Paul W. Ladenson MD, FACP1
1Professor and Director, Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine
The author has received grants for clinical research or educational activities from or served as advisor or consultant to Abbott Laboratories and Genzyme Corporation during the past year.
Recombinant thyroid-stimulating hormone has not been approved by the FDA for treatment of nodular goiter and postoperative ablation of thyroid gland remnant tissue.
Thyroid disorders are the most common endocrine conditions encountered in clinical practice. Persons of either sex and any age can be affected, although almost all forms of thyroid disease are more frequent in women than in men, and many thyroid ailments increase in frequency with age. The presentation of thyroid conditions can range from clinically obvious to clinically silent. Their consequences can be widespread and serious, even life-threatening. With proper testing, the diagnosis and differential diagnosis can be established with certainty, and effective treatments can be instituted for almost all patients.
States of thyroid dysfunction include hypothyroidism and thyrotoxicosis, both of which have ubiquitous metabolic and organ-specific consequences that result in a wide variety of clinical presentations and complications. Thyrotoxicosis is sometimes referred to as hyperthyroidism, but the latter term is more properly limited to forms of thyrotoxicosis in which there is an overproduction of thyroid hormones by the gland.
Both categories of thyroid dysfunction are further classified as overt or mild. In overt thyroid dysfunction, the concentrations of thyrotropin (thyroid-stimulating hormone [TSH]) and one or both thyroid hormones are outside of their normal ranges. In mild thyroid dysfunction, the serum TSH level is abnormal, but the serum thyroid hormone concentrations remain within their reference ranges. Although the terms clinical and subclinical are often used in reference to overt and mild thyroid dysfunction, respectively, these states are actually defined on the basis of biochemical criteria, not of clinical manifestations.
In the Third National Health and Nutrition Survey (NHANES III), thyroid function tests were assessed in a group of 17,353 persons 12 years of age or older whose makeup reflected the geographic and ethnic diversity of the United States population.1 Hypothyroidism was identified in 4.6% (0.3% overt and 4.3% mild), and thyrotoxicosis was found in 1.3% (0.5% overt and 0.7% mild) [see Figure 1].
Figure 1. Prevalence of Abnormalities on Thyroid Function Tests
Prevalences of abnormalities on thyroid function tests in different populations in the third National Health and Nutrition Examination Survey.
Thyroid nodules (masses within the gland) are relatively common in adults. In the Framingham Study, 6% of women and 2% of men had palpable thyroid nodules.2 The prevalence of nonpalpable thyroid nodules incidentally detected by imaging studies such as sonography and CT has been reported to be as high as 27% in adults.3 Diffuse thyroid gland enlargement (goiter) is declining in prevalence-a tendency that reflects the increase in levels of dietary iodine in the United States. Whereas goiter was identified in 3% of persons in a 10-state United States survey in the 1970s, it was self-reported by less than 0.5% of persons in the more recent NHANES III.4,5
Thyroid cancer is the 14th most common malignancy in the United States, with an estimated annual incidence of 23,600 new cases and a female-to-male ratio of 3 to 1.6 However, the epidemiology of thyroid cancer is more important than this incidence ranking would imply, for two reasons. First, thyroid cancer is currently the malignancy with the fastest rising incidence in the United States, with increases of 3.8% annually from 1992 to 2001. Second, because treatment is highly effective, with 95% or more of patients surviving, there may be about 300,000 thyroid cancer survivors in the United States, all of whom require monitoring for recurrent disease.
Hypothyroidism is a common disorder that occurs more commonly in women than in men; in both sexes, the incidence increases during and after middle life.7 In the NHANES III, 2% of persons 65 years and older had overt hypothyroidism, and 14% had mild hypothyroidism.1Prevalences of thyroid dysfunction were also higher in whites and Mexican Americans than in blacks (5%, 4%, and 2%, respectively).
Certain individuals are at higher risk for developing hypothyroidism, including those with a family history of autoimmune thyroid disorders8; postpartum women9; those with a history of head and neck or thyroid irradiation or surgery; those with certain other autoimmune endocrine conditions10 (e.g., type 1 diabetes mellitus, adrenal insufficiency, and ovarian failure); and those with certain nonendocrine autoimmune disorders (e.g., celiac disease, vitiligo, pernicious anemia, and Sjögren syndrome). Hypothyroidism also develops more frequently in persons with Down syndrome or Turner syndrome.
ETIOLOGY AND GENETICS
The causes of hypothyroidism vary, depending on whether the disease is congenital or acquired. In addition, the causes of primary hypothyroidism (i.e., disease of the thyroid gland itself) differ from those of secondary (central) hypothyroidism, which involves deranged hypothalamic-pituitary control of the gland.
Endemic iodine deficiency remains an important cause of congenital hypothyroidism in certain regions of the world. Even with sufficient dietary iodine, congenital hypothyroidism affects one in 4,000 infants because of thyroid gland dysgenesis (as related, for example, to mutant PAX8 and TTF1 genes) or inherited defects in thyroid hormone synthesis (e.g., mutations in the genes that code for thyroid peroxidase, sodium-iodide symporter, and thyroglobulin). Absent or ineffective TSH responsiveness can be the result of mutations in the genes affecting pituitary thyrotrope differentiation (e.g., POU1F1 and PROP1) or the structures of the thyrotropin-releasing hormone (TRH) receptor, the TSH b chain, and the TSH receptor. A mutation in the gene for Gsa, which mediates adenylate cyclase activation in thyroid cells, causes hypothyroidism in pseudohypoparathyroidism. Inherited resistance to thyroid hormone can be caused by mutations in the b isoform of the nuclear triiodothyronine (T3) receptor.
Autoimmune thyroiditis, also called Hashimoto disease, is far and away the leading cause of hypothyroidism.11 Its autoimmune pathogenesis is evidenced by the lymphocytic infiltration of the thyroid, the presence of circulating thyroid autoantibodies and activated CD4+ T cells specific for thyroid antigens, and the expression of antigen-presenting major histocompatibility complex (MHC) class II proteins by thyrocytes. There is a genetic predisposition to autoimmune thyroiditis, and a polygenic basis for this predisposition is suggested by linkage to several genetic loci in affected kindreds.12 Because autoimmune thyroiditis is more common in populations with higher dietary-iodine content, it has been postulated that high levels of dietary iodine cause an increase in thyroglobulin antigenicity. Thyroid autoimmunity can be initiated by interferon-alfa therapy and can cause either hypothyroidism or hyperthyroidism.13 Discontinuance of immunomodulatory therapy often reverses this effect.
Other causes of thyroid injury
Thyroid surgery or thyroid irradiation—whether in the form of radioactive iodine therapy for thyrotoxicosis or external-beam radiotherapy for head and neck malignancies14—commonly results in hypothyroidism. In hemochromatosis, iron infiltration of the gland can cause thyroid failure. Transient primary hypothyroidism also occurs with lymphocytic thyroiditis (also known as postpartum or painless thyroiditis) and subacute thyroiditis.
Drug and toxins causing hypothyroidism
Long-term administration of iodine in pharmacologic quantities, such as with amiodarone15 or iodine-containing expectorants, can inhibit thyroid hormone production, particularly in patients with underlying autoimmune thyroiditis. Lithium carbonate interferes with hormone release from the thyroid gland, resulting in transient TSH elevation in one third of patients and sustained hypothyroidism in 10%; those with autoimmune thyroiditis are especially vulnerable.16 The antiretroviral agent stavudine and the drugs aminoglutethimide and thalidomide have also been reported to cause hypothyroidism. Industrial exposure to polybrominated and polychlorinated biphenyls and resorcinol have been reported to produce hypothyroidism in workers. Although perchlorate is capable of inhibiting thyroid hormone synthesis, this chemical has not been shown to cause hypothyroidism at concentrations reported in contaminated drinking water.17
Central (secondary) hypothyroidism
Diseases that interfere with TRH production by the hypothalamus or that impair pituitary TSH production can produce central hypothyroidism. The most common causes are pituitary adenomas and the surgical procedures or radiotherapy used to treat them.18 In addition, tumors impinging on the hypothalamus or pituitary stalk, traumatic transection of the pituitary stalk,19 and certain infiltrative diseases (e.g., sarcoidosis, hemochromatosis, and Langerhans cell histiocystosis) can interfere with hypothalamic TRH production or delivery. Pituitary thyrotrope dysfunction can be caused by lymphocytic hypophysitis; infection; metastatic disease; apoplexy (e.g., Sheehan syndrome or tumor infarction); and bexarotene, a retinoid X receptor-selective ligand used to treat cutaneous T cell lymphoma.20
Clinical hypothyroidism reflects a widespread lack of thyroid hormone actions at the genomic level in target tissues, where T3 binds to receptors that are members of the nuclear receptor superfamily.21 These T3 receptors are in turn bound to thyroid-response elements located in the regulatory regions of certain genes that increase or decrease their transcription in response to thyroid hormone. Some biochemical and clinical manifestations of hypothyroidism can be explained on the basis of specific deficiencies in molecular actions. For example, reduced expression of the hepatic low-density lipoprotein (LDL) receptor gene decreases LDL cholesterol clearance, causing hypercholestero le mia; decreased expressions of the myocardial a-myosin heavy-chain genes and the sarcoplasmic reticulum adenosine triphosphatase genes impair myocardial systolic and diastolic performance, respectively. Many other clinical aspects of hypothyroidism are not yet understood in terms of specific genomic actions. Some of these may result from putative nongenomic thyroid hormone actions on G protein-coupled membrane receptors and mitochondria.22
Classic symptoms of hypothyroidism include fatigue, lethargy, cold intolerance, weight gain, constipation, dry skin, hoarseness, slowed mentation, and depressed mood. In a study of patients with short-term hypothyroidism, 38% to 58% of patients had one or more of these clinical findings.23 However, the diagnostic accuracy of such symptoms is low. Of newly diagnosed hypothyroid patients in a case-control study by Canaris and colleagues, only 30% had any symptoms, and 17% of euthyroid control subjects had one or more of the same nonspecific complaints.24 As a result, individual symptoms had a positive predictive value of only 8% to 12%.
Inaccuracy in clinical diagnosis of hypothyroidism is attributable to various factors, including the fact that many other disorders produce similar symptoms; the typically gradual onset of thyroid hormone deficiency; and, sometimes, the impaired insight that hypothyroidism produces in some patients. Symptoms that are new or that occur in combination are more likely to represent hypothyroidism. In the Canaris study, patients with seven or more new symptoms were almost ninefold more likely to be hypothyroid than those with fewer new symptoms. In addition, more hypothyroid patients than euthyroid patients reported that their symptoms had changed from the previous year.24
Hypothyroidism can be associated with cognitive deficits, particularly memory problems.25 Although hypothyroidism is in the differential diagnosis of dementia and is not uncommonly detected in demented elderly patients, thyroid hormone treatment rarely reverses dementia in these patients.26 Other neurologic findings in hypothyroid patients can include depression, psychosis, ataxia, seizures, and coma. Hypothyroidism is a potentially reversible cause of sleep apnea. It can also cause decreases in the senses of hearing, taste, and smell.
Other special manifestations of hypothyroidism have been reported in children and adolescents. Thyroid hormone deficiency can cause growth failure, delayed or precocious puberty, muscle pseudohypertrophy, and galactorrhea.
Classic physical signs of hypothyroidism include bradycardia, diastolic hypertension, and hypothermia; coarse, cool, and pale skin; loss of scalp and eyebrow hair; hoarse, slow, and dysarthric speech; distant heart tones; diffuse nonpitting edema; and slowed deep tendon reflexes, particularly during the relaxation phase. However, none of these findings is sufficiently sensitive or specific for diagnosis. Additional signs may be identified when hypothyroid patients present with other unusual features, such as chronic heart failure, pericardial and pleural ef fusions, ileus and intestinal pseudo-obstruction, or coagulopathy.
In patients with autoimmune thyroiditis, which is the most common type of hypothyroidism, the thyroid gland can be nonpalpable, normal in size, or diffusely enlarged with an irregular contour, firm consistency, and palpable pyramidal lobe. The gland is only rarely painful and tender. There may be signs related to the other endocrine deficiency states associated with the polyendocrine failure syndromes: type 1, which includes hypoparathyroidism (Chvostek and Trousseau signs), adrenal insufficiency (hyperpigmentation), and chronic mucocutaneous candidiasis; and type 2, which includes adrenal insufficiency, type 1 diabetes mellitus, and primary ovarian failure. There can also be evidence of other associated nonendocrine autoimmune disorders, including vitiligo, atrophic gastritis, pernicious anemia, systemic sclerosis, and Sjögren syndrome.
Routine laboratory tests
Abnormalities in routine laboratory tests can be the first diagnostic clue suggesting hypothyroidism. Hypercholesterolemia and hyperhomocysteinemia are especially common in hypothyroid patients.27 In addition, hyponatremia, hyperprolactinemia, hypoglycemia, and elevations in levels of creatine phosphokinase (predominantly MM band) can all be caused by thyroid hormone deficiency.
Serum thyroid function tests
Whether it is prompted by clinical or routine laboratory test findings or performed for patient or population screening, measurement of serum TSH should usually be the first test in the diagnosis of hypothyroidism. An elevated serum TSH level identifies patients with primary hypothyroidism regardless of its cause or severity, even those with mild thyroid hormone deficiency and a serum free thyroxine (T4) concentration within the reference range. Normal serum TSH levels in disease-free populations are typically 0.4 to 4.0 µU/L. However, values are not normally distributed; the mean TSH concentration, 1.5 µU/L, is in the lower half of the reference range.1 Even a high-normal serum TSH level (e.g., 3.0 µU/L) may reflect very mild thyroid dysfunction, particularly in a patient who has other clinical or laboratory features of autoimmune thyroiditis. As a result, some authorities have recommended lowering the TSH assay's upper limit of normal to 2.5 µU/L.28
When an elevation in serum TSH is detected in a potentially hypothyroid patient, the test should be repeated, and the serum free T4concentration should be measured. This further testing confirms the diagnosis of hypothyroidism—an important step, because such patients will typically be committed to lifelong thyroid hormone therapy—and more fully defines the severity of hypothyroidism. The serum T3concentration has limited sensitivity and specificity and therefore is a poor test for hypothyroidism.
The TSH assay may fail to detect hypothyroidism in a few settings. In patients with central hypothyroidism, the serum TSH level can be low, normal, or even modestly elevated.29 The absence of an elevation in the TSH level in a patient with a low free T4 level is attributable to the synthesis of a TSH molecule that has a decreased ratio of biologic to immunologic activity.30 Central hypothyroidism should be suspected in the absence of TSH elevation if the patient has clinical features of hypothyroidism; has clinical findings suggesting a sellar mass lesion or other anterior pituitary hormone deficiencies; or has a history of head trauma or conditions known to cause hypopituitarism, such as sarcoidosis. In these settings, both the serum free T4 and TSH concentrations should be measured. Detection of a low serum free T4concentration, regardless of the TSH level, indicates the need for further testing, which may include cranial imaging, performance of a TRH stimulation test to assess TSH responsiveness, and other pituitary function testing.
There are also circumstances in which an elevated serum TSH level may not reflect hypothyroidism [see Table 1]. Euthyroid patients with renal or adrenal insufficiency may have modest TSH elevations (e.g., levels of 5 to 10 µU/L). Two rare forms of TSH-mediated hyperthyroidism that may present as clinical and biochemical hyperthyroidism with an inappropriately normal or elevated serum TSH are TSH-secreting pituitary tumors31 and isolated pituitary resistance to thyroid hormone.32 However, the elevation in levels of serum free T4, T3, or both in these patients provides a clue to the diagnosis. Circulating anti-TSH antibodies can yield falsely elevated TSH immunoassay readings.
Table 1 Causes of Elevated Serum TSH Levels
Effects of nonthyroid illnesses and drugs
Distinguishing central hypothyroidism from the thyroid function abnormalities that often accompany severe nonthyroid illnesses can be challenging. Cytokine-mediated TSH suppression can mask mild primary hypothyroidism. Furthermore, certain drugs used to treat severe illness (e.g., glucocorticoids, dopamine, and dobutamine) can normalize elevated serum TSH concentrations in patients with overt primary hypothyroidism. Conversely, false positive transient TSH elevation can be seen in patients recovering from critical illness.33 Consequently, with severely ill patients, it is best to limit thyroid function testing to those in whom there is a significant clinical suspicion of hypothyroidism; otherwise, abnormal results are much more likely to represent false positive than true positive findings. Similarly, the antiseizure medications phenytoin and carbamazepine can cause decreases in the levels of serum total T4, free T4 (as measured by immunoassay), and TSH; these findings can be confused with those of central hypothyroidism.34 In some patients who are severely ill or who are taking these antiseizure medications, free T4 measurement by equilibrium dialysis and pituitary imaging may be required to diagnose or exclude central hypothyroidism.
Given that the clinical manifestations of hypothyroidism are quite nonspecific and can be caused by myriad other medical conditions and life circumstances, the key to diagnosis is simply for the physician to keep this condition in mind. Once the possibility of hypothyroidism is entertained, serum TSH measurement can confirm or exclude the diagnosis in almost all cases. In a survey of 1,721 primary care physicians, 80% to 90% appreciated the fact that a middle-aged woman presenting with fatigue, impaired memory, or depression might have hypothyroidism and therefore would order a serum TSH concentration for such a patient; however, only half of these physicians would screen for hypothyroidism in a hypercholesterolemic patient.35
The cause of primary hypothyroidism may be evident from the history alone; for example, the patient may have previously undergone thyroid surgery or radiation therapy or may currently be taking medications known to cause hypothyroidism. When the history provides no clue, sustained primary hypothyroidism can usually be assumed to be caused by autoimmune thyroiditis. Confirmatory laboratory tests are seldom required. Nonetheless, it is sometimes helpful to confirm this diagnosis by detection of thyroid autoantibodies. Anti-thyroid peroxidase antibody assay is the most sensitive test to confirm the diagnosis of autoimmune thyroiditis. Thyroid autoantibody testing can also be useful in predicting the development of hypothyroidism in patients with mild hypothyroidism and in pregnant and postpartum women.36,37,38
Thyroid Hormone Therapy
Levothyroxine sodium (thyroxine) is the treatment of choice for patients with hypothyroidism. Thyroxine is well absorbed by the proximal small bowel. Thyroxine circulates with a 7-day half-life because of plasma protein binding, and it is metabolized in target tissues, in part by deiodination to T3. Its long half-life permits a single daily dose; its conversion to T3 in target tissues mimics normal physiology. The multiple dose strengths available in North America facilitate precise dose titration. Nonetheless, thyroxine and other thyroid hormone preparations have narrow therapeutic indexes and hence have the potential for adverse reactions with even modest overtreatment. Several studies examining the adequacy of thyroid hormone therapy in large populations and in patients in generalist and specialty practices have found that one fifth of patients with treated hypothyroidism are receiving an inadequate dose and one fifth an excessive dose.39
Dosing considerations and drug interactions
The optimal thyroxine dosage for hypothyroid patients is related to body weight. In adults, this is approximately 1.8 µg/kg/day.40 Elderly patients, whose metabolic clearance of thyroxine is reduced, have a lower dosage requirement of 0.5 µg/kg/day. The thyroxine dose is usually higher in patients who have undergone thyroidectomy than in patients with autoimmune thyroiditis, who often have residual functioning thyroid tissue. Thyroxine absorption can be decreased in patients with malabsorption from gastrointestinal disorders or previous small bowel bypass surgery. Several mineral supplements, medications, and dietary constituents can interfere with thyroxine absorption; these include iron, calcium carbonate, cholestyramine, aluminum hydroxide gel, sucralfate, soy, and perhaps dietary fiber. Metabolism of thyroxine is accelerated in the nephrotic syndrome, in other severe systemic illnesses, and with the use of phenobarbital, phenytoin, carbamazepine, and rifampin. In 75% of pregnant women, the thyroxine dose requirement is increased by 50% to 100%.41 Postmenopausal hormone replacement therapy increases the required thyroxine dose in 35% of women.42
Patient noncompliance is the most common cause of inadequate thyroxine therapy. Several observations should raise suspicion that a patient is not taking thyroxine faithfully: the apparent thyroxine dose requirement is higher than expected; thyroid function test results vary without correlation with prescribed thyroxine doses; and the serum TSH concentration is elevated, yet the serum free T4 level is in the mid- to high-normal range, reflecting improved compliance immediately before testing.
Thyroxine treatment should typically start with a dosage at the lower end of the anticipated requirement (e.g., 125 µg/day in a 70 kg adult). In otherwise healthy younger patients, there is no need to titrate the dose upward from a very low starting dose. Laboratory monitoring of treated hypothyroid patients should be performed 4 to 6 weeks after starting a new thyroxine dose or tablet formulation; thereafter, it should be performed annually. It should also be performed whenever a patient's symptoms suggest thyroid hormone deficiency or excess. The goal for most patients is to restore the TSH level to the lower half of the normal range (i.e., 1.0 to 2.0 µU/L). In patients with central hypothyroidism, the serum free T4 concentration must be monitored; treatment should usually be targeted for a concentration in the upper half of the normal range.
Metabolism of certain other drugs can be affected by the hypothyroid state and by the initiation of thyroxine treatment. Hypothyroid patients may have increased sensitivity to anesthetic and sedative agents. Reduced digoxin clearance and drug distribution volume may predispose patients to toxicity. Sensitivity to warfarin may be decreased because of slowed metabolism of vitamin K-dependent clotting factors, and restoring euthyroidism can increase the required warfarin dose.
Adverse reactions to thyroid hormone therapy
Adverse reactions to thyroxine overtreatment include symptomatic thyrotoxicosis and subclinical thyrotoxicosis with increased risks of bone loss and atrial tachyarrhythmias.43,44 The predisposition to osteoporosis is principally in postmenopausal women. Atrial fibrillation is more common in patients 60 years of age or older. Both of these complications have been shown to occur when the serum TSH concentration is suppressed to less than 0.1 µU/L.
Complications can also arise from restoring euthyroidism, particularly in patients with underlying ischemic heart disease45 (see below) and borderline adrenal cortical insufficiency. Concomitant thyroid and adrenal gland failure can occur in hypopituitarism and in the type 2 polyendocrine failure syndrome (Schmidt syndrome), which is marked by autoimmune thyroiditis and idiopathic adrenal insufficiency.
A few patients experience acute sympathomimetic symptoms soon after institution of thyroxine treatment. This syndrome is poorly understood; it can be circumvented by reducing the thyroxine dose to a very low level and advancing it slowly.
Transient scalp hair loss may occur during first few weeks of thyroxine replacement therapy. Patients can be assured that this phenomenon is temporary. Treatment of hypothyroidism sometimes reveals an underlying urticarial disorder, but true allergy to thyroxine formulations has not been well documented.
Special Therapeutic Issues
Hypothyroid patients with ischemic heart disease
Because thyroid hormone has positive inotropic and chronotropic effects, thyroid hormone therapy can exacerbate myocardial ischemia in hypothyroid patients with underlying coronary artery disease. In such patients, thyroxine therapy should be initiated at a low dosage (e.g., 25 µg/day) and titrated upward in increments of 12.5 to 25 µg every 4 to 6 weeks. Patients should be monitored vigilantly with clinical assessments and electrocardiography. Deliberate suboptimal dosing, which was previously advocated to limit myocardial oxygen demand, has been shown to actually increase the risk of progressive coronary atherosclerosis. Beta-blocker therapy should sometimes be initiated or intensified when thyroxine therapy is initiated. Hypothyroid patients who experience worsening myocardial ischemia despite these precautions can undergo coronary angioplasty and even surgical bypass grafting with minimal or no increased perioperative risk.46,47
Whether to identify and treat patients with mild hypothyroidism, defined by an elevated serum TSH level with a normal free T4 level, is controversial. There is agreement that mild hypothyroidism is highly prevalent, particularly in older women, and that clinical diagnosis is inaccurate. Diagnostic serum TSH testing and thyroxine treatment of mild hypothyroidism are clearly effective and are relatively safe and inexpensive. The outstanding issue is whether mild hypothyroidism causes clinical consequences that are important enough to justify widespread screening and therapy.48 Proponents of detection and treatment argue that it prevents progression to overt hypothyroidism in affected patients, particularly those whose serum TSH concentration is greater than 10 µU/L, who are 65 years of age or older, or who have thyroid autoantibodies, indicating underlying autoimmune thyroiditis. Advocates believe that treatment of mild hypothyroidism may reduce the risk of future atherosclerotic cardiovascular disease. They hold this view on the basis of the following observations: affected patients have higher mean cholesterol levels; most studies have shown that TSH-normalizing thyroxine therapy lowers serum total cholesterol and LDL cholesterol concentrations49; and some epidemiologic studies have found that persons with mild hypothyroidism have a higher risk of atherosclerotic cardiovascular disease.50 Some proponents are persuaded by four small, controlled, double-blind trials that showed that thyroxine therapy was more effective than placebo in improving symptoms and neuropsychologic performance in patients with mild hypothyroidism.51 On the basis of these studies, two decision and cost-effectiveness models suggested that the cost-effectiveness of screening for and treating mild hypothyroidism is comparable to that of other widely accepted preventive medicine strategies.52,53 On the other hand, opponents of screening and treatment of mild hypothyroidism point out that these putative benefits have not been rigorously confirmed by large, randomized, controlled trials.54 When physicians do recommend treatment for patients with mild hypothyroidism, the thyroxine dosage is typically lower than that for overt hypothyroidism—0.5 µg/kg/day.
Residual hypothyroid symptoms and T3 therapy
Compared with euthyroid patients, hypothyroid patients more often have constitutional and neuropsychological complaints, even when serum TSH measurements suggest adequate treatment.55 This observation may represent only ascertainment bias (i.e., symptomatic patients seeking medical care are more likely to be diagnosed and treated for hypothyroidism). However, it has been postulated that the presence of residual symptoms in thyroxine-treated patients reflects a failure to replace the small amount of T3 normally secreted by the thyroid gland. Four clinical trials in which a fraction of the thyroxine dose was replaced with a small dose of T3 failed to confirm an earlier report of significant improvement with combination thyroxine/T3 therapy.56 Combination therapy has the disadvantages of a fluctuating and supraphysiologic T3 level, a greater risk of iatrogenic thyrotoxicosis, and increased complexity and expense. Treatment with desiccated thyroid, a biologic preparation that also contains both T4 and T3, has the same disadvantages.
Severe hypothyroidism (myxedema) can become complicated by multiple organ system failure when it is profound and prolonged, especially in elderly patients who have other cardiac, pulmonary, neurologic, renal, and infectious diseases. Myxedema coma, the most severe expression of hypothyroidism, is associated with substantial mortality. Such complications of thyroid hormone deficiency can be prevented with sustained thyroxine therapy. In newly diagnosed patients, preventive measures also include giving special attention to other potentially provocative medical conditions (e.g., heart failure, renal failure, pneumonia) and medications—particularly sedative, anesthetic, and analgesic medications that suppress ventilatory drive and other central nervous system functions.
Treatment of complicated hypothyroidism includes thyroid hormone replacement and aggressive management of organ system complications that can be present. Two thyroid hormone regimens have proven efficacy for myxedema coma: (1) thyroxine in a full replacement dose (1.8 µg/kg/day), with or without a 500 mg loading dose to replete the normal body thyroxine pool57; and (2) T3 in divided doses, advocated because of the impaired T4-to-T3 conversion that occurs in critically ill patients. No trial has rigorously compared these regimens, but one small retrospective study found a higher mortality in T3-treated patients.58
The prognosis for hypothyroid patients who are properly treated with thyroxine should be excellent. However, discontinuance of thyroid hormone therapy predictably leads to recurrent hypothyroidism, with its potential for serious complications in the elderly. This occurs most often in settings of social neglect, poor access to health care, and associated neuropsychological impairment. Lesser degrees of suboptimal therapy are also associated with long-term risks. Inadequately treated patients may have increased risk of atherosclerotic cardiovascular disease, and iatrogenic thyrotoxicosis can predispose patients to osteoporosis and atrial tachyarrhythmias.
Patients with autoimmune thyroiditis, the most common cause of hypothyroidism, are at risk for certain associated conditions, for which they should be monitored. Pernicious anemia and gastric achlorhydria with consequent iron and calcium malabsorption affect 3% and 25% of autoimmune thyroiditis patients, respectively. Much less commonly, other autoimmune diseases (e.g., Sjögren syndrome and systemic sclerosis), endocrine deficiency states (adrenal insufficiency, type 1 diabetes, hypoparathyroidism, and hypogonadism), and primary thyroid lymphoma can occur.
The alert clinician will diagnose thyrotoxicosis several times each year. NHANES III found thyrotoxicosis in 0.5% of a surveyed cohort that reflected the demographics of the United States adult population.1 Three disorders account for the majority of cases: diffuse toxic goiter (Graves disease), toxic nodular goiter, and iatrogenic thyrotoxicosis in thyroid hormone-treated patients. The incidence of Graves disease in one United Kingdom community survey was one to two cases per 1,000 population annually; 2.7% of women and 0.2% of men had Graves disease or a history of Graves disease.59 The highest incidence of Graves disease is in women 30 to 60 years of age, but the disease can affect persons of virtually any age, from neonates to the very elderly. Toxic adenoma and toxic multinodular goiter are more common causes of thyrotoxicosis than Graves disease in regions where dietary iodine deficiency is prevalent; in women; and in older patients.60 Iatrogenic thyrotoxicosis has been reported in approximately 20% of thyroid hormone-treated patients.1,39,61
ETIOLOGY, GENETICS, AND PATHOGENESIS
Thyrotoxicosis can be divided into three etiologic categories: abnormal stimulation of the thyroid gland, thyroid gland autonomy, and gland inflammation with unregulated thyroid hormone release. Each of these categories includes several diseases [see Table 2].
Table 2 Etiologic Classification of Thyrotoxicosis
Graves Disease (Diffuse Toxic Goiter)
There is compelling evidence that there is a genetic predisposition to Graves disease, that the incidence is higher in women, that unknown environmental factors are involved in its initiation, and that gland stimulation by antibodies against the TSH receptor is the immediate precipitant of the condition. Identical twins and some families show increased incidences of Graves disease.62 The condition has been genetically linked to certain MHC components (e.g., HLA-B8 and HLA-DR3), which are on the surface of cells that present antigenic peptide epitopes to T cell receptors. One theory is that certain HLA-DR molecules may be better able to present TSH receptor epitopes, inciting autoimmunity. Another hypothesis is that these HLA-DR recognition sequences are involved in aberrant thymic T cell selection for tolerance. Graves disease has also been linked to polymorphisms in the gene encoding CTLA-4, a T cell receptor important for interaction with antigen-presenting cells.63 In whites, a susceptibility locus for Graves disease has been identified on chromosome 20q11.
Several environmental factors have been implicated in the initiation of Graves disease. These include stressful life events, smoking, large amounts of dietary iodine, and preceding infection with certain bacterial agents that have been postulated to induce molecular mimicry. Radiation injury to the thyroid gland may increase the risk of the condition, possibly because of increased TSH receptor exposure and immunoreactivity.
Whatever the underlying genetic and environmental factors, the vast majority of Graves disease patients have detectable antibodies that are directed against the TSH receptor and are capable of stimulating it64 [see Figure 2]. Assays using thyroid cells or their membranes can detect circulating TSH receptor autoantibody species in 70% to 90% of patients with Graves disease. These autoantibodies are capable of stimulating intracellular cyclic aden osine monophosphate production (thyroid-stimulating immunoglobulins [TSI]), inhibiting TSH receptor activation (TSH receptor inhibitory immunoglobulins), and inhibiting the binding of TSH to its receptor (TSH receptor-binding inhibitory immuno globulins [TBII]).
Figure 2. Hyperthyroidism Resulting from Deranged Activation of TSH Receptors
Certain forms of hyperthyroidism result from deranged physiologic activation of the thyroid-stimulating hormone (TSH) receptor. In Graves disease, TSH receptor autoantibodies (TRAb) bind the TSH receptor. In patients with TSH-secreting pituitary tumors, the autonomously secreted TSH overstimulates the receptor. In molar pregnancy and choriocarcinoma, high concentrations and aberrant forms of human chorionic gonadotropin (hCG) can activate the TSH receptor. In some patients with toxic adenomas, a constitutively activating somatic mutation of the TSH receptor results in autonomous secretion of thyroid hormone.
Toxic Adenoma and Toxic Multinodular Goiter
Solitary and multiple thyroid adenomas and diffusely hyperplastic thyroid tissue possess a growth advantage, and their constituent thyrocytes sometimes produce thyroid hormones autonomously (i.e., without regard to TSH regulation). These hyperplastic and neoplastic conditions cause hyperthyroidism when the mass and efficiency of functioning thyroid tissue are great enough to generate hormone excess in target tissues, including suppression of endogenous pituitary TSH production and function of extranodular thyroid tissue.65 Both genetic and environmental factors are involved in the development of this autonomous function. A twin study showed that genetic factors could account for 82% of the predisposition to nodular goiter, and familial multinodular goiter has been linked to a gene locus on chromosome 14q.66 At the same time, environmental factors (e.g., dietary iodine deficiency, goitrogens, and radiation exposure) also clearly predispose to the development of autonomously functioning thyroid tissue. Genetic and environment factors promote thyroid tissue growth by activating intraglandular growth factors (e.g., insulinlike growth factor and epidermal growth factor receptor)67 and signaling pathway proteins (e.g., Gsα and ras). Constitutively activating somatic mutations of the TSH receptor and Gsα itself have been described in 25% to 80% of toxic adenomas, more commonly in patients from regions where dietary iodine deficiency is prevalent.68
Iodine is both a substrate and a physiologic regulator of thyroid hormone synthesis. Excessive iodine intake normally inhibits thyroid hormone production by reducing the trapping of inorganic iodide and its oxidation into an organic form (organification) and by thyroid hormone release. At the same time, exposure to pharmacologic amounts of iodine (typically 1,000-fold more than the physiologic requirement of 150 µg/day) can cause hyperthyroidism, a condition termed the Jod-Basedow effect. Patients with hyperplastic and benign neoplastic thyroid conditions and those with latent Graves disease are particularly vulnerable to iodine-induced hyperthyroidism. Epidemics of thyrotoxicosis have repeatedly been observed when iodine supplementation is instituted in regions of previous dietary iodine deficiency.69However, iodine-induced hyperthyroidism can also occur in patients from iodine-sufficient environments whose thyroid glands are apparently normal, especially when excess iodine exposure is substantial and sustained, as it is with long-term amiodarone therapy.70 The precise molecular and biochemical basis for iodine-induced hyperthyroidism is poorly understood. Iodine-induced hyperthyroidism is typically transient, lasting only a few weeks, but more prolonged thyroid dysfunction can occur when iodine exposure is prolonged, as occurs with the lipid-soluble drug amiodarone and with myelographic radiocontrast agents.
Inflammation of thyroid tissue caused by infectious diseases, autoimmune processes, or pharmacologic toxicity can cause thyrocyte death, disruption of follicular architecture, and unregulated leakage of thyroid hormones from the gland into the circulation, resulting in thyrotoxicosis71 [see Table 3]. Thyroiditis-related thyrotoxicosis is typically self-limited, lasting 2 to 8 weeks, with spontaneous resolution once glandular stores of thyroid hormone are exhausted. A comparable period of transient hypothyroidism often follows because of lingering impairment of thyroid hormone synthesis, but most patients ultimately become euthyroid [see Figure 3].
Table 3 Characteristic Features of Thyroiditis
Figure 3. Thyroid Function in Acute Thyroiditis
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.
The iodine-containing antiarrhythmic agent amiodarone can cause thyrotoxicosis by two mechanisms.72 Type 1 amiodarone-induced thyrotoxicosis is caused by iodine, whereas type 2 amiodarone-induced thyrotoxicosis is the result of gland inflammation. Both forms can be severe, prolonged, and life-threatening, particularly because affected patients have underlying cardiac disease.
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.
Women with hydatidiform mole and choriocarcinoma, as well as men with metastatic testicular choriocarcinoma, 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.77
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 receptor-β 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.
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 Munchausen 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.81
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 thyrotoxicosis 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, thyrotoxicosis 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 thyrotoxicosis. A history of recent radiocontrast studies or the recent ingestion 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 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; onycholysis; 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, periorbital 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.
Routine laboratory tests
Abnormalities on routine laboratory studies can be the first clue to thyrotoxicosis. Such abnormalities include hypercalcemia, an elevated serum alkaline phosphatase 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-converting 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 µU/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 µU/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 µU/L). Second, spurious elevations of the measured TSH level, masking thyrotoxicosis, 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 hypothyroidism 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.
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, trans thy re tin [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 thyroxine-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.
Table 4 Causes of Elevated Serum Total Thyroxine Level
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 T4immunoassays 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 hyperthyroxinemia of thyrotoxicosis and that associated with thyroxine-binding globulin elevation.
Certain other conditions causing euthyroid hyperthyroxinemia 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 autoantibodies, 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 T4clearance, including acute systemic illnesses, psychosis, and treatment with amiodarone or high-dose propranolol. 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 T3concentration 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-binding globulin excess, a rare form of familial dysalbuminemic hypertriiodothyroninemia, 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.
It is vital for the physician to establish the underlying cause of thyrotoxicosis, because the etiology determines the therapy. In many patients, the history and physical examination alone are sufficient for specific diagnosis. For example, a thyrotoxic woman with a diffuse goiter and exophthalmos almost certainly has Graves disease, whereas a febrile patient with an extremely tender, wood-hard thyroid gland probably has subacute thyroiditis. In other patients, however, the underlying cause may be less certain. For example, a woman with postpartum thyrotoxicosis could have painless (postpartum) thyroiditis, Graves disease, or even factitious thyrotoxicosis—each of which would be treated quite differently. In such patients, further laboratory or radionuclide studies are needed to define the cause and optimal treatment.
The relative degrees of serum T3 and T4 elevations can provide a clue to the form of thyrotoxicosis. Predominant T3 overproduction is common in Graves hyperthyroidism and, to a lesser extent, in toxic nodular goiter (i.e., a serum T3-to-T4 [ng/dl:µg/dl] ratio greater than 20). In contrast, T4-predominant thyrotoxicosis (i.e., a serum T3-to-T4 ratio less than 15) suggests thyroiditis (subacute or lymphocytic), iodine-induced thyrotoxicosis, or exogenous T4 ingestion.
Determining the fractional thyroid uptake of radioactive iodine or pertechnetate and thyroid imaging are required for etiologic diagnosis in some patients. Hyperthyroidism from excessive thyroid hormone synthesis, as in Graves disease, is typically accompanied by increased fractional uptake of the tracer in functioning tissue. In contrast, thyrotoxicosis caused by thyroid inflammation, exogenous thyroid hormone ingestion, and iodine exposure are all associated with a low thyroid uptake. Radionuclide imaging of the thyroid gland often permits differentiation of Graves disease from toxic nodular goiter, because tracer distribution is homogeneous in the former and focal in the latter. Radionuclide imaging can also localize ectopic thyroid tissue that may be hyperfunctioning, such as substernal toxic multinodular goiter and struma ovarii, an ovarian teratoma in which a toxic adenoma can arise.
Anti-TSH receptor immunoglobulin assays have limited clinical uses in differential diagnosis and management.83 They may be helpful in confirming the diagnosis of Graves disease in clinically and biochemically euthyroid patients who have ophthalmopathy or when differentiation of Graves disease from toxic multinodular goiter is otherwise difficult and important for treatment. In pregnant women with Graves disease, the level of thyroid-stimulating immunoglobulins can predict the likelihood of fetal and neonatal thyrotoxicosis.
Other tests may be helpful in diagnosing certain other causes of thyrotoxicosis. Patients with subacute thyroiditis usually have an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein level, whereas patients with lymphocytic (silent) thyroiditis do not.88 In patients with thyrotoxicosis caused by thyroid hypersecretion or inflammation, the serum thyroglobulin concentration is high, whereas it is low in patients with factitious thyrotoxicosis. Measurements of the serum glycoprotein hormone a subunit may be useful to confirm the diagnosis of TSH-secreting pituitary adenoma, in which the molar ratio of the a subunit to intact TSH is higher than normal.
Differentiating the two causes of amiodarone-induced thyrotoxicosis is often very difficult, if not impossible. Both the iodine-induced type (type 1) and the inflammatory type (type 2) can be severe; both can be T4 predominant, and both can be associated with a low thyroid radioiodine uptake. Early reports of higher interleukin-2 levels in the inflammatory form have not been confirmed. Glandular blood flow, as defined by Doppler sonography, is decreased in some patients with the inflammatory form, but this has also proved to be an imperfect distinguishing feature in many affected patients.
Optimal treatment of patients with thyrotoxicosis depends on the underlying cause and severity of their condition and sometimes on the presence of complications that result from hyperthyroidism itself or the patient's other medical disorders. Transient thyrotoxicosis (e.g., exogenous and thyroiditis-related thyrotoxicosis) may require only symptomatic therapy with a beta-adrenergic blocking agent while awaiting spontaneous restoration of euthyroidism. Hyperthyroid Graves disease can be treated with antithyroid medication, radioiodine, or surgery; most of these patients ultimately require an ablative treatment. The hyperthyroidism caused by a toxic adenoma or toxic multinodular goiter will also respond to thionamides (e.g., methimazole and propylthiouracil [PTU]), but it almost never remits spontaneously, so radioiodine or surgery is always required. Fortunately, these three most commonly required therapies are quite comparable with regard to cost-effectiveness, and the vast majority of patients are satisfied with the treatment that they have chosen. Certain special forms of thyrotoxicosis, such as TSH-secreting pituitary adenoma and thyroid hormone intoxication, require other modes of treatment tailored to the responsible cause.
Beta-Adrenergic Blocking Agents
Beta blockers provide prompt relief from some symptoms of thyrotoxicosis, including tremor, palpitations, and anxiety. However, constitutional complaints, such as fatigue and weakness, and hypermetabolic manifestations, such as heat intolerance and weight loss, are unrelieved by beta-adrenergic blockade. These drugs are often valuable for temporary control of symptoms while awaiting a response to more definitive therapies or spontaneous remission of thyrotoxicosis. Beta blockers can be used—optimally, in combination with other drugs—to prepare patients with thyrotoxicosis for surgery. They are also useful for ventricular rate control in patients with thyrotoxic atrial fibrillation (see below). When used judiciously, beta blockers can be a component of treatment for some patients with thyrotoxic heart failure. Some beta blockers, such as propranolol, also partially inhibit extrathyroid T4-to-T3 conversion, but these agents do not otherwise address the underlying pathogenesis of thyrotoxicosis.
The thionamide antithyroid drugs inhibit iodination and coupling, which are key steps in thyroid hormonogenesis.89 Consequently, methimazole and PTU are effective treatments for forms of hyperthyroidism caused by excess thyroid hormone production by the gland, such as Graves disease. However, they are ineffective when thyrotoxicosis is caused by unregulated release of hormone from an inflamed gland, such as that which occurs in subacute thyroiditis. Overtreatment with thionamides causes hypothyroidism, so the dose must be titrated or thionamide use must be accompanied by thyroxine replacement. Compared with ablative therapies, antithyroid drugs have the advantage of lowering the long-term incidence of hypothyroidism. However, Graves disease is associated with a 25% long-term incidence of hypothyroidism, which results from the destructive effects of gland inflammation and occurs even with prolonged antithyroid drug treatment.
Thionamide treatment is an appropriate choice for patients with mild Graves disease, in whom the absence of severe manifestations (e.g., a large goiter, a very elevated serum T4 level, or ophthalmopathy) predicts a higher spontaneous remission rate. Typically, antithyroid drugs are prescribed for 6 to 24 months, after which the dose is tapered to determine whether a remission has occurred. The antithyroid drugs are also useful in four other circumstances: (1) for temporary treatment of patients with Graves disease who are unwilling to accept definitive radioiodine therapy immediately, (2) for preliminary control of hyperthyroidism before definitive radioiodine or surgical treatment, (3) for the management of pregnant women with hyperthyroidism and neonatal Graves disease, and (4) to determine whether nonspecific symptoms are in fact related to mild thyrotoxicosis.
The antithyroid drugs have several limitations. First, they typically take 3 to 8 weeks to restore euthyroidism. Although they inhibit new thyroid hormone synthesis, they do not block the gland's release of existing hormone stores, which can be plentiful in patients with goitrous Graves disease, toxic nodular goiter, and amiodarone-induced thyrotoxicosis. Second, the antithyroid drugs' actions end when the drug is discontinued. As a result, virtually all patients with toxic nodular goiter and the majority of those with Graves disease will experience relapse when the medication is stopped. Third, antithyroid drugs have potential side effects. In addition to hypothyroidism resulting from overtreatment, they cause rash, pruritus, and fever in approximately 5% of treated patients. Much less commonly, severe adverse reactions can occur, including potentially fatal granulocytosis, vasculitis, or, with PTU, hepatic failure. All thionamide-treated patients must be warned of the symptoms and signs of these problems and be advised that if such manifestations occur, they should report the manifestations and immediately discontinue the medication. The likelihood of another adverse reaction occurring if a patient is switched from one thionamide to another is poorly documented, but such cross-reactivity does occur. Consequently, it is generally advisable in this circumstance to recommend radioiodine or surgery.
For most hyperthyroid patients, methimazole, 10 to 30 mg a day, is more effective and safer than PTU. Methimazole's longer half-life permits a single daily dose, which improves compliance; in contrast, PTU must be given three times daily for sustained effect. Methimazole at dosages of less than 40 mg a day is less likely than PTU to cause agranulocytosis and is not associated with hepatic failure. In certain circumstances, however, PTU, 100 to 200 mg a day in divided doses, may be preferred. In patients with severe and complicated thyrotoxicosis (see below), PTU has the advantage of also blocking extrathyroid T4-to-T3 conversion; a benefit in pregnant women is that PTU crosses the placenta less readily than methimazole and therefore has less of an effect on fetal thyroid function.
Iodine-131 (131I) is a highly effective, safe, and convenient treatment for hyperthyroid patients with hyperthyroid Graves disease, toxic multinodular goiter, and toxic adenoma. This radioisotope of iodine is preferentially concentrated in thyrocytes, where it emits beta particles (electrons) with a short path-length that limits the field of its destructive effects to the thyroid gland. With dosing regimens that are based on estimated gland size and preliminary thyroid radioiodine fractional uptake determinations, or even with empirical doses, a single dose will provide effective treatment for approximately 75% of Graves disease patients and 50% of patients with toxic nodular goiter. Almost all of the remaining patients are cured with a second radioiodine treatment, which is usually best held until the initial dose has proved ineffective after 6 months. For patients with toxic multinodular goiter, there is limited experience with the use of recombinant thyrotropin to increase thyroid uptake of radioiodine—a strategy that might be expected to improve the cure rate and permit a reduction in the administered dose of radioiodine.
Radioiodine has limitations. It takes 1 to 2 months before irradiated thyrocytes die and hyperthyroidism resolves; during this time, patients must often be treated with adjunctive beta-adrenergic blockade, antithyroid drugs, or stable iodide (see below). Approximately 25% of patients develop a transient worsening of thyrotoxicosis 2 to 4 weeks after treatment because of radiation thyroiditis, which can also cause mild and short-lived gland discomfort. The principal side effect of radioiodine is postablative hypothyroidism, which occurs within 3 months in more than half of radioiodine-treated Graves disease patients. Furthermore, in Graves disease patients who remain euthyroid, gland failure continues to occur at a rate of 3% annually, so lifelong follow-up of their thyroid function is essential. In patients with hyperthyroidism resulting from toxic multinodular goiter and toxic adenoma, the incidence of postablative hypothyroidism is lower (approximately 25%) because the suppressed normal extranodular tissue receives much less irradiation. During the more than 65 years that radioiodine has been used to treat hyperthyroidism, the preponderance of evidence has shown no higher long-term incidence of thyroid or other malignancies. In radioiodine-treated women, no higher incidences of subsequent infertility or spontaneous abortion has been found, nor has there been a higher incidence of teratogenesis in their children. In one large follow-up study, radioiodine treatment of children and adolescents was associated with a higher subsequent incidence of benign thyroid nodules. As a result, many experts prefer to treat pediatric patients with antithyroid drugs for several years before resorting to radioiodine. However, radioiodine should not be withheld from children when hyperthyroidism is poorly controlled or side effects occur with thionamide therapy.
Radioiodine is inappropriate in several circumstances. It is absolutely contraindicated in pregnant women. All women of childbearing age should be advised to avoid pregnancy until euthyroidism is restored; this typically requires 3 to 6 months. Radioiodine is not indicated in transient forms of thyrotoxicosis, such as subacute and lymphocytic thyroiditis. Furthermore, it is ineffective in these and other forms of thyrotoxicosis in which the thyroid uptake of radioiodine is decreased, including amiodarone-induced thyrotoxicosis.
Thyroidectomy by an experienced surgeon who has a demonstrated low incidence of complications is a highly effective, prompt, and relatively safe alternative. However, transient pain and scarring are universal after thyroidectomy, and postanesthetic symptoms are common. Partial thyroidectomy has an unacceptably high rate of residual hyperthyroidism; thus, gland resection that is extensive enough to ensure success can be expected to result in postsurgical hypothyroidism. Even in the most skilled surgical hands, there is a small risk (approximately 2% to 5%) of hypoparathyroidism or injury to the recurrent laryngeal nerve. Finally, for most patients, surgery is less convenient and entails greater interruption of life commitments than does radioiodine therapy.
Despite its drawbacks, surgery is the best choice in several settings. Pregnant women with severe thionamide side effects have no alternative. In some hyperthyroid patients, other aspects of their condition may make neck surgery necessary (e.g., the patient may have a cytologically suspicious thyroid nodule or hyperparathyroidism). Amiodarone-induced thyrotoxicosis can require surgery when medical treatment is ineffective and the patient's cardiovascular and metabolic status is deteriorating. For some patients, such as those planning prolonged travel in the near future and those who cannot or will not take medications reliably, surgery is attractive because it provides prompt and certain cure. Thyroidectomy is also preferred in countries that require prolonged hospitalization for even low-dose radioiodine therapy.
Other surgical procedures play a role in the treatment of certain rare forms of hyperthyroidism. Transsphenoidal pituitary adenomectomy is typically the first step in treatment of patients with TSH-secreting adenomas, but it is curative in only one third of patients.90 Oophorectomy is appropriate when hyperthyroidism results from a toxic adenoma arising in teratomatous ovarian tissue in a patient with struma ovarii.
Stable iodide, given as either potassium iodide or Lugol solution in pharmacologic amounts (i.e., 30 mg or more a day), blocks thyroid hormone release from the gland and inhibits organification of iodide in patients with Graves disease. When combined with antithyroid drug therapy, iodide can accelerate the decline in circulating thyroid hormone concentrations. However, its effects are only temporary, dissipating after 10 to 14 days, after which hyperthyroidism recurs. Consequently, it is useful in only two settings. First, it can be employed as a short-term measure to prepare patients for thyroidectomy. Second, it can be started several days after radioiodine treatment to accelerate restoration of euthyroidism. In such patients, the irradiated gland is incapable of escaping from iodide's inhibitory effects. Iodide has infrequent side effects of rash, gastritis, and sialadenitis.
Iodinated radiocontrast agents, such as sodium iopanoate, can have two salutary effects in patients with severe thyrotoxicosis. First, they are an abundant source of iodide. Second, they inhibit T4-to-T3 conversion.
Lithium carbonate also inhibits hormone release from the thyroid gland. It is used in rare cases to accelerate recovery from severe thyrotoxicosis, as an adjunct to antithyroid medication in type 1 amiodarone-induced thyrotoxicosis, or as a short-term treatment for patients who have experienced severe thionamide side effects. Potassium perchlorate, which blocks iodide uptake by the thyroid, is a rarely used treatment of type 1 amiodarone-induced thyrotoxicosis.
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen are first-line agents for controlling thyroid pain and constitutional symptoms in subacute thyroiditis. They do not, however, accelerate recovery of normal thyroid function.
Glucocorticoids (e.g., prednisone, 40 mg/day) can be used to treat thyrotoxicosis under a few specific circumstances. When subacute thyroiditis is resistant to NSAID therapy, steroids are almost invariably effective. However, their side effects and the fact that they may prolong the overall course of subacute thyroiditis make them second-line agents. Glucocorticoid therapy is also useful in the treatment of type 2 amiodarone-induced thyrotoxicosis. Finally, when combined with high-dose antithyroid medication and iodinated radiocontrast agents, glucocorticoids can often be effective in controlling even severe thyrotoxic Graves disease within 1 week after initiation of therapy.
Other agents are employed to treat rare causes of thyrotoxicosis. Cholestyramine can be an adjunct in the treatment of patients with exogenous thyroid hormone intoxication; it interrupts the enterohepatic circulation of thyroid hormones and increases their fecal disposal. Somatostatin analogues are useful in the medical management of patients with inoperable TSH-secreting pituitary tumors or of patients whose tumors were incompletely resected.91
Atrial tachyarrhythmias can occur with even mild thyrotoxicosis. Atrial fibrillation is the most common and potentially the most serious of these dysrhythmias; atrial flutter and paroxysmal atrial tachycardia also occur. Thyrotoxic atrial fibrillation occurs more often in older persons and men, as well as in persons with intrinsic cardiac diseases, particularly when these diseases cause left atrial enlargement. Thyrotoxic atrial fibrillation can be complicated by heart failure and thromboembolism. Beta blockers are useful for ventricular rate control; they are less likely to cause hypotension than calcium channel blockers, which remain an alternative. Anticoagulation is generally advisable. Exceptions are in patients in whom thyrotoxic atrial fibrillation has been of short duration and rapidly reverts to sinus rhythm or in those with contraindications to anticoagulation. Cardioversion should generally be deferred until the patient is euthyroid. It should be attempted if spontaneous reversion to sinus rhythm does not occur by 3 months after euthyroidism has been restored92 [see 1:IV Atrial Fibrillation].
Thyrotoxic Heart Failure
When thyrotoxicosis is severe and prolonged or when the patient has intrinsic cardiac disease, heart failure can occur.93 Contributing factors can include atrial fibrillation; ventricular hypertrophy and dilatation with impaired diastolic function; failure of mitral valve leaflet apposition and resulting regurgitation; and tachycardia-induced cardiomyopathy. Typically, one or more of these factors occurs in the context of increased peripheral tissue demands, vasodilatation, and an expanded blood volume. The left ventricular ejection fraction may be normal at rest but deteriorates with exertion. Therapy includes aggressive treatment of thyrotoxicosis, ventricular rate control, restoration of sinus rhythm when possible, and optimization of blood volume and ventricular filling pressures.
Thyroid crisis—so-called thyroid storm—refers to the life-threatening constellation of fever; heart failure, often with atrial fibrillation; delirium or psychosis; and fluid and electrolyte depletion resulting from poor oral intake and gastrointestinal losses caused by vomiting or diarrhea.94 Patients with severe hyperthyroidism, underlying cardiac disease or superimposed infection, and poor access to health care are at increased risk for these complications.95 Treatment entails medical management of each individual complication and aggressive therapy for thyrotoxicosis, typically with multiple agents appropriate for the underlying cause. Because Graves disease is the most common cause of thyroid storm, treatment typically includes PTU, sodium iopanoate, and glucocorticoids.
For some patients with Graves disease, ocular and orbital involvement represents the most disabling aspect of their condition. Exposure keratitis resulting from proptosis, eyelid retraction, and lagophthalmos (inability to close the eye) causes symptoms and can be complicated by infection and ulceration. Treatment includes moistening eyedrops and lubricant ointments, sunglasses, taping the eyelids shut for sleeping, and sometimes blepharoplasty, orbital decompression surgery, and irradiation. Extraocular muscle swelling and fibrosis can cause diplopia, which can require prisms and sometimes corrective surgery. Optic nerve compression can threaten vision; it is treated acutely with high-dose glucocorticoids and definitively by orbital decompression surgery.
Although the short-term morbidity of thyrotoxicosis can be disabling, the long-term outlook is generally bright, given accurate etiologic diagnosis and appropriate therapy targeted to the specific cause. However, many patients with Graves disease ultimately require lifelong treatment of postablative hypothyroidism, and their ophthalmopathy may be an ongoing source of discomfort, cosmetic concern, and, rarely, visual impairment. Mortality and severe long-term disability are rare events that typically result from either cardiovascular complications of thyrotoxicosis or side effects of antithyroid medication or thyroid surgery.
There are several types of thyroiditis, each of which has distinct causes, clinical manifestations, and treatments [see Table 3]. Some types cause thyroid dysfunction. When thyrotoxicosis occurs in these conditions, it is a transient result of the unregulated release of hormone from the gland, whereas hypothyroidism can be transient or permanent. Goiter occurs in some of these disorders (e.g., autoimmune thyroiditis and Reidel thyroiditis), whereas it is not a prominent feature of others. Pain is characteristic of subacute thyroiditis but is an uncommon feature of the other types.
Autoimmune thyroiditis (Hashimoto disease) is a common condition, particularly in women, who are affected over 10 times more often than men. Its incidence increases with age; during and after middle life, approximately 20% of women have serologic evidence of the condition (i.e., thyroid autoantibodies), and 10% to 15% have an elevated serum TSH level secondary to thyroid hormone insufficiency. Its etiology, genetics, and pathogenesis are discussed elsewhere [see Hypothyroidism, above].
Clinical manifestations of autoimmune thyroiditis, when present, include hypothyroidism and a goiter. However, most affected patients have either no symptoms or only nonspecific ones, and they do not have significant gland enlargement. When present, the goiter is typically diffuse, modest in size, nontender, and firm with a roughened contour. Patients with the fibrous variant can have more substantial gland enlargement. Pain and tenderness are rarely present.
The presence of thyroid autoantibodies confirms the diagnosis, which can often be established on clinical grounds alone. Immunoassay for antithyroid peroxidase antibodies, which are present in 90% of patients, is the most sensitive single test96; anti-thyroglobulin antibodies are present in only 60% of patients. An elevated serum TSH concentration indicates associated primary hypothyroidism. The differential diagnosis of diffuse goiter includes simple euthyroid goiter, Graves disease, iodine-deficiency goiter, and, rarely, diffusely infiltrating malignancies (i.e., lymphoma, papillary cancer, and anaplastic cancer).
The management of patients with autoimmune thyroiditis includes thyroid hormone replacement for those who are hypothyroid and periodic thyroid function testing for those who are euthyroid but remain at risk for the development of hypothyroidism later in life. Women who have experienced transient hypothyroidism are particularly at risk. Associated goiter rarely requires any treatment, but thyroid hormone replacement sometimes results in partial gland shrinkage. The rare patient with thyroid pain may benefit from NSAIDs. The prognosis for properly treated and monitored patients is excellent. Certain other autoimmune disorders occur more often in affected patients; these can include vitiligo, pernicious anemia, adrenal insufficiency, Sjögren syndrome, and systemic sclerosis. Thyroid lymphoma is more common as well, but it is still a very rare event.
Lymphocytic thyroiditis (also known as painless thyroiditis, silent thyroiditis, or postpartum thyroiditis) is believed to be caused by cell-mediated autoimmunity. This belief is based on the fact that the gland is infiltrated with lymphocytes and the condition's incidence is highest postpartum—a time when autoimmune disorders are more common.97 The condition is relatively common in the postpartum period, affecting approximately 6% of women between 2 and 12 months after delivery or abortion. Women with thyroid autoantibodies, previous episodes of postpartum thyroiditis, or type 1 diabetes mellitus are at markedly increased risk. The condition also occurs during treatment with immunomodulatory agents (see below). Rarely, lymphocytic thyroiditis may present in women or men at other times.
Lymphocytic thyroiditis can cause several patterns of transient thyroid dysfunction: thyrotoxicosis alone, thyrotoxicosis followed by hypothyroidism, hypothyroidism alone, or, rarely, hypothyroidism followed by thyrotoxicosis. The pathogenesis of these derangements is described elsewhere [see Thyrotoxicosis, above]. In postpartum women, symptoms of thyroid dysfunction can often be overlooked or mistaken for depression. Affected patients have a modest goiter or no goiter.
Serum TSH measurement is the best first-line test to detect thyroid dysfunction in patients with lymphocytic thyroiditis. In thyrotoxic patients, the condition can be differentiated from Graves disease, which can also present postpartum, by the absence of significant goiter or eye involvement; by relatively greater concentration of serum T4 than of serum T3 (ratio > 20:1 in µg/dl:ng/dl); and by a low thyroid radioisotope uptake. In hypothyroid patients, postpartum thyroiditis can best be distinguished from autoimmune thyroiditis by whether it remits spontaneously or not. Thyroid autoantibodies are detected in many postpartum thyroiditis patients.
Management can often be expectant, without drug treatment. Symptomatic thyrotoxicosis and hypothyroidism can be treated with temporary beta-adrenergic blockade and thyroxine, respectively. One quarter of affected patients go on to develop typical autoimmune thyroiditis and permanent hypothyroidism.
SUBACUTE THYROIDITIS (DE QUERVAIN OR GRANULOMATOUS THYROIDITIS)
Subacute thyroiditis is believed to be the result of a viral infection, because of its association with prodromal symptoms, the presence of circulating viral antibody titers, and electron microscopic evidence of viral particles. Classically, episodes of subacute thyroiditis have three clinical components. First are the systemic manifestations: symptoms suggesting a viral upper respiratory tract infection, followed by malaise, fever, and chills. The second is a painful goiter, which is characteristically moderate in size, wood-hard, and extremely tender. The third is transient thyrotoxicosis, which can be quite severe. The thyrotoxicosis lasts for 2 to 8 weeks and is typically followed by transient hypothyroidism. Although the clinical features of subacute thyroiditis are usually sufficient to suggest the diagnosis, constitutional symptoms (especially high fever) can mimic other infections, and thyroid pain radiating to the ears can be confused with otitis. Thyrotoxicosis is confirmed by a low serum TSH and a high serum T4 concentration. Marked elevation of the ESR is detectable during the acute phase of the illness. Other causes of painful thyroid enlargement include hemorrhage into a thyroid nodule, which is usually asymmetrical; acute thyroiditis (see below); thyroid lymphoma or anaplastic thyroid cancer; and, very rarely, autoimmune thyroiditis or Graves disease.
Management of subacute thyroiditis entails prescription of an NSAID in high dosage. In approximately 20% of patients, this provides inadequate relief of pain and constitutional symptoms; these patients can be treated with glucocorticoid therapy (e.g., prednisone, 40 mg/day with a slow taper over 3 to 8 weeks). Transient thyrotoxic symptoms are treated with beta blockers; transient hypothyroid symptoms are treated with thyroxine. In more than 80% of cases, normal thyroid function returns and the condition does not recur.
ACUTE THYROIDITIS (SUPPURATIVE THYROIDITIS)
Acute or suppurative thyroiditis is a rare condition caused by either untreated bacterial infections of the upper respiratory tract or cervical soft tissues or by opportunistic agents in immunocompromised hosts. Hematogenous spread to the thyroid of fungal, mycobacterial, and parasitic infections have all been reported. Piriform sinus fistula, multinodular goiter, or autoimmune thyroiditis may predispose patients to acute thyroiditis.
Patients with suppurative infections typically are extremely ill, with high fever; a painful, tender, swollen thyroid gland; and erythema and warmth of overlying soft tissues. Glands infected with opportunistic pathogens (e.g., Pneumocystis jiroveci) may have more subtle signs of gland infection. Treatment requires aggressive, often parenteral, antibiotic therapy and sometimes surgical drainage.
Several drugs have been associated with painless thyroiditis and thyroid dysfunction, including amiodarone (see above). Treatment of hepatitis C with interferon alfa and interleukin-2 causes thyroid dysfunction in as many as 15% of patients; such dysfunction includes transient thyrotoxicosis with or without subsequent hypothyroidism, as well as persistent hypothyroidism and persistent hyperthyroidism (i.e., Graves disease). Lithium carbonate can exacerbate thyroid dysfunction and cause hypothyroidism in patients with underlying autoimmune thyroiditis. Rarely, pharmacologic doses of iodide can cause transient thyroiditis.
Reidel thyroiditis is an extremely rare form of invasive fibrous thyroiditis that can cause substantial goiter with compression and infiltration of adjacent structures. Some patients with this idiopathic disorder also develop hypothyroidism. It may be encountered in patients with retroperitoneal and mediastinal fibrosis. Treatment options are limited. Surgery is challenging and is limited to palliation of obstructive complications. There are reports of effective drug treatment with glucocorticoids and tamoxifen.98
Goiter, Thyroid Nodules, and Thyroid Cancer
The prevalence of goiter in populations varies inversely with dietary iodine intake. There are estimated to be 100 million persons with dietary iodine deficiency and one billion with borderline iodine sufficiency. Consequently, in some regions, goiter is almost universal, particularly in women, whereas in regions with an adequate iodine intake, goiter affects less than 5% of the population.
Etiology and Pathogenesis
Worldwide, dietary iodine deficiency is the most common cause of thyroid gland enlargement. In addition, populations have been described in which exposure to goitrogens in drinking water or dietary substances has caused endemic goiter.99 Although modest thyroid gland enlargement occurs during pregnancy, the so-called goiter of pregnancy is largely restricted to women with associated dietary iodine deficiency. Tobacco smoking has been associated with goiter development, especially in populations without ample dietary iodine. Mutations in genes encoding key proteins involved in thyroid hormone synthesis (e.g., thyroglobulin and thyroid peroxidase), can result in a compensatory goiter. Activation of the TSH receptor by TSH predictably causes diffuse goiter, as occurs in a variety of conditions, including primary hypothyroidism from autoimmune thyroiditis or drugs, TSH-secreting pituitary adenoma, and resistance to thyroid hormone. The TSH receptor can be aberrantly stimulated when thyroid-stimulating immunoglobulins or high levels of hCG bind to it or when a mutation in the TSH receptor gene itself leads to constitutive activation. For the majority of patients with hyperplastic thyroid glands arising despite sufficient dietary iodine—a condition that is sometimes apparently inherited and sometimes sporadic—the precise molecular cause remains unknown. Activation of the biochemical pathways signaling thyrocyte growth or abnormal local levels or activity of intrathyroid growth factors seems likely to be involved. Goiter can also be the result of gland infiltration with inflammatory cells (e.g., leukocytes and multinucleated giant cells in subacute thyroiditis) or tumor cells (e.g., anaplastic or diffusely infiltrating papillary thyroid cancers).
In summary, goiter can be associated with hypothyroidism, euthyroidism (nontoxic goiter), or hyperthyroidism (toxic goiter). It can be a manifestation of benign hyperplastic or neoplastic conditions, malignancy, and inflammation. In many of these disorders, thyroid gland enlargement is initially diffuse, but with time, the thyroid becomes multinodular, and it may become asymmetrical.
Diagnosis and Differential Diagnosis
For the clinician evaluating a patient with a goiter, three pragmatic questions are typically more important than the specific etiologic diagnosis. First, is the enlarged thyroid gland producing pain or other local symptoms as a result of obstruction or invasion of adjacent structures, or is it so large as to be unsightly? Second, is the goiter a manifestation of a disorder causing hypothyroidism or hyperthyroidism that requires treatment? Third, is the gland enlarged because of malignancy?
Symptoms related to a goiter reflect gland impingement on adjacent structures. A sensation of cervical fullness, tightness, or pain can occur when the enlarging gland stretches its capsule, which has sensory innervation, and compresses adjacent tissues and structures. Thyroid pain can radiate to the jaw or ears. Tracheal compression can cause cough and difficulty clearing mucus; tracheal invasion from thyroid malignancy can cause hemoptysis. Esophageal compression can produce dysphagia and, rarely, odynophagia. Compression of the recurrent laryngeal nerve results in hoarseness, a weak voice, and dysphagia for fluids; bilateral nerve dysfunction can also cause dyspnea from airway obstruction.
Inspection during deglutition often provides the first clue to the presence of a goiter. In addition, it helps distinguish true enlargement of the thyroid, which moves cephalad with swallowing, whereas subcutaneous fat does not. Any tracheal deviation, cervical vein engorgement, or visible adenopathy should also be noted. On palpation, the dimensions of the gland and its symmetry, contour, consistency, mobility, and tenderness should all be noted.
Other physical findings can provide important information. A bruit suggests either a hypervascular Graves disease gland or compression of cervical blood vessels. Venous engorgement and facial plethora that develops when the patient touches the hands together above the head (Pemberton sign) implies near obstruction of the thoracic outlet by a goiter. Signs of hypothyroidism or hyperthyroidism should, of course, be sought.
Laboratory tests and imaging studies
In all patients with goiter, the serum TSH and free T4 concentrations should be measured to assess gland function. Serologic testing for thyroid autoantibodies, especially anti-thyroid peroxidase antibody, can help establish the diagnosis of autoimmune thyroiditis, the most common cause of diffuse goiter in populations with sufficient dietary iodine.
Ultrasonography can be useful in confirming that a neck mass is, in fact, a goiter. It can define the gland size; determine whether there is diffuse heterogeneity typical of autoimmune thyroiditis or discrete nodules; and identify potentially related cervical adenopathy. A chest and lower cervical x-ray can show tracheal deviation and suggest mediastinal extension of a goiter, but computed tomography or magnetic resonance imaging provides a fuller depiction of the gland's substernal extent and its relationship to the trachea and intrathoracic structures. The decision whether or not to use iodinated radiocontrast agents with CT imaging should be thoughtfully addressed, because these agents can precipitate hyperthyroidism in patients with multi-nodular goiter and can interfere with subsequent postoperative radioiodine therapy in patients who prove to have thyroid cancer. Radionuclide imaging is seldom required in the initial assessment of patients with goiter, but it can confirm that a superior mediastinal mass concentrating radioiodine is thyroidal in origin. Radioiodine fractional uptakes and imaging can be useful in the differential diagnosis of goitrous thyrotoxicosis (see above). Assessment of ventilatory flow-volume loops can be useful in determining whether dyspnea in a patient with goitrous tracheal compression is caused by the thyroid condition. Although cytologic evaluation plays a central role in the differential diagnosis of thyroid nodules, it is required in only a small minority of patients with diffuse goiters that cannot be readily characterized with clinical, laboratory, and imaging findings.
Management of goiter addresses three key clinical issues: size, function, and potential malignancy. Treatment for thyroid dysfunction or thyroid cancer is the same as in patients without goiter. Large nontoxic, multinodular goiters causing obstructive symptoms or cosmetic concerns can be surgically excised or, if obstruction is not severe, treated with radioiodine.100 Surgery provides more prompt relief and excludes cancer with certainty, but it is associated with greater short-term morbidity than radioiodine therapy. Even goiters with substantial substernal extension can often be removed through a cervical incision. Recombinant thyrotropin can successfully augment 131I concentration by nodular goiters, which typically have only a normal fractional radioiodine uptake.101 TSH-suppressive thyroxine therapy has limited value in the treatment of most patients with goiters of significant dimensions. Published experience shows that no more than half of patients have a response, which is often only partial.102 Furthermore, long-term TSH suppression is associated with risks of bone loss and atrial fibrillation.
Complications and Prognosis
The type and probability of complications in patients with goiter depend on the underlying cause. Most patients with gland enlargement of benign cause never suffer local compressive symptoms and require treatment only if they have associated thyroid dysfunction (i.e., hypothyroidism in patients with autoimmune thyroiditis or hyperthyroidism in patients with multinodular goiter). However, large multinodular goiters can cause dyspnea from tracheal narrowing or dysphagia from esophageal compression. Recurrent laryngeal nerve impingement and dysfunction is very unusual and should raise concern of malignancy. Rarely, thyroid substernal goiter extension can cause superior vena cava obstruction. Goiter from papillary or anaplastic thyroid cancer or lymphoma can cause all of the complications associated with goiters from benign causes, as well as pain from invasion of adjacent structures, hemoptysis from tracheal invasion, and vocal cord paresis from recurrent laryngeal nerve involvement.
Epidemiology and Etiology
Thyroid nodules are palpable in 6% of women and 2% of men.2 Nonpalpable thyroid nodules can be detected by sonography in one third of women. The prevalence of nodules increases with age. The genetic and environmental factors associated with thyroid nodule development are essentially the same as those for goiter. Nodules may represent solid tissue composed of thyroid cells or colloid or represent cysts from accumulated serous fluid or blood, often from hemorrhage within a solid nodule in the gland. The majority of thyroid nodules are benign; in adults, 5% to 10% of thyroid nodules are cancerous.
Three clinical issues must be addressed in patients with thyroid nodules: the nodule's size and the resulting potential for local complications, the possibility of associated thyroid dysfunction, and malignancy.103 The same principles and approach apply to palpable thyroid nodules as to incidentally detected nodules (so-called thyroid incidentalomas) that are greater than 1.0 to 1.5 cm in diameter.104 After proper assessment, the majority of patients will be found to have none of these three problems, and they can be monitored conservatively.
Thyroid nodules are usually detected incidentally by asymptomatic patients themselves or by their physicians. Rapidly enlarging or invasive nodules may cause pain in the anterior neck, jaw, or ear. Tracheal or esophageal compression can cause cough or dysphagia, respectively. Invasion of the trachea or recurrent laryngeal nerve by tumor can produce the worrisome symptoms of hemoptysis or hoarseness, respectively. Symptoms of thyrotoxicosis suggest the possibility of toxic adenoma, whereas complaints consistent with hypothyroidism may reflect autoimmune thyroiditis and an asymmetrical goiter that is mimicking a true nodule.
The presence of pulmonary, skeletal, or neurologic symptoms suggesting metastatic disease increases concern about a primary thyroid cancer. An increased risk of thyroid cancer is also suggested by a history of childhood or adolescent irradiation; irradiation was employed until the early 1950s for thymic enlargement, tonsillitis, adenoiditis, cutaneous hemangiomas, and acne. A family history of thyroid cancer is also an indication for thorough assessment, especially if the familial disease is medullary or papillary thyroid cancer. A history of hyperparathyroidism or pheochromocytoma raises the possibility of the multiple endocrine neoplasia type II (MEN II) syndrome, which includes these disorders and medullary thyroid cancer.105 Hypercalcitoninemia in patients with metastatic medullary thyroid cancer can cause flushing, pruritus, and diarrhea.
Nodules that are fixed or associated with ipsilateral cervical adenopathy are worrisome for thyroid cancer. Nodule size and consistency are not reliable features for distinguishing benign from malignant lesions. Although multiple thyroid nodules are typical of benign multinodular goiter, a nodule that is larger, that is growing more rapidly, or that is more symptomatic than others in the gland requires the same assessment as a solitary thyroid nodule. Signs of hyperthyroidism or hypothyroidism suggest toxic adenoma or autoimmune thyroiditis, respectively. Patients with the MEN IIB (or MEN III) syndrome, which includes medullary thyroid cancer and pheochromocytoma, can have a Marfanoid body habitus and submucosal neuromas that are visible as lumps beneath the buccal mucosa and conjunctivae.
The serum TSH concentration should be measured: a low serum TSH suggests a possible toxic adenoma; a high TSH, autoimmune thyroiditis. Antithyroid antibody screening can corroborate the diagnosis of autoimmune thyroiditis in patients who actually have diffuse but asymmetrical thyroid gland enlargement. Serum calcitonin should be measured in patients with clinical features that suggest hypercalcitoninemia or the MEN II syndrome. The serum thyroglobulin assay is not helpful in distinguishing benign from malignant thyroid nodules.
For most thyroid nodules, the definitive diagnostic procedure is fine-needle aspiration to provide cytologic material for examination by an experienced pathologist. Sonographic guidance of aspiration can be useful when nodules are poorly localized by palpation or for the assessment of lesions that have a cystic component; in addition, it can sometimes be useful in identifying additional nonpalpable nodules requiring assessment.106 Radionuclide imaging currently has only a secondary role in thyroid nodule assessment. In thyroid nodule patients whose serum TSH concentration is low, a iodine-123 or technetium-99m pertechnetate scan that indicates that the nodule is “hot” (i.e., that shows a concentration of tracer in the nodule, with suppression of uptake in the remainder of the gland) provides assurance that the nodule is benign. CT and MRI have no role in the evaluation of the typical patient with a thyroid nodule unless there is substernal extension of a nodular goiter.
Clinical features of thyroid nodules are sometimes helpful but seldom provide definitive diagnosis. Sonography can confirm that an ambiguous neck mass is thyroidal. Radionuclide imaging should be limited to patients with a suppressed serum TSH concentration. The sensitivity and specificity of cytologic assessment of thyroid nodules are 97% and 95%, respectively. However, approximately 20% of nodules are cytologically indeterminate, among which approximately 15% are malignant.107 Some thyroid nodules can ultimately be definitively diagnosed only by surgical excision and histopathologic examination.
Management, Complications, and Prognosis
Most cytologically benign thyroid nodules can be managed with observation only, unless the lesion is so large as to cause discomfort, other local compressive complications, or cosmetic concern. Because cytology is not 100% sensitive for cancer exclusion, patients should be followed up for 12 to 24 months. For palpable lesions, follow-up should consist of physical examination; for nonpalpable lesions, sonography is usually advisable. Toxic adenomas diagnosed on the basis of a low serum TSH level and radionuclide confirmation of hot-nodule status can usually be assumed to be benign; treatment of associated thyrotoxicosis is, of course, indicated. Patients with cytologically malignant nodules should undergo thyroidectomy unless their general medical condition contraindicates it. Most patients with cytologically indeterminate nodules require surgery for definitive diagnosis, although if the suspicion of cancer is low, thyroid lobectomy may be worth considering. A subset of patients with cytologically indeterminate thyroid nodules (e.g., older women with multinodular goiter and no clinical features suggesting malignancy) can be followed with sonographic monitoring of the nodules' dimensions.
Thyroid cancers represent approximately 2% of clinically detected malignancies.108 The most common tumor types, arising from follicular epithelium (i.e., papillary, follicular, and Hürthle cell cancers), occur three times more often in women and increase in incidence with age. Medullary thyroid cancer arising from parafollicular C cells represents less than 10% of all thyroid cancers but has special importance because of its common familial occurrence. In the United States, the reported incidence of thyroid cancer is rising, perhaps because these tumors are being detected more easily with contemporary diagnostic tools.109
Etiology and Pathogenesis
The cause of most thyroid cancers is unknown. Genetic predisposition to papillary thyroid cancer is seen in the familial syndromes of familial adenomatous polyposis (APC gene mutation) and Cowden syndrome (PTEN gene mutations). It can also occur as familial isolated papillary thyroid cancer. Overall, however, familial cases represent less than 10% of all thyroid cancers.110 Thyroid irradiation from external sources and accidental radioiodine exposure predisposes to the development of malignant and benign thyroid tumors, as has been observed after radiotherapy (e.g., for recurrent tonsillitis and lymphoma) and after exposure to radioactive iodine fallout from a nuclear-weapon detonation or nuclear-reactor accident. Radioiodine exposure has been shown to produce a characteristic chromosomal rearrangement that creates theRET/PTC oncogene.
Progression and clinical aggressiveness of thyroid malignancies have been associated with a sequence of molecular events, including BRAFgene mutation and loss of the p53 tumor suppressor gene.111 Controversy surrounds evidence relating the development of thyroid cancer to preexisting benign thyroid conditions; to parity and estrogen therapy in women; to previous therapeutic radioiodine exposure; and to dietary factors, including iodine intake. Dietary iodine does clearly influence the distribution of thyroid cancer types, with more papillary cancers in populations with generous dietary iodine content.
Clinical manifestations and physical examination
Most thyroid cancers present as a thyroid nodule in an otherwise asymptomatic and euthyroid patient. Enlargement of the mass over weeks or months is more suspicious for cancer than longstanding stable size or very rapid appearance, which can represent hemorrhage into a preexisting benign nodule. Less commonly, patients develop complaints related to local invasion (e.g., pain, hoarseness, or hemoptysis) or distant metastatic disease (e.g., dyspnea, bone pain, or neurologic symptoms). On physical examination, nodule fixation or ipsilateral cervical adenopathy suggests thyroid cancer.
Cytologic diagnosis of thyroid cancer can often be established from material obtained by fine-needle aspiration of suspicious thyroid nodules [see Thyroid Nodules, above]. Patients with cytologically indeterminate lesions usually require surgery for definitive diagnosis. Novel molecular markers, such as BRAF in papillary thyroid cancers, may in the future permit more accurate preoperative diagnosis and exclusion of cancer in these lesions. In thyroid cancer patients who present with metastatic disease in cervical nodes, lungs, bone, and other sites, biopsy of the identified lesion often establishes the diagnosis, which can be confirmed by thyroglobulin immunostaining. Subsequent careful examination and sonographic imaging of the thyroid gland typically reveal a nodule that can then itself be subject to biopsy.
The therapeutic modalities commonly employed to treat patients with epithelial thyroid cancers are surgical thyroidectomy, radioiodine, and TSH-suppressive thyroid hormone therapy. Physicians and surgeons face the challenge of determining how aggressively these treatments should be applied to these patients, who exhibit a wide spectrum of disease behavior.112
When the diagnosis has been made preoperatively, total or near-total thyroidectomy is the procedure of choice. The rationale for bilateral thyroid excision is that papillary cancer, the most common thyroid malignancy, is often multifocal, involving the contralateral lobe in at least 20% of cases. Bilateral surgery has been shown to be associated with a lower papillary cancer recurrence rate.113 In addition, removal of all, or nearly all, normal thyroid tissue positions patients for more accurate long-term monitoring with serum thyroglobulin measurement and radioiodine imaging. When thyroid cancer is unexpectedly diagnosed after lobectomy, these potential benefits must be balanced against the risks and inconvenience of completion thyroidectomy. For patients with microscopic papillary and minimally invasive follicular cancers, unilateral surgery may be deemed to have been adequate.114 Unless regional node metastases are recognized before thyroidectomy, selective central neck compartment node excision is generally advisable, although modified radical neck dissection is justifiable when extensive nodal involvement is identified before or at the time of initial surgery.
Postoperatively, 131I is often recommended for patients with epithelial thyroid cancers, with the rationale of eradicating residual disease and ablating remnant thyroid tissue that will otherwise limit the accuracy of long-term monitoring with serum thyroglobulin and radioiodine scans. The value of adjunctive radioiodine treatment to reduce risk of tumor recurrence has been shown in retrospective and observational trials for patients with more advanced stages of disease.115 The principal factors related to an increased risk of recurrence are older patient age, larger tumor size, extrathyroidal invasion, incomplete tumor resection, and extensive and nodal metastases. In addition, certain histologic subtypes of thyroid cancer are more likely to recur, including the tall cell, columnar cell, and insular variants of papillary thyroid cancer, as well as follicular cancers with vascular invasion. Traditionally, patients have been withdrawn from thyroid hormone therapy postoperatively to effect a rise in endogenous TSH and to facilitate radioiodine uptake by residual thyroid tissue. This is effective but predictably causes clinical hypothyroidism. It has now been shown that radioiodine therapy can also be effective in euthyroid patients who are given recombinant thyrotropin.116
Patients with epithelial thyroid carcinoma require long-term thyroxine therapy both to replace thyroid hormone and to suppress TSH to reduce the risk of tumor recurrence. Typically, the thyroxine dose is increased until the lowest dosage capable of suppressing the serum TSH concentration to less than 0.1 µU/L is identified. In patients with symptoms of thyrotoxicosis or patients at low risk for tumor recurrence, the target TSH concentration may adjusted to the 0.1 to 0.5 µU/L range.
Patients treated for epithelial thyroid cancers require long-term follow-up to detect recurrent disease, which can present years after initial therapy. Serum thyroglobulin measurement has become the first-line choice for tumor detection.117 This thyroid-specific protein should be undetectable in the blood of patients who have no residual thyroid cancer and who have undergone complete ablation of normal thyroid tissue. When circulating thyroglobulin is detected—whether during thyroid hormone therapy or after TSH stimulation by either thyroid hormone withdrawal or recombinant TSH administration—imaging techniques should be employed to localize the residual disease. Cervical sonography and fine-needle aspiration of suspicious adenopathy is the most productive initial step, followed by CT of the chest and, in patients with a serum thyroglobulin concentration greater than 10 ng/ml, 18-fluorodeoxyglucose positron emission tomography. Radioiodine scanning with 123I or 131I is another monitoring technique that is particularly helpful in identifying residual normal thyroid tissue as the source of circulating thyroglobulin and in localizing iodine-avid residual cancer tissue that may be amenable to radioiodine therapy. Radioiodine imaging also requires TSH stimulation by thyroid hormone withdrawal or recombinant TSH administration.118
Additional treatment modalities may be required for patients with advanced epithelial thyroid cancers.119 Radioiodine can be employed for iodine-avid metastatic disease that is nonresectable, such as pulmonary metastases in younger patients with papillary thyroid cancer and metastatic follicular thyroid cancer in older patients. Repeat surgery may be indicated to excise recurrent cervical disease and, occasionally, other distant metastatic lesions that are solitary or that threaten to cause complications. External-beam radiotherapy can be used to treat nonresectable cervical disease, painful bone lesions, or pulmonary meta stases causing airway obstruction or hemoptysis. Chemo therapy for these tumors has only a partial response rate; moreover, the response rate is relatively low, and the risk of side effects is significant. Nonetheless, chemotherapy may be offered when other alternatives have been exhausted.
Less common and more aggressive thyroid malignancies are managed with some of the same therapeutic modalities. Med ullary thyroid cancer is treated with initial thyroidectomy.120 Thyroid hormone therapy for replacement, but not TSH suppression, is then prescribed. Patients are followed with serial calcitonin and carcinoembryonic antigen measurements. Repeat surgery, external-beam radiotherapy, and chemotherapy (which is relatively ineffective) are sometimes employed. Thyroid lymphoma, which is primary to the thyroid gland in half of cases, is diagnosable with tissue biopsy and is treated, sometimes rather effectively, with combined chemotherapy and radiation therapy. Anaplastic thyroid cancer is typically nonresectable and is also treated with combined external-beam radiotherapy and chemo therapy.121Only in exceptional cases, however, do these interventions significantly alter the grim prognosis.
Complications can occur in thyroid cancer patients as a result of the malignancy or its treatment. Local cervical invasion of the recurrent laryngeal nerve can cause temporary or permanent hoarseness, dysphagia, and dyspnea. Progression of tumor in the neck can lead to strangulation or esophageal obstruction and malnutrition. Pulmonary failure can occur with pulmonary metastases, fractures with bony involvement, paraparesis with paraspinal lesions, and other neurologic consequences with brain dissemination. Functioning metastases can cause thyrotoxicosis in patients with follicular cancer and, rarely, in patients with papillary carcinoma.
Thyroidectomy may be complicated by recurrent laryngeal nerve injury or hypoparathyroidism. Radioiodine treatment can cause gastritis with short-term symptoms, and it can cause sialadenitis, whose symptoms are dry mouth, loss of taste, and dental caries. High cumulative doses of therapeutic 131I have been associated with an increase in the risk of leukemia. External-beam radiotherapy and chemotherapy have their usual potential for adverse reactions.
The indolent growth of most thyroid tumors and the efficacy of available therapies result in a low mortality, with survival rates of 98% for papillary, 92% for follicular, and 80% for medullary cancers.122 Clinical recurrence is common, however; for example, almost one third of papillary thyroid cancers recur. Extracervical medullary cancer is incurable but generally follows a slowly progressive course. Poorly differentiated epithelial cell thyroid cancers and anaplastic thyroid cancers unfortunately can be among the most aggressive and treatment-resistant malignancies known.
Figures 2 and 3 Seward Hung.
Editors: Dale, David C.; Federman, Daniel D.