Iodide Transport

A daily dietary intake of at least 100 µg of iodine per day is required in humans to ensure adequate production of thyroid hormone. In North America, the average daily intake is higher than this, largely because of the use of iodine as a food additive.¹ In many parts of the world, however, consumption is significantly below the minimum level, and iodine deficiency is the leading cause of thyroid-related disorders.

The thyroid normally concentrates iodide 20-fold to 40-fold over the extracellular space and against an electrical gradient of approximately 40 mV. Key to this trapping action is a protein located in the basal membrane of the thyroid cell known as the sodium/iodide symporter (NIS).² NIS couples with the influx of Na⁺ down its electrochemical gradient with the simultaneous influx of I⁻ up its electrochemical gradient. An Na⁺,K⁺-ATPase acts to maintain the Na⁺ gradient. Iodide travels down its electrochemical gradient to the apical surface of the thyrocyte, where it is incorporated into thyroglobulin. More recent evidence suggests an apical membrane protein, pendrin, aids in releasing iodide into the follicular lumen.³ Mutations in the gene and coding for this protein are responsible for the common hereditary disorder Pendred’s syndrome, which is associated with mild hypothyroidism, goiter, and hearing loss.³ Mutations in the gene coding for NIS have been identified in patients with iodide trapping defects, a rare cause of congenital hypothyroidism.²

Thyroglobulin

Thyroglobulin is essential to thyroid physiology. It is a tissue-specific protein that serves as a matrix for the synthesis of hormone and as a vehicle for its storage.⁴ The human thyroglobulin gene has been cloned and is located on the long arm of chromosome 8Q24. Thyroglobulin is a large dimeric glycoprotein of approximately 660 kD, consisting in humans of two identical polypeptide chains each of 2750 amino acids. About 10% of its weight is carbohydrate, and about 0.1% to 1% is iodine. Synthesis and maturation of thyroglobulin follow a pathway typical of proteins destined for secretion. The polypeptide chain is synthesized on the surface of the rough endoplasmic reticulum. As that passes through a series of intracellular compartments, it undergoes important post-translational modifications before reaching the follicular lumen.⁵ Carbohydrate units are added to the polypeptide chain as it is translocated into the lumen of the rough endoplasmic reticulum. Folding and dimerization of the polypeptide chain occurs within this compartment, aided by folding enzymes and a group of proteins known as molecular chaperones. Perturbations of this process result in block of protein transport beyond this point and cause congenital hypothyroidism.⁵ Under normal circumstances, the properly folded thyroglobulin dimers migrate to the Golgi complex, where processing of the carbohydrate units are completed. Mature but as of yet uniodinated thyroglobulin is transferred from the Golgi complex to the apical cell surface in small vesicles.

Iodination and Thyroperoxidase

Newly formed thyroglobulin and iodide meet at the apical cell surface, where hormone synthesis occurs. This process includes (1) the oxidation of iodide; (2) its subsequent transfer to thyrosyl residues on thyroglobulin, producing monoiodotyrosine (MIT) and di-iodotyrosine (DIT); and (3) coupling of two iodotyrosine molecules, either one each of MIT and DIT to form T₃ or two of DIT to form T₄. Thyroperoxidase (TPO), an enzyme present in the apical cell membrane, is responsible for each of these steps.⁶ Hydrogen peroxide (H₂O₂), required in the iodinating and coupling reactions, is generated at the apical membrane by a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.⁷ Mutations in the TPO gene have been found in patients with congenital hypothyroidism caused by defective organification. Abnormalities in H₂O₂ generation seem to be more rare.

Under normal circumstances, iodide, when trapped, is rapidly incorporated into thyroglobulin so that little free iodide exists within the thyroid gland at any given time. The extent to which thyroglobulin is iodinated depends on the thyroid’s iodide supply. At a level of 0.5% iodine, the thyroglobulin dimer in humans contains on average 5 residues of MIT, 5 of DIT, 2.5 of T₄, and 0.7 of T₃ of a total of 132 residues of tyrosine.⁴

Hormone formation involves the coupling of two residues of iodotyrosine within the thyroglobulin polypeptide chain. At the hormonogenic site, the “acceptor” DIT receives the iodinated phenol ring of the “donor” iodothyrosyl (either MIT or DIT) located at some distal site on the polypeptide chain. In the process, the alanine side chain of the donor remains behind, now presumably in the form of hydroalanine. Iodination in vitro of low iodine human thyroglobulin indicates that certain thyrocele sites are favored for early iodination, and that three or four major sites exist for hormone formation. The most important hormonogenic site is located five residues from the amino terminal thyroglobulin, whereas a second major site is located three residues from the carboxy terminal. The locations of donor thyrosyls are incomplete. To date, only one has been identified in human thyroglobulin, and this resides in the amino terminal region of the molecule.⁴

Storage and Release of Hormone

Most mature iodinated thyroglobulin is stored in the colloid as soluble dimers, although some (approximately 10%) highly iodinated molecules associate as tetramers. The colloidal nature of the follicular lumen is caused by its high concentration of protein. This intracellular space contains a large supply of iodine and hormone available to the organism, which protects it against times of iodine deprivation.

Hormone release is initiated by the retrieval of thyroglobulin from the follicular lumen. Under stimulatory conditions in some species, this process may occur by macropinocytosis. Pseudopods form at the thyrocytes’ apical surface and engulf thyroglobulin as large colloid droplets. Under physiologic conditions in most species, however, including humans, thyroglobulin is retrieved by micropinocytosis into small vesicles. It is then passed through the endosome-lysosomal system, where the combined action of several acid proteases, including cathepsins B, D, and L, and lysosomal dipeptidase 1, releases the hormones and their iodotyrosine precursors from the polypeptide backbone.⁴ Evidence suggests the iodo-amino acids may be preferentially cleaved first, but ultimately thyroglobulin is broken down into amino acids or small peptides within the lysosomes.

When released from thyroglobulin, the thyroid hormones and their precursors enter the cytosol; there MIT and DIT are deiodinated by an iodotyrosine-specific deiodinase, and the released iodide re-enters the iodine pool. Some T₄ is deiodinated to T₃ before it is released into the circulation by 5′-iodothyronine deiodinase similar to that found in peripheral tissue.⁸ The mechanism by which T₄ and T₃ are released from the thyrocyte is unknown, but more recent evidence suggests a carrier protein may be involved.⁹

Circulating Thyroid Hormones

Less than 1% of circulating thyroid hormones exist as free iodo-amino acids. The remainder are bound in reversible, noncovalent linkage to one of several plasma proteins.¹⁰ In humans, the most important of these is thyroxine-binding protein (TBG), accounting for approximately 70% of circulating hormone. The TBG molecule has one hormone-binding site with a very high affinity for T₄ and lower affinity for T₃. A second plasma protein transthyretin accounts for approximately 10% of circulating T₄ and T₃. Each transthyretin molecule has two hormone-binding sites, but the affinity of the first is lower than that of TBG, and that of the second site is very low for both hormones. Albumin also serves as a thyroid hormone transport protein. Although it has low affinity, its abundance allows it to account for 10% to 20% of bound circulating hormone.

The bound hormones are in equilibrium with the minute fraction of free circulating hormone that is available for use in peripheral tissue. Under euthyroid conditions, approximately 0.2% of T₄ and about 0.3% of T₃ in circulation is unbound. The larger free-to-bound ratio of T₃ to T₄ is caused by the lower affinity of TBG for T₃.¹¹ To date, no change in thyroid state has been attributed to abnormalities in these hormone-binding proteins, despite their apparent role in thyroid function homeostasis.

Metabolism of Thyroid Hormones

T₄ must first be deiodinated to T₃ to exert most of its biologic actions. Because little T₃ is directly synthesized on thyroglobulin, this transformation becomes an important step in hormonogenesis. Three iodothyronine deiodinases are present in mammals.⁸ These are membrane-bound enzymes that are closely related structurally and are distinguished by the presence of selenocysteine at their active sites. Each has distinctive substrate preferences, activity characteristics, inhibitor sensitivities, and relative tissue specificity. Type I and II deiodinases, through their combined action, are responsible for generating approximately 80% of the total T₃ production.

Type I deiodinase is the primary source of circulating T₃ and is found in liver, kidney, and thyroid (where it is activated by TSH) tissues, and to a lesser extent in other tissues. Type I deiodinase is positively regulated by thyroid hormones and is greatly reduced under pathophysiologic states, such as starvation and nonthyroidal illnesses. It is inhibited by the antithyroid drug propylthiouracil. Type II deiodinase is present primarily in the central nervous system, the pituitary, the placenta, and the skin, and has more recently been found in the thyroid.¹² Its major role is thought to be in the local production of T₃, but it may also contribute to circulating T₃. In contrast to type I deiodinase, the type II enzyme is negatively regulated by thyroid hormone and is unaffected by propylthiouracil. Type III deiodinase inactivates T₄ and T₃ by inner ring deiodination in the five position, forming reversed T₃. The enzyme is present in the adult brain, skin, and placenta, and is present in high levels in fetal tissues, where it is thought to be important in protecting developing tissue from excess levels of thyroid hormone.¹³

Control of Thyroid Function

The anterior pituitary is the primary internal regulator of thyroid function, influencing virtually all phases of thyroid metabolism.¹⁴ It secretes TSH, also known as thyrotropin, which is a 28- to 30-kD lipoprotein consisting of two subunits, α and luteinizing hormone. The α subunit is common to the pituitary hormones follicle-stimulating hormone and luteinizing hormone and to chorionic gonadotropin. The α subunit is unique to TSH, however, and is responsible for the binding of the hormone to its receptor in the basal membrane of the thyroid cell. On interaction with TSH, the receptor, a member of a family of G protein–coupled receptors, undergoes conformational changes that activate one or two regulatory pathways. Most TSH effects are mediated by the activation of the cyclic adenosine monophosphate (cAMP) pathway; others involve the Ca²⁺/phosphatidylinositol cascade. The pathway used to elicit a given effect may vary among species. TSH stimulates the efflux of iodide into the follicle and the resorption of colloid into the cell within minutes. Later effects include increased expression of the NIS, thyroglobulin, and TPO genes; stimulation of H₂O₂ production; promotion of glycosylation; and increased production of T₃ relative to T₄.

Circulating levels of TSH are controlled by the opposing influences of thyroid hormone and of thyrotropin-releasing hormone (TRH) from the hypothalamus.¹⁵ The latter is a modified tripeptide secreted to the anterior pituitary by way of the hypothalamohypophyseal portal system. TRH binds to the plasma membrane of the thyrotrope and stimulates the release of TSH and the expression of its gene. Levels of circulating TSH are under strict control by the thyroid in a classic negative feedback system. As levels of thyroid hormone increase in response to TSH stimulation, T₄ and T₃ block the TRH-stimulated release of TSH in the thyrotrope. The thyroid hormones also act indirectly by inhibiting TRH gene expression in the hypothalamus.

Iodine supply is the major external factor influencing the thyroid state. Autoregulatory mechanisms present in the thyroid help to compensate for variations in iodide intake. In response to increasing doses of iodine, the thyroid initially increases hormone synthesis, but then reverses this process as intrathyroidal levels of iodide reach a critical level, and further organification is inhibited.

Withdrawal of iodide from the diet leads to a rapid decrease in serum T₄ and an increase in serum TSH. Serum T₃ levels initially are unaffected, but eventually decline with prolonged withdrawal. In response to TSH stimulation, the thyroid increases iodide uptake and organification, alters the distribution of iodo-amino acids within thyroglobulin by increasing the ratios of MIT to DIT and T₃ to T₄, and increases the intrathyroidal conversion of T₄ to T₃ by type I and II deiodinases.⁸ With prolonged iodine deficiency, TSH-stimulated cell proliferation eventually leads to goiter.

Antithyroid Agents

Antithyroid drugs can inhibit thyroid hormone synthesis secretion or metabolism.¹⁶ Common agents and their major actions are summarized in Table 123-1. Numerous agents used in the treatment of nonthyroidal illnesses may have profound effects on thyroid hormone production. Notable among these are the iodinated radiocontrast agents that are potent inhibitors of thyroid hormone deiodination, and can interfere with hepatic uptake of T₄ and binding of T₃ to nuclear receptors.¹⁷ The antiarrhythmic agent amiodarone, which is also heavily iodinated, elicits similar alterations in thyroid hormone metabolism and action. Lithium, used in the treatment of bipolar illness, is a potent inhibitor of thyroid hormone release and acts by blocking thyroglobulin endocytosis.¹⁸

Table 123-1 Drugs Used in Hyperthyroidism

Thyroid Hormone Mechanism of Action

The thyroid has multiple effects on development, growth, and metabolism. The effects on development are widespread phylogenetically and can be dramatically observed during the course of amphibian metamorphosis. The appropriate levels of thyroid hormone during fetal and neonatal stages in humans are crucial for the normal maturation of the central nervous system, muscle, bone, and lung. In severe cases of thyroid hormone deficiency during this period, the syndrome of cretinism results with its associated mental retardation, deafness, mutism, and stunted growth.¹⁹ Similarly, an excess of thyroid hormone during these critical developmental periods can result in neurologic abnormalities. The metabolic effects of thyroid hormone seem to be confined to birds and mammals, presumably evolving in response to the increased metabolic pressures of thermogenesis. Oxygen consumption and the metabolism of proteins, carbohydrates, and fats all are under thyroid hormone control.

Most effects of thyroid hormone are now believed to be exerted by interactions with specific nuclear thyroid hormone receptors, resulting in the altered expression of specific genes.²⁰ T₄ has little affinity for the nuclear receptors and first must be converted to T₃ to be effective. The receptors themselves belong to a large superfamily of nuclear receptors, which includes the steroid hormones, retinoic acid, and vitamin D. The thyroid hormone receptors are closely related isoforms, despite being encoded by two different genes (α and β).

The thyroid hormones may have some nongenomic actions, including plasma and mitochondrial membrane transport, familiarization of actin in astrocytes, and modulation of the activities of several enzymes including type II deiodinase. Such nongenomic effects tend to occur rapidly and, in contrast to nuclear events, T₄ may be as effective as, or more so than, T₃.

Circulating Thyroid Hormone Measurement

Radioimmunoassay remains the standard method for measuring serum total T₄, although isotopic methods may also be used. Previous methods, none of which are used today, include the protein-bound iodine test, the butanol extraction iodine test, and T₄ measurement by column or by competitive protein binding. Although the serum total T₄ measurement generally reflects the functional status of the thyroid gland, many factors may alter total T₄ levels without changing the individual’s thyrometabolic status. The most common of these, in an ambulatory individual, is a change in concentration of TBG. High or low TBG states, with their respective increases and decreases in total T₄ concentrations, do not affect metabolic status.

Elevated total T₄ levels may also occur when there is production of endogenous antibodies to T₄, especially in patients with Hashimoto’s thyroiditis or other autoimmune disorders, and occasionally in patients with Waldenström’s macroglobulinemia associated with a benign monoclonal gammopathy.²¹ Another condition of elevated total T₄ level is peripheral resistance to thyroid hormone. Individuals with this condition may have goiter, and they may be hyperactive.²² Patients with this disorder are euthyroid. Although rarely found, this disorder has led to inappropriate treatment for hyperthyroidism.

The most widely used measurement of thyrometabolic status is measurement of serum free T₄ by equilibrium dialysis.²³ When measured by the dialysis method, free T₄ is not affected by changes in binding protein concentrations or by nonthyroidal illness. This method is cumbersome and expensive, and it is not routinely performed. Commercial free T₄ levels are most commonly measured by immunoassay techniques, but their reliability is suboptimal because they may be affected by illness or significant changes in binding proteins.²⁴ The clinical usefulness of free T₄ measurements by any method may be limited.²⁵

Although the thyrometabolic status is best reflected by the free T₄ level, from a clinical standpoint, an index or estimate of free T₄ is generally adequate. The free T₄ index is obtained by multiplying the serum total T₄ and an indirect assessment of thyroglobulin. Serum thyroglobulin is generally estimated by one of two methods—the thyroid uptake test and the T₃ uptake test.²⁵ The thyroid uptake test is directly proportional to thyroglobulin levels in serum, whereas the T₃ uptake test is inversely proportional to thyroglobulin levels.²⁶ The result, by use of either method, is that variances in serum thyroglobulin levels are largely eliminated, and the calculated free T₄ index accurately reflects actual free T₄ status. Extreme changes in thyroglobulin levels, or the presence of the severe nonthyroidal illness, may result in poor correlation between calculated and measured free T₄ levels.

T₃ is measured in serum by radioimmunoassay. Similar to T₄, T₃ is bound to thyroglobulin, although less avidly. Alterations in thyroglobulin levels result in changes in total T₃ (but not free T₃) concentrations. As with serum T₄, an estimate or index of free T₃ may be obtained by using the same formula employed in calculating the free T₄ index. Because most T₃ is derived from peripheral metabolism of T₄, clinical states or pharmacologic agents that impair normal T₄ metabolism result in lower T₃ levels.

The principles used for obtaining the serum T₃ are to determine the severity of hyperthyroidism and to confirm the diagnosis of suspected thyrotoxicosis in cases in which serum T₄ levels are normal or equivocal. In addition, the serum T₃ may be indicated in evaluating patients with autonomously functioning thyroid adenomas, in whom so-called T₃ toxicosis may be present. Such patients may have normal or borderline elevated serum T₄ levels along with suppressed serum TSH levels.²⁷

Serum Thyrotropin Measurement

Until approximately 10 years ago, virtually all clinical TSH assays were performed by radioimmunoassay. By the mid-1980s, many commercial laboratories began using more sensitive immunometric TSH methods with either monoclonal or polyclonal antibodies. Functional sensitivity of these assays represented a 10-fold improvement in sensitivity over radioimmunoassay methods. More recently, nonisotopic immunometric TSH assays have been developed with a chemiluminescent label. These newer assays have a 10-fold greater sensitivity than the early immunometric TSH assays and are 100 times more sensitive than radioimmunoassay methods. These latest TSH assays, with a sensitivity of 0.01 mU/L, are currently termed third-generation TSH assays and represent the most sensitive method for detecting TSH level.²⁸

The clinical application of TSH detection may be summarized as follows:

The fact that serum TSH is abnormal in hypothyroidism and hyperthyroidism would seem to make it ideally suited as a screen of thyroid status because, with rare exceptions, a normal TSH level would suggest normal thyroid hormone homeostasis. Experience in ambulatory individuals suggests that a normal TSH virtually excludes the possibility of thyroid dysfunction.³⁴ In addition, the serum TSH level is more sensitive than the serum T₄ level as a test for thyroid dysfunction because TSH can detect subclinical thyroid disorders in which serum total T₄ (and T₃) is usually normal. As a result of advances in TSH methodology, measurement of circulating thyroid hormones may become assigned to a second line of assessment of suspected thyroid dysfunction. Many investigators believe that the serum TSH is preferable as a screening method for thyrometabolic status.^11,29 Figure 123-2 is an algorithm for the use of TSH level in the evaluation of thyroid function.

Figure 123-2. Algorithm for using the thyroid-stimulating hormone (TSH) level in the evaluation of thyroid function.

Serum Thyroglobulin Measurement

Thyroglobulin is elevated in the serum of patients with nearly all types of thyroid disorders, limiting its usefulness as a diagnostic test. Its greatest clinical value is in managing patients with well-differentiated thyroid carcinoma. An elevated or increasing thyroglobulin level (after initial surgical and ablation therapy) suggests persistence or recurrence of tumor.³⁵ Thyroglobulin is measured by either radioimmunoassay or immunometric technique. Although antithyroid antibodies may cause interference with accurate thyroglobulin measurement in 10% of individuals, in these patients measurements of thyroglobulin and antithyroglobulin antibodies may be used concurrently to provide information regarding the tumor status.³⁵

Thyroid Antibody Status

Circulating antithyroid antibodies, specifically antimicrosomal (AMA) and antithyroglobulin (ATA) antibodies, are usually present in patients with autoimmune thyroid disease.³⁶ Since the introduction of immunoassay techniques, the term antithyroperoxidase (anti-TPO) has become interchangeable with AMA. AMAs are detectable in more than 90% of patients with chronic autoimmune thyroid disease; nearly 100% of patients with Hashimoto’s thyroiditis and more than 80% of patients with Graves’ disease have positive titers.³⁷ Although ATAs are more specific than AMAs, they are less sensitive, and they are not as useful in the detection of autoimmune thyroid disease.³⁸ Elevated levels of AMA are also frequently positive in various other organ-specific autoimmune diseases, such as lupus, rheumatoid arthritis, autoimmune anemia, Sjögren’s syndrome, type 1 diabetes mellitus, and Addison’s disease.³⁹

Approximately 15% of adults (especially women) in the United States have elevated AMA titers.³¹ Prevalence of positive AMA titers increases with age, as does the incidence of primary hypothyroidism. The presence of a positive AMA titer should alert one to the possibility of hypothyroidism. Individuals with positive AMA and elevated TSH levels, even with normal serum total T₄ levels (subclinical hypothyroidism), had a 3% to 5% per year likelihood of clinical hypothyroidism developing.⁴⁰ In this manner, determination of AMA levels may be useful in the diagnosis of individuals with suspected autoimmune thyroid disease and in providing prognostic information when used in conjunction with TSH levels.

Thyroid-Stimulating Antibody Measurement

The immunopathogenesis of Graves’ disease was first suspected in the mid-1950s, when it was observed that injecting sera of patients with Graves’ disease into rats produced a prolonged uptake of radioactive iodine in the rat thyroid glands. The term long-acting thyroid stimulator (LATS) was coined.⁴¹ Later, LATS was characterized as a 7S immunoglobulin, and in recent years several assays have been developed for the detection of LATS, or thyroid-stimulating antibodies. Two methods are commonly used; one depends on generation of cAMP, and the other is a radioreceptor method that relies on the TSH binding inhibitory properties of the immunoglobulin. The cAMP-generating assay is termed thyroid-stimulating immunoglobulin, and it is detectable in 90% to 95% of hyperthyroid patients with Graves’ disease. The other assay detects stimulating and blocking antibodies termed TBII; it is detected in 85% of patients with hyperthyroid Graves’ disease.⁴² Thyroid-stimulating antibody measurements are not indicated for the routine diagnostic evaluation of suspected Graves’ disease, but they may be useful when the diagnosis of Graves’ disease is not evident.

Radioactive Iodine Uptake Test

The thyroidal radioactive iodine uptake test is performed by administering an isotope of iodine (usually ¹²³I) orally and measuring the percentage of the ¹²³I trapped by the thyroid gland. The test is usually performed 24 hours after administration of the isotope, although this may be done earlier. Before the development of sensitive and specific assays for thyroid hormones, the radioactive iodine uptake test was used as an adjunct to differentiate hyperthyroid from hypothyroid states, with elevated and low radioactive iodine uptake values implying hyperthyroidism and hypothyroidism. Today, the principal usefulness of this test is in differentiating hyperthyroidism into high-uptake or low-uptake states. Radioactive iodine uptake generally provides an accurate estimate of the thyroid gland’s functional activity, provided that the iodide pool has not been expanded by iodine-containing drugs or radiocontrast materials.

Pathophysiology

Thyrotoxicosis results from the unregulated release of T₄ and T₃ from the thyroid gland or the ingestion of excessive amounts of T₄, T_3, or both. It may be due to increased T₄ and T₃ synthesis and release because of intrinsic thyroid disease, excessive TSH, or, theoretically, excessive TRH secretion, or the production of other thyroid-stimulating hormones, such as TSH receptor stimulating autoantibody and chorionic gonadotropin. It also may be caused by the destruction of thyroid tissue with the subsequent release of stored T₃ and T₄.

Most patients with thyrotoxicosis have increased production of T₄ and T₃ and increased serum T₄ and T₃ concentrations. The increases in the production rate of T₃ and serum T₃ concentrations are characteristically greater than the increases found in T₄. Some patients with thyrotoxicosis have high serum T₃ concentrations, but normal serum T₄ concentrations. This is called T₃ thyrotoxicosis; in these patients, T₃ production is increased relative to that of T₄, even more than is the case in the usual patient with thyrotoxicosis. There are, however, no characteristic clinical manifestations of T₃. It is most common in patients whose thyrotoxicosis is due to a toxic thyroid adenoma or recurrent Graves’ disease, but it may be due to hyperthyroidism of any cause. It is more common in regions where iodine intake is limited, and is rare in the United States. The abnormality responsible is probably relative intrathyroidal iodide deficiency.

Table 123-2 lists the causes of thyrotoxicosis. The cause of thyrotoxicosis can usually be identified with reasonable certainty by history and physical examination. The most important findings to elicit concern are the duration of symptoms, the degree and pattern of thyroid enlargement, and the presence or absence of thyroid pain and tenderness.

Table 123-2 Etiology of Thyrotoxicosis

Graves’ Disease

Graves’ disease is the most common cause of thyrotoxicosis. It most commonly occurs in women 30 to 60 years old, but may occur in children and in men and women of any age. It is fundamentally an autoimmune disorder consisting of one or more of the following: hyperthyroidism (with thyrotoxicosis), diffuse thyroid enlargement, infiltrative ophthalmopathy (exophthalmos), localized myxedema (dermopathy), and thyroid acropachy. Toxic goiter may appear alone or may be seen before, during, or after ophthalmopathy develops. Ocular signs range from mild periorbital puffiness to severe extraocular muscle dysfunction with proptosis, corneal ulceration, and optic neuritis and blindness. The extrathyroidal manifestations of Graves’ disease can occur in the absence of thyroid disease.

The major gross anatomic abnormality in patients with Graves’ thyrotoxicosis is diffuse thyroid enlargement. Microscopic examination reveals hypertrophy and hyperplasia of the thyroid follicular cells.

The natural history of Graves’ thyrotoxicosis varies considerably among different patients. Some patients have a single episode of thyrotoxicosis (and Graves’ disease) that subsides spontaneously in a few months or years. Other patients have lifelong thyrotoxicosis, and still others have repeated remissions and relapses. In patients who are treated with an antithyroid drug, the occurrence of a remission of Graves’ disease means that prolonged therapy is not required. Although the disease potentially undergoes spontaneous remission, prolonged antithyroid medication, ¹³¹I ablation, or surgery is usually necessary to control the thyrotoxicosis.

Well-differentiated thyroid cancer is approximately two times more prevalent in patients with Graves’ disease than the general population.⁵⁰ Well-differentiated thyroid cancers may contain TSH receptors that can be stimulated by the thyroid-stimulating immunoglobulins. These tumors associated with Graves’ disease tend to be larger and more aggressive and have more local invasion with more regional lymph node metastases than cancers occurring without Graves’ disease.⁵¹ When a palpable, hypofunctional thyroid nodule is found in a patient with Graves’ disease, it has about 45% probability of being a thyroid malignancy.⁵¹ A palpable hypofunctional nodule in a diffuse toxic goiter of Graves’ disease should be regarded with great suspicion and, if proven to be malignant, should be managed aggressively.⁵⁰

An antithyroid drug and ¹³¹I are the two best treatments for patients with Graves’ thyrotoxicosis. Both methods are effective, safe, and relatively inexpensive. They represent treatments for hyperthyroidism, rather than for the autoimmune process itself, although some antithyroid drugs may also have an immunosuppressive effect. The antithyroid drugs used in the United States are methimazole and propylthiouracil (PTU). These drugs inhibit thyroid hormone biosynthesis by inhibiting the oxidation and organification of iodine and the coupling of iodotyrosines, reactions that are catalyzed by thyroid peroxidase.⁵² PTU also inhibits the thyroidal and extrathyroidal conversion of T₄ to T₃.⁵³ Both medications are concentrated in the thyroid, and intrathyroidal concentrations, especially of methimazole, remain high for considerably longer than do serum concentrations.⁵⁴

Methimazole and PTU have immunosuppressive actions that may contribute to the occurrence of remissions of Graves’ disease. Both drugs reduce the number of intrathyroidal T cells and inhibit lymphocyte function, including thyroid autoantibody production in vitro, although the latter actions require very high concentrations.⁵⁵

The initial goal of antithyroid drug therapy is to inhibit thyroidal T₄ and T₃ synthesis almost completely. Neither drug has an effect on the release of thyroid hormones stored in the thyroid gland, and their onset of action is relatively slow, depending on the severity of disease, size of the goiter, drug dosage, and timing. Release of intrathyroidal hormone stores, which may be substantial, continues until they are depleted.

Adverse reactions to antithyroid drugs are uncommon and probably occur with equal frequency with either methimazole or PTU. Pruritus, urticaria or other rashes, arthralgia or myalgia, and fever occur in approximately 5% of patients taking either drug.¹⁶ Both drugs may result in dysgeusia. The most dangerous adverse effect is agranulocytosis, which occurs in 0.2% or less of patients taking these medications.⁴⁶ Rare adverse effects include aplastic anemia, thrombocytopenia, hepatocellular hepatitis (with PTU), cholestatic hepatitis (with methimazole), and a lupus-like vasculitis (with PTU).^56,57

Inorganic iodine inhibits thyroid hormone secretion, primarily by inhibiting thyroglobulin proteolysis, and inhibits thyroidal iodine transport, oxidation, and organification.⁵² These actions require only a few milligrams of iodine daily, which may be administered in dosages of 5 to 10 drops of a saturated solution of potassium iodide (Lugol’s solution) several times daily. This compound is often given in preparation for thyroidectomy, for its antithyroid action and because it reduces thyroid blood flow, theoretically reducing hemorrhage at the time of surgery. Lithium carbonate shows antithyroid action similar to that of inorganic iodine and has proved effective in doses of 300 mg three or four times daily.⁵⁸ Cholestyramine, when added to thionamides and β-blockers, leads to a more rapid decrease in thyroid hormone levels, especially in the first few weeks.⁵³

β-Blockers are valuable in the management of hyperthyroidism. Independent of alteration of thyroid function, these drugs minimize many of the sympathetic overdrive symptoms found in hyperthyroidism, such as tachycardia, excessive sweating, nervousness, tremors, and hyperdynamic cardiac activity. They are contraindicated in patients with severe thyrotoxic cardiomyopathy and heart failure, but may benefit patients with atrial fibrillation and heart failure.⁵⁹ β-Blockers are useful for reducing symptoms of thyrotoxicosis before and for several weeks after ¹³¹I therapy, before subtotal thyroidectomy, in thyroiditis, and in thyroid storm.

In the United States, radioactive iodine is the preferred management for most adults, and for children in cases where thionamides fail or where the patient does not respond well to these medications. The goal of ¹³¹I therapy is to reduce the amount of functioning thyroid tissue, and its efficacy is independent of whether a remission of Graves’ disease occurs. A major advantage of ¹³¹I therapy for patients with Graves’ thyrotoxicosis are that usually only a single dose is necessary, it reduces thyroid size to normal in most patients, and it is safe.⁶⁰ Thionamides should be stopped for about 3 days before and after radioactive iodine therapy, which is usually effective in 2 to 4 months.

Radioactive iodine usually causes a transient exacerbation of thyrotoxicosis and rarely precipitates thyroid storm. This occurs within 1 to 2 weeks and is caused by radiation-induced thyroiditis; it is a major problem in seriously thyrotoxic or elderly patients. Thyrotoxicosis may also be exacerbated by stopping thionamides before radioactive iodine therapy. Hypothyroidism is not so much a complication of ¹³¹I treatment as an almost inevitable consequence of it. Early hypothyroidism, defined as occurring within 1 year after treatment, is caused by the acute destructive effects of ¹³¹I. Its frequency ranges from 40% to 80% in patients treated with higher doses of radioactive iodine.⁶¹ Lower doses result in early hypothyroidism less often and persistent thyrotoxicosis more often.

Some physicians have been reluctant to treat young adults and especially adolescents and children with ¹³¹I. The reasons are that it might cause thyroidal or other tumors or gonadal damage, or the patient may be pregnant, which is an absolute contraindication to the treatment. ¹³¹I crosses the placenta and can destroy the fetal thyroid, and care must be taken to ensure that any woman about to be treated with ¹³¹I is not pregnant.

Surgical therapy for thyrotoxic Graves’ disease is effective and expeditious. The classic operation for surgical treatment of Graves’ disease is subtotal thyroidectomy. Performing this operation either unilaterally or bilaterally, a narrow margin of thyroid tissue in the superolateral aspect of the thyroid where the recurrent laryngeal nerve enters the larynx is preserved by dividing across thyroid tissue at that location.⁶² This operation provides the additional benefit of preserving the blood supply to the superior parathyroid gland on one or both sides. The intended goal of subtotal thyroidectomy is to leave 3 to 6 g of thyroid tissue, providing the benefit that patients become euthyroid without hormone replacement therapy.³² The amount of thyroid tissue remnant preserved directly affects the recurrence rate of hyperthyroidism and the development of long-term hypothyroidism.⁶³ For patients who have larger remnants preserved, an increased incidence of recurrent hyperthyroidism is noted that can often be treated efficiently with radioactive iodine ablation because of the preserved small amount of residual thyroid tissue.⁶⁴ Patients in whom more complete thyroid removal is performed are generally guaranteed to have resolution of their hyperthyroidism; however, long-term hypothyroidism would be the outcome of therapy.⁶⁵

Authors favoring more complete surgical resection of thyroid tissue in the form of near-total thyroidectomy for Graves’ disease point out that long-term hypothyroidism may be easily remedied by appropriate hormone replacement therapy, whereas recurrent hyperthyroidism, as a result of leaving behind a larger than intended thyroid remnant, carries with it the need for further treatment.⁶⁶ Arguments have been raised in favor of subtotal thyroidectomy as a means by which complications such as permanent hypoparathyroidism and recurrent laryngeal nerve injury may be avoided.⁶⁶ The rate of permanent recurrent laryngeal nerve injury approaches zero, however, as does the rate of long-term hypocalcemia, in patients operated by experienced surgeons.⁶⁷ The general recommendation for the surgical approach in patients with indications for thyroidectomy is a near-total thyroidectomy, completely eliminating the potential for recurrent or persistent hyperthyroidism.^68,69

The absolute indications for surgical treatment for Graves’ disease are in patients who have significant adverse reactions to thionamide drugs and cannot be appropriately blocked before radioactive iodine administration.⁷⁰ Included in this category are patients with very severe skin reactions, hepatic damage, or agranulocytosis. Other indications for surgery in patients with Graves’ disease include very large thyroid glands in excess of 75 g and neoplasia either suspected or proven within the setting of diffuse toxic nodular goiter.

Surgical therapy is relatively indicated in young women of childbearing age, who wish to attempt achieving pregnancy or who are in the process of lactating and want to continue to do so. An additional relative indication for surgery as opposed to radioactive iodine is moderate or severe ocular symptoms related to Graves’ ophthalmopathy. Ophthalmopathy may be worsened with radioactive iodine administration secondary to the development of tissue edema and worsening of the ocular symptoms.⁷¹

Patients undergoing surgery for Graves’ thyrotoxicosis require preoperative preparation so as not to induce thyrotoxicosis on induction of general anesthesia and subsequent manipulation of the thyroid intraoperatively. This is accomplished by administering antithyroid drug treatment 4 to 6 weeks and inorganic iodine treatment for 7 to 10 days preoperatively. Treatment with a β-adrenergic antagonist drug for several weeks, with or without concomitant inorganic iodide for 10 to 14 days, also has proved to be safe and effective preoperative therapy.⁷²

Postoperative problems after thyroidectomy include wound hematoma, transient or permanent hypocalcemia, vocal paresis or paralysis, recurrent thyrotoxicosis, and transient or permanent hypothyroidism. The frequency of nonthyroid complications is low, especially in experienced surgical hands. Transient hypocalcemia may occur secondary to temporary hypoparathyroidism or the healing of thyrotoxic osteopenia. The incidence of wound hematoma is less than 1%, as is the incidence of permanent hypoparathyroidism. In addition, the risk of permanent injury to the recurrent laryngeal nerves in the setting of initial surgery is a fraction of 1%.⁷⁴

Thyroiditis

The thyrotoxicosis that occurs in all forms of thyroiditis is caused by T₄ and T₃ release from thyroglobulin as a result of thyroid inflammation and disruption of thyroid follicles. Because the stores of thyroglobulin are limited, and the new T₄ and T₃ synthesis ceases, thyrotoxicosis is generally transient. Approximately half of patients with subacute or granulomatous thyroiditis have clinical manifestations of thyrotoxicosis, and a significant proportion of the remainder have high serum T₄ and T₃ concentrations.⁷⁵ This illness is dominated by nonspecific systemic manifestations of inflammation, including fever, malaise, and myalgias. In addition, local symptoms of thyroid pain and tenderness are also noted that may be severe. Approximately 50% of the patients have a history of a recent upper respiratory tract infection preceding the illness. Any manifestations of thyrotoxicosis together with thyroid pain and tenderness are usually short-lived, lasting approximately 4 to 6 weeks or less. This inflammatory and thyrotoxic phase may be followed by transient hypothyroidism, but permanent hypothyroidism is rare. The thyroid gland is usually firm in consistency and may be quite hard. Cervical lymphadenopathy is uncommon. If pursued, thyroid radionuclide uptake scanning is generally low, and ultrasonography reveals thyroid hypoechogenicity.⁷⁶

Indirect evidence suggests that subacute thyroiditis may be a viral illness, but conclusive proof is lacking. The disorder has been associated with mumps, influenza, adenovirus, and other viral infections, and small epidemics of subacute thyroiditis have been reported.⁷⁷

The inflammatory and the thyrotoxic components of subacute thyroiditis may be so mild and transient that no therapy is required. More often, thyroid pain and tenderness result in sufficient discomfort to warrant anti-inflammatory therapy. Salicylates in dosages of 2.4 to 3.6 g daily or high doses of other nonsteroidal anti-inflammatory drugs usually provide effective relief. Patients with severe thyroid pain and tenderness and patients who do not improve readily and quickly with one of these medications should be treated with prednisone in a dosage of approximately 40 mg daily for 3 to 4 weeks, after which the dose should be gradually reduced and then discontinued to minimize the likelihood of recurrence. Anti-inflammatory therapy promptly relieves not only the symptoms of subacute thyroiditis, but also probably reduces thyroid hormone release, accelerating recovery from thyrotoxicosis. Thyrotoxicosis itself usually requires no therapy, but in patients in whom thyrotoxic symptoms may become a problem, a β-adrenergic drug may be administered for approximately 1 to 2 weeks.

Thyrotoxicosis, which is caused by thyroid inflammation in the absence of thyroid pain and tenderness, is known as painless or silent thyroiditis and has also been termed subacute lymphocytic thyroiditis. It is an uncommon cause of thyrotoxicosis. In contrast to Graves’ disease, it occurs in almost equal proportions of men and women. The thyroid gland is not painful or tender and does not appear enlarged, or perhaps only slightly enlarged. In contrast to subacute thyroiditis, there is generally no history of antecedent upper respiratory tract infection. Generally, no extrathyroidal manifestations of Graves’ disease are present in this disorder. When present, the thyrotoxicosis associated with painless thyroiditis lasts 2 to 6 weeks and is followed by either recovery or transient hypothyroidism that lasts an additional 2 to 8 weeks. Approximately half of the patients later had goitrous autoimmune thyroiditis, hypothyroidism, or both. Painless thyroiditis with thyrotoxicosis likely may represent a variant form of chronic autoimmune thyroiditis.

Radiation-induced thyroid follicular necrosis and inflammation occur regularly after ¹³¹I therapy and occasionally are sufficiently intense to cause exacerbations of thyrotoxicosis, with or without thyroid pain and tenderness. These complications of ¹³¹I therapy are most likely to occur 1 to 2 weeks after treatment, last 1 to 2 weeks, and then subside spontaneously.

Acute suppurative thyroiditis is most commonly caused by Staphylococcus aureus, hemolytic streptococcus, or Streptococcus pneumoniae, but occasionally is caused by other organisms, such as Fusobacterium and Haemophilus.⁷⁸ This bacterial infection of the thyroid gland may be the result of trauma, hematologic seeding from a distant infected site, or direct extension from a deep cervical infection. The infection is usually localized to a single lobe, and most commonly develops an abscess cavity that may rupture through the glans capsule, extending into the mediastinum or the deep neck spaces along fascial planes. This disorder is especially common in children, in whom a prodrome of malaise is followed by the acute onset of fever, neck pain and tenderness, severe systemic symptoms, and marked leukocytosis. Referred pain to the homolateral mandible and ear may be present, and typically the child fixes the head and neck in a single position similar to torticollis. Localized tenderness over the gland and pain on head movement is commonly noted. This disorder may be difficult to distinguish from subacute nonsuppurative thyroiditis, but the pain is generally more severe, the thyroid hormone levels are generally normal, the erythrocyte sedimentation rate is normal, and the leukocyte count is high. Although the diagnosis is generally made on clinical grounds, needle aspiration of the abscess cavity establishes the bacterial organism causing the infection.

The initial therapy is the administration of high-dose antibiotics, usually penicillinase-resistant penicillin together with a cephalosporin, although antibiotics that cover anaerobic organisms should be considered. Antibiotic therapy that is started before the cavitary phase of the infection may be successful in limiting the progression of infection. When an abscess has been shown on needle aspiration, however, surgical drainage is usually required. Drainage may involve a partial thyroidectomy to remove all evidence of abscess and necrotic tissue and to prevent recrudescence. The neck should be drained externally until purulence ceases, and antibiotics should be continued for at least 2 weeks after the surgical procedure. Thyrotoxicosis during the course of infection and post-treatment hypothyroidism rarely develop in this entity in contrast to other types of inflammatory thyroiditis.

Exogenous Thyrotoxicosis

Thyrotoxicosis may occur as a result of either intentional or accidental administration of inappropriately high doses of thyroid hormone initiated by caregivers or patients themselves. Important clues to the presence of exogenous thyrotoxicosis are the absence of thyroid enlargement or the failure of thyroid enlargement to regress much if the treatment was given for this purpose. This occurs together with normal or low serum T₄ concentrations if the patient is taking T₃ or preparations containing T₃. These patients also show low thyroid radioactive iodine uptake values and low serum thyroglobulin concentrations. Despite the ability of iodine supplementation to decrease the size of goiter and to improve thyroid function in patients living in regions of endemic goiter, it has the potential to induce thyrotoxicosis in these same patients. This usually occurs as a result of a preexisting thyroid abnormality that results in autonomous thyroid secretion—Graves’ disease or, more commonly, a nodular goiter—but insufficient iodine intake to permit excessive production of T₄ and T₃. Iodine-induced thyrotoxicosis may also occur in nonendemic goiter regions.⁷⁹ Most of these patients have autonomously functioning thyroid tissue, such as a multinodular goiter or a thyroid adenoma, that transports iodide poorly.

Amiodarone, because it contains iodine, can cause iodine-induced thyrotoxicosis in patients with nodular goiter.⁸⁰ It may also cause painless thyroiditis that is sufficiently severe to cause thyrotoxicosis, apparently because of a direct toxic effect of the drug or one of its metabolites.

Approximately 2% of patients who are treated with interferon-α have thyrotoxicosis develop, caused mostly by painless thyroiditis, but sometimes by overt Graves’ disease.⁸¹ This thyrotoxicosis is generally more subclinical than overt.

Toxic Thyroid Adenoma

Toxic uninodular goiters or toxic thyroid adenoma are autonomously functioning thyroid neoplasms.⁸² Among patients with these adenomas, about 20% have overt and 20% have subclinical thyrotoxicosis at the time of diagnosis.⁸³ Although these neoplasms occur in adults of all ages and occasionally in children, most patients having thyrotoxicosis are in older age groups. Hemorrhagic infarction of a nontoxic thyroid adenoma may result in a transient thyrotoxicosis.⁸⁴

The characteristic finding in patients with toxic thyroid adenoma is a solitary thyroid nodule, which is usually 3 cm or more in diameter. Radionuclide uptake imaging of the thyroid shows intense nuclear uptake in the location of the palpable nodule and nearly complete absence of uptake in the remainder of the thyroid gland.

Management of the toxic adenoma is required unless spontaneous infarction occurs because the resultant thyrotoxicosis is usually permanent. Definitive treatment may be obtained by either surgical resection of the adenoma through thyroid lobectomy or ¹³¹I ablative therapy. Definitive ¹³¹I therapy carries a slight to moderate risk of either transient or permanent hypothyroidism after completion of therapy, although with appropriate dosing of ¹³¹I, this risk may be minimized. Surgical resection may be carried out after 4 to 6 weeks of antithyroid drug administration and a 7- to 10-day course of inorganic iodine therapy in the form of Lugol’s solution. Complications after lobectomy are generally exceedingly rare, and the surgical resection is usually definitive, resulting in no evidence of recrudescent thyrotoxicosis or evidence of hypothyroidism.⁸⁵

An alternative approach that is performed more commonly in Europe than in the United States is the percutaneous administration of ethanol directly into the adenoma by use of ultrasound needle guidance. Although there may be some discomfort associated with the injections, long-term complications are rare, and it seems to be a safe procedure done in appropriately experienced hands. The shortcoming of this technique is that it may require multiple treatment sessions. This approach may be desirable in patients who are poor candidates for surgical resection and who wish to avoid exposure to radioactive iodine.

Toxic Multinodular Goiter

Thyrotoxicosis may occur late in the natural history of multinodular goiter, usually in women 50 years old or older. The characteristic patient with this disorder has a long history of thyroid enlargement with insidious development of subclinical and then subsequently overt thyrotoxicosis. These patients generally do not have ophthalmopathy or localized myxedema and do not undergo spontaneous remissions; thyrotoxicosis generally persists until the autonomous thyroid tissue is destroyed.

¹³¹I is generally the treatment of choice for patients with thyrotoxicosis caused by a multinodular goiter, primarily because spontaneous remission does not occur, and because surgical resection generally requires removal of most of the thyroid gland. Patients who are not candidates for radioactive iodine therapy or who refuse this modality may undergo surgery after preparation with an antithyroid medication and inorganic iodine therapy, similar to patients being treated for Graves’ disease surgically. The usual operation is either bilateral subtotal thyroidectomy or near-total thyroidectomy with preservation of a 3- to 6-g remnant of thyroid tissue. Surgery is more effective in rapidly reducing the effects of thyrotoxicosis than is ¹³¹I, and is attractive in terms of volume reduction of goiter size. Surgery may be more likely to result in long-term or permanent hypothyroidism.⁸⁶

Ectopic Thyrotoxicosis

The only recognized etiologies of thyrotoxicosis secondary to excessive ectopic thyroid hormone secretion are dermoid tumors and teratomas of the ovary. Most of the uncommon patients with substantial amounts of thyroid tissue in their tumors (struma ovarii) who have thyrotoxicosis also have Graves’ disease or a multinodular goiter.⁸⁷ They have one of the common causes of thyrotoxicosis, affecting the thyroid gland and the ectopic thyroid tissue within the ovarian tumor. In the absence of a functional thyroid gland because of surgical removal or radioactive iodine ablation, the ovarian tumor may be the only source of excessive thyroid hormone in these patients when it contains a toxic thyroid adenoma.⁸⁸

Special Situations in Thyrotoxicosis

Prevalence

Hypothyroidism affects women fourfold to sixfold more often than men and increases with advancing age. The National Health and Nutrition Examination Survey (NHANES III), a sample of 17,353 individuals 12 years old and older representing the geographic and ethnic distribution of the U.S. population from 1988 to 1994, reported a prevalence of clinical hypothyroidism at 0.3% and subclinical hypothyroidism at 4.3%.⁹⁴ Thyroid peroxidase antibodies were elevated in 11.3%, and thyroglobulin antibodies were elevated in 10.4%. Thyroid peroxidase antibody positivity was associated with hypothyroidism (and hyperthyroidism), but thyroglobulin antibodies were not.

Etiology

Hypothyroidism can be classified (in order of decreasing frequency) as thyroid (primary), pituitary (secondary), or hypothalamic (tertiary) failure and thyroid hormone receptor resistance. Causes of primary hypothyroidism are listed in Box 123-1. Worldwide, the most common cause of hypothyroidism is iodine deficiency. In iodine-sufficient areas, such as the United States, the most common cause is chronic autoimmune (Hashimoto’s) thyroiditis. With current administered doses of ¹³¹I for patients with Graves’ disease, approximately 90% become hypothyroid by the first year.⁹⁵ External neck irradiation in a cohort of 1677 patients with Hodgkin’s disease followed for a mean of 9.9 years was associated with a cumulative incidence of hypothyroidism of 30.6%, highlighting the importance of continued clinical and biochemical evaluation.⁹⁶

Clinical Features

The severity of clinical features depends on the severity of thyroid hormone deficiency, rather than etiology. Individuals with mild hypothyroidism with elevated TSH but normal free T₄ (subclinical hypothyroidism) may have few or no symptoms. At the opposite extreme, individuals with severe hypothyroidism may have myxedema coma. Even in individuals with overt biochemical hypothyroidism, severity of symptoms varies. Generally, patients are more symptomatic if hypothyroidism develops rapidly. Elderly patients have fewer symptoms than younger patients.⁴ Common symptoms of hypothyroidism, such as fatigue, constipation, dry skin, and cold intolerance, may be mistakenly misinterpreted as part of the normal aging process.

Hypothyroidism should be suspected in individuals with goiter and risk factors (Box 123-2). With the widespread use of the serum TSH assay, hypothyroidism is frequently detected at an earlier stage. The classic symptoms and signs of hypothyroidism are now less frequently found (Box 123-3).

Otolaryngologic Manifestations

Goitrous Hypothyroidism

The most common cause of goitrous hypothyroidism in adults in the United States is autoimmune thyroiditis (Hashimoto’s disease).¹⁰⁵ Other less common causes are drugs (lithium, amiodarone, sulfisoxazole, large doses of iodides, aminosalicylic acid, interferon, and antithyroid drugs), infiltration of the gland with tumor or inflammatory processes, and familial defects in thyroid hormonogenesis.

Transient Hypothyroidism

Hypothyroidism resulting from Hashimoto’s thyroiditis is transient in approximately 10% of cases. Spontaneous remission is associated with the presence of a larger goiter, a high initial TSH level, and a family history of thyroid disease.¹⁰⁶ Autoimmune thyroid dysfunction may become apparent after surgery for Cushing’s disease.¹⁰⁷ Smoking increases the metabolic effects of overt and subclinical hypothyroidism in a dose-dependent way.¹⁰⁸

Excessive Iodine Intake

In iodine-sufficient areas of the world such as the United States, excess iodine intake can cause hypothyroidism in individuals with autoimmune thyroiditis, ¹³¹I-treated or surgically treated Graves’ disease patients, and patients treated with hemithyroidectomy for thyroid nodules.⁴⁶ Hypothyroidism may develop in individuals taking amiodarone, especially individuals with an underlying thyroid abnormality. Thyroid autoantibodies are risk factors for the development of hypothyroidism.¹⁰⁹

Endemic Goiter

Endemic goiter is uncommon in the United States, but TSH levels are elevated in more than 50% of patients with this disorder, many of whom have no clinical features of thyroid failure.¹¹⁰

Familial Hypothyroidism

Kindreds with hypothyroidism usually have inherited defects in hormonogenesis, but rarely may have generalized thyroid hormone resistance.¹¹¹

Nongoitrous Hypothyroidism

Nongoitrous hypothyroidism is most often caused by thyroid disease—most commonly autoimmune diffuse thyroid atrophy and management of Graves’ disease with ¹³¹I, thionamides, or thyroidectomy—but may be caused by pituitary and hypothalamic disorders.^112,113

Hypothyroidism after Laryngectomy and Radiotherapy

Hypothyroidism may start within 4 months of surgery, but may not become clinically apparent for 1 year.¹¹⁴ In a multivariate analysis of 221 patients, risk factors for hypothyroidism were high radiation dose, combination of radiotherapy and cervical surgery, time from therapy, and no shielding of the midline neck. Patients receiving irradiation to the neck—particularly patients undergoing neck dissections or total laryngectomy—should have routine thyroid function studies performed every 3 to 6 months the first year after management and annually thereafter.

Subclinical Hypothyroidism

Nonthyroidal Illness

TSH elevation may occur in conditions other than hypothyroidism, including recovery from nonthyroidal illness, also known as sick euthyroid syndrome. Hospitalized and critically ill patients may have a decreased free T₄ index or free T₄ concentration by radioimmunoassay. When measured by equilibrium dialysis, however, free T₄ is normal or elevated. In one report, serum total T₄ levels less than 3 µg/dL were associated with mortality in 84% of critically ill patients.¹³⁶ In a randomized prospective study, T₄ treatment in an intensive care unit did not alter mortality.¹³⁷

Laboratory Diagnosis

There is a set-point for optimal serum free T₄ concentration in a given individual. Because of the log-linear relationship between serum TSH and T₄ concentrations, small changes in free T₄ from this set-point lead to relatively large changes in TSH by negative feedback. The most sensitive test for hypothyroidism is an elevated serum TSH. In subclinical hypothyroidism, TSH is elevated, whereas free T₄ remains normal. If the disorder progresses to overt hypothyroidism, free T₄ is decreased (see Table 123-3 for thyroid function tests in hypothyroidism and other low T₄ syndromes). Radioactive iodine uptake is not indicated for the diagnosis of hypothyroidism because low, normal, or high values can occur, depending on the cause.

Central hypothyroidism caused by pituitary or hypothalamic disorder shows a low free T₄ and TSH that is low, inappropriately normal, or mildly elevated. TRH stimulation testing of TSH has traditionally been used to distinguish between these two entities, but is unreliable.^138,139

Management

Oral synthetic levothyroxine (T₄) is the therapy of choice to correct hypothyroidism. Gastrointestinal absorption is 81%.¹⁴⁰ Because the plasma half-life of T₄ is long (6.7 days),¹⁴¹ once-daily administration leads to stable T₄ and T₃ concentrations. Numerous brand name (Euthyrox, Levothroid, Levoxyl, Synthroid, Unithroid) and generic preparations of T₄ are available, each in varying doses with different color-coded tablets to allow dose titration at precise increments. In one study, comparison of two brand-name and two generic preparations in the United States showed bioequivalency.¹⁴² Equivalent doses of different formulations of T₄ are generally interchangeable. One should repeat the TSH level 4 to 6 weeks after switching, however.^140,143

In young, otherwise healthy adults, a full replacement dose can be prescribed at 1.6 µg/kg/day for nonmalignant conditions. In patients with known coronary disease, patients with multiple coronary risk factors, and elderly patients who may have previously silent coronary disease, conservative therapy with an initial dose of 25 µg/day is advisable. One should repeat TSH measurements with dose adjustment every 4 to 6 weeks (four to six half-lives of T₄) until serum TSH normalizes or cardiac symptoms arise that may limit therapy to less than a full replacement dose. In individuals without residual thyroid tissue, such as a patient with thyroid cancer who has undergone thyroidectomy, the mean T₄ dose required to achieve euthyroidism is generally higher (2.1 µg/kg/day).¹⁴⁴

In patients with primary hypothyroidism, the goal of therapy is to normalize the serum TSH level. After initiation or change in dose of T₄, TSH should be repeated in 4 to 6 weeks. Ultimately, TSH measurements are needed annually, or sooner depending on clinical status. In individuals with central hypothyroidism, free T₄ alone should be normalized, also with repeat measurements free in 4 to 6 weeks. The use of the patient’s symptoms to judge the adequacy of T₄ dosing is frequently inaccurate. When subjective symptoms were used to determine T₄ dosing, patients chose a dose that produced mild hyperthyroidism.¹⁴⁵

Potential adverse effects of overtreatment with an excessive dose of T₄ include bone loss in postmenopausal, but not premenopausal, women,^146,147 and in elderly patients, cardiac complications, including cardiac arrhythmias, heart failure, angina, and myocardial infarction.⁸⁸ Occasionally, patients have manic behavior develop with T₄ replacement. Severe behavioral manifestations of T₄ therapy for juvenile hypothyroidism are uncommon, but mild behavioral symptoms and poorer school achievement may occur in approximately 25% of patients, who represent the most severe cases at the time of diagnosis.¹⁴⁸

Poor patient compliance with taking thyroid hormone leads to therapeutic failure. Alternatives to a daily regimen include twice-weekly¹⁴⁹ or once-weekly regimens.¹⁵⁰ These probably should not be used in patients with coronary artery disease. Numerous medications may bind to and interfere with intestinal absorption of T₄, including aluminum hydroxide,¹⁵¹ ferrous sulfate,¹⁵² sucralfate,¹⁵³ cholestyramine,⁹⁴ and calcium carbonate.¹³⁹ Thyroid hormone administration should be separated in time from these medications by a few hours.

Thyroid hormone preparations that contain T₃ alone (e.g., Cytomel), combinations of T₄ and T₃ (e.g., Thyrolar), and desiccated thyroid extract (Armour Thyroid) should not be used for the treatment of hypothyroidism. Serum T₃ levels fluctuate widely because of the short half-life of T₃. Temporary T₃ therapy is indicated in patients with thyroid cancer who have undergone thyroidectomy and await thyroid remnant ablation to shorten the period of hypothyroidism. T₃ can be discontinued 2 weeks before ¹³¹I.¹⁵⁴ In addition, temporary switching from T₄ to T₃ therapy in individuals undergoing thyroid hormone withdrawal whole-body scanning also reduces the period of hypothyroidism.

Thyroid hormone requirements are increased during pregnancy by an average of 45%¹⁵¹ because of an estrogen-mediated increase in TBG, fetal T₄ transfer, and increased T₄ clearance. Serum TSH should be obtained at each trimester of pregnancy. If the T₄ dose requires adjustment, TSH should be remeasured in 4 weeks with further dose adjustment as necessary. After delivery, the prepregnancy T₄ dose should be resumed.¹⁵⁵ A hypothyroid woman starting oral estrogen therapy such as with hormone replacement therapy may also require a higher thyroid hormone dose,¹⁵⁶ and TSH should be obtained 3 months after initiation of estrogen to determine whether a dose increase is needed. Increases in dose may be necessary in patients who start medications that increase T₄ catabolism (e.g., phenytoin, carbamazepine, phenobarbital, rifampin), have gastrointestinal malabsorption, or have nephrotic syndrome develop.¹⁵⁷ A decreased thyroid hormone dose requirement may be seen in elderly patients¹⁵⁸ and in women with breast cancer treated with androgens.¹⁵⁹

Myxedema Coma

Myxedema coma, a thyroid emergency, is a late manifestation of hypothyroidism, and is characterized by coma or precoma with severe clinical manifestations of myxedema. An underlying infection or other precipitating cause of the myxedema coma is usually present. Patients characteristically have extreme hypothermia, bradycardia, pleural and pericardial effusions, hyponatremia, hypoventilation, respiratory acidosis, and hypoxia. Focal or generalized seizures typically precede the coma.

Management is with large doses of intravenous T₄ and hydrocortisone. Although management is usually instituted without laboratory confirmation, the clinical diagnoses should be certain before large doses of intravenous T₄ are given. Supportive care includes intubation and assisted ventilation, cautious warming, support of blood pressure, and management of infection. Mortality rates are approximately 50% and depend on the severity of superimposed illnesses and underlying coronary heart disease.

Surgery

With mild to moderate hypothyroidism, postoperative complications are frequent, but are rarely serious or lasting, and necessary surgery should not be postponed simply to replete thyroid hormone.¹⁶⁰ This is not true for patients with severe myxedema, who should be given preoperative thyroid hormone except in the most urgent surgical emergencies or uncontrolled ischemic heart disease.

In euthyroid patients, total T₄ tends to decrease in the first postoperative day, then spontaneously normalizes in 7 days; the same occurs in hypothyroid patients, but T₄ levels do not normalize until thyroid supplementation is given.¹⁶¹ It is usually unnecessary to increase the postoperative dose of T₄, however, and almost never necessary to use parenteral T₄, unless the patient cannot take medication by mouth for several weeks. If parenteral T₄ therapy is necessary, half of the patient’s usual daily T₄ dose is ordinarily given, and attention is given to the patient’s cardiac status because this therapy may precipitate cardiac arrhythmias, angina, and heart failure.

Cardiac and pulmonary problems are prevalent in elderly patients with hypothyroidism. The prevalence of coronary artery disease is high, but the diagnosis is easily overlooked because patients often have few symptoms because of their low metabolic activity or because they fail to communicate their symptoms clearly.¹⁰³ Pericardial effusions are often apparent and rarely cause tamponade. Patients with severe hypothyroidism also respond poorly to stress by having hypothermia and hypotension develop, and they do not have tachycardia develop in response to infection or hypotension. Shock responds poorly to vasoconstrictors.

Patients with severe hypothyroidism often display upper airway obstruction caused by oropharyngeal muscle dysfunction and tissue infiltration with mucopolysaccharide.¹⁶² They may have central sleep apnea, insensitivity to hypoxia and hypercarbia,¹⁶³ and respiratory muscle weakness,¹⁶⁴ changes that often lead to severe postoperative hypoxia and difficulty in weaning from a ventilator. These defects are reversible with T₄ replacement therapy, but obstructive sleep apnea may be more closely related to obesity and male gender than hypothyroidism.¹⁶⁵

A von Willebrand’s disease–like defect is common in hypothyroidism, which may lead to bleeding.^166,167 It resolves promptly with infusion of desmopressin, suggesting that it acts through the β-adrenergic receptor.⁸⁹ This can be helpful in the acute management of bleeding. It resolves permanently with T₄ therapy.^168,169