Thyroid Part 3

Chorionic Gonadotropin-Mediated Hyperthyroidism

Human chorionic gonadotropin (hCG), which is structurally similar to TSH, can stimulate the TSH receptor and increase thyroid function when circulating in high concentration or when variant forms of either hCG or the TSH receptor increase the affinity of their hormone receptor interaction73 [see Figure 3]. In fact, during the first trimester of normal pregnancy, when a marked physiologic elevation of hCG occurs, a modest rise in the serum free T4 level and a decline in the serum TSH level are typically seen.74 An exaggeration of this phenomenon can cause thyrotoxicosis, as can trophoblastic tumors.

Trophoblastic tumors Women with hydatidiform mole and choriocarcinoma, as well as men with metastatic testicular chori-ocarcinoma, can develop hyperthyroidism as a result of very high concentrations of circulating hCG.75 Furthermore, these tumors have been shown to produce a variant form of hCG with heightened TSH receptor stimulatory properties.

Gestational transient thyrotoxicosis Mild transient thyrotoxicosis occurs late in the first trimester of pregnancy in 1% to 3% of white women and in as many as 11% of Asian women.76 The serum hCG level is higher in affected pregnant women than in those who remain euthyroid. Furthermore, gestational thyrotoxicosis appears to be more common in women who have hyperemesis gravidarum or twin pregnancies, both of which are characterized by higher serum hCG concentrations. A rare form of familial gestational thyrotoxicosis has been reported in which a mother and daughter both had recurrent hyperthyroidism during their pregnancies and were found to have a mutant TSH receptor with increased affinity and signaling responsiveness to hCG.

Table 3 Characteristic Features of Thyroiditis

Form of Thyroiditis	Presumed Etiology	Classic Pattern of Thyroid Dysfunction	Other Clinical Manifestations	Treatment
Autoimmune	T cell-mediated autoimmunity	Hypothyroidism	Firm small-to-medium goiter	Thyroxine for hypothyroidism
Lymphocytic (painless, silent, postpartum)	T cell-mediated autoimmunity?	Transient thyrotoxicosis followed by hypothyroidism	Painless small goiter	Observation, beta blockade for thyrotoxicosis, thyroxine for hypothyroidism
Subacute (de Quervain)	Viral infection?	Transient thyrotoxicosis followed by hypothyroidism	Painful and tender hard goiter	NSAID or glucocorticoid, beta blockade for thyrotoxicosis, thyroxine for hypothyroidism
Acute (suppurative)	Bacterial, fungal, and protozoal infections	Thyroid dysfunction (rare)	Painful, tender, and inflamed goiter	Antibiotic therapy, surgical drainage
Amiodarone-induced type 1	Iodine-induced hyperthyroidism	Thyrotoxicosis	Normal-size nontender gland	Thionamide antithyroid medication
Amiodarone-induced type 2	Inflammatory thyroiditis, precise cause unknown	Transient thyrotoxicosis	Normal-size nontender gland	Glucocorticoids
Riedel (invasive fibrous)	Idiopathic fibrosis?, autoimmune?	Hypothyroidism in one third of patients	Enlarging, hard, fixed mass	Surgery, glucocorticoids, tamoxifen

NSAID—nonsteroidal anti-inflammatory drug

TSH-Mediated (Central) Hyperthyroidism

Hyperthyroidism can be caused by excessive TSH secretion in two rare conditions: TSH-secreting pituitary adenoma and the syndrome of isolated central resistance to thyroid hormone.78 Excessive and relatively autonomous TSH production by pituitary tumors predictably results in goitrous hyperthyroidism.79 The TSH produced by TSH-secreting pituitary tumors has increased bioactivity, and normal inhibition of TSH release by dopamine has been shown to be defective in these patients. However, the fundamental cause of these tumors, which often cosecrete other pituitary hormones, is unknown.

Isolated central resistance to thyroid hormone is a rare inherited condition in which impaired negative feedback of thyroid hormone on pituitary thyrotropes leads to TSH hypersecretion and hyperthyroidism.80 In one patient with isolated central resistance to thyroid hormone, a novel mutation in the thyroid hormone re-ceptor-| gene was identified. In patients with this syndrome, unlike those with generalized resistance to thyroid hormone, other target tissues for thyroid hormone, such as the brain, heart, and liver, respond normally to the resulting thyrotoxicosis.

Exogenous Thyrotoxicosis

Iatrogenic thyrotoxicosis is relatively common, occurring in 20% of thyroid hormone-treated patients.1,39,61 Possible explanations for this condition include improved patient compliance with therapy, decreased metabolic clearance of thyroid hormones with aging, a substantial decrease in body weight, an increase in underlying gland function in patients with treated Graves disease or nodular goiter, and discontinuance of medications that interfere with thyroid hormone absorption or that accelerate its metabolism. Factitious thyrotoxicosis is sometimes prompted by a desire to enhance energy and weight loss; it can also occur through the complex psychopathology of Mun-chausen syndrome. Accidental or suicidal thyroid hormone intoxication can be life-threatening; its clinical manifestations may take 12 to 48 hours to become fully expressed, necessitating close observation even of asymptomatic patients, especially children.

Figure 3 In acute thyroiditis, inflammation of thyroid tissue leads to unregulated leakage of thyroid hormones from the gland into the circulation. The resulting thyrotoxicosis typically lasts 2 to 8 weeks and ends spontaneously as the glandular hormone stores are exhausted. A comparable period of hypothyroidism often follows, because of impaired thyroid hormone synthesis, but in most patients, the gland gradually returns to normal function.

Diagnosis

Clinical Manifestations

The classic symptoms of thyrotoxicosis are familiar to every third-year medical student—weight loss despite good appetite, heat intolerance, tremor, palpitations, and anxiety—yet even experienced clinicians are often slow to make the diagnosis, for several reasons. First, many common symptoms of thyroid hormone excess are nonspecific, such as fatigue, insomnia, dyspnea, and atypical chest pain. Second, patients can present with atypical chief complaints: weight gain; anorexia, nausea, and vomiting; muscle weakness; headache; urticaria; and, in elderly patients, apathy without sympathomimetic symptoms. Severe thy-rotoxicosis may also present as heart failure, delirium, or an apparent febrile illness. Third, thyrotoxicosis can occur without the full complement of findings associated with Graves disease (e.g., prominent goiter and ocular findings). For example, thyro-toxicosis can be overlooked in a postpartum woman with weight loss and anxiety from acute lymphocytic thyroiditis, in a middle-aged man with bilateral earache reflecting radiation pain from subacute thyroiditis, and in the older patient with "failure to thrive" related to toxic nodular goiter. Fourth, new thyrotoxic complaints often arise in patients who have been otherwise entirely well and in whom the symptoms can potentially be discounted as a minor intercurrent illness or life stress. Finally, the spectrum of thyrotoxicosis includes entirely asymptomatic disease that nonetheless can have potential health consequences related to mild thyroid hormone excess.

A history of exposure to certain drugs, radiocontrast dye, homeopathic or traditional medicines, and dietary supplements can sometimes be the key to diagnosis. For example, a history of therapy with thyroid hormone, amiodarone, or interferon alfa suggests both the possibility and the likely cause of thyrotoxico-sis. A history of recent radiocontrast studies or the recent inges-tion of kelp may suggest iodine-induced hyperthyroidism. The family history is also often important in revealing a predisposition to autoimmune thyroid disease, nodular goiter, or, in rare cases, inherited forms of thyrotoxicosis.

Physical Examination

Physical signs related to thyrotoxicosis are often the key to diagnosis and differential diagnosis. Classic signs accompanying thyrotoxicosis can include an anxious, hyperactive demeanor and pressured speech; tachycardia, systolic hypertension, and widened pulse pressure; velvety, warm, and moist skin; ony-cholysis; flaxen, oily hair; staring gaze and lid lag; prominent apical impulse and systolic flow murmur; and proximal leg muscle weakness and tremor.

Certain findings on physical examination are characteristic of specific etiologies of thyrotoxicosis [see Table 3]. In Graves disease, patients typically have a symmetrical, rubbery goiter that is nontender and smooth or subtly lobulated; an audible bruit is sometimes noted. They may also have subtle or prominent eye findings, including episcleral injection, conjunctival swelling, pe-riorbital edema, proptosis, limitation of extraocular motility, and impaired visual acuity or color vision. Less commonly, these patients may have pretibial myxedema, an orange peel-like thickening of the soft tissues of the anterior aspect of the lower leg from subcutaneous mucopolysacharide deposition; rarely, they may have clubbing of the fingers. Graves disease patients may also have physical signs of associated disorders, such as vitiligo and prematurely gray hair, which often escape detection without specific inquiry.

Other findings may suggest other etiologies for thyrotoxicosis. A solitary palpable thyroid nodule or multinodular goiter suggests the possibility of toxic adenoma or toxic multinodular goiter, respectively. Modest thyroid enlargement with an exquisitely tender, wood-hard gland may represent subacute thyroiditis. Thyrotoxic symptoms and signs in a pregnant woman may reflect hCG-related hyperthyroidism or, in a postpartum woman, acute lymphocytic thyroiditis. Signs of an expanding sellar mass lesion or other syndromes of pituitary hormone excess (e.g., acromegaly, Cushing syndrome, or galactorrhea) may suggest the presence of a TSH-secreting pituitary adenoma.

Laboratory Tests

Routine laboratory tests Abnormalities on routine laboratory studies can be the first clue to thyrotoxicosis. Such abnormalities include hypercalcemia, an elevated serum alkaline phos-phatase concentration, and a serum total or LDL cholesterol concentration that is either low or that is lower than previously documented for that patient. Serum ferritin, angiotensin-con-verting enzyme, and testosterone-binding globulin concentrations are all increased in thyrotoxicosis, and such increases may suggest the diagnosis. New significant atrial arrhythmias detected by electrocardiography, particularly atrial fibrillation, mandate testing for thyrotoxicosis.

Serum thyroid function tests Serum TSH measurement is a highly sensitive way to diagnose or exclude all common forms and degrees of thyrotoxicosis.82 Physiologic inhibition of pituitary thyrotrope function by thyroid hormones results in a serum TSH concentration that is low—almost invariably, less than 0.1 ^U/L in patients with thyrotoxicosis. When the TSH assay is employed to diagnose thyrotoxicosis, it must have a detection limit low enough to distinguish normal from low values; a functional sensitivity to less than 0.02 ^U/L has been recommended.83 The serum TSH concentration is so sensitive in detecting thyroid hormone excess that it can be suppressed even when a patient’s serum thyroid hormone concentration rises but remains within the reference range for that population—so-called subclinical thyrotoxicosis (see below).

In a few circumstances, however, TSH measurement can be inaccurate in the diagnosis of thyrotoxicosis. First, in patients with rare forms of TSH-mediated thyrotoxicosis (see above), the serum TSH concentration can be elevated, inappropriately normal, or only modestly decreased (i.e., 0.1 to 0.5 ^U/L). Second, spurious elevations of the measured TSH level, masking thyro-toxicosis, can occur with rare analytic problems, such as the presence of interfering anti-TSH autoantibodies. Third, there are other causes of a low serum TSH level, including central hypothy-roidism and severe nonthyroidal illnesses. Whenever one of these circumstances is suspected, serum free T4 and T3 levels should be obtained to rule out thyrotoxicosis definitively.

Table 4 Causes of Elevated Serum Total Thyroxine Level

Thyrotoxicosis

Increased serum protein binding

Increased serum thyroxine-binding globulin concentrations

Inherited

Estrogen (pregnancy, exogenous, tumor produced)

Hepatitis

Hepatoma

HIV infection

Drugs (methadone, heroin, clofibrate, 5-fluorouracil)

Familial dysalbuminemic hyperthyroxinemia

Increased serum transthyretin binding or concentrations

Inherited

Carcinoma of the pancreas

Hepatoma

Inhibition of T₄-to-T₃ conversion

Medical illnesses

Drugs (high-dose propranolol, amiodarone)

Test artifacts (assay interference from anti-T₄ immunoglobulins)

Serum T4 and T3 measurements are useful to confirm the diagnosis of thyrotoxicosis, define its severity, and monitor the response to treatment. However, elevated serum total thyroid hormone concentrations are not specific for thyrotoxicosis84 [see Table 4]. Because most of the circulating thyroid hormones are bound to plasma proteins (e.g., thyroxine-binding globulin, transthyretin [thyroxine-binding prealbumin], and albumin), conditions that increase the concentration or binding affinity of these proteins can cause euthyroid hyperthyroxinemia—an increase in the total serum T4 level without elevation of the small fraction (0.03% for T4) of biologically active free hormone. The most common such condition is the estrogen-induced increase in thyrox-ine-binding globulin level that occurs in women who are pregnant or who are taking estrogen preparations. Conversely, a decrease in binding of thyroid hormone by plasma proteins, such as occurs with nephrotic syndrome or androgen use, can mask the diagnosis of thyrotoxicosis on the basis of total T4 measurement.

The serum free (or unbound) T4 concentration can help distinguish thyrotoxicosis from euthyroid hyperthyroxinemia. Although equilibrium dialysis is the most accurate approach to free T4 measurement, it is technically demanding and few laboratories perform it. Free T4 immunoassays are now widely available and relatively inexpensive. They provide much the same information and have largely supplanted the free T4 index, which provides an estimate of the unbound T4 concentration on the basis of partition of radiolabeled thyroid hormone between plasma proteins and a binding resin. Both the free T4 immunoassay and free T4 index can reliably differentiate between the hyperthyrox-inemia of thyrotoxicosis and that associated with thyroxine-binding globulin elevation.

Certain other conditions causing euthyroid hyperthyroxine-mia still cannot be reliably differentiated from thyrotoxicosis with conventional methods of measuring free T4. For example, free T4 immunoassays often report falsely elevated values in patients with familial dysalbuminemic hyperthyroxinemia, in which a mutant albumin binds T4 with increased affinity.85 Similarly, increased transthyretin binding of thyroxine caused by a mutant transthyretin gene or acquired transthyretin overproduction by hepatic or pancreatic neoplasms can yield deceptively elevated free T4 immunoassay values.86 T4-binding autoanti-bodies, which occasionally develop in patients with autoimmune thyroiditis, can cause spurious serum T4 elevation.87 Hyperthyroxinemia can also occur with disorders and medications that reduce T4 clearance, including acute systemic illnesses, psychosis, and treatment with amiodarone or high-dose propra-nolol. Finally, patients with the syndrome of generalized resistance to thyroid hormone typically have elevated serum total and free T4 and T3 concentrations.

In summary, hyperthyroxinemia is not pathognomonic of thyrotoxicosis. Clinical information—such as the presence of symptoms and signs of thyrotoxicosis or other conditions or the use of medications associated with hyperthyroxinemia—often permit a straightforward differentiation of thyrotoxicosis from euthyroid hyperthyroxinemia. Serum TSH measurement is invaluable in distinguishing all common forms of thyrotoxicosis, in which serum TSH is low, from euthyroid hyperthyroxinemia, in which serum TSH is usually normal.

Serum total and free T3 concentrations are elevated in most patients with thyrotoxicosis caused by increased thyroid T3 production and increased extrathyroid conversion of T4 to T3. Less than 5% of hyperthyroid patients have T3 thyrotoxicosis (i.e., a high serum T3 concentration and a normal serum T4 concentration). An elevated serum total T3 concentration is not entirely specific for thyrotoxicosis, because it can also occur with thyroxine-bind-ing globulin excess, a rare form of familial dysalbuminemic hy-pertriiodothyroninemia, and anti-T3 autoantibodies. Serum T3 assays are useful clinically for fully defining the severity of certain forms of hyperthyroidism, particularly Graves disease; in addition, they are useful, along with the free T4 concentration, for monitoring the response to treatment of thyrotoxicosis.