Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

66.Diagnosis of Hypothyroidism

Paul W. Ladenson

Since the syndrome of myxedema was described more than a century ago, criteria for the diagnosis of hypothyroidism have evolved from clinical observation to bioassays, increasingly specific measurements of thyroid hormones in serum, and quantitation of endogenous thyrotropin (thyroid-stimulating hormone, TSH) production. Accurate diagnosis of hypothyroidism requires awareness of the clinical features that define a patient's risk for thyroid hormone deficiency and proper use of the two tests usually required to confirm the disorder: serum TSH and free thyroxine (T4) assays. These sensitive and specific measures of thyroid function have largely resolved the inaccuracy associated with the clinical diagnosis of hypothyroidism. However, they also have introduced new diagnostic challenges. First, we now appreciate that there are many patients with few clinical manifestations of hypothyroidism and mild thyroid hormone deficiency that is revealed only by serum TSH measurements—a disorder defined as mild or subclinical hypothyroidism (1). Second, thyroid test abnormalities are common in patients with nonthyroidal illness (2). Consequently, clinicians must still integrate clinical observations with laboratory test results to properly diagnose and manage patients with hypothyroidism.


Three types of clinical evidence suggest hypothyroidism: symptoms and signs consistent with thyroid hormone deficiency; evidence of disease, previous treatment, or exposure known to cause thyroid or pituitary failure; and the presence of disorders associated with increased risk of chronic autoimmune thyroiditis.


Thyroid hormone deficiency may present as an obvious clinical syndrome (e.g., cretinism or myxedema). Clinical manifestations are also often present in patients with mild to moderate hypothyroidism. In one large population survey, individuals with a greater number of typical symptoms, particularly if they were new complaints, were more likely to have thyroid function test results that confirm the diagnosis (3). However, symptoms were present in only 30% of biochemically hypothyroid patients, whereas 17% of euthyroid people had the same complaints. As a result, the positive predictive value of individual symptoms was only 8% to 12%. Consequently, although symptom scoring scales with significant predictive power have been described (4), they remain too insensitive and nonspecific for definitive diagnosis (5).

Even in patients with overt biochemical hypothyroidism, symptoms and signs may be minimal or absent (5a). Several factors account for the subtlety with which hypothyroidism can present: its insidious onset, the presence of mild thyroid hormone deficiency, and the passivity that accompanies hypothyroidism in many patients. Furthermore, many of the symptoms of hypothyroidism are nonspecific (e.g., fatigue and constipation), as are several of the physical findings (e.g., dry skin and weight gain). Among patients with symptoms potentially attributable to hypothyroidism in a primary care setting, the diagnosis is established in only 1% to 4% (6,7). Moreover, hypothyroidism can have age- and sex-specific presentations (e.g., impaired growth in children, menorrhagia in menstruating women, and dementia in the elderly).

Predisposition to Hypothyroidism

Hypothyroidism should be suspected when there is evidence of an underlying thyroid, pituitary, or hypothalamic disorder known to cause thyroid failure, or when some previous treatment has destroyed thyroid, pituitary, or hypothalamic tissue. For example, the presence of a diffuse goiter, a common manifestation of chronic autoimmune thyroiditis, should prompt laboratory evaluation for hypothyroidism (see Chapter 47). A history of previous thyroid surgery or radioactive iodine therapy likewise suggests possible primary hypothyroidism, which can occur both soon or many years after either treatment. This is particularly true in patients with Graves' disease, which may eventually cause hypothyroidism even without destructive therapy (8). Neck surgery and external radiation therapy for lymphoma (9) and head and neck cancer (10) also frequently cause hypothyroidism (see Chapter 50).

Clinical evidence of hypothalamic or pituitary disease should raise suspicion of central hypothyroidism, also known as secondary or hypothyrotropic hypothyroidism (see Chapter 51) (7). Hypothalamic disorders that can cause thyrotropin-releasing hormone (TRH) deficiency include tumors and granulomatous diseases. The pituitary's thyrotropic cells can be affected by endocrine and other tumors, treatment for them, inflammation, or hemorrhage. Therefore, other evidence of hypopituitarism, such as growth failure, hypogonadism, adrenal insufficiency, or diabetes insipidus; an expanding sellar mass lesion (e.g., headache, bitemporal hemianopsia); or a pituitary tumor secreting hormones other than TSH should prompt evaluation for hypothyroidism.

Risk factors for hypothyroidism include a variety of drugs, of which lithium carbonate and amiodarone are the most commonly used (11) (see Chapter 11C). Iodine in pharmacologic quantities, such as occurs with amiodarone therapy (12), can cause hypothyroidism in patients with underlying thyroid disease by interfering with thyroid hormone synthesis and release (see Chapter 11F). Phenytoin, carbamazepine, and rifampin, which increase the clearance of T4, can cause hypothyroidism in patients with limited thyroid reserve (13) (see Chapter 11C). Patients with mycosis fungoides who are treated with the selective retinoid-X receptor ligand bexarotene can develop central hypothyroidism due to the drug's suppression of TSH production (13a).

Chronic Autoimmune Thyroiditis and Hypothyroidism

The patient's personal and family histories and presence of a goiter on physical examination may provide clues to the presence of chronic autoimmune thyroiditis and therefore the presence of hypothyroidism. Treatment with interferon-α has been associated with a high incidence of autoimmune thyroiditis and hypothyroidism that can be reversible after use of the agent is discontinued (14). Because of the genetic predisposition to chronic autoimmune thyroiditis, patients with affected family members are at increased risk for having hypothyroidism. Certain other endocrine deficiencies believed to have an autoimmune pathogenesis also are associated with chronic autoimmune thyroiditis, including idiopathic adrenal insufficiency, autoimmune diabetes mellitus, hypoparathyroidism, and primary ovarian failure. Patients with several other autoimmune disorders, including vitiligo, atrophic gastritis, pernicious anemia, systemic sclerosis, and Sjögren's syndrome, are also at increased risk of autoimmune thyroiditis.


Several laboratory test abnormalities may suggest hypothyroidism but are not specific tests for it. They include hypercholesterolemia, hyperprolactinemia, anemia, hyponatremia, hyperhomocysteinemia, and elevated levels of the skeletal muscle–associated isoenzymes creatine phosphokinase and lactic dehydrogenase. Other abnormalities that may indicate the presence of hypothyroidism are x-ray or echocardiographic evidence of pericardial effusion or impaired myocardial contractility. Diffuse flat T waves and low voltage are also present in patients with more overt hypothyroidism.

Failure of thyroid hormone production causes a decline in serum (and plasma) T4 concentrations. Serum triiodothyronine (T3) concentrations also decline, but not until hypothyroidism is severe. Most patients with overt hypothyroidism have primary thyroid disease, which results in low serum T4 and high serum TSH concentrations. In contrast, the infrequent patients with central hypothyroidism most often have low serum T4 concentrations and low or normal serum TSH concentrations. It is important to remember, however, that even these serum thyroid function test findings are not entirely specific for hypothyroidism. Abnormal serum thyroid hormone–binding protein concentrations may mask or falsely suggest hypothyroidism (see next section). Serum TSH concentrations may be elevated despite normal serum T4 concentrations when hypothyroidism is mild (subclinical hypothyroidism). Furthermore, some patients with central hypothyroidism actually have slightly elevated serum TSH concentrations due to secretion of TSH that is immunoreactive but bioinactive (15).

Serum Thyroxine Determinations

The serum total T4 concentration can be measured accurately by competitive protein-binding assays that use either anti-T4 antibodies or serum thyroid hormone–binding proteins (see Chapter 13). Because most (99.97%) of the T4 in serum is bound to thyroxine-binding globulin (TBG), transthyretin (TTR, or thyroxine-binding prealbumin), and albumin, low concentrations of one or more of these serum proteins and drug-induced inhibition of T4 binding to them result in low serum total T4 concentrations (hypothyroxinemia) that can be misconstrued as indicating hypothyroidism (Table 66.1). Conversely, increased serum protein binding of T4 may mask hypothyroidism.


Mimicking conditions—hypothyroxinemia

   Decreased serum TBG concentration


      Drugs: androgens, glucocorticoids

      Nephrotic syndrome

      Severe liver dysfunction

   Competitive inhibition of T4 binding

      Drugs: salicylate, furosemide

      Nonthyroidal illnesses

Masking conditions

   Increased serum TBG concentration


      Estrogen: pregnancy, exogenous, tumoral production

      Hepatitis, hepatoma

      HIV infection

      Drugs: methadone, heroin, clofibrate, 5-fluorouracil

Familial dysalbuminemic hyperthyroxinemia

Increased transthyretin binding


   Pancreatic and hepatic tumors

HIV, human immunodeficiency virus; TBG, thyroxine-binding globulin; T4, thyroxine.

Measurement of serum free T4 resolves most of these problems. Although equilibrium dialysis and ultrafiltration are the most accurate methods for determining serum free T4, serum free T4 radioimmunoassays and the serum free T4 index are adequate for this purpose in most circumstances, and they are simpler, quicker, and less costly. Almost all serum free T4 assays have excellent sensitivity for detection of hypothyroidism in symptomatic patients. The serum free T4 index is the product of the serum total T4 and the thyroid hormone–binding ratio (THBR, also known as the T3 uptake or T4 uptake) (16) (see Chapter 13). Serum free T4 assay techniques usually yield comparable values. The THBR value, however, can sometimes provide additional useful information in patients with nonthyroidal illness, in whom the values are often normal or high despite low calculated serum free T4 index values and free T4 concentrations; in contrast, THBR values are low in most patients with hypothyroidism (17).

The principal shortcoming of serum T4 determinations is the prevalence of low values in hospitalized patients with nonthyroidal illness. For example, in one study about 20% of patients admitted to an inpatient medical service had low serum total T4 concentrations, and 12% of these patients had low free T4 index values (18).

Serum TSH Determinations

Assay of serum TSH is an exquisitely sensitive test for identifying patients with any degree of primary hypothyroidism. As thyroid hormone production decreases in patients with any form of thyroid injury, serum TSH increases. The decrease in thyroid secretion may be small and not sufficient to reduce the serum total or free T4 concentration to below the reference range. Because an elevated serum TSH concentration identifies primary hypothyroidism, the analytic sensitivity of the TSH assay (i.e., the least detectable TSH concentration) is not critical in using this test to study patients suspected of having hypothyroidism.

The combination of an elevated serum TSH with a normal free T4 value defines the syndrome of mild or subclinical hypothyroidism. Several small studies have shown that some of these patients have symptoms (19,20) or hypercholesterolemia (1,21) that respond specifically to T4 therapy. Furthermore, patients with an isolated elevation of the serum TSH concentration are at increased risk for progression to hypothyroidism (22), particularly if they also have circulating antithyroid antibodies indicative of autoimmune thyroiditis (see Chapter 47) (23,24).

Serum TSH measurements alone do not identify all patients with hypothyroidism. Some patients with central hypothyroidism have normal serum TSH concentrations, although in others they are low or even modestly elevated. Furthermore, serum TSH concentrations may be high in conjunction with high total and free serum T4 concentrations in patients with two unusual conditions: generalized thyroid hormone resistance and TSH-induced thyrotoxicosis, which can, in turn, be caused by TSH-secreting pituitary adenomas or by isolated pituitary resistance to thyroid hormone (25,26). However, in T4-treated hypothyroid patients, this combination of results is most often due to erratic ingestion of T4 medication (27). Serum TSH concentrations may also be transiently elevated during recovery from nonthyroidal illness (28) and painful subacute and postpartum lymphocytic thyroiditis (see Chapter 11D).

Serum TSH concentrations are often low in patients with nonthyroidal illness (29), but suppression of TSH secretion is seldom, if ever, great enough to mask primary hypothyroidism. The exception to this rule may be the hypothyroid patient who has a severe nonthyroidal illness and ho is receiving dopamine or glucocorticoid therapy, each of which inhibit TSH secretion. Differentiating the hypothyroxinemia of nonthyroidal illness from central hypothyroidism can often be accomplished by serial testing of thyroid function. It also requires careful consideration of clinical and laboratory clues suggesting hypothalamic or pituitary disease (e.g., atrophic testes in men, a low serum cortisol concentration or lack of an elevated serum follicle-stimulating hormone concentration in postmenopausal women). In some patients, cranial imaging is required to exclude disorders causing central hypothyroidism.

Other Measures of Thyroid Hormone Action

A variety of physiologic measures and serum constituents have been used to quantify thyroid hormone action in peripheral tissues, among them determinations of serum cholesterol, ankle reflex relaxation time, and myocardial contractility. The accuracy of these tests has been evaluated in management of central hypothyroidism (30), for which they would theoretically be particularly useful in the absence of reliable TSH guidance. However, none of these peripheral tissue response parameters is sufficiently sensitive or specific for hypothyroidism to be useful clinically. Similarly, measurement of basal body temperature is a very poor diagnostic test for hypothyroidism.


It is important to distinguish between case finding and screening for hypothyroidism. Case finding refers to laboratory testing of individual patients or well-defined populations (e.g., those previously treated with radioiodine), whereas screening implies wide-scale testing of large populations, either indiscriminately or based on broad demographic criteria (e.g., older women). Two strategies may be used in case finding or screening: measurement of serum TSH or free T4. The choice should be based on the pretest probability of hypothyroidism, the potential for confounding influences in assay interpretation, and cost. With respect to case finding, patients can be categorized as having low, moderate, or high risk for hypothyroidism based on published studies of patients with different conditions (Table 66.2). In patients with a low risk for hypothyroidism, a single test should be used. The serum TSH is preferable when detection of subclinical hypothyroidism is important, when coexisting nonthyroidal illness may cause hypothyroxinemia, or when both hypothyroidism and thyrotoxicosis must be excluded. The serum free T4 index or free T4 should be used when central hypothyroidism is a possibility. If either test result is abnormal, the other measurement should be done before any intervention is undertaken. In patients at moderate or high risk for hypothyroidism or those who have symptoms or signs of hypothyroidism in the absence of any of the risk factors listed in Table 66.2, serum TSH and free T4 or free T4 index should both be measured (Fig. 66.1). A high serum TSH value and a low serum free T4 value nearly always confirm the diagnosis of primary hypothyroidism; the rare exception is a patient who has central hypothyroidism and is producing bioinactive TSH. A high serum TSH value—albeit usually less than 25 mU/L—and a normal serum free T4value are diagnostic of mild or subclinical hypothyroidism. If the serum TSH is low or normal and the serum free T4 is low, the diagnosis is central hypothyroidism, nonthyroidal illness, or the thyroxine-lowering effect of certain drugs, such as phenytoin. The distinction between these two possibilities must be based on the context in which the patient is encountered, the presence of other manifestations of hypothalamic or pituitary disease, and the results of follow-up determinations.


Patients or conditions with low risk (prevalence < 2%)

   Adults and children at routine visits


   Psychiatric patients

   Elderly patients


   Sleep apnea

Patients or conditions with moderate risk (prevalence 3%–10%)

   Goiter or thyroid nodular disease

   Lithium carbonate therapy

   Associated autoimmune diseases, such as pernicious anemia

   Graves' ophthalmopathy

   Postpartum women

Patients or conditions with high risk (prevalence > 10%)

   Chronic autoimmune thyroiditis

   Previous treatment for thyrotoxicosis

   Previous high-dose neck radiation therapy

   Suspected hypopituitarism

   Amiodarone therapy

FIGURE 66.1. Laboratory assessment of hypothyroidism.

With regard to population screening for hypothyroidism, or thyroid dysfunction in general, the recommendations of professional societies and expert consensus panels differ widely (Table 66.3). One society recommends TSH screening of all adults over 35 years (31), whereas another supports screening only for women over 50 years of age (32). Some panels restrict their recommendations for thyroid function screening to women before or during early pregnancy (33,34). Others advise against laboratory screening for adults under 60 years of age (35), or find insufficient evidence to support population screening for thyroid dysfunction at all (36,37). A decision and cost-effectiveness model of every-5-year TSH screening for women and men beginning at age 35 estimated the cost of this intervention to be $9,200 and $22,300 per quality-adjusted life-year in women and men, respectively (38). These amounts are considerably less than those widely considered reasonable for detection of other conditions, such as hypertension, hypercholesterolemia, and breast cancer, in asymptomatic adult populations.



Summary of Recommendation

American College of Physicians, 1998 (32)

Only office-based screening for women 50 years and older is recommended.

American Thyroid Association, 2000 (31)

Adults, particularly women, should be screened for thyroid dysfunction by measurement of the serum thyroid-stimulating hormone (TSH) concentration beginning at age 35 years and every 5 years thereafter in the context of the periodic health examination.

 Individuals with clinical manifestations potentially attributable to thyroid dysfunction and those with risk factors for its development may require more frequent TSH testing.

American Association of Clinical Endocrinologists, 2002 (33)

Screening for thyroid dysfunction by TSH measurement should be routine in women before or during the first trimester of pregnancy.

American Academy of Family Physicians, 2002 (35)

Screening for thyroid dysfunction at the periodic health examination for individuals under 60 years of age (except neonates) is not recommended.

National Academy of Clinical Biochemistry, 2003 (34)

Women should be screened for screening for thyroid dysfunction using serum TSH and thyroperoxidase autoantibodies (TPOAb) either prepregnancy or during first trimester to detect mild thyroid insufficiency and assess their risk for postpartum thyroiditis.

Consensus Development Conference, 2004a(36)

There is insufficient evidence to support population-based screening. Aggressive case finding is appropriate in pregnant women, women over 60 years of age, and others at high risk for thyroid dysfunction.

U.S. Preventive Services Task Force (USPSTF), 2004 (37)

There is insufficient evidence to recommend for or against routine screening for thyroid disease in adults.

aExpert panel nominated by a planning committee composed of representatives of the American Thyroid Association, the American Association of Clinical Endocrinologists, and the Endocrine Society.

It is important for health professionals and payers responsible for developing policies related to thyroid screening procedures to appreciate two things. First, their protocols should not interfere with the ability of practitioners to pursue appropriate case finding for hypothyroidism in individual patients or populations at high risk. Second, the recommendations of professional societies differ widely, and those guidelines that do not currently support screening do so because of a lack of evidence, not because studies have shown that the practice is futile or harmful. Decision makers should pay attention to new data addressing this issue, particularly concerns regarding undiagnosed hypothyroidism in women who are or plan to become pregnant.


Although clinical findings suggest the cause of hypothyroidism in most patients, it is crucial that these be supported by the serum TSH to exclude those with central hypothyroidism. These latter patients may be endangered by the failure to recognize and treat other consequences of hypopituitarism, particularly adrenal insufficiency and pituitary mass lesions.

Antithyroid thyroid peroxidase (anti-TPO or antimicrosomal) or antithyroglobulin antibodies are present in more than 90% of patients with chronic autoimmune thyroiditis. Although detection of these antibodies indicates that this disorder is the probable cause of primary hypothyroidism, the practical value of these assays is greater in other settings, for example, in predicting the likelihood of progression of mild thyroid failure (22,23,24), increasing suspicion of underlying thyroid disease in hypothyroxinemic patients with nonthyroidal illness, and predicting postpartum thyroiditis (39).

Several tests have little or no value in diagnosing or defining the cause of hypothyroidism, or are outmoded. Serum T3 measurements are insensitive because the values are normal in about one third of overtly hypothyroid patients. Furthermore, they are nonspecific because the values are subnormal in many patients with nonthyroidal illness (Chapter 11D). TRH stimulation testing can be helpful in identifying patients with mild central hypothyroidism, but it is no more useful than basal serum TSH measurements in identifying subclinical primary hypothyroidism. TRH tests also fail to distinguish reliably between hypothalamic and pituitary hypothyroidism, and between these two disorders and nonthyroidal illness (2).


Despite the several sensitive and usually specific tests for accurate evaluation of patients with potential hypothyroidism, certain clinical problems occasionally remain unresolved. The evaluation of hypothyroxinemic patients with nonthyroidal illness would be aided by more practical techniques to quantify the biologically active free thyroid hormone fractions in serum and tissues. Simple methods of quantifying tissue thyroid hormone responsiveness—in addition to serum TSH assay—would be very useful, but all foreseeable approaches are nonspecific and, like serum TSH, may not be generalizable beyond the organ system assessed.


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