsequent development of radiation thyroiditis. Subtotal thyroidectomy is advocated for Graves' disease in young patients with large goiters, children who are allergic to anti-thyroid drugs, pregnant women (usually in the second trimester) who are allergic to anti-thyroid drugs, and patients who prefer surgery over anti-thyroid drugs or radioactive iodine. Radioactive iodine or surgery is indicated for definitive therapy in toxic nodular goiter.

The anti-thyroid drug dosage should be minimized to keep the serum FT₄ index in the upper half of the normal range or slightly elevated. As pregnancy progresses, Graves' disease often improves, and it is not uncommon for patients either to be on very low doses or off anti-thyroid drugs completely by the end of pregnancy. Therefore the anti-thyroid drug dose should be reduced, and maternal thyroid function should be frequently monitored to decrease chances of fetal hypothyroidism. Relapse or worsening of Graves' disease is common after delivery, and patients should be monitored closely. Methimazole up to 20 mg daily in nursing mothers reportedly has no effect on thyroid function in the infant (Azizi et al., 2003), and propylthiouracil is thought to cross into breast milk even less than methimazole.

β Adrenergic receptor antagonists (Chapter 12) are effective in antagonizing the sympathetic/adrenergic effects of thyrotoxicosis, thereby reducing the tachycardia, tremor, and stare, and relieving palpitations, anxiety, and tension. Either propranolol, 20-40 mg four times daily, or atenolol, 50-100 mg daily, is usually given initially. Propranolol or esmolol can be given intravenously if needed. Ca²⁺ channel blockers (diltiazem, 60-120 mg four times daily) can be used to control tachycardia and decrease the incidence of supraventricular tachyarrhythmias (Chapters 27 and 29). These drugs, however, should be used as an adjunct to anti-thyroid drug therapy for more rapid improvement of adrenergic-related symptoms and not as the only treatment for hyperthyroidism. Usually only short-term treatment with β adrenergic receptor antagonists or Ca²⁺ channel blockers is required, 2-6 weeks, and it should be discontinued once the patient is euthyroid.

Other drugs that are useful in the rapid treatment of the severely thyrotoxic patient are agents that inhibit the peripheral conversion of thyroxine to triiodothyronine. Dexamethasone (0.5-1 mg, two to four times daily) and the iodinated radiological contrast agents iopanoic acid (500-1000 mg once daily) and sodium ipodate (oragrafin) (500-1000 mg once daily) are effective in preoperative preparation; neither iopanoic acid nor sodium ipodate is available in the U.S. Cholestyramine has been used in severely toxic patients to bind thyroid hormones in the gut and thus block the enterohepatic circulation of the iodothyronines (Mercado et al., 1996). Immunotherapy has been used for Graves' hyperthyroidism and ophthalmopathy. The B-lymphocyte depleting agent rituximab, when used with methimazole, prolongs remission of Graves' disease (El Fassi et al., 2009). A novel approach that has been successful only in vitro uses low-molecular-weight antagonists of the TSH receptor (Neumann et al., 2008). This approach has the potential to provide a rapid and targeted treatment for Graves' disease.

Treatment includes supportive measures such as intravenous fluids, antipyretics, cooling blankets, and sedation. Anti-thyroid drugs are given in large doses. Propylthiouracil is preferred over methimazole because it also impairs peripheral conversion of T₄→T₃. The recommended initial dose of propylthiouracil is 200-400 mg every 6-8 hours (Nayak and Burman, 2006). Propylthiouracil and methimazole can be administered by nasogastric tube or rectally if necessary. Neither of these preparations is available for parenteral administration in the U.S.

Oral iodides are used after the first dose of an anti-thyroid drug has been administered. The agents mentioned earlier as adjuvant therapies of thyrotoxicosis may be usefully applied. Hydrocortisone (100 mg intravenously every 8 hours) can be used in the setting of hypotension both as an inhibitor of conversion of thyroxine to triiodothyronine and as supportive therapy of possible relative adrenal insufficiency (Nayak and Burman, 2006). Finally, treatment of the underlying precipitating illness is essential.

The most studied example, thiocyanate, differs from the others qualitatively; it is not concentrated by the thyroid gland but in large amounts may inhibit the organification of iodine. Thiocyanate is produced following the enzymatic hydrolysis of certain plant glycosides. Thus, certain foods (e.g., cabbage) and cigarette smoking result in an increased concentration of thiocyanate in the blood and urine, as does the administration of sodium nitroprusside. Indeed, cigarette smoking has been reported to worsen both subclinical hypothyroidism (Müller et al., 1995) and Graves' ophthalmopathy (Bartalena et al., 1998b). Dietary precursors of thiocyanate may be a contributing factor in endemic goiter in certain parts of the world, especially in Central Africa, where the intake of iodine is very low.

Among other anions, perchlorate (ClO₄^–) is 10 times as active as thiocyanate (Wolff, 1998). The various NIS inhibitors, perchlorate, thiocyanate, and nitrate, are additive in inhibiting iodine uptake (Tonacchera et al., 2004). Perchlorate blocks the entrance of iodide into the thyroid by competitively inhibiting the NIS. Perchlorate is transported by NIS using a different stoicheiometry, electroneutral, compared with that seen with transport of iodine (Dohan et al., 2007). Although perchlorate can be used to control hyperthyroidism, it has caused fatal aplastic anemia when given in excessive amounts (2-3 g daily). Perchlorate in doses of 750 mg daily has been used in the treatment of Graves' disease and amiodarone-iodine–induced thyrotoxicosis (National Academy of Sciences/National Research Council [NAS/NRC], 2005). Perchlorate can be used to "discharge" inorganic iodide from the thyroid gland in a diagnostic test of iodide organification. Other ions, selected on the basis of their size, also have been found to be active; fluoroborate (BF₄^–) is as effective as perchlorate.

Ammonium perchlorate is an essential oxidizer in the production of rocket fuel, and water supplies have been contaminated with perchlorate derived from the sites of production. A National Academy of Sciences Committee recommended a reference dose of perchlorate exposure of 0.0007 mg/kg per day that would produce no adverse effect. This level of no effect is much higher than that found in most water supplies, indicating a low risk of perchlorate exposure influencing thyroid function (NAS/NRC, 2005). The reference dose was primarily derived from a 2-week study in normal volunteers that determined the daily dose of perchlorate that produced no effect on thyroid function or ¹²³I uptake (Greer et al., 2002). There remain concerns that accumulated perchlorate exposure from multiple sources and combined exposure to other iodine uptake inhibitors may impair thyroid function, especially as it might affect pregnant women and young children (Miller et al., 2009). A study in the U.S. showed a correlation between perchlorate exposure and an increase in serum TSH (still within the normal range), only among women with low iodine intake (Blount et al., 2006). Men and women with adequate iodine intake did not show any influence of perchlorate on thyroid function. Others have argued that the risk of thyroid dysfunction from perchlorate exposure is extremely low and there is little evidence to support this view (Charnley, 2008). A study among pregnant women living in areas of very high natural perchlorate contamination showed no effect on maternal thyroid function or pregnancy outcome for mother or infant (Tellez et al., 2006). Although reassuring, the high iodine content in this region may limit the effects of perchlorate. Because the primary mode of toxicity of perchlorate is inhibition of iodine uptake, the best approach to reduce susceptibility is to maintain adequate iodine intake, especially during pregnancy (Becker et al., 2006).

Lithium has a multitude of effects on thyroid function; its principal effect is decreased secretion of thyroxine and triiodothyronine (Takami, 1994), which can cause overt hypothyroidism in some patients taking Li⁺ for the treatment of mania (Chapter 16).

In euthyroid individuals, the administration of doses of iodide from 1.5-150 mg daily results in small decreases in plasma thyroxine and triiodothyronine concentrations and small compensatory increases in serum TSH values, with all values remaining in the normal range. However, euthyroid patients with a history of a wide variety of underlying thyroid disorders may develop iodine-induced hypothyroidism when exposed to large amounts of iodine present in many commonly prescribed drugs (Table 39–6), and these patients do not escape from the acute Wolff-Chaikoff effect (Roti et al., 1997). Among the disorders that predispose patients to iodine-induced hypothyroidism are treated Graves' disease, Hashimoto's thyroiditis, postpartum lymphocytic thyroiditis, subacute painful thyroiditis, and lobectomy for benign nodules. The most commonly prescribed iodine-containing drugs are certain expectorants (e.g., potassium iodide), topical antiseptics (e.g., povidone iodine), and iodinated radiological contrast agents.

Before surgery, iodide is sometimes employed alone, but more frequently it is used after the hyperthyroidism has been controlled by an anti-thyroid drug. It is then given for 7-10 days immediately preceding the operation. Optimal control of hyperthyroidism is achieved if anti-thyroid drugs are first given alone. If iodine also is given from the beginning, variable responses are observed; sometimes the effect of iodide predominates, storage of hormone is promoted, and prolonged anti-thyroid treatment is required before the hyperthyroidism is controlled. These clinical observations may be explained by the capacity of iodide to prevent the inactivation of thyroid peroxidase by anti-thyroid drugs (Taurog et al., 1996).

Another use of iodide is to protect the thyroid from radioactive iodine fallout following a nuclear accident, military exposure, or large scale radioiodination procedures in laboratories. Because the uptake of radioactive iodine is inversely proportional to the serum concentration of stable iodine, the administration of 30-100 mg of iodide daily will markedly decrease the thyroid uptake of radioisotopes of iodine. Following the Chernobyl nuclear reactor accident in 1986, ∼10 million children and adults in Poland were given stable iodide to block the thyroid exposure to radioactive iodine from the atmosphere and from dairy products from cows that ate contaminated grass (Nauman and Wolff, 1993).

Strong iodine solution (Lugol's solution) is widely used and consists of 5% iodine and 10% potassium iodide, which yields a dose of 8 mg of iodine per drop. The iodine is reduced to iodide in the intestine before absorption. Saturated solution of potassium iodide (SSKI) also is available, containing 50 mg per drop. Typical doses include 16-36 mg (2-6 drops) of Lugol's solution or 50-100 mg (1-2 drops) of SSKI three times a day. A potassium iodide product (thyroshield) is available over the counter in the U.S. to take in the event of a radiation emergency and block the uptake of radioiodide into the thyroid gland. The adult dose is 2 mL (130 mg) every 24 hours, as directed by public health officials, with specific dose recommendations in children and infants based on age and weight.

Untoward Reactions. Occasional individuals show marked sensitivity to iodide or to organic preparations that contain iodine when they are administered intravenously as a supplement (e.g., sodium iodine [iodopen]) during total parental nutrition therapy. The onset of an acute reaction may occur immediately or several hours after administration. Angioedema is the outstanding symptom, and laryngeal edema may lead to suffocation. Multiple cutaneous hemorrhages may be present. Also, manifestations of the serum-sickness type of hypersensitivity—such as fever, arthralgia, lymph node enlargement, and eosinophilia—may appear. Thrombotic thrombocytopenic purpura and fatal periarteritis nodosa attributed to hypersensitivity to iodide also have been described.

The severity of symptoms of chronic intoxication with iodide (iodism) is related to the dose. The symptoms start with an unpleasant brassy taste and burning in the mouth and throat as well as soreness of the teeth and gums. Increased salivation is noted. Coryza, sneezing, and irritation of the eyes with swelling of the eyelids are commonly observed. Mild iodism simulates a "head cold." The patient often complains of a severe headache that originates in the frontal sinuses. Irritation of the mucous glands of the respiratory tract causes a productive cough. Excess transudation into the bronchial tree may lead to pulmonary edema. In addition, the parotid and submaxillary glands may become enlarged and tender, and the syndrome may be mistaken for mumps parotitis. There also may be inflammation of the pharynx, larynx, and tonsils. Skin lesions are common and vary in type and intensity. They usually are mildly acneform and distributed in the seborrheic areas. Rarely, severe and sometimes fatal eruptions (ioderma) may occur after the prolonged use of iodides. The lesions are bizarre; they resemble those caused by bromism, a rare problem, and as a rule involute quickly when iodide is withdrawn. Symptoms of gastric irritation are common, and diarrhea, which is sometimes bloody, may occur. Fever is occasionally observed, and anorexia and depression may be present.

Fortunately, the symptoms of iodism disappear spontaneously within a few days after stopping the administration of iodide. The renal excretion of I^– can be increased by procedures that promote Cl^– excretion (e.g., osmotic diuresis, chloruretic diuretics, and salt loading). These procedures may be useful when the symptoms of iodism are severe.

Effects on the Thyroid Gland. The chemical behavior of the radioactive isotopes of iodine is identical to that of the stable isotope, ¹²⁷I. ¹³¹I is rapidly and efficiently trapped by the thyroid, incorporated into the iodoamino acids, and deposited in the colloid of the follicles, from which it is slowly liberated. Thus the destructive β particles originate within the follicle and act almost exclusively on the parenchymal cells of the thyroid, with little or no damage to surrounding tissue. The γ radiation passes through the tissue and can be quantified by external detection. The effects of the radiation depend on the dosage. When small tracer doses of ¹³¹I are administered, thyroid function is not disturbed. However, when large amounts of radioactive iodine gain access to the gland, the characteristic cytotoxic actions of ionizing radiation are observed. Pyknosis and necrosis of the follicular cells are followed by disappearance of colloid and fibrosis of the gland. With properly selected doses of ¹³¹I, it is possible to destroy the thyroid gland completely without detectable injury to adjacent tissues. After smaller doses, some of the follicles, usually in the periphery of the gland, retain their function.

Hyperthyroidism. Radioactive iodine is a valuable alternative or adjunctive treatment of hyperthyroidism (Brent, 2008). Stable iodide (non-radioactive) used as treatment for hyperthyroidism, however, may preclude treatment and imaging with radioactive iodine for weeks after the stable iodide has been discontinued. A urinary iodine measurement can be performed to monitor the iodine load. In those patients exposed to stable iodide, a 24-hour radioiodine measurement of a tracer dose of ¹²³I should be performed before ¹³¹I administration to ensure there is sufficient uptake to accomplish the desired ablation.

Dosage and Technique. ¹³¹I, 7000-10,000 rads per gram of thyroid tissue, is administered orally. The effective dose for a given patient depends primarily on the size of the thyroid, the iodine uptake of the gland, and the rate of release of radioactive iodine from the gland subsequent to the nuclide's deposition in the colloid. Comparison studies have shown little advantage of a standard individualized dose, based on gland weight and radioactive iodine uptake, over a fixed dose (Jarl⊘v et al., 1995). For these reasons, the optimal dose of ¹³¹I, expressed in terms of microcuries taken up per gram of thyroid tissue, varies in different laboratories from 80-150 μCi. The usual total dose is 4-15 mCi.

The lower doses produce a lower incidence of hypothyroidism in the early years after treatment; however, many patients with late hypothyroidism may go undetected, and the ultimate incidence of hypothyroidism is probably no less than with the larger doses. In addition, relapse of the hyperthyroid state, or initial failure to alleviate the hyperthyroid state, is increased in patients receiving lower doses of ¹³¹I. Thus, many endocrinologists recommend initial treatment with thyroid ablative doses of ¹³¹I, with subsequent treatment for hypothyroidism. There also is evidence that pretreatment with an anti-thyroid drug reduces the therapeutic efficacy of ¹³¹I. The medication, therefore, should be discontinued ∼1 week before the therapeutic dose of ¹³¹I therapy and only resumed 3 days after ¹³¹I (Walter et al., 2007). If the anti-thyroid drug cannot be discontinued, the effect can be overcome by adjusting to a higher radioiodine dose.

Course of Disease. The course of hyperthyroidism in a patient who has received an optimal dose of ¹³¹I is characterized by progressive recovery. Beginning a few weeks after treatment, the symptoms of hyperthyroidism gradually abate over a period of 2-3 months. If therapy has been inadequate, the necessity for further treatment is apparent within 6-12 months. It is not uncommon, however, for the serum TSH to remain low for several months after ¹³¹I therapy, especially if the patient was not rendered euthyroid before receiving the radioactive iodine. Occasionally, this delayed recovery of the hypothalamic-pituitary-thyroid axis results in a picture of central hypothyroidism, with low circulating thyroid hormones. Thus, assessing radioactive iodine failure based on TSH concentrations alone may be misleading and should always be accompanied by determination of free T₄ and usually serum T₃ concentrations. Furthermore, transient hypothyroidism, lasting up to 6 months, may occur in up to 50% of patients receiving a dose of ¹³¹I calculated to result in euthyroidism (Aizawa et al., 1997). This is less of a problem if the patient receives a higher, ablative dose of ¹³¹I because hypothyroidism occurs far more frequently and persists.

Depending to some extent on the dosage schedule adopted, 80% of patients are cured by a single dose, ∼20% require two doses, and a very small fraction require three or more doses before the disorder is controlled. Patients treated with larger doses of ¹³¹I almost always develop hypothyroidism within a few months.

β Adrenergic antagonists, anti-thyroid drugs, or both, or stable iodide, can be used to hasten the control of hyperthyroidism while awaiting the full effects of the radioactive iodine.

Several analyses of groups of patients treated ≥10 years previously suggest that the eventual rate may exceed 80%. However, it now appears that the incidence of hypothyroidism also increases progressively after subtotal thyroidectomy or after anti-thyroid drug therapy, and such failure of glandular function is probably part of the natural progression of Graves' disease, no matter what the therapy. Although cancer death rate is not increased after radioiodine therapy, there is a small but significant increase shown in specific types of cancer, including stomach, kidney, and breast (Metso et al., 2007). This finding is especially significant because these tissues all express the iodine transporter NIS and may be especially susceptible to radiation effects.

It is essential that patients treated with radioiodine understand that the resulting hypothyroidism will require lifelong treatment and monitoring. Because there are variations in the interval of time from treatment to the development of hypothyroidism, patients must have regular thyroid function testing after radioiodine. Also, once diagnosed, it is difficult to ensure that patients who need the hormone actually take it. Because the health risks of untreated subclinical hypothyroidism are becoming increasingly evident (Biondi and Cooper, 2008), hypothyroidism, either subclinical or overt, requires long-term follow-up to ensure adequate thyroid hormone status and optimal replacement therapy.

Another disadvantage of radioactive iodine therapy is the long period of time that is sometimes required before the hyperthyroidism is controlled. When a single dose is effective, the response is most satisfactory; however, when multiple doses are needed, it may be many months or a year or more before the patient is well. This disadvantage can be largely overcome if the initial dose is sufficiently large. Other disadvantages include possible worsening of ophthalmopathy after treatment (Bartalena et al., 1998a). Radioactive iodine treatment can induce a radiation thyroiditis, with release of preformed thyroxine and triiodothyronine into the circulation. In most patients, this is asymptomatic, but in some there can be worsening of symptoms of hyperthyroidism and rarely cardiac manifestations, such as atrial fibrillation or ischemic heart disease and very rarely thyroid storm. Pretreatment with anti-thyroid drugs should reduce or eliminate this complication and is indicated especially in those with underlying cardiac disease or the elderly. Finally, salivary gland dysfunction may be seen, especially after the higher doses used for the treatment of thyroid cancer (Mandel and Mandel, 2003). Sialogogic agents to hasten the transit of radioiodine through the salivary glands are used by many clinicians but have unproven efficacy. Salivary gland damage is most strongly linked to the cumulative dose of radioiodine.

The risk of inducing hypothyroidism is less in nodular goiter than in Graves' disease, perhaps because of the normal progression of the latter and the preservation of nonautonomous thyroid tissue in the former. Usually, larger doses of radioactive iodine are required in the treatment of toxic nodular goiter than in the treatment of Graves' disease. Radioactive iodine has been used to decrease the size of large nontoxic multinodular goiters that are causing compressive symptoms in patients who are otherwise poor operative risks. Although surgery remains the treatment of choice for patients with compressive multinodular goiters, radioactive iodine therapy may benefit elderly patients, especially those with cardiopulmonary disease. The uptake in multinodular goiters may be low, so some have increased radioiodine uptake by administration of exogenous recombinant human TSH (thyrotropin alfa [thyrogen]) (Duntas and Cooper, 2008), but caution should be exercised because this treatment may induce transient elevations in serum thyroxine and triiodothyronine that could result in excessive stimulation of the heart.

Contraindications. The main contraindication for the use of ¹³¹I therapy is pregnancy. After the first trimester, the fetal thyroid will concentrate the isotope and thus suffer damage; even during the first trimester, radioactive iodine is best avoided because there may be adverse effects of radiation on fetal tissues. The risk of causing neoplastic changes in the thyroid gland has been an ongoing concern since radioactive iodine was first introduced, and only small numbers of children have been treated in this way. Indeed, many clinics have declined to treat younger patients for fear of causing cancer and have reserved radioactive iodine for patients older than some arbitrary age, such as 25 or 30 years. Because experience with ¹³¹I is now vast, these age limits are lower than they were in the past. The most recent report by the Cooperative Thyrotoxicosis Therapy Follow-up Study Group shows no increase in total cancer mortality following ¹³¹I treatment for Graves' disease (Ron et al., 1998). Furthermore, there was no increase in the occurrence of leukemia following large-dose ¹³¹I therapy for thyroid cancer, although there was an increase in colorectal cancers in this population (de Vathaire et al., 1997). These data strongly suggest that laxatives be given to all patients receiving ¹³¹I therapy for treatment of thyroid cancer to decrease the risk of future digestive tract malignancies. Transient abnormalities in testicular function have been reported following ¹³¹I therapy for treatment of thyroid cancer, but no long-term effects on fertility in either men or women have been demonstrated (Dottorini et al., 1995; Pacini et al., 1994). Patients with allergies to iodine contrast agents or to topical iodide-containing products should not have any adverse reaction to ¹³¹I. The amount of elemental iodine contained in the treatment is not greater than that contained in iodized salt or flour that is part of regular dietary intake.

Thyroid Carcinoma. Because most well-differentiated thyroid carcinomas accumulate very little iodine, stimulation of iodine uptake with TSH is required to treat metastases effectively. Currently, endogenous TSH stimulation is evoked by withdrawal of thyroid hormone replacement therapy in patients previously treated with near-total thyroidectomy with or without radioactive ablation of residual thyroid tissue. Total-body ¹³¹I scanning and measurement of serum thyroglobulin when the patient is hypothyroid (TSH >35 mU/L) help to identify metastatic disease or residual thyroid bed tissue. Depending on the residual uptake or the presence of metastatic disease, an ablative dose of ¹³¹I ranging from 30 mCi to >150 mCi is administered, and a repeat total body scan is obtained 1 week later. The precise amount of ¹³¹I needed to treat residual tissue and metastases is controversial. Thyrotropin alfa (recombinant human TSH) is now available to test the ability of thyroid tissue, both normal and malignant, to take up radioactive iodine and to secrete thyroglobulin (Haugen et al., 1999). Thyrogen allows assessment of the presence of metastatic disease, without the necessity for patients to stop their suppressive levothyroxine therapy and become clinically hypothyroid. Thyrotropin alfa is approved for diagnostic scanning and for thyroid remnant ablation after thyroidectomy in thyroid cancer patients, but not for treatment of metastatic disease. (Duntas and Cooper, 2008; Pacini and Castangna, 2008).

TSH-suppressive therapy with levothyroxine is indicated in all patients after treatment for thyroid cancer. The goal of therapy usually is to keep serum TSH levels in the subnormal range, although relaxing the degree and duration of suppression, especially for stage 1 and 2 cancers, is now recommended (Burmeister et al., 1992; Cooper et al., 2006). Follow-up evaluation every 6 months is reasonable, along with determination of serum thyroglobulin concentrations (Spencer and LoPresti, 2008). Patients with a rise in thyroglobulin but no detectable disease on whole-body scan require additional imaging and consideration of alternative treatments including surgery and external radiation (Kloos, 2008). A rise in serum thyroglobulin concentration is often the first indication of recurrent disease. The prognosis in patients with thyroid cancer depends on the pathology and size of the tumor and is generally worse in older individuals. Overall, the vast majority of patients with thyroid cancer will not die of their disease. Papillary cancer is usually not aggressive; the 10-year survival rate exceeds 80%. Follicular cancer is more aggressive and can metastasize via the bloodstream. Still, prognosis is fair and long-term survival is common. Even in patients with metastatic, differentiated thyroid cancer, ¹³¹I therapy is very effective and may be even curative (Cooper et al., 2006). Anaplastic cancer is the exception: It is highly malignant with survival usually <1 year. Medullary thyroid carcinomas do not accumulate I^– and cannot be treated with ¹³¹I.

Chemotherapy in Thyroid Cancer

Advanced and metastatic poorly differentiated papillary and follicular thyroid cancer often does not concentrate iodine sufficient for therapy with ¹³¹I (Kloos, 2008). There have been significant advances in targeted chemotherapy for thyroid cancer (Sherman, 2009). Recent advances in the molecular genetics of thyroid cancer have resulted in the identification of oncogenic mutations in the BRAF and RAS genes, known to activate the MAPK signaling pathway. Medullary thyroid carcinoma is associated with mutations in the RET gene, which also enhance MAPK signaling. These findings have led to a number of successful clinical trials in poorly differentiated papillary and follicular thyroid cancer and medullary thyroid cancer. Treatment with inhibitors of receptor tyrosine kinases, vascular endothelial growth factor (VEGF), and the VEGF receptor have produced partial response rates in the range of 30%. Agents studied include axitinib, gefitinib, imatinib, motesanib, sorafenib, sunitinib, and vandetanib (Sipos and Shah, 2010). Single agents in poorly differentiated thyroid cancer have most commonly produced disease stabilization, although combining agents to target multiple growth-promoting pathways may improve the disease response.