Paul M. Yen
Robert I. Gregerman, MD wrote this chapter in previous editions.
Disturbances of thyroid growth and function are among the most common endocrinologic disorders encountered in ambulatory practice. Excessive production of the iodine-containing thyroid hormones thyroxine (T4) and triiodothyronine (T3) results in hyperthyroidism orthyrotoxicosis; decreased hormone production results in hypothyroidism (Fig. 80.1). Generalized enlargement of the thyroid, regardless of cause, is termed goiter. Focal enlargement of the thyroid is termed a nodule and is usually benign. Either goiter or focal enlargement may be associated with abnormal thyroid function. Goiter can produce anatomic changes ranging from simply cosmetic to obstruction of contiguous structures such as the trachea and esophagus. Thyroid carcinoma is not uncommon, but rarely results in invasive or metastatic disease. Thyroiditis is a term that encompasses a diverse group of disorders characterized by acute, subacute, or chronic inflammation of the thyroid gland.
Thyroid Physiology
Thyroid Regulatory Mechanisms
The principal regulatory mechanism of the thyroid is the hypothalamic–pituitary–thyroid negative feedback control system. The hypothalamus secretes thyrotropin-releasing hormone (TRH), which travels via the hypophyseal portal system to the pituitary, where it stimulates release of thyroid-stimulating hormone (TSH). TSH stimulates many aspects of thyroid activity, including hormone synthesis, thyroid growth, and the release of thyroid
P.1337
hormones. Secretion of TRH by the hypothalamus and TSH by the pituitary is inhibited by the thyroid hormones, and thus forms a negative feedback loop.
|
FIGURE 80.1. Production rates by the thyroid and in the periphery of thyroid hormones and their mean concentrations in the plasma. |
The thyroid hormones are unique because they are the only substances in the body that contain the trace element iodine. The minimal daily requirement of iodide is only about 100 to 200 µg, an amount that is determined by obligatory loss, mainly through the kidney. In the United States, and in most developed countries, the minimal daily requirement is enormously exceeded by dietary intake because of the addition of iodide to dietary salt (“iodized salt”); for example, iodized salt provides about 1,000 µg of iodine a day in an average diet. Thus, iodide deficiency and its consequence, iodide-deficiency goiter, are no longer common in the United States, but are still major problems in many parts of the world (1) (see also Goiter and Iodide Deficiency).
The thyroid actively concentrates iodide across its plasma membrane by a sodium-iodide symporter (NIS) (2). NIS transports a number of anions other than iodide, a phenomenon that has been exploited diagnostically and therapeutically, for example, the pertechnetate anion, TcO4-, as the radioactive isotope 99MTc (technetium 99m), has been widely used for thyroid imaging.
After uptake into the cell, iodide is transported into the lumen of thyroid follicles where, through a series of enzymatic reactions, it is incorporated into thyroglobulin to form thyroid hormones, T4 and T3. TSH is the important stimulator that affects virtually every stage of thyroid hormone synthesis and release.
Any chemical substance that interferes with thyroid hormone function or release may lower blood hormone concentration and induce compensatory hypertrophy of the gland (goiter) via stimulation of TSH secretion. Perchlorate, now used therapeutically only occasionally, inhibits NIS. The thiocarbamide “antithyroid” drugs (e.g., propylthiouracil and methimazole) interfere with hormone synthesis by blocking the incorporation of iodide into the tyrosines (organification), and with coupling reactions in iodothyronine formation, but they have more effect on coupling than on organification. Lithium ion (currently in wide use for the treatment of affective disorders; see Chapter 24) interferes with thyroglobulin proteolysis and hormone release and may result in goiter and, occasionally, hypothyroidism. Lithium also interferes with the action of TSH on the thyroid, and therefore some cases of hypothyroidism caused by lithium are not associated with goiter. Iodide itself in pharmacologic amounts interferes with hormone formation and release and in some individuals is a goitrogen.
Metabolic Effects of Thyroid Hormone
The thyroid hormones exert their actions through a variety of mechanisms. A classic thyroid hormone effect is on metabolic rate. Measurement of basal metabolic rate (BMR) was the basis for the first laboratory method for clinical assessment of thyroid status. The numerous known actions of thyroid hormones range from specific stimulation of mitochondrial oxidative metabolism to the nuclear regulation of protein synthesis. Thyroid hormones also exert specific regulatory effects on membrane function (e.g., potentiation of catecholamine effects). This action of thyroid hormones explains the signs of exaggerated sympathetic activity in hyperthyroidism and the effectiveness of the therapy of this condition by β-adrenergic blockade.
Hormone Transport
The thyroid hormones in the blood are T4 and T3. Both hormones are tightly, but reversibly, bound to several plasma proteins, mainly thyroxine-binding globulin (TBG). In the normal person, 65% to 70% of the thyroid hormones are bound to TBG; approximately 15% to the secondary carrier, transthyretin (TTR), formerly called thyroxine-binding prealbumin; and approximately 15% to albumin. Variations of TBG occur in many clinical states and account for most of the changes in T4 concentration seen in a variety of diseases, including hypothyroidism and hyperthyroidism. Small quantities of T4 (0.03%) and T3 (0.3%) are not protein bound but are free and in rapid equilibrium with the protein-bound fraction (“free T4” and “free T3”).
The concentrations of free T4 and T3 in serum are thought to reflect the bioactive hormones exerting an effect on the tissues. Clinical thyroid status in a number of conditions correlates with free T4 rather than with total
P.1338
hormone in serum. A good example of this correlation is the normal pregnant state in which total T4 is high but in which there is no clinical or laboratory evidence of free thyroid hormone excess. The elevation is the result of increased glycosylation (sialation) and binding capacity of TBG and of an estrogen-mediated increase in the binding protein's concentration in serum.
In some pathologic states that affect the quantity of TBG in serum (Table 80.1), and hence the total T4, the absolute concentration of free T4 may not adjust to a normal value. During a variety of nonthyroidal illnesses, undefined factors in serum other than the concentration of TBG and TTR appear to determine the free hormone concentration, presumably by decreasing the affinity of the interaction of binding proteins with T4 (see below).
|
TABLE 80.1 Factors Affecting Thyroxine-binding Globulin (TBG) |
||||||||||||||||||||
|
Metabolism and Interconversion of Thyroid Hormones
Virtually all tissues metabolize and degrade the thyroid hormones, but the liver is quantitatively the most important as a site at which regulation of hormone degradation occurs. T4 metabolism is the major source (80%) of circulating T3 in the normal individual. The normal thyroid secretes mainly T4 and only a small amount of T3 (Fig. 80.1). Only in hyperthyroidism, iodine deficiency, and certain other pathologic circumstances is T3 sometimes the predominantly secreted hormone.
Approximately 85% of the T4 secreted is ultimately deiodinated and further degraded. The physiologically most important pathway involves conversion of approximately 35% of the T4 to metabolically active T3, which is itself further deiodinated. About an equal amount of T4 is converted to reverse triiodothyronine (rT3) (Fig. 80.1). rT3 is a metabolite that is not active in promoting calorigenesis or other actions of thyroid hormone. In a variety of pathologic states, the formation of T3 is inhibited, whereas that of rT3 is reciprocally enhanced, for example, “sick euthyroid syndrome.” Measurement of rT3 has some usefulness (e.g., in the differential diagnosis of the “euthyroid sick syndrome;” see Hypothyroidism: Differential Diagnosis) but is not done routinely.
Thyroid Hormone Transporters and Receptors
Although there was evidence of the existence of multiple thyroid hormone transporters in different tissues, only recently have some of these transporters been characterized at the molecular level (3). Organic anion transporters and amino acid transporters have been shown to facilitate cellular thyroid hormone uptake.
After transport into the cell and nucleus, T3 interacts with thyroid hormone receptors (TRs) that bind thyroid hormone as well as specific deoxyribonucleic acid (DNA) sequences in enhancer elements (thyroid hormone response elements) located in the promoters of target genes (4). Recent microarray studies have demonstrated the large variety and number of genes that are positively and negatively regulated by TRs.
Laboratory Tests of Thyroid Function and Thyroid Disease
All thyroid function tests assess secretory activity of the thyroid gland indirectly. Measurements of serum hormone concentrations, the most commonly used tests, cannot be equated directly with the rates of hormone production, although they reflect those rates when serum binding of hormones is normal. However, various illnesses, drugs, and alterations of physiologic state affect serum binding. Accordingly, proper interpretation of serum hormone concentrations demands concomitant assessment of serum binding.
Thyroid-Stimulating Hormone (Thyrotropin)
The serum TSH is an indicator of the functional state of the hypothalamic–pituitary negative feedback system. An elevated TSH implies that subnormal concentrations of thyroid hormones are present in the circulating blood. A low (“suppressed”) TSH implies that excessive amounts of thyroid hormone are being produced and are inhibiting the pituitary's output of TSH. However, these considerations apply only under usual physiologic conditions.
Serum TSH is invariably elevated in primary hypothyroidism because of reduced feedback inhibition by the decreased concentrations of thyroid hormones produced by a failing thyroid gland. The measurement of serum TSH is important both in the diagnosis of primary hypothyroidism and in monitoring the adequacy of thyroid hormone replacement therapy (see Hypothyroidism, Treatment). Elevation of serum TSH is the most sensitive indicator of hypothyroid status, but not every elevated TSH indicates hypothyroidism.
Elevations of TSH were for many years reliably measured by radioimmunoassay, but the available assays were not sufficiently sensitive to measure the suppression of TSH that occurs in hyperthyroidism. However, newer
P.1339
immunoradiometric (second-generation) and chemiluminescent (third-generation) assays quantitate TSH within the normal and subnormal range (up to 0.1 mIU/L and 0.01mIU/L, respectively). As a result, the determination of TSH enables the distinction of mild TSH suppression caused by nonthyroidal illness from hyperthyroidism (5).
TSH should be measured when the clinician suspects hypo- or hyperthyroidism or to monitor patients during maintenance therapy of hypothyroidism. Additionally, TSH should be measured in patients with a family history of thyroid disease; with nonthyroidal autoimmune conditions; or with hypercholesterolemia. There are a few conditions in which measurement of TSH alone is not recommended because it can be diagnostically misleading. These include acute psychiatric illness; pituitary or hypothalamic disease; and during the first trimester of pregnancy. Additionally, TSH levels can be variably high or low during the course of a variety of nonthyroidal illnesses, especially in hospitalized patients.
Serum Thyroxine and Triiodothyronine
Measurements of the concentration of T4 (“total T4”) and T3 in serum, as determined by protein binding (T4), or radioimmunoassay, or other specific methods, are commonly used and are important tests of thyroid function. However, interpretation of a given value of T4 must consider whether its binding to serum proteins is normal. Accordingly, T4 must be measured in conjunction with some separate test that assesses its binding to serum protein carriers, including TBG, the major binding protein for the thyroid hormones. In routine practice, this is done by determining the free T4 or the free T4 index (FTI; see Free T4, Free T3, and Free T4 Index). In uncommon situations in which hyperthyroidism is suspected, the free T3 should also be measured, but it is not a routine test (see Free T4, Free T3, and Free T4 Index).Table 80.2 lists the normal values of the common tests.
Free T4, Free T3, and Free T4 Index
The free (non–protein-bound) T4 of serum is reported as a single number but is determined by separate measurements of (a) the percentage of non–protein-bound T4 (best performed by equilibrium dialysis using a tracer amount of isotopic T4, added to the serum) and (b) the total T4. Their arithmetic product equals and is reported as the free T4 (expressed as ng%, ng/dL, or pmol/L). The dialyzable (non–protein-bound) T4, which normally approximates only about 0.03% of the total, is not ordinarily reported but is used by the laboratory to calculate the free T4 in absolute units. Free T4 can also be measured directly by a sensitive assay. Equilibrium dialysis, although an expensive technique, is the gold standard for free T4 determinations. Other expensive methods that determine the free T4 are in wide use include immunoenzymometric assays (IEMA), which use enzyme signals; immunofluorometric assays (IFMA), which use fluorophores as signals; immunochemiluminometric assays (ICMA), which use chemiluminescent molecules as signals; and immunobioluminometric assays (IBMA), which use bioluminescent signal molecules
|
TABLE 80.2 Thyroid Function Testsa |
||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||
The free T4 hypothesis has been helpful as a physiologic concept. Determination of the free T4 for clinical purposes is also often useful and sometimes essential. In some clinical states, such as during estrogen therapy, both T4 and TBG are elevated and thyroid status is accurately reflected by the free T4; the dialyzable fraction is decreased by the increased TBG, but because the total T4 is elevated, the free T4 is normal. In hyperthyroidism, free T4 reflects thyroid status better than total T4 because the altered metabolic state of hyperthyroidism itself lowers TBG; consequently, in some cases of hyperthyroidism, a normal or borderline elevation of total T4 is associated with a clearly elevated free T4. In hypothyroidism the opposite may be true; TBG is often elevated and the free T4 is decreased more than is the total T4. Under any of these circumstances, the free T4 is a more sensitive test of thyroid status than the total T4.
Free T3
The T3 in serum, like T4, is mainly protein bound, also to TBG, but that fraction that is not bound is termed the free T3. The measurement is made by equilibrium dialysis (see Laboratory Tests of Thyriod Function and Thyroid Diseases and also Free T4, Free T3, and Free T4 Index.) Free T3
P.1340
is not a routine test, but cases of very rare “free T3 toxicosis” can be diagnosed with this test (see Hypothyroidism Caused by Excessive Secretion of T3).
Free T4 Index
Although this test is being replaced by direct free T4 measurements, it was the mainstay for estimating serum FT4 levels for many years. In most, but not all, cases, FTI closely parallels free T4. In the laboratory the FTI involves simple measurement of the binding of tracer T3 (T3uptake) to an inert material plus separate measurement of the total T4 in the sample.
The T3 uptake is often not reported as a separate test or value (as a percent) but is incorporated into the FTI calculation. T3 uptake (T3U) is not to be confused with the concentration of T3 in serum. The T3U measurement is not a thyroid function test at all but merely provides an indirect estimate of the concentration of serum TBG. To a smaller extent, T3U is influenced by the quantity of T4 in serum (i.e., by the degree of saturation of the T4 [and T3] binding sites on TBG). Although direct measurement of TBG is now available, T3U is much simpler. Technically, the T3U is measured by adding a tracer quantity of T3 and a nonspecific T3 binding absorbent (resin) to a sample of serum to be tested. The tracer distributes itself between nonspecific binding sites on the resin and specific binding sites on TBG. Resin-bound tracer is inversely related to the quantity of TBG in the serum; the more TBG to bind the T3, the less available to be bound to resin. The test result is expressed either as a percentage uptake of tracer into the resin or as a ratio of the test sample to that of the laboratory's control serum (“T3U ratio”). Tracer T4 has been used as an alternative to T3; the results are similar, but T3 is used for technical reasons.
The usefulness of the T3U is in interpreting a given level of T4. A high (or low) T4 can be interpreted as reflecting increased (or decreased) T4 secretion only if the serum binding of T4 is normal (i.e., only if the TBG [T3U] is normal); the FTI value corrects for the level of TBG, providing a more accurate assessment of thyroid function. For convenience, the T4 and T3U have been combined to give the FTI by simply multiplying one number times the other. The index is also sometimes confusingly designated the “T7” or “T12”.
In severely ill patients of the type more likely to be hospitalized than to be ambulatory, the FTI may be misleading. In such cases the resin uptake is elevated, not necessarily because TBG is low but as the result of the appearance in serum of a nonspecific inhibitor of hormone binding that affects the distribution of tracer T3 between sites in serum and sites on the resin. Both the free T4 and FTI tests must be interpreted with caution in any patient with severe nonthyroidal illness.
Thyroidal Radioiodide Uptake Tests
These tests were introduced before measurements of serum hormones were available and are now rarely, if ever used, to ascertain hormonal status of patients. The rate of tracer iodide accumulation (131I, 123I) in the thyroid can be measured by using times ranging from a few minutes to the plateau of accumulation (24 hours). The diagnostic usefulness of the thyroidal radioiodide uptake (RaIU) in the United States is also seriously limited by the high iodide content of the diet from the iodization of table salt. This has resulted in RaIU values that are usually too low to discriminate normal function from hypofunction, so the test is now useless for the diagnosis of hypothyroidism. It is still of occasional diagnostic usefulness in hyperthyroidism, but because results are normal in up to 50% of cases of proven hyperthyroidism, a normal RaIU does not exclude the diagnosis. These limitations not withstanding, one important use of the test is in patients with hyperthyroidism associated with thyroiditis (see Thyroiditis). If this condition is suspected, a RaIU is important; a low value helps deter inappropriate therapy. Determination of the RaIU is sometimes used in the selection of dosage in radioiodide therapy. The RaIU is subject to interference by various chemical agents, especially iodide-containing drugs and the radiographic media used in pyelograms, cholecystograms, and in computed tomography (CT) contrast imaging.
Immunologic Tests
Assay of antibodies to thyroidal constituents (thyroglobulin, microsomes), so-called thyroid autoantibodies, is useful in determining the presence of autoimmune thyroiditis, in the differential diagnosis of goiter, and in predicting the significance of elevations of TSH (seeHypothyroidism and Goiter and Iodide Deficiency). The term microsomal antibodies is synonymous with thyroid peroxidase antibodies. Assays for thyroid-stimulating immunoglobulin (TSI) (see Graves Disease) are readily available. TSI measurements are useful in the pregnant hyperthyroid patient because high levels are associated with an increased likelihood of neonatal hyperthyroidism caused by placental transfer of the stimulator. The original test for TSI, a bioassay called the long-acting thyroid stimulator (LATS) test, still performed in some laboratories, is not useful.
Fine-Needle Aspiration, Needle Biopsies, and Imaging
Fine-needle aspiration (FNA) for cytologic examination or biopsy of the thyroid is now routine in most centers. Although the procedure often failed to distinguish benign adenomas from well-differentiated follicular carcinomas, it appears that new immunologic methods hold promise (6). FNA (by use of a 25-gauge needle) with cytologic
P.1341
examination is simple, virtually painless, and without complications (see Thyroid Nodules). The procedure is ordinarily performed by an endocrinologist or a pathologist. A few centers use needle biopsy (aspiration or cutting), usually performed only if the simpler FNA is not sufficiently informative. In the hands of an appropriate operator, needle biopsy is probably more definitive and, because it is performed with local (cutaneous) anesthesia, is ordinarily painless. The only significant complication is local hemorrhage, but this is an uncommon, usually minor, problem. Ultrasound is often used to guide FNA and may lead to additional information, especially when cystic lesions are present.
Various imaging techniques are available to delineate the anatomy of the thyroid and to distinguish functional from nonfunctional nodules, a consideration in the differential diagnosis of thyroid neoplasms. The two commonly used techniques are radioisotopic scanning (scintiscan) and ultrasonography. CT and magnetic resonance imaging are not useful for evaluating nodules, although they have a place in evaluating substernal extension of goiter and in localizing metastatic lesions, as does 18F-fluorodeoxyglucose positron emission tomography (PET) scanning. The isotope most widely used in scintiscans of the thyroid is 99MTc pertechnetate (TcO4-), but 123I is the isotope of choice. However, tumors that can take up 123I but not accumulate pertechnetate in rare circumstances, and thus may give misleading information on the functional state of a nodule. Ultrasonography, now often the initial imaging procedure, is the best technique for determining the size of the thyroid; the number, size, and characteristics of nodules; and whether a nodule is cystic or solid, an important point in differential diagnosis of these lesions. Ultrasonography also provides an objective basis for evaluation of changes in the size of nodules with medical therapy. Both isotopic imaging and ultrasonography can determine whether a nodule is truly single or is in fact one of many in a multinodular gland.
|
TABLE 80.3 Nonthyroidal Illness: Effects on T4, Free T4, TBG, and TSH in Plasmaa,b |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nonspecificity of Thyroid Function Tests in Nonthyroidal Illness
Thyroid function tests are frequently nonspecifically altered in many nonthyroidal diseases and by drugs and hormones (7, 8, 9, 10); that is, these tests are not specific for thyroid disease when severe illness is present (Table 80.3). Moreover, a variety of drugs and hormones affect both thyroid function and tests that assess the hypothalamic–pituitary–thyroid axis (Tables 80.1 and 80.4). T4, free T4, FTI, T3, and TSH may all be affected. Although much of the information on this subject comes from studies of hospitalized patients in whom up to 30% will show one or more abnormalities on admission, ambulatory patients are probably also affected. Some examples are presented below.
Effects of Gonadal and Adrenal Hormones on Thyroid Function Tests
Estrogens (pregnancy, contraceptives) raise and androgens lower T4, but not free T4 or FTI, by altering serum TBG. Glucocorticoids inhibit thyroid activity acutely by interfering with TSH secretion, lowering TSH levels, and affecting the pituitary's responsiveness to TRH. The serum T4 is lowered during chronic glucocorticoid therapy, mainly because of a decrease of TBG.
Liver Disease
Various alterations of thyroid function tests are produced by liver disease. Early in infectious hepatitis, the T4 level is elevated secondary to an increase of TBG. Chronic liver disease produces many abnormalities in an unpredictable
P.1342
fashion. T4 may be increased or decreased in parallel with TBG and the T3U. Free T4 is often elevated with no obvious relationship to the TBG. T3 is usually low. A frequent and unexplained abnormality is elevation of TSH, although the response to TRH is not exaggerated as it is in hypothyroidism. RaIU is often elevated in acute alcoholic hepatitis with or without cirrhosis and in some cases of cholangitis. These changes have been attributed to both iodide depletion and acceleration of T4 metabolism.
|
TABLE 80.4 Drug and Hormone Effects on T4, Free T4, TBG, and TSH |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Renal Disease
The nephrotic syndrome is often associated with depressed T4 and TBG. The decrease of the T4 is likely caused by a decrease in TBG and an increase in clearance of both TBG and T4. In chronic renal disease, the average T4, free T4, and TBG, are not significantly different from normal, but the range is greater and values may exceed the usual normal limits. Some patients with severe chronic renal failure receiving long-term dialysis show a progressive decrease of T4; the mechanism is not known but the prognosis for survival in such patients is poor (see Hypothyroidism versus the Euthyroid Sick Syndrome). As expected in any chronic illness, the serum T3 is often depressed.
Infections, Malnutrition, and Drugs
The T4 may drop early in the course of acute infection and free T4 may rise. Neither change is accounted for by an alteration of TBG. During starvation or severe caloric restriction, serum T3 falls; free T4 is often increased without relation to the TBG. Serum T3 is often decreased in the elderly, a change that has been attributed to aging but may in large part be caused by diminished food intake and nonspecific illness (11). Closely correlated alterations of T3U and serum TBG have been reported in protein-calorie malnutrition. Some pharmacologic agents affect thyroid hormone levels (Table 80.4). Phenytoin (Dilantin) and carbamazepine promote thyroid hormone metabolism and lower T4 and free T4 into the hypothyroid range, but the TSH is normal. The apparently low free T4 is an artifact of routine methodology and is an excellent example of how misleading this test can be in some circumstances (12). Heparin acutely elevates the free T4; following heparin administration, the heparin in the specimen can cause stimulation of lipoprotein lipase that liberates free fatty acids that inhibit T4 binding to serum proteins. β-Adrenergic blockers decrease serum T3 by inhibition of the normal T4 deiodination route; rT3 is increased. A similar decrease of T3 through reduced hepatic metabolism of
P.1343
T4 is produced by propylthiouracil, dexamethasone, amiodarone, and the radiopaque contrast media used for visualization of the gallbladder. In the case of the latter agents, additional mechanisms are operative because these compounds may also elevate T4 and TSH, an effect attributed to their differential inhibition of conversion of T4 and T3 in the pituitary and the periphery. Amphetamine abuse may increase serum T4, presumably by central stimulation of TSH release (7). In human immunodeficiency virus (HIV) infection, patients have increased T4 and TBG early in the disease, but no change in T3 and low rT3. T4 and T3 can be decreased in advanced stages of the disease.
Altered Serum Thyroxine Caused by Inherited and Other Abnormalities of Protein Binding
In addition to those diseases or drugs that alter T4 levels by affecting binding of the hormone to TBG, altered protein binding also occurs in inherited disorders of TBG excess, TBG deficiency, increased concentration of thyroxine-binding prealbumin, and increases in the number of T4 binding sites on an albumin variant (familial dysalbuminemic hyperthyroxinemia). The first two conditions are X-linked. The latter two conditions, inherited as autosomal dominants, are rare. In all these conditions, the free T4 is normal (7).
Alterations of Serum Thyroxine in Nonthyroidal Illness Not Caused by Abnormalities of Protein Binding
Elevations of T4 that are unexplained by changes in thyroxine binding are common. These situations are difficult to distinguish from hyperthyroidism. Included are the elevation of T4 seen in acute nonthyroidal illness, in psychiatric disease, and as the effect of some drugs. The stress of serious illness may also lower T4 and simulate hypothyroidism (see Hypothyroidism versus the Euthyroid Sick Syndrome), but such severe illness is rarely encountered in ambulatory patients. An exception may be seen in patients receiving dialysis for chronic renal failure. Abnormal thyroid hormone levels in these situations and diseases that are regularly associated with such changes (7, 8, 9) are described briefly below.
Increase of Serum Thyroxine during Nonspecific Illness: Euthyroid Hyperthyroxinemia
Although the phenomenon of decreased serum T4 during severe illness is now widely recognized, the frequent occurrence of increased T4(and free T4) caused by illness is not generally appreciated. The increase of T4 is modest, and the T4 generally does not exceed about 15 µg. This problem is commonly seen in severely ill elderly patients in whom it raises the issue of hyperthyroidism (11). Similar findings have been reported in hyperemesis gravidarum.
Acute Psychiatric Disease
Restlessness, hyperactivity, tachycardia, and tremor are often seen as part of severe acute psychiatric illness. Clinical suspicion of hyperthyroidism (because of tachycardia, tremor, sweating) leads to thyroid function tests and laboratory results consistent with this diagnosis. Such patients may have elevated T4, FTI, and T3. The TSH may not be suppressed (13). In some series, up to one-third of acutely hospitalized psychiatric patients have an elevated T4. Although the phenomenon is documented only in hospitalized patients, it may be encountered in any severely disturbed person. The T4 returns to normal within 1 to 2 weeks of clinical improvement of the psychiatric disturbance. This phenomenon may represent a form of centrally driven hyperthyroidism (13).
Increased Serum Thyroxine Caused by Resistance to Thyroid Hormones
Rare but well-recognized cases of increased T4 unaccompanied by binding protein abnormalities are seen with the syndrome of resistance to thyroid hormone. Originally described as a familial syndrome of increased T4, goiter, deaf mutism, and some degree of hypothyroidism with delayed bone maturation and epiphyseal stippling, the most common phenotype is actually that of elevated T4, increased or inappropriately normal TSH, in a person without symptoms of major hypo- or hyperthyroidism. The abnormality occurs both sporadically and in familial form, and is probably part of a heterogeneous group of disorders with variable inheritance (14). Most cases are caused by abnormal (mutant) thyroid hormone receptors.
Statistical Considerations in the Clinical Interpretation of Thyroid Function Tests
No single numerical value divides normal from abnormal in any thyroid function test. The upper and lower limits of normal for serum T4, FTI, and T3 are arbitrarily set, as they are for most tests at ±2 standard deviations from the mean. By definition, therefore, 2.5% of an apparently normal population will have abnormal values at each end of the distribution. To complicate the issue, a small number of hyperthyroid or hypothyroid patients have values that fall clearly within the normal range. In addition to the statistical overlap, both biologic (i.e., day to day) variation and unavoidable analytical error further obscure the dividing line between normal and abnormal. For example, 95% confidence limits for the analytic variation of a single T4 test are ±1 µg/dL at the upper and lower limits of the normal range. For all these reasons and because of the occasional instance of laboratory or reporting error, a single laboratory determination should not be relied on to establish or exclude a diagnosis. All abnormal values should be confirmed before therapy is undertaken, and borderline values should be repeated before diagnostic conclusions
P.1344
are drawn. Premature institution of therapy may obscure the diagnosis.
|
TABLE 80.5 Causes of Thyrotoxicosisa |
|||
|
Hyperthyroidism and Thyrotoxicosis
Thyrotoxicosis is defined as any condition in which the cells of the body are exposed to excess amounts of circulating thyroid hormone.Hyperthyroidism is any condition in which thyrotoxicosis is attributable to hyperfunction of the thyroid gland. Often the terms are used interchangeably, although they do not mean precisely the same thing.
|
TABLE 80.6 Signs and Symptoms of Thyrotoxicosis |
||||||||||||||||||||||||
|
Essentially, the same presentation may result from any of several different pathologic processes (Table 80.5), and selection of proper therapy demands that the correct underlying diagnosis is established. The most common cause of hyperthyroidism is Graves disease, an autoimmune process also known as diffuse toxic goiter. Only slightly less common is hyperthyroidism caused by a hyperfunctioning multinodular goiter (toxic nodular goiter). Occasionally, hyperthyroidism is caused by a solitary hyperfunctioning adenoma (“hot nodule”). Thyrotoxicosis also has been seen with increasing frequency as a transient phenomenon in the evolution of thyroiditis (see Thyroiditis) (15,16). In addition, the induction of thyrotoxicosis by iodide and iodide-containing drugs (e.g., amiodarone) and contrast media should be considered for those patients who have had such exposures (see below) (17). The other causes of hyperthyroidism listed in Table 80.5 are rare and are not usually encountered in ordinary practice.
Clinical Presentation and Diagnosis of Thyrotoxicosis
Clinical History
The presentation of patients with thyrotoxicosis is highly variable (Table 80.6). The severity is determined not only by the degree of hormone excess but also by its rapidity of onset, its duration, and the age of the patient. The “typical” thyrotoxic patient has one or more of the following spontaneous complaints: nervousness, weight loss, palpitations (which at first may be intermittent), enlarging neck mass (goiter), change in appearance of the eyes (Graves disease), or symptoms of heart failure. These symptoms usually have been present anywhere from a few weeks to a year or longer. Careful questioning often reveals other symptoms.
P.1345
The so-called nervousness in thyrotoxicosis is often irritability, inability to concentrate, restlessness, or overt emotional lability, but it is a tremor of the hands that most often leads the patient to express this complaint. Impairment of normal sleep pattern with frequent wakening is common. Some patients with anxiety may experience tachycardia, tremor, irritability, and weakness simulating thyrotoxicosis. The “anxiety” of thyrotoxicosis is more likely to appear as irritability and hyperkinesis than as an expressed feeling of being anxious. Primary anxiety disorders are either related to identifiable stresses, coexist with symptoms of depression, or have distinctive characteristics that make them recognizable (see Chapter 22). In depression, weight loss is invariably accompanied by anorexia, a relatively unusual symptom of thyrotoxicosis.
Weight loss classically occurs despite increased appetite, although often no obvious change in appetite is noticed or there may be anorexia, especially in elderly patients. The only prominent gastrointestinal symptom is increased frequency of bowel movements, but actual diarrhea is not seen.
The heat intolerance of hyperthyroidism is often apparent only on questioning. Commonly, the patient admits to having reduced the number of covers used on the bed at night or to the development of new and unusual habits, such as sleeping in the nude or with feet extended from under the blankets. Sweating is increased but is not usually a spontaneous complaint and may be denied.
As the disease progresses in severity, skeletal muscle wasting occurs, which tends to involve especially the limb girdle musculature, producing a proximal myopathy. This process results in weakness, expressed, for example, as great difficulty in climbing stairs or, on examination, in arising from a squatting position. Exertional dyspnea without evidence of cardiac failure is common and may be related to the myopathy.
Skin changes are hardly ever noticed by the patient, and “silky skin” or hair (a “classic” symptom) is only occasionally seen on examination. Hair loss is common, usually noticed as thinning of the scalp hair by women. Other skin changes include occasional cases in light skinned people of diffuse hyperpigmentation with darkening noted mostly over extensor surfaces of elbows, knees, and small joints. In African American patients, darkening of the skin is common, but its occurrence is discovered only by questioning.
Physical Findings
The thyroid is visibly or palpably enlarged in almost all children and adult patients with hyperthyroidism; however, in the adult population greater than 65 years old, the thyroid may not become enlarged. Asymmetric enlargement is common, especially in patients with toxic nodular goiter. Extreme vascularity of the gland in Graves disease may result in palpable or audible blood flow; a bruit is usually heard over the enlarged lobes but occasionally is best heard more rostrally over the superior thyroidal arteries. A bruit over the thyroid of a hyperthyroid patient is usually diagnostic of Graves disease; this finding is not present in patients with toxic nodular goiter.
Cardiovascular findings include sinus tachycardia, systolic flow murmurs, wide pulse pressure commonly, and atrial fibrillation occasionally. It is a common belief that most patients with hyperthyroidism at least have a tachycardia, but in fact only 50% of patients, regardless of age, have an increased heart rate. The apex impulse is often prominent and forceful. Cardiac failure may develop in severe cases of long duration, especially in the elderly.
The eye findings can be separated into those that occur as a result of thyroid hormone excess and those that are part of the ophthalmopathy of Graves disease (see Graves Disease, Opthalmopathy) (18). Excessive thyroid hormone enhances sympathetic tone and the innervation of the eyelids is partially under sympathetic control. Lid retraction with increased scleral visibility above and below the iris (prominent “whites” of the eyes), along with infrequent blinking, leads to the striking “stare” so commonly seen. Failure of the lid to follow movements of the globe (“lid lag”) is another manifestation of the same process.
Clubbing of the fingers and toes is rare (thyroid acropachy) and is distinguishable radiographically from that seen in pulmonary disease. A common sign is separation of the distal portion of one or more fingernails from their nail bed (onycholysis; “dirty fingernail” sign). A fine rapid tremor, usually detected in the hands, is a common physical finding.
In some patients, particularly elderly ones, the clinical picture may not suggest thyrotoxicosis. Such patients may have only unexplained weight loss or weakness. Occult neoplasm may first be suspected, and the diagnosis of hyperthyroidism may be missed entirely or considered only after extensive evaluation fails to yield a diagnosis. These are the patients with severe but not clinically obvious disease, termed in the past apathetic hyperthyroidism. The term was used to describe patients who did not have obvious activation of the sympathetic nervous system (e.g., tachycardia, lid retraction, tremor). Apathetic hyperthyroidism is only rarely encountered today because of increased awareness on the part of clinician and modern diagnostic techniques that have led to earlier detection of hyperthyroidism.
Congestive heart failure, atrial fibrillation, or new-onset or worsening angina pectoris may be the presenting manifestation of thyrotoxicosis.
Laboratory Diagnosis
When prominent symptoms are present, the usual thyroid function tests substantiate the diagnosis in almost all cases: an increase in free T4and a suppressed TSH. If
P.1346
these results are borderline or normal, the serum T3 must be measured, because hyperthyroidism may be caused by elevation of T3 alone. However, so-called T3 toxicosis (see Hyperthyroidism Caused by Excessive Secretion of T3, Triiodothyronine (T3) Toxicosis) occurs in less than 5% of all cases.
The amount of tracer iodide accumulation (131I, 123I) in the thyroid can be measured using RaIU studies. The uptake of radioactive iodide tracers (RaIU) is increased in Graves disease. RaIU studies are useful when the absence of classical features of Graves disease makes it important to distinguish it from thyroiditis (see Thyroiditis: Thyrotoxicosis Associated with Thyroiditis).
Both antithyroglobulin and antimicrosomal antibodies are elevated in Graves disease but are not useful diagnostically. Assays for TSI are available but usually are not necessary for the diagnosis of Graves disease.
Graves Disease
Graves disease is a complex disorder comprising toxic goiter, ophthalmopathy, and occasionally dermopathy. At any given time during the course of the disease, one of these manifestations may be an isolated finding. Graves ophthalmopathy and Graves dermopathy can occur independently of thyroid hormone excess. It is generally accepted that ophthalmopathy and dermopathy are closely related but separate and overlapping immunologic disorders.
Recognition of Graves disease in a typical case is not difficult. However, its insidious onset and the absence of eye or thyroid findings in early disease may delay the diagnosis for months or years.
Various abnormal immunoglobulins are found in the serum of patients with Graves disease. Some of these immunoglobulins have TSH-like activity and are designated TSIs; they are antibodies to the normal receptor sites for TSH. The reasons for development of abnormal immunoglobulins in Graves disease are not clearly understood. It is currently thought that Graves disease is a failure of T-cell surveillance rather than a response to thyroid antigens released from a thyroid damaged by unknown causes.
Ophthalmopathy
When Graves ophthalmopathy is present, there is forward protrusion of the globe. This process may be unilateral at first and is often asymmetric. The protrusion represents true proptosis and contributes an additional component to the stare produced by increased sympathetic tone. Extraocular muscle weakness may occur and results in limitation of ability to converge and to perform extreme movements of gaze; strabismus and diplopia are its more severe manifestations.
The serum of some patients with Graves ophthalmopathy contains a factor that produces exophthalmos and other abnormalities of orbital tissues in test animals. There is interstitial edema in the extraocular muscles, increased connective tissue, fatty infiltration, and infiltration with lymphocytes (18). Eventually, gross degenerative changes, such as fibrosis, may occur.
The exact frequency of ophthalmopathy in Graves disease is unknown, but most patients have either no obvious infiltrative eye involvement or show only minimal to moderate proptosis, which generally stabilizes at a tolerable level. Severe exophthalmos occurs in no more than a few percent of cases of Graves disease.
Graves ophthalmopathy and thyroid hyperactivity often coincide; in 85% of cases, the two occur within 18 months of each other. However, the ophthalmopathy may occur years before or after the onset of hyperthyroidism. Even if the patient is euthyroid (normal T4 and T3), the thyroid can frequently be shown to be autonomous, as demonstrated by a nonsuppressible RaIU and a suppressed TSH. In this phase of the disease, the thyroid's activity is driven by TSIs rather than TSH, but the serum thyroid hormones are within the range of normal. Without evidence of either thyroid hyperfunction, disturbance of the negative feedback system (suppression of TSH), or dermopathy, the diagnosis of Graves ophthalmopathy cannot always be made with absolute assurance. Indeed, other diseases of the orbit or retro-orbital space must be considered. CT of the skull and the orbital contents and/or high-resolution sonography are useful diagnostic tools. These procedures can visualize the enlarged extraocular muscles typical of Graves ophthalmopathy, although such enlargement is also seen in pseudotumor. In cases of Graves ophthalmopathy without overt hyperthyroidism, other aspects of Graves disease usually become apparent eventually, but several years may elapse before that occurs.
Proptosis becomes more than a cosmetic concern when the eyelids fail to close, especially when the patient is sleeping, setting the stage for exposure keratitis or corneal ulceration. This problem may be relieved by the application of liquid tears (available over the counter) and the wearing of eye patches at night and sunglasses in bright sunlight or on windy days. Paresis of the extraocular muscles producing diplopia can also be troublesome and may require use of an eye patch or corrective surgery. The most disturbing, but fortunately uncommon, eye involvement is severe chemosis (marked inflammation and edema) of the conjunctivae and periorbital soft tissues. Ophthalmopathy of this severity is termed malignant or infiltrative exophthalmos. Rarely, optic neuritis leading to blindness occurs.
Treatment of severe ophthalmopathy is best provided by an ophthalmologist who has experience with the problem, working in close collaboration with an endocrinologist. Corticosteroids (e.g., prednisone, 60 mg/day for
P.1347
1 to 2 weeks, tapered over 6 to 8 weeks) are useful for patients with severe periorbital and conjunctival edema and inflammation. Other therapy, if warranted, includes low-dose orbital radiation, an established and useful therapy (19). Surgical decompression is only rarely needed and is reserved for patients with severe proptosis. There is considerable controversy about which therapy is optimal. It should also be noted that patients with severe Graves ophthalmopathy can have worsened eye symptoms with radioactive iodine therapy, which can be blocked prophylactically by corticosteroids.
Dermopathy
A unique, albeit unusual, finding in Graves disease, consists of somewhat circumscribed areas of mucopolysaccharide deposition, typically over the shins, termed pretibial myxedema. This unfortunate designation unjustifiably suggests a relationship between the very different type of generalized mucopolysaccharide deposition in severe hypothyroidism (myxedema) and the localized deposition in Graves disease. No relationship exists between these processes. The lesions usually have sharp raised margins and may have an orange peel-like appearance. The affected area is often intensely pruritic.
Therapy
Hyperthyroidism caused by Graves disease may be a self-limited process that terminates within two years in approximately in one-third of patients. In a few of these individuals, the disease recurs decades later. This natural history strongly influences selection of therapy. Other therapeutic considerations relate to the age of the patient and the presence or absence of complications of the hyperthyroidism, its severity, and the presence of comorbid conditions.
Because there are currently no means of controlling the underlying cause of the disease, presumed to be TSI production, therapy is designed to interfere with thyroid hormone synthesis by drugs or by ablation of thyroid tissue by radioiodide or surgery (20). Antithyroidal therapy and radioablation are the most commonly used treatments, with the latter the preferred choice among endocrinologists in the United States.
Antithyroid Drugs
Antithyroid drugs predictably control excessive production of thyroid hormone in essentially all cases, although in only approximately 20% to 40% of cases will a permanent remission of the hyperthyroidism be seen upon drug withdrawal. Males are much less likely to achieve remission (20%) than females (40%), and younger patients (younger than age 40 years) are less likely (33%) than older patients (older than 40 years) (48%) (21). Relapses may occur early or later (within 6 months to a year) or after apparent remission. Late relapses are uncommon, except in postpartum patients. It is not generally appreciated that about half of the patients who have a permanent remission will become hypothyroid between 15 and 20 years after successful treatment.
In the United States, only two thiocarbamide (thionamide) drugs are available, propylthiouracil (PTU) and methimazole (Tapazole). Other equally effective thiocarbamides are used in other countries. Propylthiouracil, unlike methimazole, in addition to its effects in inhibiting thyroid hormone synthesis, also inhibits conversion of T4 to T3 in peripheral tissues. On the other hand, methimazole is longer acting than propylthiouracil and may be given on a less-frequent dosage schedule, thereby facilitating compliance. In most adults with hyperthyroidism, 100 to 150 mg of propylthiouracil (available in 50-mg tablets) every 8 hours or 15 to 30 mg of methimazole (available in 5- and 10-mg tablets) every 24 hours usually suffice as initial therapy, whereas maintenance is often possible with 50 to 100 mg of propylthiouracil twice daily or 5 to 10 mg of methimazole once a day. The FT4 level (not the TSH) which can remain suppressed, should be measured after about 2 weeks of treatment, at 1 month and every 2 to 3 months thereafter. If at these relatively low maintenance dosages of antithyroid drug the serum FT4 falls below normal, efforts to titrate the dosage downward are often tedious and unsuccessful. An euthyroid state can be achieved under these circumstances by the addition of oral T4, usually at a somewhat-less-than-full replacement dose. Additionally, it should be recalled that antithyroid drug therapy never induces permanent remission in patients with toxic nodular goiter (see below), which is the diagnosis in about half of the thyrotoxic patients older than age 55 years.
Although the recommended dosages of antithyroid drugs control the disease in most cases, some individuals may need higher dosages. Severely ill patients should be given larger doses from the beginning. Although the risk of an adverse drug effect is theoretically increased, this should not be a consideration under such circumstances. To achieve total blockade of hormone synthesis, as much as 400 mg of propylthiouracil every 6 to 8 hours may be necessary. Because methimazole has a longer duration of action, it need not be given so often, but 30 to 40 mg three times daily may be needed in rare cases.
Drug therapy should continue for 12 to 24 months before discontinuation of the drug is considered, although conflicting clinical evidence suggests that lasting remission may not be related to duration of therapy beyond the point at which the patient becomes euthyroid. Patients who have continued to require large doses of drugs are almost certain not to have achieved remission. On the other hand, reduction of thyroid size during therapy is thought by some clinicians to be predictive of lasting clinical remission. Measurement of titers of TSI may be useful in predicting that remission has occurred (22), but
P.1348
such measurements are not widely available and also are not highly accurate predictors. If it appears that remission may have been reached, antithyroid drug therapy is stopped and the patient is observed. Routine determination of serum T4 every 3 to 4 weeks for 3 to 6 months allows early recognition of the return of thyroid overactivity.
Minor side effects of drug therapy occur in 1% to 5% of patients. Skin rashes, the most common side effect, are usually seen in the first months of therapy and often disappear even if therapy is continued. Antihistamine drugs are useful in controlling these rashes and the associated urticaria and pruritus that sometimes occur. Neutropenia is not uncommon but is usually not severe and is dose related. If the absolute number of polymorphonuclear neutrophils falls below 2,000, the dosage should be reduced, but the drug need not be immediately discontinued. The white blood cell count should be monitored after several weeks of therapy and after increases of drug dosage. If the side effects are not tolerated, a switch to the other thiocarbamide allows continuation of therapy in about half of the cases. Major complications of drug therapy occur in less than 0.1% of cases. Agranulocytosis is the most dreaded complication. Unlike neutropenia, thiocarbamide-induced agranulocytosis from antileukocyte antibodies is not dose related and is of such sudden onset that routine blood counts are of no help in prevention. However, the patient should be instructed to contact the physician promptly if severe sore mouth or sore throat and fever occur. Immediate hospitalization is probably indicated. Most patients with agranulocytosis eventually recover, albeit after a stormy course. Other toxic reactions include drug fever, arthralgias, and hepatitis. Elevations of aminotransferase activity are commonly seen in patients receiving propylthiouracil. If other liver enzymes are normal, the drug may be continued, but persistent laboratory evidence of hepatocellular damage indicates a need to discontinue therapy. Aminotransferase activity should be measured every 3 to 6 months. Methimazole is rarely a cause of cholestatic jaundice in patients taking the drug; hepatic enzymes (including serum alkaline phosphatase) should be measured at baseline and as indicated thereafter. (However, thyrotoxic patients often have elevations of serum hepatic enzyme activity at onset of their disease, particularly alkaline phosphatase activity.)
Adrenergic Antagonists
Many symptoms and signs of thyrotoxicosis are related to sensitization of the sympathetic nervous system and are in large measure abolished by β-adrenergic-blocking drugs. The indications for use of a beta blocker in hyperthyroidism are severe tachycardia, tremor, sweating, and agitation. Although beta blockers are effective for relief of these manifestations of hyperthyroidism, they do not appreciably affect excessive metabolic rate or reverse the catabolic state of severe cases. β1-selective agents (e.g., atenolol, nadolol, metoprolol) are probably preferable to avoid unwanted side effects in susceptible individuals (e.g., asthmatics). Other uses for β-blockers are in the prevention of symptoms during a trial of withdrawal of an antithyroid drug when blood hormone levels can be used to assess the progress of therapy and while awaiting the effects of 131I therapy. Most patients require a β-blocker in a dose equivalent to atenolol, 100 mg/day. The drug should be discontinued as soon as the patient is rendered euthyroid (T4 normal).
Iodide (Nonradioactive)
Nonradioactive (stable) iodide (127I) for the treatment of hyperthyroidism should be reserved for patients with severe illness or for patients with significant comorbidity. Occasionally, iodide therapy produces severe dermatitis. Use of iodide may preclude for many weeks the use of radioactive iodide, the uptake of which by the thyroid will be greatly diminished.
However, iodide is the best agent available for inhibiting hormone release and is useful in patients who need rapid correction of the hyperthyroid state. Iodide also has a time-honored place in preoperative preparation (see Chapter 93) for thyroidectomy to reduce vascularity of the gland. When given for several weeks after radioiodide therapy, iodide seems especially effective in accelerating restoration of euthyroid status. When given in this setting, some endocrinologists advocate initiating antithyroid drug therapy for at least 2 days before starting iodide therapy and continuing combined therapy for 2 months.
The standard dosage of iodide is 1 drop of a saturated solution of potassium iodide (40 mg) diluted in several ounces of water or juice once daily; higher dosages are often given but are unnecessary because a dose of only 5 mg produces a maximal effect. Lugol solution, containing iodine and iodide, is an obsolete pharmacologic concoction and has no virtue over iodide alone.
Iopanoic Acid Therapy
This drug, an oral cholecystogram contrast agent, is a potent inhibitor of the conversion of T4 to T3. Some experts believe it is a useful clinical adjunct for the rapid correction of hyperthyroidism (see Thyroid Storm (Thyrotoxic Crisis)).
Radioactive Iodide Therapy
Radioactive iodide (131I) is uniformly effective therapy; it is simple to administer and inexpensive. In the United States, unlike Japan and, to a lesser degree, Europe, it is the preferred form of therapy for most adults with Graves disease. The rapidity of response is dependent on dose and on the size of the gland, but improvement is often apparent in a few weeks and euthyroidism (or
P.1349
hypothyroidism) is achieved usually within a few months. Single-dose radioiodide produces a hypothyroid state in most patients.
Some endocrinologists advocate the use of deliberately ablative doses of 131I. This approach to therapy simplifies patient management, accelerates restoration of the euthyroid state, and is reasonable in view of the high probability of eventual posttherapy hypothyroidism regardless of dose. In the past, elaborate schemes have been used to estimate the required dose of 131I. Unfortunately, none has proven helpful because the variability of the thyroid's sensitivity to radiation, the most important determinant of effect, is not measurable. Ablative doses are typically 12 to 15 mCi. Antithyroid drugs are often used initially to render the patient euthyroid, then interrupted for 96 hours before the 131I is given to maximize iodine uptake, and can be reinstituted 24 to 48 hours afterward. Radioactive iodide can be administered only by an appropriately licensed physician, usually a nuclear medicine physician or an endocrinologist. A few precautions are necessary. In women of child-bearing age, a negative serum test for pregnancy must be obtained by the therapist immediately before the therapy dose is given because exposure of a fetus to radiation is unacceptable. In the United States, women who have a young child at home are given no more than 8 mCi and are instructed to avoid prolonged close contact (e.g., sharing a bed) for a week. Lactating women should not nurse for a month after therapy.
The undocumented notion has long persisted that radiation thyroiditis may produce excessive release of thyroid hormones 7 to 14 days after therapy, with the possibility of consequent worsening of the clinical state. Thus, precarious patients (e.g., those in congestive heart failure) are best brought to euthyroid status or are at least significantly improved by antithyroid drug therapy before ablation with 131I. At 3 months after 131I therapy, when the short-term radiation effect becomes maximal, the antithyroid drug can be discontinued or tapered, provided that the laboratory and clinical evidence indicates return to euthyroid status. Adjunctive therapy with a β-blocker is useful during this period to ameliorate possibly emerging symptoms if the dose of 131I proves to have been inadequate. If the laboratory evidence indicates continuing hyperthyroidism, another dose of 131I is required. Therapy with 131I is always successful if enough 131I is given. “Failure” after one or more doses is never an indication for surgery or indeterminate therapy with antithyroid drug. Rather, additional 131I should be given to complete the process.
Surgical Therapy
For many years surgical ablation of the thyroid (e.g., subtotal thyroidectomy) was the main therapy for hyperthyroidism. Currently, it is rarely used except for patients who cannot, or elect not, to be treated with antithyroid drugs or 131I therapy. In the hands of experienced surgeons, subtotal thyroidectomy is effective therapy, attended by minimal morbidity. However, complications include the small but real risk of anesthetic and operative mortality, recurrent laryngeal nerve damage with vocal cord paralysis, permanent hypoparathyroidism, and most commonly, hypothyroidism.
Hyperthyroidism Associated with Multinodular Goiter (Toxic Nodular Goiter) or with a Solitary (“Hot”) Nodule
Toxic nodular goiter is usually seen in adults in midlife or in the elderly. Although the typical patient with Graves disease usually relates symptoms extending over a few months to a year, the history in toxic nodular goiter is often much longer, and many years usually pass before a diagnosis is made. Because of the typical patient's age and the duration of illness, severe cardiac or musculoskeletal involvement is common.
Toxic nodular goiter appears to arise in the evolution of some cases of nodular goiter. Most nodular goiters (see Goiter) are initially TSH dependent (i.e., RaIU is suppressible with exogenous thyroid hormone). Eventually, some of these goiters develop autonomous areas, with other regions of relatively decreased activity. Nodular goiters at this stage of evolution do not secrete enough hormone to produce clinical hyperthyroidism, but 20% of cases nevertheless can be shown to have nonsuppressible function. Some of these autonomously functioning goiters evolve to a stage in which excessive production of hormone and subclinical (see Subclinical Hyperthyroidism) or clinical hyperthyroidism (low TSH, elevated T4 and T3, with or without overt clinical symptoms) ensues.
Therapy of toxic nodular goiter is best accomplished with 131I. Large doses, in the range of 15 to 30 mCi, are usually necessary and may have to be repeated more than once. Hypothyroidism occurs much less commonly after 131I therapy for nodular goiter than for Graves disease. If the clinical situation demands prompt relief of the hyperthyroidism, an antithyroid drug can be used after the therapeutic dose of131I because the response to radioiodide is often slow and/or multiple doses may be needed. Otherwise, 131I given alone is simple therapy, without side effects, and easily monitored by measurements of serum T4. With ablative therapy (large doses), thyrotoxicosis may be controlled in several weeks or with smaller doses, in several months. Other therapeutic considerations including the use of adjunctive therapy follow those outlined for the therapy of Graves disease with one exception: in hyperthyroidism caused by a solitary toxic nodular goiter, antithyroid drugs alone, although effective while administered, will not produce a lasting remission. The same is true for hyperthyroidism caused by a hot nodule (see Thyroid Nodules).
P.1350
Hyperthyroidism Caused by Excessive Secretion of T3
Triiodothyronine (T3) Toxicosis
In most cases of hyperthyroidism, the thyroid secretes excessive quantities of both T4 and T3. However, in perhaps 5% of all cases, T3 is the predominant hormone secreted. So-called T3 toxicosis may occur in hyperthyroidism caused by Graves disease, toxic multinodular goiter, or autonomous adenoma. The patient who appears clinically hyperthyroid but whose T4 is normal or low should have serum T3 measured. T3toxicosis sometimes occurs early in the course of hyperthyroidism caused by Graves disease and can develop during therapy with an antithyroid drug, in which case the dosage should be increased. Continuing clinical findings of hyperthyroidism during such therapy, despite a normal or low T4,raise the possibility that T3 toxicosis is now present and that more, rather than less, antithyroid drug is needed. The treatment of T3 toxicosis is the same as is that of other forms of hyperthyroidism.
Free T3 Toxicosis
On rare occasions, hyperthyroidism is suspected on clinical grounds and yet the only clue is a low TSH. T4, free T4, FTI, and serum T3 (total) are all normal. Such patients may have the entity of “free T3 toxicosis” (23). Only a few cases have been reported. These patients may have some anatomic thyroid abnormality or thyroid autonomy (e.g., nodule, multinodular goiter) but the condition can apparently occur without such abnormalities. The only biochemical abnormality of serum hormones in these individuals, aside from a low TSH, is an elevation of their serum free T3. T3, like T4, is mainly protein bound, but T3 is much less tightly bound than T4. Free T3 is measured, like free T4, by equilibrium dialysis. The metabolic effects of an elevation of free T3 are clinically identical to that of an increased free T4.
Factitious Hyperthyroidism
When clinical hyperthyroidism is found in a patient without goiter or true exophthalmos (proptosis), suspicion of factitious hyperthyroidismmay be warranted. As in true hyperthyroidism, the TSH will be suppressed and the T4 will be elevated. However, the RaIU test will be very low, and the thyroid will be normal-sized on sonogram. Such findings suggest either the presence of thyroiditis with hyperthyroidism (seeThyroiditis) or ingestion of thyroid hormone. Measurement of thyroglobulin may help differentiate between these two possibilities (thyroglobulin levels will be low if thyroid hormone is being ingested).
Subclinical Hyperthyroidism
The term subclinical hyperthyroidism has been applied to the clinical state in which the TSH is suppressed but the free T4 and free T3concentrations are within the normal range (24, 25, 26). By definition, the patients are asymptomatic. This condition can occur in the absence of thyroid hormone administration or during treatment with T4 for replacement or TSH suppression. In one large series, subclinical hyperthyroidism was associated with a threefold increased risk in people age 60 years or older of developing atrial fibrillation (but not overt hyperthyroidism) over 10 years (25). In that study there were no other adverse outcomes; in fact, the condition may spontaneously abate, that is, the TSH normalizes (26) (see Screening for Thyroid Disease in Healthy Patients). Very few patients with only a low TSH subsequently develop clinical hyperthyroidism with elevation of T4 or T3 concentrations. Thus, the term subclinical hyperthyroidism, which is based only on a suppressed TSH, may be misleading.
Thyroid Storm (Thyrotoxic Crisis)
Thyroid storm, a severe exacerbation of hyperthyroidism, is rarely encountered. When thyroid storm does occur, it is usually in the setting of severe medical or surgical stress imposed on a patient with uncontrolled or unrecognized hyperthyroidism. Clinical features of full-blown thyroid storm include fever, sometimes to the level of extreme hyperpyrexia; marked tachycardia; great irritability; diarrhea; hypotension; and cardiovascular collapse. Thyroid storm often progresses rapidly to delirium and coma. Any severe exacerbation of hyperthyroidism demands immediate hospitalization and urgent consultation with an endocrinologist.
Hypothyroidism
Hypothyroidism, the metabolic state resulting from an inadequate level of circulating thyroxine, is common. Most cases can be diagnosed even when symptoms and signs are minimal, provided that the clinician considers the diagnosis and seeks appropriate laboratory confirmation. The manifestations of hypothyroidism are varied and to a large measure age-dependent. Myxedema is the term for a severe form of hypothyroidism that results in deposition of mucopolysaccharides in the skin and other tissues, producing a characteristic appearance and a constellation of physical findings. The term myxedema is commonly but incorrectly used interchangeably withhypothyroidism. Primary hypothyroidism is the term used to indicate that the hormone deficiency results from a disease or other process within the thyroid gland. Secondary hypothyroidism or central hypothyroidism is much less common and results from
P.1351
lack of thyrotropin (TSH) secretion, a consequence of pituitary or, rarely, hypothalamic disease. The thyroid is usually smaller than normal and is not palpable. Serum TSH, using a second- or third-generation assay, may be low, but TSH assay in this situation can be misleading. Biologically inactive but immunoreactive TSH is often produced so that the measured TSH can be normal or even elevated. Abnormal TSH glycosylation accounts for this phenomenon. Almost invariably the hypothyroidism is part of a decrease in pituitary function involving trophic hormones in addition to TSH with concomitant hypogonadism or adrenal insufficiency. Causes include postpartum necrosis, pituitary tumor, pituitary apoplexy, and granulomatous disease, or sometimes an autoimmune process involving failure of other endocrine glands. Some cases occur without identifiable cause and are termed idiopathic (see also Chapter 81).
Etiology
The most common cause of hypothyroidism worldwide remains dietary iodide deficiency. In the United States, iodide deficiency no longer exists because iodide, for more than half a century, has been added to dietary salt to prevent goiter. Most cases of hypothyroidism in this country are a result of autoimmune destruction of the thyroid, either with or without goiter (see below). Goitrous autoimmune thyroiditis is also called Hashimoto thyroiditis. At a later stage, the gland atrophies and a goiter is no longer palpable. Almost all remaining cases are iatrogenic, the result of therapy of hyperthyroidism, although it should be recalled that hypothyroidism also seems to be a late outcome of Graves disease, regardless of treatment (see Graves Disease). External radiation of the neck (e.g., for nonthyroidal neoplastic disease) can also cause thyroid atrophy and subsequent hypothyroidism.
Autoimmune destruction of the thyroid may occur in association with other autoimmune glandular disorders, especially adrenal insufficiency (Schmidt syndrome) and autoimmune ovarian failure (polyglandular failure) and with diseases such as pernicious anemia. High titers of antibodies to thyroid antigens (thyroglobulin, microsomes) are seen in 90% of cases. An easily overlooked form of hypothyroidism is that which occurs postpartum (see Postpartum Thyroid Dysfunction). Table 80.7 classifies the causes of hypothyroidism.
Drug-Induced Hypothyroidism
Although a variety of drugs can produce hypothyroidism that is, invariably, associated with goiter formation, only a few in current use have such an effect. Lithium, widely used for the treatment of manic-depressive illness, is one such agent. If goiter occurs, lithium need not be stopped; addition of thyroxine relieves the hypothyroidism and causes regression of the goiter. Overtreatment of hyperthyroidism with an antithyroid drug will, of course, produce hypothyroidism. Iodide in pharmacologic amounts is an antithyroid drug and also occasionally produces goiter and hypothyroidism. However, most adults who are susceptible to the antithyroid action of iodide have an underlying thyroid abnormality, such as Hashimoto thyroiditis or radioiodide-treated Graves disease. Amiodarone, an antiarrhythmic agent, contains iodine and can produce hypothyroidism in up to 13% of patients treated with this drug (see Thyroid Dysfunction Caused by Iodide or Amiodarone).
|
TABLE 80.7 Clinical Classification of Hypothyroidisma |
||
|
Clinical Features
Hypothyroidism in the adult is highly variable in presentation. Onset is usually insidious, often occurring over many years, with the result that the symptoms go unappreciated by patient and clinician alike. The nonspecificity of the symptoms also contributes to the delayed diagnosis. No predictable progression of symptoms is apparent, but easy fatigability, lethargy, increased sleep requirement (and, sometimes, sleep apnea), cold intolerance, muscle aching, and stiffness are perhaps the most common early symptoms. The skin is dry and may show scaling. Hair loss is common. The eyebrows become sparse, and the face is “puffy” (i.e., full) because of cutaneous deposition of mucopolysaccharides, with edema of the periorbital areas. The voice often becomes low pitched and rough. Constipation is common and may be severe enough to produce megacolon. Diminished hearing, especially in older persons, is easily overlooked or is attributed to aging. Ordinarily, the affected individual becomes abnormally placid, but agitation or frank psychosis may occur. In the elderly, depression is the most common psychiatric
P.1352
accompaniment of hypothyroidism. Despite common medical belief, the few available studies demonstrate that dementia caused by hypothyroidism is rare, if it occurs at all. Coexistence of the two processes in the elderly is, however, not uncommon. Paresthesias and pain in the hands from carpal tunnel syndrome may occur. Diminished sexual function is the rule. Women often experience menorrhagia. Rarely, galactorrhea may be seen in women of child-bearing age. Fertility is diminished, but pregnancy may occur and normal delivery is possible. The newborn is euthyroid, unless the mother's hypothyroidism is drug related or the hypothyroidism is of the rare familial athyrotic variety.
Subclinical Hypothyroidism
The most common stage of hypothyroidism likely to be encountered in ambulatory patients is mild hypothyroidism, commonly termed subclinical hypothyroidism. By definition, such an individual has an elevated TSH but serum thyroid levels that, although within the normal range, are lower, presumably, than they should be for that person (27). This condition is strongly age and gender dependent; it is found in 16% of men and 21% of women older than age 74 years (11,28). It is characterized by nonspecific but suggestive symptoms and few clinical findings. One study suggests that some of these patients improve after therapy with L-thyroxine (29). Many older women have minimal elevations of TSH (6 to 10 µU) despite normal levels of T4 (see Screening for Thyroid Disease in Healthy Patients). Only those with elevated thyroid autoantibodies are likely to develop overt clinical or laboratory hypothyroidism (50% over 5 years). The significance of minimal TSH elevation in the remainder of this group is unclear. The possibility that the immunoreactive TSH may not reflect its bioactivity has not been excluded in such patients.
Severe Hypothyroidism with Myxedema
In spontaneous cases of hypothyroidism, only with severe long-standing disease does extensive deposition of mucopolysaccharide occur, producing the clinical state of myxedema. Rarely, myxedema may develop rapidly (1 to 2 months) after radioiodide or surgical ablation of the thyroid for hyperthyroidism or after abrupt withdrawal of thyroxine replacement therapy.
In myxedema, a variety of manifestations can be appreciated on physical examination, and of course they vary with the severity and duration of the disease. The skin, in addition to being dry and scaling, is typically cool. The scaling may be extensive, and large flakes may be shed from the elbows and knees. The subcutaneous tissues may be infiltrated by mucopolysaccharides so the skin appears to be “thickened” or “doughy.” In the elderly, atrophy of the epidermis may occur simultaneously, producing a stiff, translucent, parchmentlike appearance. Yellow-orange discoloration of the skin from carotene deposition may be evident, especially in the palms. The presence of edema is not obvious because pitting is not noted except in extreme cases complicated by hypoproteinemia. An exception is the collection around the eyes of “bags of water” (lymphedema). This finding is not, however, specific for hypothyroidism. The tongue is sometimes enlarged. The heart rate is usually slow (sinus bradycardia). The heart may appear enlarged, because of either dilation of the myocardium or pericardial effusion. Pleural effusions and ascites may also be present, sometimes even in cases that are otherwise not clinically severe. Indeed, such effusions may be erroneously attributed to malignancy. Hyponatremia, clinically indistinguishable from the syndrome of inappropriate antidiuretic hormone (ADH) excess, may be present (see Chapter 81). Evidence suggests that this phenomenon is not ADH dependent; it disappears slowly as the patient is treated with T4. The deep tendon reflexes characteristically show a delay in their relaxation phase, the so-called hung-up reflex. This is a highly suggestive finding but may be seen occasionally in other diseases. Mental functioning is slowed, as reflected in characteristically slow speech. The reading speed may be greatly reduced. Hearing loss may be severe or of a degree apparent only on audiometric testing. Cerebellar dysfunction, if present, is usually evident only on extensive neurologic testing, but in rare cases is grossly apparent as ataxia.
Myxedema Coma
Myxedema coma is a severe, often fatal, state that is a rare complication of long-standing disease and is typically seen in an elderly patient. Myxedema coma is often associated with or precipitated by pneumonia, peritonitis, or some other serious infection, the presence of which may not be immediately apparent. Severe respiratory failure is a major feature and can be caused by a variety of factors, ranging from upper airway obstruction to impaired chest wall mechanics. Because elderly patients often become hypothermic on exposure to cold or during sepsis, the diagnosis of myxedema coma is more commonly considered than actually confirmed. However, if myxedema coma is suspected, the patient should be hospitalized in an intensive care setting under the care of an endocrinologist, with administration of intravenous levothyroxine therapy.
Laboratory Findings
In primary hypothyroidism, the combination of low serum T4, low FTI index (or free T4), and high TSH is diagnostic. Difficulties in diagnosis are encountered only in occasional
P.1353
cases. The serum T3 is usually low, but because T3 decreases in a variety of nonthyroidal illnesses ranging from malnutrition to liver disease, its measurement is not useful for diagnosis of hypothyroidism. Furthermore, the T3 is normal in many patients with mild hypothyroidism. In hypothyroidism caused by pituitary or hypothalamic disease, the TSH may be “normal,” or low (see Chapter 81).
In hypothyroid patients, a common laboratory finding is elevation of serum enzymes that originate in skeletal muscle: creatine kinase and, to lesser extents, serum aspartate aminotransferase, serum alanine aminotransferase, and lactic dehydrogenase. Fractionation studies show that when these enzymes are elevated in hypothyroidism, they do not originate in cardiac muscle. Virtually all phenotypic abnormalities of hyperlipoproteinemia have been observed in hypothyroid patients and are reversible when thyroid hormone is replaced (see Chapter 82). Other abnormalities include electrocardiographic changes (e.g., flattened or inverted T waves, minor ST-segment depressions, and low amplitude QRS complexes) and abnormalities of blood gas measurements caused by hypoventilation. Anemia, usually normocytic and normochromic, may be present, as well as macrocytic anemia of coexistent vitamin B12 deficiency (pernicious anemia). An abnormality of red cell shape (spiculation) also has been described in hypothyroidism.
Hypothyroidism versus the Euthyroid Sick Syndrome
Serum thyroid hormone levels drop during starvation and illness. In mild illness, this involves only a decrease in serum T3 levels. However, as the severity of the illness increases, both serum T3 and T4 levels drop. Severely ill patients with these abnormalities of thyroid function are not hypothyroid despite the low hormone levels in blood, and the condition has been called the “euthyroid sick syndrome” or “nonthyroidal illness syndrome.” The diagnosis of hypothyroidism in severely ill patients thus may be difficult (8,9). The free T4 and free T3are usually low; however, TSH may be low, normal, or moderately elevated, depending on the stage of the illness. Serum rT3 is often elevated. In such complicated cases, it generally is best to defer assessment of thyroid dysfunction until the patient is stable, unless there is a compelling reason to think the outcome of the serious illness would be improved. Diagnostic findings of overt hypothyroidism (markedly increased TSH and low T4) can be relied on, if present, and appropriate treatment can be instituted.
Although the euthyroid sick syndrome has been clearly recognized only in hospitalized, severely ill patients, it probably also occurs in less-dramatic form in chronically ill, nonhospitalized people (9). Many patients with chronic renal failure undergoing hemodialysis appear to fall into this group. The mechanisms underlying this phenomenon appear to involve a combination of factors, including accelerated T4metabolism, impairment of TSH secretion (2,9), and impairment of T4 binding to serum proteins. Most of these pathophysiologic abnormalities probably are due to excessive amounts of circulating cytokines (interleukin-1β, tumor necrosis factor, and others) that are produced during severe illness.
Treatment
T4 is the best preparation for ordinary use in replacement. T4 (levothyroxine, sodium L-thyroxine, and the U.S. brand names Synthroid, Levothroid, Levoxyl, and Unithroid) is available in color-coded tablets of 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, and 300 µg. T3(liothyronine, Cytomel) is available in 5-, 25-, and 50-µg tablets. Although T3 is also effective, it has no special advantage for routine therapy of hypothyroidism and has the distinct disadvantage that the serum T4 or T3 cannot be monitored to determine adequacy of replacement (because T4 levels remain low and T3 levels may fluctuate). Thyroglobulin preparations and desiccated thyroid (“thyroid extract”) should no longer be used.
Experts have different opinions concerning the merits of generic versus brand names of T4 for use in replacement therapy (30). Concern has been expressed over the bioavailability of hormone in certain generic preparations and even lack of standardization of certain brands of T4, but clinically significant problems are unlikely to be encountered with any of the preparations available in the United States.
Rate of Replacement with Thyroxine
Traditionally, initiation of thyroid hormone replacement therapy has been cautious and has used dosage schedules that ensure slow restoration of the patient to a normal metabolic state. Although this principle is conservative and rational, the practice is often unnecessary. Therapy must be adjusted to the individual case, but with several points kept in mind. If the patient is not elderly and has never had overt cardiac disease, overcautious initiation of therapy will result only in needless prolongation of the hypothyroid state. If the patient has evidence of pre-existing cardiac disease or is frail and elderly, therapy should be started at a low dosage: 12.5 to 25 µg of T4 a day initially, with 25-µg increases at 4-week intervals, as tolerated. Only rarely will serious heart disease, such as angina pectoris, prevent at least partial replacement therapy sufficient to eliminate myxedema, and most, if not all, unpleasant symptoms of hypothyroidism.
The usual hypothyroid patient, without complicating medical problems, may be started on full daily replacement
P.1354
dosage. Even with this therapeutic approach, the clinical response will be slow. One can expect several months to pass before restoration of a normal metabolic state. The objective of therapy should be to restore the clinically euthyroid state if at all possible. The variability of optimal dosage among individuals is too great to rely on weight-based formulas. Most people need about 125 µg (0.125 mg) per day; and only rarely require as much as 200 µg (0.2 mg). If a larger dose seems to be needed, nonadherence should be suspected (see Chapter 4). Monitoring T4 dosage changes is best done by measuring TSH and free T4 levels, initially at 4 weeks after treatment, and then 4 to 6 weeks after any dose changes. TSH measurements alone can be made once the dose is stabilized. If desired, a single weekly dose of T4 can be used; the dosage is slightly more than seven times the daily dosage (31). The once-weekly dosage has the advantage that it can be more easily supervised, if the circumstances warrant. Because there is decreased clearance of T4 with aging, elderly patients may require only 100 µg per day or less for maintenance; as little as 50 or 75 µg often suffices. The T4 requirement during pregnancy is increased by about one-third (32).
Thyroid Hormone Replacement with Thyroxine versus a Combination of Thyroxine and Triiodothyronine
Thyroid hormone replacement therapy has evolved from the use of crude extracts or powdered preparations of thyroid gland (desiccated thyroid) to use of one or two synthetic thyroid hormones, T4 and T3. When T4 is given alone, hypothyroid patients are rendered clinically and biochemically euthyroid (normal) as measured by serum levels of T4, T3, and TSH. Serum T3 is derived from T4 by deiodination in nonthyroidal (peripheral) tissues. In normal persons, secretion of T3 from the thyroid amounts to only about 6 µg per day. Nonetheless, for some time clinicians have noted that a significant minority of patients who are receiving only T4 for replacement report a greater sense of well-being when taking approximately 50 µg of T4 more than that which restored their TSH to the normal range (3). In a small study, a number of patients were switched from T4 alone to a combination of T4 and T3; they had significantly improved mood and neurologic function on extensive neuropsychological testing (33). However, the available information from several subsequent studies did not support a routine switch from T4 monotherapy to a combination of T4 and T3.
For patients on routine thyroid hormone replacement therapy, judicious use of small amounts of T3 along with T4 (10 µg per 100 µg of T4) may be symptomatically beneficial for occasional patients, but may cause side effects in others (34), and thus it is not generally recommended by this author.
Importance of Avoiding Overtreatment during Thyroxine Replacement Therapy
Considerable concern has been expressed about whether T4 replacement therapy or overtreatment with T4 can lead to osteoporosis, because bone demineralization is a known complication of hyperthyroidism. Several studies show that T4-treated patients, except for those with a history of hyperthyroidism, do not have decreased bone mineral density (35,36). In keeping with those conclusions, a recent study of women 65 years of age and older who were treated with T4 showed no increase in fracture rate for those whose TSH was maintained in the normal range (0.5 to 5.5 mU/L) or even for those in the “borderline to low” range (0.1 to 0.4 mU/L). However, women whose TSH was suppressed below 0.1 mU/L had a threefold increased risk of hip fracture and a fourfold increased risk of vertebral fracture. Unfortunately, neither measurements of serum T4 nor the dosages of T4 were presented. Thus, the possibility exists that only women with overly elevated levels of thyroid hormone were subject to elevated risk of fracture (37), in which case these women may simply have been inadequately monitored. It should also be recalled that the elderly often need substantially less T4 for replacement than younger persons; failure to appreciate this fact could have contributed to these fractures. Moreover, women older than 65 years with already compromised age-related decreases of bone mineral density, may be an especially high-risk group for the effects of overtreatment. The same concerns could be raised with respect to cardiovascular risk.
Thyroid Dysfunction Caused by Iodide or Amiodarone
Excess iodide from a variety of sources can induce hyperthyroidism if the patient ingesting it was previously iodide depleted. In that case, a toxic nodular goiter, or, less often, “latent” Graves disease, may become manifest. This phenomenon is called the Jod-Basedow effect and is more commonly seen in Europe than in the United States. In parts of the world where there is adequate iodine in the diet, excess iodide may cause hypothyroidism, especially if a patient has underlying thyroid disease, such as autoimmune thyroiditis.
Amiodarone (an antiarrhythmic agent; see Chapter 64) contains approximately 40% iodine and, in the United States, is the most likely source of excess iodide, released when the drug is metabolized. The intact drug also can exert a number of effects on the thyroid and on thyroid hormone metabolism; it markedly inhibits peripheral conversion of T4 to T3 and coincidentally increases the serum concentration of T4 and free T4.
There are two mechanisms by which amiodarone induces thyrotoxicosis (38). The first is by the Jod-Basedow
P.1355
phenomenon (type I amiodarone-induced thyrotoxicosis) in which amiodarone serves as substrate for overproduction of thyroid hormone in a susceptible gland. The second, which is much more common in this country, is from direct drug toxicity that results in thyroid cell destruction with release of preformed thyroid hormones (type II amiodarone-induced thyrotoxicosis) until the gland is depleted of its hormonal stores (1 to 3 months). Potential distinguishing features between the two forms include diffuse or multinodular goiter and increased color Doppler flow in type I; and low RaIU uptake, decreased color Doppler flow and increased serum interleukin 6 in type II. Treatment includes methimazole and perchlorate for type I and glucocorticoids for type II. β-Blockers can be used as an adjunctive treatment for both types of amiodarone-induced thyrotoxicosis. Patients with type I have prolonged hyperthyroidism lasting 6 to 9 months after discontinuation of amiodarone, whereas in type II patients, euthyroidism typically is restored within 3 to 5 months. Type I patients generally return to a normal thyroid state, and type II patients can have transient hypothyroidism, which evolves to permanent hypothyroidism in some cases. Treatment of amiodarone-induced thyrotoxicosis should be supervised by an endocrinologist.
In the United States, hypothyroidism caused by amiodarone (13% of all patients) is more common than thyrotoxicosis (2%). Most of the former cases are presumably a result of iodide-induced effects in persons with subclinical autoimmune thyroiditis.
Thyroiditis
Thyrotoxicosis Associated with Thyroiditis
Various types of thyroiditis occasionally may be associated with short-lived self-limited thyrotoxicosis. The explanation for this phenomenon has been that the destructive inflammatory process causes release of preformed thyroid hormone. The thyrotoxicosis invariably disappears within a few months.
A RaIU measurement should be obtained in all patients with thyrotoxicosis who do not clearly have Graves disease (i.e., who do not have associated eye findings) or toxic nodular goiter. A very low RaIU establishes the diagnosis of hyperthyroidism associated with thyroiditis and allows the physician to avoid inappropriate therapy (radioiodide or surgery).
Long-term followup studies of these patients show that about half persist in having some degree of thyroid abnormality: antithyroid antibodies or goiter, recurring bouts of thyrotoxicosis, elevation of TSH (decreased thyroid reserve), and, occasionally, hypothyroidism (16).
Lymphocytic Thyroiditis (Silent Thyroiditis)
Lymphocytic thyroiditis is a distinct variant of the thyroiditis–thyrotoxicosis syndrome. Patients have a modestly enlarged nontender thyroid gland. No history of viral illness can be obtained. The RaIU is very low, whereas the T4 and T3 levels are high and the TSH level is low. About half of the cases have significant elevations of thyroid antibodies, and about half of these high titers subside within a few months. A propensity of the condition to occur in the postpartum period has been noted, sometimes in successive pregnancies and sometimes followed by the development of hypothyroidism (see Postpartum Thyroid Dysfunction). On biopsy (not ordinarily recommended) the changes that are seen differ from those of the peak phase of classic subacute thyroiditis (see Subacute Thyroiditis), but the latter, in its late stage of evolution, may be indistinguishable from that of lymphocytic thyroiditis. Whether lymphocytic thyroiditis with spontaneously resolving thyrotoxicosis (silent thyroiditis) is a new disease, as has been suggested by some, or is a newly recognized variant of subacute thyroiditis is a matter of debate (16).
Hashimoto Thyroiditis
Hashimoto thyroiditis is common (see Hypothyroidism and Table 80.7). The process is painless and usually produces only modest enlargement of the thyroid. Nodularity is the rule, and the consistency on palpation is classically rubberlike. Distinction from other nontoxic nodular goiters is made by the presence of high titers of thyroid autoantibodies in the serum of approximately 90% of patients with Hashimoto thyroiditis.
Subacute Thyroiditis
Subacute thyroiditis, also known as granulomatous or de Quervain thyroiditis, is common. Many mild cases are probably never diagnosed. The term subacute is often deceiving and sometimes inappropriate. Although the onset may be insidious, it is perhaps just as often acute over several days. Many patients give a history of recent antecedent upper respiratory tract infection.
The earliest symptoms may be referred pain, usually to the ear, but pain can appear to originate in the jaw or occiput. This phase may last a few hours or days before tenderness and discomfort in the thyroid area become apparent. Rarely, the patient is concerned only with the referred pain and is unaware of thyroidal tenderness until examination makes it apparent. When the onset is acute, the symptoms and signs are more likely to be severe. Initially, pain and swelling of the thyroid are often unilateral, but the process usually does not remain localized for more than a few days. Systemic symptoms include fever, especially in acute
P.1356
cases, and a sensation of intense fatigue and malaise. The course may be protracted with symptoms persisting for months, although usually they subside within a week or two.
The erythrocyte sedimentation rate is elevated. Early in the disease, the thyroidal RaIU is depressed (but that may be so in many normal people), and serum T4 may be slightly elevated. Mild cases have no or only borderline abnormalities of these tests. Significant titers of thyroid autoantibodies are not common but can be seen.
Clinical hyperthyroidism can be seen with subacute thyroiditis. Rarely, hypothyroidism occurs and lasts for several months. Permanent hypothyroidism is unusual. A variant of this syndrome has been described in which neither hypothyroidism nor hyperthyroidism is present but symptoms of severe systemic illness with fever and weight loss dominate (39).
Therapy
Therapy of subacute thyroiditis is symptomatic. The patient should be strongly reassured about the benign self-limited character of the disorder. No controlled studies of drug efficacy for symptom relief are available. Widespread practice indicates that thyroid tenderness often responds within several days to aspirin in doses sufficient to maintain therapeutic (anti-inflammatory) blood levels with prompt relapse if the dose is reduced to analgesic levels. There is little published experience with nonsteroidal anti-inflammatory agents, but these agents are probably as effective as aspirin. More potent analgesics, such as codeine, may be necessary if the neck pain is severe. In less than 10% of cases, the process may be severe enough to require glucocorticoid therapy (30 to 60 mg of prednisone daily or equivalent). A glucocorticoid produces prompt relief of pain and tenderness but, if the disease is severe enough to require its use, will usually be necessary for weeks to several months. Relapse is common when glucocorticoid therapy is discontinued, and retreatment may be necessary.
Pyogenic (Suppurative) Thyroiditis
Pyogenic or suppurative thyroiditis, also known as acute thyroiditis, is rare, and most clinicians will never encounter a case. The thyroid infection usually follows bacteremia but can occur as an isolated primary event. The gland shows typical signs of an acute inflammatory process.
Riedel Thyroiditis
Riedel thyroiditis is another rare but indolent and painless form of thyroiditis. The intense induration associated with this process makes the clinical differentiation from infiltrating neoplasm difficult.
Thyroid Dysfunction During Pregnancy and Postpartum
Hyperthyroidism during Pregnancy
Hyperthyroidism complicates about one to two pregnancies per thousand. However, the disease is almost always easily controlled in the mother, and when this is the case, infants are unaffected and there is not any obvious increase in the incidence of congenital anomalies. In contrast, uncontrolled hyperthyroidism leads to preeclampsia, low birth weight, a high percentage of stillbirths, and congestive heart failure in the mothers. If hyperthyroidism is suspected, free T4 and TSI assays are the preferred tests. Alterations in TBG make total T4 and T3assays difficult to interpret, and TSH levels may be low in euthyroid pregnant women. TSI measurements are useful in the pregnant hyperthyroid patient because high levels are associated with an increased likelihood of neonatal hyperthyroidism caused by placental transfer of the stimulating antibodies. Occasionally, the newborn infant is hyperthyroid at birth as a result of this passive transfer of stimulating antibodies. The clinician who will care for the newborn should always be alerted to this possibility.
Although there have been no prospective clinical trials, consensus opinion is that hyperthyroidism in pregnancy should be treated with an antithyroid drug regardless of whether it is caused by Graves disease or toxic nodular goiter (32,40). Surgery has been used successfully during pregnancy but has no advantage and may be associated with increased fetal loss. Radioactive iodide is contraindicated.
There is little to choose between the two available drugs, although in the United States, propylthiouracil is favored for pregnant women. Methimazole may be associated with an increased incidence of the infrequent congenital skin anomaly, aplasia cutis (1 in 2,000 normal births), a small (up to 3 cm) hairless patch on the head or neck that usually disappears spontaneously after a few years.
Therapy with antithyroid drugs during pregnancy is guided by the consideration that both drugs freely cross the placenta and, in large doses, can produce goiter and hypothyroidism in the infant. The dosage of antithyroid drugs should therefore be the minimal amount adequate to control the hyperthyroidism. A dose of drug that totally blocks hormone synthesis given along with a replacement amount of thyroxine is a scheme that is inappropriate during pregnancy, because it may lead to the use of larger doses of antithyroid drug than are absolutely necessary. When ordinary doses of antithyroid drug are used, the fetus is usually born euthyroid and without a goiter, but as a
P.1357
precaution, some experts reduce the dosage during the last 2 months of pregnancy and, if clinical circumstances permit, discontinue the drug entirely in the last month. This is often possible, because hyperthyroidism during pregnancy tends to ameliorate spontaneously as the pregnancy progresses, although exacerbation in the postpartum period is not unusual. Iodide as an adjunct should not be used during pregnancy because the fetal thyroid is especially susceptible to the goitrogenic effect of iodide.
Conventional thionamide drug therapy (i.e., propylthiouracil and methimazole are used in the United States; see Graves Disease, Antithyroid Drugs) does not preclude nursing. Infants show no effects from the small amounts of the drug that do get into breast milk, at least at daily doses of up to 20 mg of methimazole or 750 mg of propylthiouracil. Intellectual and somatic development is normal in the children of mothers who are receiving an antithyroid drug who are breast-feeding their infants.
Management of Hypothyroidism during Pregnancy
Concern has been expressed over the adverse effects of maternal thyroid hormone deficiency in hypothyroid women receiving T4replacement therapy during pregnancy on the subsequent neuropsychological development (intelligence quotient [IQ]) of the child (41). Even a minor degree of maternal hypothyroxinemia may be harmful to the development of the fetal brain. This issue has been carefully reviewed and a strong case made for the avoidance of any T4 deficiency in the mother during pregnancy, especially in the critical early phase of fetal brain development (41,42). A recent study suggested that the relative T4 deficiency occurs early, and recommended increasing the replacement T4 dose by one-third as soon as the patient knows she is pregnant (43). Dependence on a low maternal TSH as an indicator of thyroid hormone adequacy in the first trimester is unreliable, as human chorionic gonadotropin (hCG) levels are high. Free T4(or FTI) and not total T4 is the appropriate measurement for assessing adequacy of thyroxine dosage, given the elevation of TBG in pregnancy. Moreover, free T4 should be measured by equilibrium dialysis, because in the presence of elevated TBG other methods can yield spuriously high and therefore misleadingly reassuring values (44).
Postpartum Thyroid Dysfunction
Postpartum thyroid dysfunction is common, occurring in some 17% of women in one study (45). Because of its high frequency, a good case has been made for routine screening (46). Both hyperthyroidism and hypothyroidism can occur; in some individuals, one state follows the other. The hypothyroid variation may be transient, lasting only 1 to 4 months, and is most likely to occur in the first 8 months postpartum. However, in 30% of cases the hypothyroidism is permanent. Many cases that are not permanent are caused by the transient occurrence of thyroid-blocking antibodies. Most cases show antimicrosomal (thyroid peroxidase) antibodies; antithyroglobulin antibodies are uncommon. In the United States, the hyperthyroid variety has been associated with postpartum lymphocytic thyroiditis (see Thyrotoxicosis Associated with Thyroiditis). Postpartum hypothyroidism is often misdiagnosed as postpartum depression, and the two conditions are common and can coexist (47). Some women have repeated bouts of postpartum thyroid dysfunction with successive pregnancies. Thyroid abnormalities after pregnancy also have long-term implications as a risk factor for later development of both Graves disease and, especially, permanent hypothyroidism (17% of patients over 5 to 16 years in one series; 23% over 2 to 4 years in another series [48]). Of special interest is the increased incidence (25%) in women with type 1 diabetes, a threefold increase over nondiabetic patients. Because of this high incidence, assessment of TSH and thyroid peroxidase antibodies is recommended 3 months postpartum for all type 1 diabetic patients (49).
Screening for Thyroid Disease in Healthy Patients
Because thyroid diseases are common and clinical diagnosis can be difficult (see also Subclinical Hyperthyroidism and Subclinical Hypothyroidism), a rational argument can be made in favor of attempting to detect clinically inapparent thyroid disease by laboratory tests in individuals without overt symptoms (50,51). On the other hand, a recent U.S. Preventative Service Task Report by the U.S. Public Health Service did not find any evidence for or against screening asymptomatic adults for thyroid disease when clinical outcomes of treating identified patients were considered (52). In contrast, the American Thyroid Association recommends screening every 5 years for persons older than age 35 years (53), and the American College of Physicians recommends screening for female patients older than age 50 years with one or more general symptoms that could be associated with thyroid disease (54). Thus, some experts now favor a case-finding approach—that is, testing only patients who are seeing a practitioner for symptoms—although there is not uniform agreement (50,53). In patients who exhibit any clinical findings that could conceivably be attributable to thyroid disease, laboratory testing should be done, but this approach should probably not be termed screening. Some success has been achieved by presenting a list of thyroid-related symptoms at the time of the patient's visit (55).
The results of screening for thyroid disease, using sensitive TSH tests and appropriate followup of abnormal values, are remarkably consistent in various populations
P.1358
(50,51,56,57). Approximately 1% of apparently healthy individuals, all ages included, are found to be hypothyroid. Many fewer individuals are shown to be hyperthyroid (0.1% to 0.2%). Women older than age 40 years have the most thyroid disease; young men have essentially none. Asymptomatic patients with elevated or depressed levels of TSH may have subclinical hypothyroidism or subclinical hyperthyroidism (see Subclinical Hyperthyroidism), respectively.
Some limitations of screening for thyroid disease with sensitive TSH assays should be kept in mind. For example, in these assays, the TSH is undetectable in patients with hyperthyroidism, a finding that is sensitive but not specific; many sick people and even “normal” elderly patients are found to have low levels of TSH (56,58).
Goiter
A goiter is a thyroid gland that has undergone generalized enlargement. The term goiter should not be applied to a gland that is enlarged by a single nodule, although many physicians continue to do so. The term implies nothing about the functional state of the gland. Goiter is the most common thyroid abnormality. Diffuse goiter, also called simple goiter, is a gland that, on gross examination, is uniformly and symmetrically enlarged without apparent irregularities. Most goiters are, in fact, multinodular, as revealed by palpation, sonography, or thyroid scan.
In some areas of the world, thyroid enlargement is so prevalent that it is termed endemic goiter. Before the widespread introduction of iodized salt, endemic goiter was common in the United States, but this is no longer the case. Endemic goiter, a term that for practical purposes is synonymous with iodine deficiency goiter, is now found principally in geographically isolated areas of the underdeveloped world, but some of these areas are vast, such as much of China, central Asia, and Africa. Moreover, some parts of Europe, such as Germany—which never iodized its salt supply—and parts of Italy, Switzerland, Denmark, and other countries, are still areas of low iodide intake and increased prevalence of goiter. The term sporadic goiter refers to thyroid enlargement as now encountered in the United States and other developed areas where iodide intake is adequate. Sporadic goiter is now seen in a small percentage of the U.S. population and increases in frequency with age. Its cause is unknown, but it is clearly not iodide deficiency.
Any process that prevents the synthesis of normal quantities of thyroid hormones, including iodide deficiency, produces goiter. If impairment of hormone synthesis is severe enough, goiter formation is associated with reduction of serum T4 (but not T3), eventually to be followed by clinical hypothyroidism. The mechanism of the thyroid enlargement in this situation is increased pituitary TSH secretion via activation of the negative feedback system. The resulting increased thyroid mass is a compensatory mechanism that may allow sufficient hormone synthesis to occur so that the patient remains euthyroid.
Drugs that interfere with thyroid hormone synthesis (e.g., thiocarbamides, lithium, iodides, etc.) can also lead to goiter. Withdrawal of a goitrogenic drug may result in regression of the goiter, as will simultaneous administration of enough T4 or T3 to suppress endogenous TSH secretion. The degree of regression depends on how long the goiter has been present. Long-standing goitrous enlargement is associated with the development of multiple large nodules, which are less likely to regress or to do so only incompletely.
Diagnosis
A visible or easily palpable mass in the base of the neck is the usual mode of presentation of goiter. Occasionally, especially in the elderly, an enlarged thyroid is neither visible nor readily palpable but is incidentally found by radiography of the chest or esophagus when either a retrosternal mass is noted or the trachea or esophagus is found to be deviated. The high iodide content of the sporadic goitrous thyroid enhances its radiograph density and identity. Confirmation of the nature of a neck mass as an enlarged thyroid gland and precise determination of its size are now most economically and accurately performed by ultrasonographic examination. CT is accurate in delineating the relationship of a goiter to contiguous structures but is much less useful in defining the thyroid itself.
Except in subacute thyroiditis, pain is not a usual symptom with a goiter but can develop during cyst formation or hemorrhage, a fairly common event, usually accompanied by rapid and sometimes painful enlargement of a portion of the gland. Obstruction of the trachea or esophagus can be produced by goiter, but dysphagia should not be readily attributed to minor degrees of thyroid enlargement. Hoarseness may occur because of involvement of the recurrent laryngeal nerve, but this is rare in patients with benign enlargement and its occurrence is suggestive, although not diagnostic, of thyroid malignancy.
Confronted with a goiter, the clinician's first thought should not be cancer. Most goiters (some 95%) represent benign disease (59). The frequency of carcinoma in multinodular goiter has been debated for years. Unwarranted concern has resulted in countless unnecessary operations. The assessment of goiter as a benign condition assumes, however, that malignancy has been excluded. The diagnosis of malignancy in a multinodular goiter is discussed below (see Thyroid Nodules and Thyroid Carcinomas).
Clinical and laboratory assessment of thyroid function should be made in all cases of goiter. Although most goiters are associated with normal serum thyroid hormone levels and a euthyroid state, either hypothyroidism or
P.1359
hyperthyroidism may be present. Tests should include serum TSH and FTI or free T4. Antithyroglobulin or antimicrosomal (thyroid peroxidase) antibodies in serum should be routinely sought in all cases of goiter. Titers of such antibodies are elevated in the blood of 90% of patients with goiters caused by autoimmune (Hashimoto) thyroiditis. A goiter plus a high titer of antibody is essentially diagnostic of this disorder, which often leads to a hypothyroid state (see above). A proper history will point to possible drug-related goiter. Rapidity of enlargement may help differentiate benign from malignant lesions. The presence of pain helps to identify fairly common cases of subacute thyroiditis and exceedingly rare cases of anaplastic carcinomas (see below).
Both the tissue and the functional status of the gland change with time, sometimes rather rapidly, and hence a precise diagnosis may not be possible at a single examination. Goiter in association with hyperthyroidism suggests Graves disease or toxic nodular goiter. Hypofunction in association with goiter is likely to represent goitrous autoimmune (Hashimoto) thyroiditis (see Hypothyroidism). If the clinical and laboratory assessments indicate normal thyroid function, as is usually the case, a diagnosis of euthyroid goiter is made. Rarities such as an infiltrative process (amyloid disease, metastatic neoplasm) and the inherited defects of hormone synthesis (organification or coupling defects) also should be kept in mind (Table 80.7).
Multinodular enlargement almost always indicates a process of many years’ standing. Differentiation of diffuse enlargement from nodular enlargement often requires ultrasonograph examination because small nodules are missed on physical examination, whereas ultrasonography detects nodules as small as 0.5 cm in diameter. In contrast, an optimally performed scintiscan may show only irregular (“patchy”) uptake of tracer, but even the best isotope technique can delineate nodules of only about 0.5 cm or more in size and is less sensitive than ultrasonography. A goiter composed of many small nodules may appear on scintiscan to be homogeneous and nonnodular.
Treatment with Suppressive Therapy
Suppression Therapy with Thyroxine
Although the cause of thyroid enlargement in sporadic goiter is unknown, its development nevertheless depends on the presence of TSH. Administration of a physiologic quantity of thyroid hormone results in suppression of TSH release. When TSH secretion is chronically suppressed in this manner, an enlarged thyroid may regress, if only partially, or at least cease to enlarge and form new nodules. The larger and more long-standing the goiter, the less likely is regression to occur. Only occasionally does a sporadic nodular goiter regress significantly (59). This has led some to suggest that small sporadic goiters should not be treated with suppression, but treated expectantly or offered surgery or 131I therapy (see Treatment with Suppressive Therapy, Surgery, Radioiodide Therapy).
Suppression therapy is often and properly performed for cosmetic reasons. Suppression therapy is also clearly indicated for individuals with many years of life expectancy, during which time mechanical obstructive problems may develop. However, little is to be gained by treatment of patients whose glands are relatively small and not a cosmetic problem, or are unchanged in size over many years. Previously, a clear and unequivocal indication for therapy was the patient who had already had surgery for goiter (subtotal or lobe resection); however, the benefits of such treatment have been challenged (60,61).
Dosage of Thyroxine (or Triiodothyronine)
Suppression therapy should be accomplished with T4. The dosage should not be excessive lest subclinical or iatrogenic hyperthyroidism (seeHyperthyroidism and Thyrotoxicosis) be produced. T4 at an initial dose of 125 µg per day is usually ample. T3 (Cytomel), 25 µg per day (at bedtime or in divided doses twice a day) may also be used for suppression but has no clear-cut advantage over T4.
Monitoring of Suppression Therapy
To avoid iatrogenic hyperthyroidism, suppression therapy must be monitored by periodic determination of both the serum TSH (by use of a second- or third-generation assay) and the T4. The importance of monitoring is not only to establish that the dose of T4 is adequate and that the TSH is lowered only to the proper level, but that the production of T4 by the gland is suppressible. Older literature clearly indicated that 20% of nontoxic nodular goiters are autonomous; that is, their function as measured by RaIU cannot be suppressed with doses of T4 that should have completely suppressed TSH production. These studies antedate the era of sensitive TSH measurements. Systematic studies are not available, but one would expect that in most of these cases TSH would be low before suppression (subclinical hyperthyroidism), and therefore if suppression were attempted, the T4 could rise into the hyperthyroid range as exogenous T4 is added to that being produced by the thyroid.
At one time T3 was more popular as suppression therapy than it is today. When T3 is given, the serum T4 falls to a level below normal if the thyroid is indeed suppressible.
Time Course of Therapeutic Response
If the treated gland is diffusely enlarged and nonnodular or micronodular, obvious regression by 6 months can be expected in about half of cases. Glands with larger nodules are less likely to respond, and a second year of
P.1360
treatment will probably be needed before regression is apparent. Even if significant regression is not accomplished, prevention of further glandular enlargement is a reasonable goal and may make the undertaking worthwhile. A baseline ultrasonograph examination with determination of gland volume and repeat examinations at followup visits at 6-month or 1-year intervals provide objective assessment of a therapeutic response.
Several years are usually necessary to discern regression of a long-standing multinodular goiter, and during that time, one or more of the larger nodules may become more easily palpable as the relatively normal portions of the gland regress. Some confusion may occur if this is interpreted as a progression of the disease or as the development of a malignant nodule. Serial ultrasonograph examinations will help avoid this error.
Once started, suppression therapy is usually continued indefinitely but can be terminated or withdrawn if regression occurs. Most goiters recur if treatment is discontinued, but therapy can be reinstituted. Suppression therapy does not lead to permanent loss of TSH secretion, even after decades of thyroid hormone administration, although occasional individuals may manifest a brief period of hypothyroidism when prolonged suppression therapy is discontinued.
Surgery
Suppression therapy is slow and produces a significant response in less than half of cases. The efficacy of suppression is much clearer in patients with single nodules (62) than in those with multinodular goiters. Some also believe that the risks of inadvertent overtreatment and the need for careful monitoring make suppression an unattractive mode of therapy (59). Goiters large enough (more than 150 mL in volume) to produce not only tracheal deviation but also significant tracheal compression, as assessed by plain radiograph views, by CT of the trachea, or by flow-loop respirometry (see Chapter 60), or large enough to interfere with swallowing are now uncommon in the United States. In these significantly symptomatic cases, surgery, although attended by significant morbidity, may be considered if an experienced surgeon is available.
Radioiodide Therapy
In recent years, many endocrinologists have used 131I to treat patients with goiters (59). This approach is preferable, especially in the elderly or in patients with other serious medical problems (63)—even in patients with relatively large goiters (64).
Doses of 25 to 125 mCi are necessary. Although the response is slow, useful reduction in the size of the goiter can be achieved over 1 year (64). Nearly half of the patients develop hypothyroidism after therapy (63).
Thyroid Neoplasms
Thyroid Nodules
One of the most common abnormalities of the thyroid is a localized area of enlargement commonly known as a nodule. The approach to evaluation and treatment of a nodule is not standardized among thyroidologists. In evaluating a thyroid nodule, the possibility of malignancy is the main concern. However, current data indicate that at least 95% are benign adenomas or cysts; the remaining ones are lesions of varying degrees of malignancy, almost all of low grade. Even those that are termed malignant on histologic grounds almost always behave clinically as benign lesions, and clinically aggressive thyroid carcinoma is unusual.
Nodules are usually discovered by the patient as a visible or palpable lump or incidentally by a clinician or dentist during an examination. As with most newly discovered masses, the patient's concern is whether the lump is a cancer. Immediate reassurance of the patient by the practitioner is the correct response for the following reasons: First, the lump is unlikely to be a cancer (5% chance) and, second, even if it is a cancer, it is very unlikely to require either urgent or intensive therapy or involve a fatal outcome because most thyroid “cancers” simply do not behave at all like the frequently lethal varieties of cancer familiar to most patients. Thyroid cancer is one of the least-common causes of cancer death (see below). Having been reassured, the patient will still need a workup (see Thyroid Neoplasms and Thyroid Carcinomas) and additional information.
Most truly solitary nodules are benign adenomas and are encapsulated. The growth of most benign adenomas, hypofunctional although they may be, seems to depend on endogenous TSH, but other poorly defined factors are now thought to be involved (65). Although usually hypofunctioning, follicular adenomas may exhibit normal or greater than normal function (i.e., they take up iodine and elaborate and secrete thyroid hormone, sometimes enough to produce hyperthyroidism). Adenomas that are functional but independent of TSH are termed autonomous.
Benign thyroid nodules are present in up to 50% of the population, depending on age and on how they are detected (65). Whether a relatively small nodule (less than a 1.5-cm diameter) is detected by palpation reflects in turn the skill and effort of the examiner, the self-awareness of the patient, and the anatomy of the individual's neck. In a group of more than 200 patients with thyroid nodules (4% of 5,000 patients examined only by palpation, ages 30 to 60 years) followed for 15 years, none developed clinically evident malignancy. In that population, “new” (palpable) thyroid nodules continued to appear at a rate of about 1 in 1,000 people per year, about twice as frequently in women as in men (66).
P.1361
The Question of Carcinoma in the Multinodular Thyroid
For many years, occult thyroid carcinoma was defined as any lesion (nodule) 1.5 cm or less in diameter that on histologic examination appeared malignant. Most of these were undetectable by palpation or scan and were incidental findings at thyroid surgery or at autopsy (seeThyroid Carcinomas: General Considerations). Much evidence suggested that these lesions were not of clinical significance. Sonography (or occasionally palpation) now frequently identifies a lesion of 1 to 1.5 cm that is then subjected to FNA and reported by the cytopathologist as a thyroid carcinoma. Subsequently, without consideration of its size, the lesion is surgically removed without regard for its clinically innocuous character. Yet no new concepts or data have evolved in recent years to suggest that these small lesions now need surgical removal when previously they were properly ignored. The new reality is that identification of these small lesions, cytopathologically, is likely to lead to thyroidectomy.
The risk of clinically significant carcinoma in a nodular goiter is low. Recent evidence suggests that overall one can expect approximately 5% of multinodular glands to harbor such a lesion, about the same as for single nodules (59), a figure that has decreased from a high of approximately 20% only a few years ago. The true incidence is probably closer to the lower number and may be even less than 5% (67). It seems clear that therapy should be as conservative as possible, consistent with the patient's and clinician's levels of comfort.
Diagnosis
General Considerations
The major concern with most nodules is malignancy. The diagnostic workup and therapeutic approach to these lesions should be determined by a number of considerations initially based upon history and physical examination. Age, history of irradiation, male sex, family history of medullary thyroid carcinoma, as well as various physical findings including size (>1.0 cm) should be considered (Table 80.8). Once the “solitary” nodule has been discovered, there are three diagnostic options: ultrasonography, FNA, scintiscan.
Ultrasonography
The main advantage of obtaining a sonogram as the first diagnostic maneuver after discovery of a nodule is that, even in expert hands, many solitary nodules turn out to be only one of many in a multinodular goiter (68). Obviously, the expertise of the examiner in palpating the thyroid will strongly influence the results, but most practitioners are not expert in the examination of nodular thyroids. The sonogram is objective and excludes the need for further workup when the solitary nodule turns out to be a multinodular gland. Although some may still believe that “dominant” nodules in a multinodular gland should be suspect, the chance that one is dealing with clinically significant thyroid carcinoma in a multinodular gland is low (see Thyroid Neoplasms, The Question of Carcinoma in the Multinodular Thyroid) (59). Cysts will also be discovered by sonogram, and render further workup unnecessary. If, with ultrasonography, the nodule is truly solitary and greater than 1.0 cm in diameter, one should proceed to FNA.
|
TABLE 80.8 Thyroid-Nodule Risk Factors Associated with Malignancy |
|
|
Fine-Needle Aspiration
Some clinicians believe that all newly discovered nodules should be excised. For such circumstances FNA helps to avoid unnecessary operations. However, when clinicians have an initial approach that is conservative, universal institution of FNA may increase the number of unnecessary operative excisions. Reasons include frequently indeterminate cytopathologic findings and discovery of papillary carcinomas that might have been adequately treated by suppression. Nonetheless, recent surveys indicate that FNA (with measurement of TSH) is the diagnostic procedure of choice of the majority of endocrinologists in the United States when faced with a patient with an apparently solitary thyroid nodule (69,70).
FNA with cytologic examination, because of its simplicity and safety, has largely replaced biopsy with a conventional cutting needle in the evaluation of a solitary thyroid nodule. It is possible under optimal conditions to make an accurate diagnosis (concerning possible malignancy) in more than 90% of cases with FNA, although it is difficult or impossible to distinguish benign adenomas from many well-differentiated follicular carcinomas (71), an important limitation of the technique. Multiple aspirations (six have been recommended as ideal) should be obtained to ensure adequate sampling for cytology (71). If inadequate material is obtained, the FNA should be
P.1362
repeated. However, it must be stressed that the most important consideration in the use of needle aspiration is the expertise of the pathologist who examines the biopsy material. Ultrasound-guided FNA can improve recovery of tissue from specific regions of the nodule.
If FNA reveals a cancer (papillary or follicular), no further diagnostic studies are indicated and surgery should be undertaken (see Thyroid Neoplasms, Thyroid Carcinomas). If the aspiration yields cystic fluid (clear or “chocolate” brown, indicating old hemorrhage) and no troublesome cosmetic tissue remains, a followup physical examination and ultrasound in 6 to 12 months is adequate. If FNA reveals a benign adenoma and if thyroid function tests are normal, no treatment is necessary unless the nodule increases in size. Of course, suppression therapy can be used for cosmetic considerations.
Patient Experience
FNA with a 25-gauge needle is essentially painless, but cutaneous anesthesia is preferred by some. Multiple aspirations are made, often through a single skin puncture. No significant bleeding is likely to occur, although ecchymoses often result.
Scintiscan: Hot, Warm, and Cold Nodules
Most patients will be evaluated initially by FNA or ultrasonography, but a scintiscan may be done as the first step. It will identify a hot, warm, or cold nodule and, sometimes, a multinodular goiter (although ultrasonography is a better technique to demonstrate multinodularity). The scan does not need to be combined with a measurement of thyroidal RaIU, a procedure that adds no useful information but increases the cost of the workup.
Autonomous (Hot) Nodule
If uptake of isotope is exclusively concentrated in the nodule (hot), the nodule is considered to be autonomous (72). When an adenoma produces an amount of hormone equal to or greater than that of the output of the normal gland, TSH becomes suppressed; the remaining normal tissue then becomes relatively inactive and may not be visible, or may be only poorly visible, by scintiscan.
Management of a hot nodule depends on whether an excessive amount of thyroid hormone is being produced. If the amount of hormone produced by the adenoma considerably exceeds normal, thyrotoxicosis may be clinically apparent, at least in retrospect. Usually T4 and T3are produced in excess, although hyperthyroidism caused by T3 alone (T3 toxicosis) is fairly common with such hyperactive nodules (15). If TSH is suppressed and if the free T4 or FTI is normal, the T3 should be determined and, if this is normal, the free T3.
The natural history of the hot nodule is variable. Over a 10-year interval, about one-third of nodules show little change, one-third become frankly hyperactive, and the remainder become cold, sometimes with obvious hemorrhagic infarction and cystic degeneration. Treatment of the hot nodule that is producing hyperthyroidism can be satisfactorily accomplished with surgery or radioactive iodine, although hypothyroidism may result with the latter. Several studies have shown that hot nodules can be safely and effectively ablated nonsurgically by injection with ethanol. The advantage over radioiodide is that hypothyroidism does not occur (73). Prophylactic ablative therapy is not indicated if hyperthyroidism is not present. Suppression therapy with thyroid hormone will, of course, be ineffective and lead to iatrogenic hyperthyroidism. An antithyroid drug will control the excessive thyroid hormone production initially, but must be continued indefinitely, and thus is not as good as surgery or radioiodide.
Warm Nodule
On the initial scan, some nodules are not unequivocally cold or hot; instead, they appear to take up some tracer, but not to the exclusion of the remainder of the gland. Their status can be further defined by repeating the scan after several weeks of suppression. Some prove to be autonomous and can be managed as a hot nodule; others prove to be cold and should be managed as described below.
Cold Nodule
If the scan shows no accumulation (“uptake”) of isotope in the nodule (located by a marker), it is considered to be nonfunctional (i.e., “cold”); most nodules fall into this category. Because most “cold” nodules (nonfunctioning on scintiscan)—variously estimated at 75% to 95% of all nodules encountered—are benign lesions, the overall risk of malignancy is small. The risk is smaller still when it is realized that the remaining lesions are usually clinically nonaggressive papillary or follicular carcinomas. Although most cold nodules are benign, these are the lesions that are considered suspect and thus need to be subjected to FNA or followed closely by ultrasonography.
Management Strategy for the Solitary Thyroid Nodule
The following strategy is recommended to assess a nodule. Ultrasonograph imaging should be obtained to confirm a solitary nodule, and then FNA should be performed. If the cytology is benign, no further evaluation is necessary except observation of the nodule. If the cytology is positive for papillary thyroid cancer, surgery is indicated; if it shows follicular neoplasm, an 123I scan should be performed. If there is uptake of the nodule, no further treatment is warranted; however, if there is no uptake of the nodule, then the nodule is suspicious for thyroid cancer and the patient should be referred for surgery. Lastly, if an insufficient sample is obtained for diagnosis, the FNA should be repeated.
P.1363
Thyroid Carcinomas
General Considerations
Approximately 75% to 85% of thyroid carcinomas are of the papillary variety; 5% to 15% are follicular carcinomas. Anaplastic and medullary carcinomas probably account for no more than 5% of the total. The relative frequency of the various types of thyroid carcinomas is markedly age dependent.
Occult thyroid carcinoma (defined as a lesion with the histologic appearance of carcinoma but less than 1.5 cm in diameter) is found at autopsy in 5% to 10% of U.S. and European populations, and in 30% of Japanese samples. Death from thyroid carcinoma is as rare in Japan as in the United States. Clearly, occult carcinoma behaves as a benign disease and does not warrant aggressive management.
In the United States, more than 10,000 new cases of thyroid carcinoma are seen each year, but only about 1,500 persons die of this disorder. Most of these deaths result from anaplastic tumors (50%) or from unusually aggressive follicular carcinomas. A few deaths are attributable to aggressive papillary tumors and medullary carcinomas.
Papillary Carcinoma
Followup at 10 years indicates a recurrence rate of approximately 20% and a mortality rate of 1.3% after subtotal resection versus 10% and 0.5%, respectively, after total removal of the gland in patients with papillary carcinoma. This small difference was statistically significant in one retrospective study and currently strongly influences the surgical approach. The complication rate for total thyroidectomy (hypoparathyroidism, vocal cord paralysis) is high. As a result, many surgeons have now adopted a modified or near-total thyroidectomy. In this procedure the affected side is completely removed; most of the contralateral lobe is also removed, but the posterior capsule is left, together with the tip of the upper pole. Whether this approach will succeed in reducing complications remains to be established. Conservative surgeons generally support more limited surgery (74). Visibly involved lymph nodes are always removed, but radical neck dissection is not justified even in the presence of obviously involved nodes (65,75). The presence of cervical node metastases at operation or the extent of lymphadenectomy does not seem to influence either recurrence or death rate. The death rate in lesions under 2.5 cm without local invasion and without evident distant metastases at the time of surgery is less than 1% in 10 years and is 4% to 8% in the less-favorable categories (65,75).
Follicular Carcinoma
Well-differentiated follicular carcinomas have been very difficult or impossible to distinguish from benign follicular adenomas on cytopathologic grounds. Thus when the cytology of the FNA of a nodule shows follicular cells, thyroidectomy is often performed. Recently, new immunologic markers such as galectin-3 have shown promise in distinguishing benign follicular neoplasms from malignant ones (6). Additionally, genomic profiling and cluster analysis of ribonucleic acid (RNA) obtained from nodules may be useful in distinguishing benign from malignant follicular lesions and thereby spare some patients needless surgery (76).
Follicular carcinoma can be more aggressive than papillary carcinoma, tends to be angioinvasive, and may metastasize to bones and lungs. The tumor may bypass regional lymph nodes, a marked difference from papillary disease. The most important prognostic feature is invasion of tumor, either through the tumor capsule or into blood vessels. At least one report suggests that, unlike papillary carcinoma, primary tumor size at presentation does not appear to influence prognosis (77). In contrast, in another series not a single patient died who was under 45 and who had an intrathyroidal tumor less than 2.5 cm in diameter (78).
The clinical presentation may be very different from that of papillary disease as the patient may already have metastatic disease involving lungs, bone, brain, or spinal cord at the time of initial diagnosis. In these cases, the primary tumor may be relatively small and initially overlooked. Only rarely do the metastases produce sufficient thyroid hormones to cause thyrotoxicosis.
The surgical approach to follicular carcinoma should be that taken for papillary carcinoma. Suppression therapy with thyroid hormone replacement is routine. Postoperative ablative therapy with radioiodide appears warranted (78), especially for those patients with overtly invasive disease.
Postoperative Therapy for Papillary and Follicular Carcinomas and Its Monitoring
Thyroid-Stimulating Hormone Suppression
Suppression of TSH after surgical treatment of differentiated thyroid cancer is of proven benefit, definitely lowering recurrence and mortality rates. However, supraphysiologic doses of T4 for long-term TSH suppression can result in iatrogenic hyperthyroidism, usually asymptomatic, but in some instances leading to cardiac hypertrophy, atrial fibrillation, and bone demineralization. Nonetheless, the consensus view is that long-term postthyroidectomy TSH suppression is essential. Unfortunately, the optimal level of suppression is unknown. In practice, a sensitive second- or a third-generation TSH assay should be used to monitor the suppression dose of T4. During replacement/suppression therapy some experts titrate the T4 dosage to at least the minimal amount necessary to keep the TSH below the limit of normal (0.4 to
P.1364
0.5 mU/L) but above 0.1 mU/L. At this level, the development of cardiac complications is avoided and normal bone metabolic parameters are maintained. Others, however, titrate T4 dosage to the limit of detection of TSH in a third-generation assay (0.01 mU/L) and believe that the minimal effect on cardiac function is not clinically significant (79).
Radioiodide Ablation of Residual Tumor
Postoperative therapy with full replacement doses of T4 suppresses endogenous TSH, reduces recurrence, and is routine in all cases. In addition, postsurgical ablative therapy with radioactive iodide has a role in those cases of localized disease that need to be treated. Although some have argued that the patient with a minimal papillary lesion may not need such therapy, it is clear that any patient with a large locally invasive lesion or metastases should receive ablative therapy with 131I. In cases with an intermediate-size lesion, without invasion of the thyroid capsule, and without lymph node metastases, the recurrence rate is greatly reduced by treatment with radioiodide, and deaths from recurrent disease may be completely abolished. The hesitation to use radioiodide routinely stems from the fear of radiation-induced leukemia, a problem that is a significant risk only at high (cumulative) dosage of 131I.
Therapy with 131I after surgery requires that the patient's residual tumor is stimulated by TSH to take up a maximal amount of the dose of isotope. This is accomplished by withdrawal of T4 for 4 weeks. The first course of post-TSH 131I (typically 100 to 150 mCi) therapy is usually given several months after recovery from initial surgery, with additional courses at approximately yearly intervals until posttherapy scans show that no residual functioning tissue in the thyroid bed or metastatic tumor tissue can be detected. A recent study has suggested that recombinant TSH can be used with radioactive iodine to treat low risk thyroid cancer (87).
Monitoring Serum Thyroglobulin
The ideal method for monitoring residual disease is to render the patient hypothyroid, and then measure serum thyroglobulin. Levels below 2 ng/mL suggest no tumor burden. If the level is elevated, an 123I or 131I thyroid scan should be performed to look for focal uptake (80). Typically, these studies are done 6 months after radioablation. Until recently, this was accomplished by withdrawal of T4replacement/suppression therapy for 3 to 4 weeks, thus allowing endogenous TSH to rise. However, during the last 1 or 2 weeks of this interval, many individuals experience distressing symptoms of rapidly developing hypothyroidism, which then continue for several weeks even after reinstitution of T4 therapy. It is no longer necessary to withdraw T4, and this period of discomfort can now be avoided, because recombinant human TSH has become available for routine use (81). Typically given by injection as two doses over 2 days, the recombinant human TSH primes the residual thyroid tissue and tumor as effectively as endogenous TSH after T4 withdrawal. Use of recombinant human TSH is a significant advance for reducing morbidity in this situation. In general, at least one evaluation after T4 withdrawal should be done in low-risk patients, and if there is no evidence of recurrent cancer, the patient can be evaluated annually with recombinant human TSH.
In patients with persistent remission, it may be possible to monitor serum thyroglobulin periodically while the patient is undergoing T4suppression. If the thyroglobulin is undetectable with the TSH suppressed, it is likely that no tumor remains.
Medullary Carcinoma
Medullary carcinoma accounts for 1% to 2% of all thyroid cancers. The tumors arise from the parafollicular or C cells and produce thyrocalcitonin. Both sporadic and familial varieties occur. The sporadic case typically presents as a solitary nodule, whereas the familial variety is often multifocal and part of a multiple endocrine adenomatosis syndrome. Diarrhea occurs in some patients. Thyrocalcitonin in serum is elevated in the basal state or after stimulation with calcium or pentagastrin infusion. Some authorities advocate obtaining at least a basal (unstimulated) serum thyrocalcitonin level as part of the initial evaluation of all nonfunctional thyroid nodules (82,83). Although such routine measurement of thyrocalcitonin is not ordinarily done in the United States, it is common practice in Europe. When surgical excision is performed before regional nodes have become involved, 90% of patients survive for 10 years. Once the nodes are involved, only a 40% 10-year survival can be expected. Medullary carcinoma does not appear to respond to suppression therapy with thyroid hormone.
Anaplastic Carcinoma
Fortunately, anaplastic carcinoma is distinctly uncommon; its frequency depends on the age of the population. Anaplastic carcinoma is rare in children and in adults younger than age 35 years. By age 50 years, as many as 10% of cases of thyroid carcinoma are caused by anaplastic disease, and by age 80 years, by which time the overall incidence of thyroid carcinoma has fallen markedly, nearly half of the cases that do occur are of this variety. The disease is locally invasive in a highly aggressive fashion and quickly produces pain, dysphagia, hemoptysis, and hoarseness. Death usually occurs within 6 to 12 months. However, surgically resectable disease without evidence of metastases, even if it has extended outside the thyroid capsule, can be associated with long-term survival (20% to 30%). It is important to distinguish the small cell type of anaplastic carcinoma from lymphoma of the thyroid. This rare disease, unlike anaplastic carcinoma, is radiosensitive and amenable to chemotherapy.
P.1365
Radiation-Associated Thyroid Carcinoma
Low-dose irradiation of the thyroid is a stimulus to thyroid carcinogenesis, with a latency period of one to several decades (84). The radiation may be from an external source or from radioiodide as has occurred after nuclear bomb fallout or the nuclear reactor accident at Chernobyl. Public health authorities recommend stockpiling stable iodide for distribution to exposed persons in case of a nuclear plant accident. A single dose of 50 mg of sodium iodide would suffice to protect the thyroid in such an event.
In recent years, papillary and follicular thyroid carcinomas have been reported to occur in increased incidence in patients who received radiation therapy years earlier for conditions such as enlarged tonsils or adenoids, or an enlarged thymus, or for acne. A distinction must be made between treatment with penetrating external radiation and local irradiation with point sources (radium rod and plaque treatment). It has not been possible to relate thyroid carcinoma to the limited exposure that occurs with point sources of radiation.
No relationship has been seen between radiation and the development of medullary or anaplastic carcinoma, but radiation-induced cancers appear to present more often with dissemination than those occurring spontaneously, an argument for early detection (82). Accordingly, high-resolution thyroid scintiscans or sonograms should be part of the followup of patients previously exposed to radiation, because nonpalpable lesions can be detected. The only blood test of value is determination of serum thyroglobulin, elevation of which predicts the development of nodules (85).
The approach to the patient with a history of irradiation to the head and neck is not currently standardized. Examination of the patient at 2- to 3-year intervals should suffice. Routine isotopic scintigraphy or sonographic examination of the thyroid to detect patients with nonpalpable lesions is probably indicated. Many nonpalpable lesions (0.5 to 1.0 cm) can be detected by these methods. Thyroid suppression with T4 is recommended even for patients with nodules detected only by scintigraphy or sonography. If careful followup reveals an increase in the size of the nodule despite suppression, surgery should be performed.
Surgical therapy should involve the same approach as that for nonirradiated patients (i.e., near-total thyroidectomy), although the earlier practice of lobectomy still has its advocates (86). All patients who have had surgery for benign or malignant nodules should receive suppression therapy with thyroid hormone. Recurrence of benign nodules, but not malignant ones, is greatly reduced (84).
Radiation of the head and neck predisposes patients not only to thyroid cancer but to salivary gland tumors with a ratio of benign to malignant lesions similar to that of nodules in the thyroid. The incidence of benign neural tumors (neurilemomas, acoustic neuromas) and parathyroid adenomas is also increased. External radiation can also ablate thyroid tissue and produce hypothyroidism. This has been seen, for example, in mantle irradiation for Hodgkin disease and can occur after combined surgery and irradiation for head and neck cancers.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
P.1366