Thyroid hormone is essential for normal development, especially of the central nervous system (CNS). In the adult, thyroid hormone maintains metabolic homeostasis and influences the function of virtually all organ systems. Thyroid hormone contains iodine that must be supplied by nutritional intake. The thyroid gland contains large stores of thyroid hormone in the form of thyroglobulin. These stores maintain systemic concentrations of thyroid hormone despite variations in iodine availability and nutritional intake. The thyroidal secretion is predominantly the prohormone thyroxine, which is converted in the liver and other tissues to the active form, triiodothyronine. Local activation of thyroxine also occurs in target tissues (e.g., brain and pituitary) and is increasingly recognized as an important regulatory step in thyroid hormone action. Serum concentrations of thyroid hormones are precisely regulated by the pituitary hormone, thyrotropin (TSH), in a negative-feedback system. The predominant actions of thyroid hormone are mediated via nuclear thyroid hormone receptors (TRs) and modulating transcription of specific genes.
Overt hyperthyroidism and hypothyroidism, thyroid hormone excess or deficiency, are usually associated with dramatic clinical manifestations. Milder disease often has a more subtle clinical presentation and is identified based on abnormal biochemical tests of thyroid function. Maternal and neonatal hypothyroidism, due to iodine deficiency, remains the major preventable cause of mental retardation worldwide. Treatment of the hypothyroid patient consists of thyroid hormone replacement. Treatments for hyperthyroidism include anti-thyroid drugs to decrease hormone synthesis and secretion, destruction of the gland by the administration of radioactive iodine, or surgical removal. In most patients, disorders of thyroid function can be either cured or have their diseases controlled. Likewise, thyroid malignancies are most often localized and resectable. Metastatic disease often responds to radioiodide treatment but may become highly aggressive and unresponsive to conventional treatment.
The thyroid gland produces 2 fundamentally different types of hormones. The thyroid follicle produces the iodothyronine hormones thyroxine (T4) and 3,5,3′-triiodothyronine (T3). The thyroid’s parafollicular cells (C cells) produce calcitonin (see Chapter 44).
BIOSYNTHESIS OF THYROID HORMONES. The thyroid hormones are synthesized and stored as amino acid residues of thyroglobulin, a complex glycoprotein made up of 2 apparently identical subunits (330 kDa each) and constituting the vast majority of the thyroid follicular colloid. The thyroid gland is unique in storing great quantities of potential hormone in this way, and extracellular thyroglobulin can represent a large portion of the thyroid mass. The major steps in the synthesis, storage, release, and interconversion of thyroid hormones are summarized in Figure 39–1 and described as follows:
Figure 39–1 Major pathways of thyroid hormone biosynthesis and release. Abbreviations: Tg, thyroglobulin; DIT, diiodotyrosine; MIT, monoiodotyrosine; TPO, thyroid peroxidase; HOI, hypoiodous acid; EOI, enzyme-linked species; D1 and D2, deiodinases; PTU, propylthiouracil; MMI, methimazole.
A. Uptake of Iodide. Iodine ingested in the diet reaches the circulation in the form of iodide ion (I–). Under normal circumstances, the I– concentration in the blood is very low (0.2-0.4 μg/dL; ~15-30 nM), but the thyroid actively transports the ion via a specific membrane-bound protein, termed the sodium-iodide symporter (NIS). As a result, the ratio of thyroid to plasma iodide concentration is usually between 20 and 50 and can exceed 100 when the gland is stimulated. Iodide transport is inhibited by a number of ions such as thiocyanate and perchlorate. Thyrotropin (thyroid-stimulating hormone [TSH]) stimulates NIS gene expression and promotes insertion of NIS protein into the membrane in a functional configuration. Thus, decreased stores of thyroid iodine enhance iodide uptake, and the administration of iodide can reverse this situation by decreasing NIS protein expression. 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.
B. Oxidation and Iodination. The oxidation of iodide to its active form is accomplished by thyroid peroxidase. The reaction results in the formation of monoiodotyrosyl (MIT) and diiodotyrosyl (DIT) residues in thyroglobulin just prior to its extracellular storage in the lumen of the thyroid follicle.
C. Formation of Thyroxine and Triiodothyronine from Iodotyrosines. The remaining synthetic step is the coupling of 2 diiodotyrosyl residues to form thyroxine (T4) or of a monoiodotyrosyl and a diiodotyrosyl residue to form triiodothyronine (T3). These oxidative reactions also are catalyzed by thyroid peroxidase. Intrathyroidal and secreted T3 are also generated by the 5′-deiodination of thyroxine.
D. Resorption; and Proteolysis of Colloid; E. Deiodination of DIT/MIT; F. deiodination of T4; G. Secretion of Thyroid Hormones. Because T4 and T3 are synthesized and stored within thyroglobulin, proteolysis is an important part of the secretory process. This process is initiated by endocytosis of colloid from the follicular lumen at the apical surface of the cell, with the participation of a thyroglobulin receptor, megalin. This “ingested” thyroglobulin appears as intracellular colloid droplets, which apparently fuse with lysosomes containing the requisite proteolytic enzymes. TSH enhances the degradation of thyroglobulin by increasing the activity of thiol endopeptidases of the lysosomes, which selectively cleave thyroglobulin, yielding hormone-containing intermediates that subsequently are processed by exopeptidases. The liberated hormones then exit the cell mostly as T4, some as T3, via a process of deiodination (Figure 39–2) that also occurs peripherally (Figure 39–3).
Figure 39–2 Pathways of iodothyronine deiodination.
Figure 39–3 Deiodinase isozymes. D1, type I iodothyronine 5′-deiodinase; D2, type II iodothyronine 5′-deiodinase; D3, type III iodothyronine 5-deiodinase; BAT, brown adipose tissue.
CONVERSION OF T4 TO T3 IN PERIPHERAL TISSUES. The normal daily production of T4 is estimated to range between 80 and 100 μg; that of T3 is between 30 and 40 μg. Although T3 is secreted by the thyroid, metabolism of T4 by 5′, or outer ring, deiodination in the peripheral tissues accounts for ~80% of circulating T3. In contrast, removal of the iodine on position 5 of the inner ring produces the metabolically inactive 3,3′,5′-triiodothyronine (reverse T3 or rT3; Figure 39–2). Under normal conditions, ~40% of T4 is converted to each of T3 and rT3, and ~20% is metabolized via other pathways, such as glucuronidation in the liver and excretion in the bile. Normal circulating concentrations of T4 in plasma range from 4.5-11 μg/dL; those of T3 are ~1/100 of that (60-180 ng/dL). 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.
There are 3 iodothyronine deiodinases. Forms 1 and 2 (D1, D2) convert T4 to T3. D1 is expressed primarily in the liver and kidney, and also in the thyroid and pituitary (Figure 39–3). It is upregulated in hyperthyroidism; downregulated in hypothyroidism, and inhibited by the anti-thyroid drug propylthiouracil. 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 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. D2 is regulated by T4 such that elevated levels of the enzyme are found in hypothyroidism and suppressed levels are found in hyperthyroidism. Type 3 deiodinase (D3) catalyzes inner ring- or 5-deiodination, the main inactivating pathway of T3 metabolism; D1 performs this function to some extent. D3 is found at highest levels in the CNS and placenta, and is also expressed in skin and uterus. The 3 deiodinases contain the rare amino acid selenocysteine in their active sites. Mutations in 1 such protein, SECIS binding protein 2, are associated with abnormal circulating thyroid hormone levels.
TRANSPORT OF THYROID HORMONES IN THE BLOOD. The thyroid hormones are transported in the blood in strong but noncovalent association with certain plasma proteins.
Thyroxine-binding globulin (TBG) is the major carrier of thyroid hormones. It is a glycoprotein that binds 1 molecule of T4 per molecule of protein with a very high affinity (Kd’ is ~10–10 M). T3 is bound less avidly. T4, but not T3, 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 T4 with aKd ~10–7 M. Albumin also can bind T4 when the more avid carriers are saturated, but its physiological importance is unclear. Binding of thyroid hormones to plasma proteins protects the hormones from metabolism and excretion, resulting in their long half-lives in the circulation. The free (unbound) hormone is a small percentage (~0.03% of T4 and ~0.3% of T3) of the total hormone in plasma. The differential binding affinities for serum proteins also contribute to establishing the 10- to 100-fold differences in circulating hormone concentrations and half-lives of T4 and T3.
Only the unbound hormone has metabolic activity. Because of the high degree of binding of thyroid hormones to plasma proteins, changes in either the concentrations of these proteins or the binding affinity of the hormones for the proteins has major effects on the total serum hormone levels. Certain drugs and a variety of pathological and physiological conditions can alter both the binding of thyroid hormones to plasma proteins and the amounts of these proteins (Table 39–1).
Factors that Alter Binding of Thyroxine to Thyroxine-Binding Globulin
DEGRADATION AND EXCRETION. T3 and T4 can deiodinated but can also be metabolized by ether cleavage, conjugation, and oxidative decarboxylation.
T4 is eliminated slowly from the body, with a t1/2 of 6-8 days. In hyperthyroidism, the t1/2 is shortened to 3-4 days, whereas in hypothyroidism it may be 9-10 days. In conditions associated with increased binding to TBG, such as pregnancy, clearance is retarded. The opposite effect is observed when binding to protein is inhibited by certain drugs (see Table 39–1). T3, which is less avidly bound to protein, has a t1/2 of 1 day.
The liver is the major site of non-deiodinative degradation of thyroid hormones; T4 and T3 are conjugated with glucuronic and sulfuric acids 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.
FACTORS REGULATING OF THYROID HORMONE SECRETION. Thyrotropin or TSH is a glycoprotein hormone with α and β subunits analogous to those of the gonadotropins (see Table 38–2). TSH is secreted in a pulsatile manner and circadian pattern (levels are highest during sleep at night). TSH secretion is controlled by the hypothalamic peptide thyrotropin-releasing hormone (TRH) and by the concentration of free thyroid hormones in the circulation. Extra thyroid hormone inhibits transcription of both the TRH gene and the genes encoding the α and β subunits of TSH, which suppresses the secretion of TSH and causes the thyroid to become inactive and regress. Any decrease in the normal rate of thyroid hormone secretion by the thyroid evokes an enhanced secretion of TSH. Additional mechanisms mediating the effect of thyroid hormone on TSH secretion appear to be a reduction in TRH secretion by the hypothalamus and a reduction in the number of TRH receptors on pituitary cells (Figure 39–4).
Figure 39–4 Regulation of thyroid hormone secretion. Myriad neural inputs influence hypothalamic secretion of thyrotropin-releasing hormone (TRH). TRH stimulates release of thyrotropin (TSH, thyroid-stimulating hormone) from the anterior pituitary; TSH stimulates the synthesis and release of the thyroid hormones T3 and T4. T3 and T4 feed back to inhibit the synthesis and release of TRH and TSH. Somatostatin (SST) can inhibit TRH action, as can dopamine and high concentrations of glucocorticoids. Low levels of I– are required for thyroxine synthesis, but high levels inhibit thyroxin synthesis and release.
THYROTROPIN-RELEASING HORMONE. TRH is a tripeptide (L-pyroglutamyl-L-histidyl-L-proline amide) synthesized by the hypothalamus and released into the hypophyseal-portal circulation where it interacts with TRH receptors on thyrotropes in the anterior pituitary. The binding of TRH to its receptor, a GPCR, stimulates the Gq-PLC-IP3-Ca2+ pathway and activates PKC, ultimately stimulating the synthesis and release of TSH. Two TRH receptors have now been identified, TRH-R1 and TRH-R2, as well as selective analogs for these receptors. Somatostatin, dopamine, and glucocorticoids inhibit TRH-stimulated TSH secretion.
ACTIONS OF TSH ON THE THYROID. TSH increases the synthesis and secretion of thyroid hormone. These effects follow the binding of TSH to its receptor (a GPCR) on the plasma membrane of thyroid cells. Binding of TSH to its receptor stimulates the Gs-adenylyl cyclase–cyclic AMP pathway. Higher concentrations of TSH activate the Gq-PLC pathway. Multiple mutations of the TSH receptor result in clinical thyroid dysfunction.
IODINE AND THYROID FUNCTION. Normal thyroid function requires an adequate intake of iodine; without it, normal amounts of hormone cannot be made, TSH is secreted in excess, and the thyroid becomes hyperplastic and hypertrophic. The enlarged and stimulated thyroid becomes remarkably efficient at extracting the residual traces of iodide from the blood, developing an iodine gradient that may be 10 times normal; in mild-to-moderate iodine deficiency, the thyroid usually succeeds in producing sufficient hormone and preferentially secreting T3. In more severe iodine deficiency, adult hypothyroidism and cretinism may occur. High levels of iodine inhibit thyroxine synthesis and release. In some areas of the world, simple or nontoxic goiter is prevalent because of insufficient dietary iodine. The addition of iodate to table salt (NaCl) provides a convenient iodine supplement. In the U.S., iodized salt provides 100 μg of iodine per gram. The recommended daily allowances for iodine range from 90-120 μg for children, 150 μg for adults, 220 μg for pregnancy, and 290 μg for lactation. Vegetables, meat, and poultry contain minimal amounts of iodine, whereas dairy products and fish are relatively high in iodine.
THYROID HORMONE TRANSPORT. Transmembrane passage of thyroid hormones appears to be mediated by monocarboxylic acid transporter 8 (MCT8, SLC16A2; see Table 5–2). MCT8 is widely expressed, including in liver, heart, and brain. MCT10 also transports T4 and T3 and is widely expressed, but its physiological importance for thyroid hormone transport in vivo is unknown. The organic anion transporter OATP1C1 preferentially transports T4 rather than T3, is highly expressed in brain capillaries, and has been hypothesized to be responsible for the transport of T4 across the blood-brain barrier (see Chapter 5).
MEDIATION OF EFFECTS BY NUCLEAR RECEPTORS. Thyroid hormone action is mediated largely by the binding of T3 to TRs, which are members of the nuclear receptor superfamily of transcription factors.
T3 binds to TRs with ~10-fold greater affinity than does T4, and T4 is not thought to be biologically active in normal physiology. TRs bind to specific DNA sequences (thyroid hormone response elements [TREs]) in the promoter/regulatory regions of target genes. The transcription of most target genes is repressed by unliganded TRs and induced following the binding of T3. In the unliganded state, the TR ligand-binding domain interacts with a corepressor complex that includes histone deacetylases and other proteins. The binding of T3 causes replacement of the corepressor complex by a coactivator complex that includes histone acetyltransferases, methyltransferases, and other proteins. Other thyroid hormone target genes, such as those encoding TRH and the TSH subunits, are negatively regulated by T3. The mechanism is not well defined, but these genes tend to be induced by the unliganded TR in addition to being repressed by T3.
Two genes encode TRs: THRA and THRB. THRA encodes the receptor TRα1. TRα1 is expressed in most cell types, but its major activities are in the regulation of heart rate, body temperature, skeletal muscle function, and the development of bone and small intestine. Alternative splicing of the TRα primary transcript results in the production of TRα2, which lacks part of the ligand-binding domain (LBD), does not bind T3, and has not known function. A cryptic promoter within intron 7 of THRA drives the production of small proteins that contain only a portion of the TRα LBD and appear to play a role, along with TRα1, in GI development. The THRB gene has 2 promoters that lead to the production of TRβ1 and TRβ2. These receptors have unique amino terminal domains but otherwise are identical. TRβ1 is ubiquitous; TRβ2 has a highly restricted pattern of expression. Mutations in THRB cause the syndrome of resistance to thyroid hormone. TRβ1 mediates specific effects in liver metabolism (including the hypocholesterolemic effect of T3); TRβ2 has roles in the negative feedback by T3 on hypothalamic TRH and pituitary TSH and in the development of retinal cones and the inner ear.
NONGENOMIC EFFECTS OF THYROID HORMONE. TRs are found outside the nucleus where they can exert biological effects via rapid nongenomic mechanisms.
TRs associate in a T3-dependent manner with the p85α subunit PI3 kinase, resulting in the activation of PKB/Akt. The PI3K/Akt pathway has myriad effects. For example, it stimulates NO production by endothelial cells, which leads to vasodilation; hence, T3 administration causes rapid vasodilation. There also is evidence for nongenomic actions of thyroid hormone via a plasma membrane receptor within integrin αVβ3. This putative receptor binds extracellular T4 in preference to T3, resulting in activation of MAP kinase. The importance of nongenomic 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), an interaction of unknown relevance in humans.
MAJOR CLINICAL EFFECTS OF THYROID HORMONES
GROWTH AND DEVELOPMENT. Thyroid hormone plays a critical role in brain development by mechanisms that are incompletely understood. The absence of thyroid hormone during the period of active neurogenesis (up to 6 months postpartum) leads to irreversible mental retardation (cretinism) and is accompanied by multiple morphological alterations in the brain. These severe morphological alterations result from disturbed neuronal migration, deranged axonal projections, and decreased synaptogenesis. Thyroid hormone supplementation during the first 2 weeks of postnatal life prevents the development of these disturbed morphological changes. The actions of thyroid hormones on protein synthesis and enzymatic activity are not limited to the brain; most tissues are affected by the administration of thyroid hormone or by its deficiency. The extensive defects in growth and development in cretins vividly illustrate the pervasive effects of thyroid hormones in normal individuals.
Cretinism is usually classified as endemic (caused by extreme iodine deficiency) or sporadic (a consequence abnormal thyroid development or a defect in the synthesis of thyroid hormone). The affected child is dwarfed, with short extremities, mentally retarded, inactive, uncomplaining, and listless. Other manifestations include puffy face, enlarged tongue, dry and doughy skin, slow heart rate, and decreased body. For treatment to be fully effective, the diagnosis must be made long before these changes are obvious. In regions of endemic iodine deficiency, iodine replacement is best instituted before pregnancy. Screening of newborn infants for deficient thyroid function is carried out in the U.S. and in most industrialized countries.
THERMOGENIC EFFECTS. Thyroid hormone is necessary for both obligatory thermogenesis (the heat resulting from vital processes) as well as for facultative or adaptive thermogenesis.
Only a few organs, including the brain, gonads, and spleen, are unresponsive to the thermogenic effects of T3. Obligatory thermogenesis is the result of T3 making most biological processes thermodynamically less efficient for the sake of producing heat, but the pathways involved and their quantitative contributions have yet to be fully defined. The capacity of T3 to induce the skeletal muscle Ca++-dependent ATPase (SERCA1) contributes to thermogenesis by stimulating the cycling of calcium between cytosol and sarcoplasmic reticulum. Other than in brown adipose tissue, there is no evidence that uncoupling of phosphorylation is a major thermogenic mechanism. Regardless of the mechanism, thermogenesis is highly sensitive to thyroid hormone around the physiological range: small changes in L-thyroxine replacement doses may significantly alter resting energy expenditure in the hypothyroid patient. The ability of T3 to stimulate thermogenesis has evolved along with ancillary effects to support this action, such as the stimulation of appetite and lipogenesis.
CARDIOVASCULAR EFFECTS. Hyperthyroid patients have tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increasedpulse pressure. Hyperthyroidism is a relatively common cause of atrial fibrillation. Hypothyroid patients have bradycardia, decreased cardiac index, pericardial effusion, increased peripheral vascular resistance, decreased pulse pressure, and elevation of mean arterial pressure.
T3 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 If in the sinoatrial node. Several proteins that comprise the If channel are induced by T3’ including HCN2 and HCN4. T3 also appears to have a direct nongenomic vasodilating effect on vascular smooth muscle, which may contribute to the decreased systemic vascular resistance and increased cardiac output of hyperthyroidism.
METABOLIC EFFECTS. Thyroid hormone stimulates the expression of hepatic low-density lipoprotein (LDL) receptors and the metabolism of cholesterol to bile acids, such that hypercholesterolemia is a characteristic feature of hypothyroidism.
Thyroid hormone has complex effects on carbohydrate metabolism. Thyrotoxicosis is an insulin-resistant state. Post-receptor defects are manifested by depleted glycogen stores, enhanced gluconeogenesis, and increased rate of glucose absorption from the gut. Compensatory increases in insulin secretion result in hyperinsulinemia. There may be impaired glucose tolerance or even clinical diabetes, but most hyperthyroid patients are euglycemic. Conversely, hypothyroidism results in decreased absorption of glucose from the gut, decreased insulin secretion, and a reduced rate of peripheral glucose uptake. Glucose metabolism generally is not affected in a clinically significant manner in nondiabetic patients, although insulin requirements decrease in the hypothyroid patient with diabetes.
DISORDERS OF THYROID FUNCTION
THYROID HYPOFUNCTION. Hypothyroidism, known as myxedema when severe, is the most common disorder of thyroid function.
Worldwide, hypothyroidism resulting from iodine deficiency remains a common problem. In nonendemic areas where iodine is sufficient, chronic autoimmune thyroiditis (Hashimoto thyroiditis) accounts for most cases; this disorder is characterized by high levels of circulating antibodies directed against thyroid peroxidase and, sometimes, against thyroglobulin; antibodies directed at the TSH receptor may be present. The conditions are examples of primary hypothyroidism, failure of the thyroid gland itself. Central hypothyroidism occurs much less often and results from diminished stimulation of the thyroid by TSH because of pituitary failure (secondary hypothyroidism) or hypothalamic failure (tertiary hypothyroidism). Hypothyroidism present at birth (congenital hypothyroidism) is the most common preventable cause of mental retardation in the world.
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. Diagnosis requires the finding of an elevated serum TSH or, in cases of central hypothyroidism, a decreased serum free T4.
THYROID HYPERFUNCTION. Thyrotoxicosis is a condition caused by elevated concentrations of circulating free thyroid hormones. Increased thyroid hormone production is the most common cause, with the common link of TSH receptor stimulation and increased iodine uptake by the thyroid gland as shown by the measurement of the percentage uptake of 123I or 131I in a 24-h radioactive iodine uptake (RAIU) test.
TSH receptor stimulation is either the result of TSH receptor stimulating antibody in Graves disease or somatic activating TSH receptor mutations in autonomously functioning nodules or a toxic goiter. In contrast, thyroid inflammation or destruction resulting in excess “leak” of thyroid hormones or excess exogenous thyroid hormone intake results in a low 24-h RAIU. The term subclinical hyperthyroidismis defined as those with a subnormal serum TSH and normal concentrations of T4 and T3. Atrial arrhythmias, excess cardiac mortality, and excessive bone loss have been associated with this profile of thyroid function tests.
Graves disease is the most common cause of high RAIU thyrotoxicosis. Graves disease is an autoimmune disorder characterized by increased thyroid hormone production, diffuse goiter, and IgG antibodies that bind to and activate the TSH receptor. As with most types of thyroid dysfunction, women are affected more than men, with a ratio ranging from 5:1-7:1. Graves disease is more common between the ages of 20 and 50, but it may occur at any age. Graves disease is commonly associated with other autoimmune diseases. 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. Toxic uninodular/multinodular goiter accounts for 10-40% of cases of hyperthyroidism and is more common in older patients. A low RAIU is seen in the destructive thyroiditides and in thyrotoxicosis in patients taking excessive doses of thyroid hormone.
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. Some individuals may show extensive muscular wasting as a result of thyroid myopathy. The most severe form of hyperthyroidism is thyroid storm (see section below on therapeutic uses of anti-thyroid drugs).
THYROID FUNCTION TESTS. Measurement of the total hormone concentration in plasma may not give an accurate picture of the activity of the thyroid gland; total hormone concentration changes with alterations in amount and affinity of TBG in plasma.
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 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 are subject to influences of altered serum binding proteins, nonthyroid disease, and other drugs. 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. The TSH assay can differentiate between normal and thyrotoxic patients, who should exhibit suppressed TSH values. 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.
THERAPEUTIC USES OF THYROID HORMONE
The major indications for the therapeutic use of thyroid hormone are for hormone replacement therapy in patients with hypothyroidism and for TSH suppression therapy in patients with thyroid cancer.
THYROID HORMONE PREPARATIONS. Synthetic preparations of the sodium salts of the natural isomers of the thyroid hormones are available and widely used for thyroid hormone therapy.
Levothyroxine. Levothyroxine sodium (L-T4, LEVOTHROID, LEVOXYL, SYNTHROID, UNITHROID, others) is available in tablets and as a lyophilized powder for injection. Table 39–2 lists drugs and other factors that may influence levothyroxine dosage requirements. 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. The serum T4 peaks 2-4 h after oral ingestion, with plasma t1/2~7-days. 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. Follow-up blood tests typically are done ~6 weeks after any dosage change due to the 1-week plasma t1/2 of T4. In situations where patients cannot take oral medications or where intestinal absorption is in question, levothyroxine may be given intravenously once daily at a dose ~80% of the patient’s daily oral requirement.
Liothyronine. Liothyronine sodium (L-T3) is the salt of triiodothyronine and is available in tablets (CYTOMEL) and in an injectable form (TRIOSTAT, others). Liothyronine absorption is nearly 100% with peak serum levels 2-4 h 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 t1/2= 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 3 times per day typically yields a normal serum free T3 in an athyreotic individual.
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:T3ratio, also are available. A 60-mg (1 grain) desiccated thyroid tablet is approximately equivalent in activity to 80 μg of thyroxine.
THYROID HORMONE REPLACEMENT THERAPY IN HYPOTHYROIDISM. Thyroxine (L-T4, levothyroxine sodium) is the hormone of choice for thyroid hormone replacement therapy due to its consistent potency and prolonged duration of action. With this therapy, one relies on the types 1 and 2 deiodinases to convert T4 to T3 to maintain a steady serum level of free T3.
The average daily adult replacement dose of levothyroxine sodium is 1.7 μg/kg body weight (0.8 μg/lb). Dosing should generally be based on lean body mass. 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. 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. Controlled trials give no evidence that combination therapy with T4 T3 provides a better therapeutic response than does T4 alone. Monotherapy with levothyroxine most closely mimics normal physiology and generally is preferred.
Hypothyroidism During Pregnancy. Due to the increased serum concentration of TBG induced by estrogen, the expression of type 3 deiodinase by the placenta, and the small amount of transplacental passage of L-T4 from mother to fetus, a higher dose of L-T4 is often required in pregnant patients. Overt hypothyroidism during pregnancy is associated with fetal distress, impaired psychoneural development in the progeny, and mildly impaired psychomotor development in the children and preterm delivery. Women should increase their levothyroxine dosage by ~30% as soon as pregnancy is confirmed. Most measure a serum TSH in the first trimester and then adjust the thyroxine dose based on this result. Subsequent dosage adjustments based on serum TSH, measured 4-6 weeks after each adjustment, should be made to bring the TSH into the lower portion of the reference range.
MYXEDEMA COMA. Myxedema coma is a rare syndrome that represents the extreme expression of severe, long-standing hypothyroidism. Myxedema coma occurs most often in elderly patients during the winter months. Cardinal features of myxedema coma are: hypothermia, respiratory depression, and decreased consciousness.
Intravenous administration of thyroid hormone is advised. Therapy with levothyroxine is begun with a loading dose of 250-500 μ followed by a daily full replacement dose.
CONGENITAL HYPOTHYROIDISM. Success in the treatment of congenital hypothyroidism depends on the age at which therapy is started. If therapy is instituted within the first 2 weeks of life, normal physical and mental development can be achieved.
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. 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.
THYROID CANCER. The mainstays of therapy for well-differentiated thyroid cancer (papillary, follicular) are surgical thyroidectomy, radioiodine, and levothyroxine to suppress TSH. 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.
Thyroid Nodules. Thyroid nodules usually are asymptomatic, although they can cause neck discomfort, dysphagia, and a choking sensation. 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.
ADVERSE EFFECTS OF THYROID HORMONE. Adverse effects of thyroid hormone generally occur only upon overtreatment and are similar to the consequences of hyperthyroidism.
ANTI-THYROID DRUGS AND OTHER THYROID INHIBITORS
Myriad compounds are capable of interfering, directly or indirectly, with the synthesis, release, or action of thyroid hormones (Tables 39-2 and 39–3). Several types are clinically useful:
Factors Influencing Oral Levothyroxine Therapy
• Anti-thyroid drugs, which interfere directly with the synthesis of thyroid hormones
• Ionic inhibitors, which block the iodide transport mechanism
• High concentrations of iodine, which decrease release of thyroid hormones from the gland and also may decrease hormone synthesis
• Radioactive iodine, which damages the thyroid gland with ionizing radiation
Adjuvant therapy with drugs that have no specific effects on thyroid hormone synthesis is useful in controlling the peripheral manifestations of thyrotoxicosis, including inhibitors of the peripheral deiodination of T4 to T3, β adrenergic receptor antagonists, and Ca2+ channel blockers.
The anti-thyroid drugs with clinical utility are the thioureylenes, which belong to the family of thioamides. Propylthiouracil is the prototype (Figure 39–5).
Figure 39–5 Anti-thyroid drugs of the thiamide type.
Mechanism of Action. Anti-thyroid drugs inhibit the formation of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin; they also inhibit the coupling of these iodotyrosyl residues to form iodothyronines. The drugs are thought to inhibit the peroxidase enzyme. Inhibition of hormone synthesis results in the depletion of stores of iodinated thyroglobulin as the protein is hydrolyzed and the hormones are released into the circulation. In addition to blocking hormone synthesis, propylthiouracil partially inhibits the peripheral deiodination of T4 to T3. Methimazoledoes not have this effect; this provides a rationale for the choice of propylthiouracil over other anti-thyroid drugs in the treatment of severe hyperthyroid states or of thyroid storm.
ADME. The anti-thyroid compounds currently used in the U.S. are propylthiouracil (6-n-propylthiouracil) and methimazole (1-methyl-2-mercaptoimidazole; TAPAZOLE, others). In Europe, carbimazole (NEOMERCAZOLE), a carbethoxy derivative of methimazole, is available, and its anti-thyroid action is due to its conversion to methimazole after absorption. Pharmacological properties of propylthiouracil and methimazole are shown in Table 39–4.
Pharmacokinetic Features of Anti-thyroid Drugs
Untoward Reactions. The incidence of side effects from propylthiouracil and methimazole as currently used is relatively low. Agranulocytosis is the most serious reaction, usually occurring in the first few weeks or months of therapy but sometimes later. Patients should be instructed to immediately report the development of sore throat or fever, and should discontinue their anti-thyroid drug and obtain a granulocyte count. Agranulocytosis is reversible upon discontinuation of the offending drug, and the administration of recombinant human granulocyte colony-stimulating factor may hasten recovery. Mild granulocytopenia, if noted, may be due to thyrotoxicosis or may be the first sign of this dangerous drug reaction; frequent leukocyte counts are then required.
The most common reaction is a mild urticarial papular rash that often subsides spontaneously without interrupting treatment, but it sometimes calls for the administration of an antihistamine, corticosteroids, and changing to another. 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.
THERAPEUTIC USES. The anti-thyroid drugs are used in the treatment of hyperthyroidism:
• As definitive treatment, to control the disorder in anticipation of a spontaneous remission in Graves disease
• In conjunction with radioactive iodine, to hasten recovery while awaiting the effects of radiation
• To control the disorder in preparation for surgical treatment
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 t1/2, 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 h. When doses >300 mg daily are needed, further subdivision of the time of administration to every 4-6 h is occasionally helpful. 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.
Response to Treatment. The thyrotoxic state usually improves within 3-6 weeks after the initiation of anti-thyroid drugs. The clinical response is related to the dose of anti-thyroid drug, the size of the goiter, and pretreatment serum T3 concentrations. The rate of response is determined by the quantity of stored hormone, the rate of turnover of hormone in the thyroid, the t1/2 of the hormone in the periphery, and the completeness of the block in synthesis imposed by the dosage given. Hypothyroidism may develop as a result of overtreatment. 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. 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.
Thyrotoxicosis in Pregnancy. Thyrotoxicosis occurs in ~0.2% of pregnancies and is caused most frequently by Graves disease. Anti-thyroid drugs are the treatment of choice; radioactive iodine is clearly contraindicated. Both propylthiouracil and methimazole cross the placenta equally, and either may be used safely in the pregnant patient, although the concern for propylthiouracil-associated liver failure in pregnancy may favor the use of methimazole. Carbimazole is used in the EU during pregnancy and is rarely associated with congenital gut abnormalities. 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. 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, and propylthiouracil is thought to cross into breast milk even less than methimazole.
Adjuvant Therapy. Several drugs that have no intrinsic anti-thyroid activity are useful in the symptomatic treatment of thyrotoxicosis. ~ Adrenergic receptor antagonists (see 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 4 times daily, or atenolol, 50-100 mg daily, is usually given initially. Ca2+ channel blockers (diltiazem, 60-120 mg 4 times daily) can be used to control tachycardia and decrease the incidence of supraventricular tachyarrhythmias. 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.Immunotherapy has been used for Graves hyperthyroidism and ophthalmopathy. The B-lymphocyte depleting agent rituximab, when used with methimazole, prolongs remission of Graves disease.
The ionic inhibitors are substances that interfere with the concentration of iodide by the thyroid gland. These agents are anions that resemble iodide: thiocyanate, perchlorate, andfluoroborate, all monovalent hydrated anions of a size similar to that of iodide.
Thiocyanate differs from the rest qualitatively; it is not concentrated by the thyroid gland but in large amounts may inhibit the organification of iodine. Perchlorate is 10 times as active as thiocyanate. Perchlorate blocks the entrance of iodide into the thyroid by competitively inhibiting the NIS. Perchlorate can be used to control hyperthyroidism; however, when given in excessive amounts (2-3 g daily), it has caused fatal aplastic anemia. Perchlorate in doses of 750 mg daily has been used in the treatment of Graves disease. The various NIS inhibitors (perchlorate, thiocyanate, and nitrate) are additive in inhibiting iodine uptake. Lithium decreases secretion of T4 and T3, which can cause overt hypothyroidism in some patients taking Li+ for the treatment of mania (see Chapter 16).
Iodide is the oldest remedy for disorders of the thyroid gland. In high concentration, iodide can influence several of the important functions of the thyroid gland. Iodide limits its owntransport and acutely and transiently inhibits the synthesis of iodotyrosines and iodothyronines (the Wolff-Chaikoff effect). An important clinical effect of high [I–]plasma is inhibition of the release of thyroid hormone.
RESPONSE TO IODIDE IN HYPERTHYROIDISM. The response to iodides in patients with hyperthyroidism is often striking and rapid: Release of thyroid hormone into the circulation is rapidly blocked, and its synthesis also is mildly decreased. In the thyroid gland, vascularity is reduced, the gland becomes much firmer, the cells become smaller, colloid reaccumulates in the follicles, and the quantity of bound iodine increases. The maximal effect occurs after 10-15 days of continuous therapy. Iodide therapy usually does not completely control the manifestations of hyperthyroidism, and the beneficial effect disappears. The uses of iodide in the treatment of hyperthyroidism are in the preoperative period in preparation for thyroidectomy, and in conjunction with anti-thyroid drugs and propranolol, in the treatment of thyrotoxic crisis.
Another use of iodide is to protect the thyroid from radioactive iodine fallout following a nuclear accident or military exposure. 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. Strong iodine solution (Lugol solution) consists of 5% iodine and 10% potassium iodide, which yield a dose of 8 mg of iodine per drop. Potassium iodide–saturated solution (KISS) also is available, containing 50 mg per drop. Typical doses include 16-36 mg (2-6 drops) of Lugol solution or 50-100 mg (1-2 drops) of KISS 3 times a day. A potassium iodide product (THYROSHIELD) is available over the counter 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 h, as directed by public health officials. 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 39–5), and these patients do not escape from the acute Wolff-Chaikoff effect.
Commonly Used Iodine-Containing Drugs
UNTOWARD REACTIONS. Occasional individuals show a marked sensitivity to iodide. Angioedema is the prominent symptom, and laryngeal edema may lead to suffocation. Multiple cutaneous hemorrhages may be present; manifestations of the serum-sickness type of hypersensitivity (e.g., 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, coryza, sneezing, and irritation of the eyes with swelling of the eyelids commonly occur. Mild iodism simulates a “head cold.” 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. Skin lesions are common and vary in type and intensity. 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 generally involute quickly when iodide is withdrawn. Symptoms of gastric irritation are common, and diarrhea, which is sometimes bloody, may occur. Fever, anorexia, and depression may be present. The symptoms of iodism disappear within a few days after stopping the administration of iodide. 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.
The primary isotopes used for the diagnosis and treatment of thyroid disease are 123I and 131I. 123I is primarily a short-lived γ-emitter with a t1/2 of 13 h and is used in diagnostic studies. 131I has a t1/2 of 8 days and emits both γrays and β particles. More than 99% of its radiation is expended within 56 days. 131I is used therapeutically for thyroid destruction of an overactive or enlarged thyroid and in thyroid cancer for thyroid ablation and treatment of metastatic disease.
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. With properly selected doses of 131I, it is possible to destroy the thyroid gland completely without detectable injury to adjacent tissues.
THERAPEUTIC USES. Radioactive iodine finds its widest use in the treatment of hyperthyroidism and in the diagnosis of disorders of thyroid function. The clearest indication for radioactive iodine treatment is hyperthyroidism in older patients and in those with heart disease. Radioactive iodine also is the best form of treatment when Graves disease has persisted or recurred after subtotal thyroidectomy and when prolonged treatment with anti-thyroid drugs has not led to remission. Finally, radioactive iodine is indicated in patients with toxic nodular goiter. Sodium iodide 131I (HICON, others) is available as a solution or in capsules containing carrier-free 131I suitable for oral administration. Sodium iodide 123I is available for scanning procedures.
HYPERTHYROIDISM. Radioactive iodine is a valuable alternative or adjunctive treatment of hyperthyroidism. Stable iodide (nonradioactive) may preclude treatment and imaging with radioactive iodine for weeks after the stable iodide has been discontinued. In those patients exposed to stable iodide, a 24-h 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. 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.
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. 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. Depending to some extent on the dosage schedule adopted, 80% of patients are cured by a single dose, ~20% require 2 doses, and a very small fraction require 3 or more doses before the disorder is controlled. β Adrenergic antagonists, anti-thyroid drugs, or both, or stable iodide, can be used to hasten the control of hyperthyroidism.
Advantages. With radioactive iodine treatment, the patient is spared the risks and discomfort of surgery. The cost is low, hospitalization is not required in the U.S., and patients can participate in their customary activities during the entire procedure, although there are recommendations to limit exposure in young children.
Disadvantages. The chief consequence of the use of radioactive iodine is the high incidence of delayed hypothyroidism. 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. This finding is especially significant because these tissues all express the iodine transporter NIS and may be especially susceptible to radiation effects. 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.
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; only small numbers of children have been treated in this way. Many clinics decline to treat younger patients and reserve radioactive iodine for patients older than 25-30 years.
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. 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. Thyrogen (recombinant human TSH) is now available to test the capacity of thyroid tissue, both normal and malignant, to take up radioactive iodine and to secrete thyroglobulin. Thyrogen allows assessment of the presence of metastatic disease, without the necessity for patients to stop their suppressive levothyroxine therapy and become clinically hypothyroid. 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. A rise in serum thyroglobulin concentration is often the first indication of recurrent disease.