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.
Definitions
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.
Epidemiology
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].
Thyroid nodules
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 non-palpable 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 HI.45
Thyroid cancer
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
Epidemiology
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.1 Prevalences 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 hy-pothyroidism, 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 Sjogren 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.
Congenital Hypothyroidism
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 sym-porter, 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 | chain, and the TSH receptor. A mutation in the gene for Gsa, which mediates adenylate cyclase activation in thyroid cells, causes hypothyroidism in pseudohypoparathy-roidism. Inherited resistance to thyroid hormone can be caused by mutations in the | isoform of the nuclear triiodothyronine (T3) receptor.
Figure 1 Prevalences of abnormalities on thyroid function tests in different populations in the third National Health and Nutrition Examination Survey.
Acquired Hypothyroidism
Autoimmune thyroiditis 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 thy-roiditis, 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 interfer-on-alfa therapy and can cause either hypothyroidism or hyper-thyroidism.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 hypothy-roidism 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 perchlo-rate 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
Pathogenesis
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 su-perfamily.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 hypercholesterole-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 hy-pothyroidism 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
Diagnosis
Clinical Manifestations
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.
Physical Examination
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 hy-pothyroid patients present with other unusual features, such as chronic heart failure, pericardial and pleural effusions, 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 non-palpable, 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 hy-poparathyroidism (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 Sjogren syndrome.
Laboratory Tests
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 hypothy-roidism 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 ^U/L.
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Table 1 Causes of Elevated Serum TSH Levels |
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Primary hypothyroidism |
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Central hypothyroidism* |
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Recovery after nonthyroidal illnesses |
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Renal insufficiency |
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Adrenal insufficiency |
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Drugs |
|
Metoclopramide |
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Phenothiazines? |
|
Analytic problems |
|
Anti-TSH antibodies |
|
Anti-mouse immunoglobulin antibodies |
*Attributable to TSH with reduced biologic-to-immunologic activity ratio.
However, values are not normally distributed; the mean TSH concentration, 1.5 ^.U/L, is in the lower half of the reference range.1 Even a high-normal serum TSH level (e.g., 3.0 ^U/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 ^U/L.28
When an elevation in serum TSH is detected in a potentially hypothyroid patient, the test should be repeated, and the serum free T4 concentration 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 T3 concentration 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 sarcoido-sis. In these settings, both the serum free T4 and TSH concentrations should be measured. Detection of a low serum free T4 concentration, 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 ^U/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.
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 dobuta-mine) 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.
Differential diagnosis
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.
