Paul W. Ladenson
Thyrotoxicosis often presents as a distinctive clinical syndrome readily confirmed by the findings of a low serum thyrotropin (thyroid-stimulating hormone, TSH) concentration and high serum thyroid hormone concentrations. Nonetheless, there are challenges in the clinical and laboratory diagnosis of the disorder. Clinically, there may be delay in appreciating that commonly encountered symptoms, such as nervousness or palpitations, are manifestations of thyrotoxicosis. Physicians and patients also may fail to recognize atypical and occult clinical presentations. Diagnostic testing is important to differentiate thyrotoxicosis from other conditions causing real and apparent elevations in serum thyroid hormone concentrations (1) and to distinguish among its specific causes so that the most appropriate treatment is used.
CLINICAL DIAGNOSIS
The symptoms and signs of overt thyrotoxicosis often result in a virtually pathognomonic clinical picture. Clinical diagnostic indices based on these symptoms and signs accurately identify most patients with overt thyrotoxicosis (2), but they have not been prospectively applied to primary care populations and correlate poorly with its biochemical severity (3). There is considerable variability among patients in particular clinical features and their severity. For example, although weight loss despite good appetite is a classic manifestation of thyrotoxicosis, some patients gain weight and others are anorectic (4). Furthermore, elderly patients may have few or none of the usual symptoms and signs of thyrotoxicosis (4), a syndrome termed apathetic thyrotoxicosis, but instead present with cardiovascular problems or weight loss. Certain other syndromes, such as atrial fibrillation and systolic hypertension; hypercalcemia, nephrolithiasis, and osteoporosis; new unexplained headache; persistent vomiting and hyperdefecation; or muscle weakness should also suggest thyrotoxicosis. Severe thyrotoxicosis may mimic febrile illnesses, heart failure due to primary cardiac disease, or toxic delirium. Thus, the clinical manifestations of thyrotoxicosis can vary considerably, and the diagnosis must be suspected clinically before it can be established or excluded by biochemical studies.
In most patients, the cause is Graves' disease, which may have unique clinical manifestations of its own, including urticaria, pruritus, or enlargement of the thymus or spleen. Hyperthyroid Graves' disease is often accompanied by ophthalmopathy; rare patients have localized myxedema or thyroid acropachy (see the sections on ophthalmopathy and localized myxedema and thyroid acropachy in Chapter 23). The presence of exophthalmos, whether symmetric or not, or other extrathyroidal signs of Graves' disease should prompt laboratory assessment for thyrotoxicosis. Furthermore, certain groups have an increased risk for developing Graves' disease, including women in the third through sixth decades of life, patients with a family history of autoimmune thyroid disease, and those with certain other disorders with an autoimmune pathogenesis (e.g., pernicious anemia, autoimmune diabetes mellitus, and myasthenia gravis). Patients who smoke cigarettes (5), are receiving the immunomodulatory agents interferon-α and interleukin-2 (6), or have a history of previous high-dose neck irradiation (7) are also at increased risk for developing Graves' disease.
Clinical features also may identify patients with less common forms of thyrotoxicosis. Patients with thyrotoxicosis caused by subacute (de Quervain's) thyroiditis have thyroid pain and tenderness and constitutional complaints, including fever, night sweats, and malaise. Those with toxic nodular goiter are usually older, and their thyrotoxicosis may have been provoked by recent exposure to iodine-containing medications (e.g., radiographic contrast agents). Detection of a thyroid nodule or multinodular goiter warrants screening for overt or subclinical thyrotoxicosis. The iodine-containing antiarrhythmic agent amiodarone can also provoke iodine-induced hyperthyroidism in patients without thyroid nodules as well as a painless thyroiditis that can cause transient thyrotoxicosis. Silent (painless, postpartum, or lymphocytic) thyroiditis most often affects women 2 to 8 months postpartum (see Chapter 27) but can occur after abortion. Rarely, it can occur in women who have not been pregnant and in men. Factitious thyrotoxicosis is most likely to occur in health-care workers or persons with access to thyroid hormone preparations, for example, those with a family member or canine pet taking thyroid hormone.
CLUES FROM ROUTINE LABORATORY TESTS
Certain abnormalities detected by routine biochemical screening also may suggest the presence of thyrotoxicosis. These include hypercalcemia, an elevated serum alkaline phosphatase concentration, and a serum cholesterol concentration that is either low or lower than previously determined. The concentrations of certain less commonly measured substances, including ferritin and angiotensin-converting enzyme, are also increased in thyrotoxicosis. The presence of thyrotoxicosis should be considered when atrial arrhythmias are detected by electrocardiography.
LABORATORY TESTING
Biochemical confirmation of thyrotoxicosis has traditionally been based on detection of elevated serum total and free thyroxine (T4) and triiodothyronine (T3) concentrations (8). Most patients have high serum concentrations of both hormones, but some have isolated increases of either T4 or T3. Although serum thyroid hormone measurements are useful for detecting thyrotoxicosis and monitoring treatment of it, they have two limitations. First, there are other causes of high serum T4 or T3 concentrations. Second, some thyrotoxic patients have serum T4 and T3 concentrations within the upper portion of the normal range. The development of sensitive assays for serum TSH has greatly simplified the diagnostic approach to thyrotoxicosis. TSH assays also have expanded the spectrum of thyrotoxicosis to include mild or subclinical thyrotoxicosis (see Chapter 79), in which suppression of the serum TSH to less than 0.1 mU/L occurs despite normal serum T4 and T3 levels.
SERUM THYROXINE DETERMINATIONS
The serum total T4 concentration can be measured accurately by competitive protein-binding assays using either anti-T4 antibodies or serum thyroid hormone–binding proteins. Most (99.97%) of the T4 in serum is bound to thyroxine-binding globulin (TBG), transthyretin (TTR, or thyroxine-binding prealbumin), or albumin. An increase in the concentration or thyroid hormone-binding of any of these serum proteins, especially TBG, can cause a high serum total T4concentration (hyperthyroxinemia), which can be misconstrued as thyrotoxicosis (Table 44.1). Conversely, decreased T4 binding by serum proteins may mask excess thyroid hormone production.
TABLE 44.1. CAUSES OF ELEVATED SERUM THYROXINE CONCENTRATIONS
Thyrotoxicosis
Increased serum protein binding
Increased serum thyroxine-binding globulin concentrations
Inherited
Estrogen: pregnancy, exogenous, tumoral production
Hepatitis, hepatoma
HIV infection
Drugs: methadone, heroin, clofibrate, 5-fluorouracil
Familial dysalbuminemic hyperthyroxinemia
Increased serum transthyretin binding or concentrations
Inherited
Carcinoma of pancreas, hepatoma
Psychiatric and medical illness
Drugs
Propranolol (high doses)
Amiodarone
Radiographic contrast agents used for cholecystography
Anti-T4 immunoglobulins
Determining the serum free T4 concentration resolves most potential pitfalls associated with increased serum protein binding of T4. Although equilibrium dialysis and ultrafiltration are the most accurate techniques for serum free T4 measurement, serum free T4 immunoassays and the serum free T4 index readily differentiate thyrotoxicosis from the most common cause of hyperthyroxinemia, which is TBG excess. Furthermore, free T4 immunoassays and the serum free T4 index are simpler, quicker, and less costly. Most serum free T4 immunoassays employ an analogue of T4 that does not bind to thyroid hormone–binding proteins. The free T4 index is the product of the serum total T4and the thyroid hormone–binding ratio (THBR; also known as the T3 or T4 uptake) (9). These assays are discussed in detail in Chapter 13.
Other conditions that cause euthyroid hyperthyroxinemia may be more difficult to differentiate from thyrotoxicosis. Patients with familial dysalbuminemic hyperthyroxinemia have a mutated form of albumin that binds T4 with increased affinity, increasing the serum total serum T4 concentration (10,11). Because the mutated albumin usually binds T3 poorly, the THBR value is typically normal, and therefore the serum free T4 index value is deceptively high. Serum free T4 analogue immunoassay methods also may yield falsely elevated values in this condition. Similarly, increased TTR binding of T4, which occurs as both an inherited trait (12) and in patients with carcinoma of the pancreas or liver (13), causes an increased serum total T4 concentration. Thyroid hormone–binding antibodies, which may be present in patients with chronic autoimmune thyroiditis or other autoimmune disorders, may cause spurious elevations in serum T4or T3 concentrations (14).
Hyperthyroxinemia also may occur as a result of disorders that transiently increase the secretion of TSH (or chorionic gonadotropin) or disorders and medications that reduce T4 clearance. For example, in one study of patients admitted to an inpatient medical service, modest elevations in serum total T4 and free T4 index values were found in 4% and 12%, respectively (15). Two disorders—acute psychosis (16,17) and hyperemesis gravidarum (18)—have been associated with a substantial prevalence of euthyroid hyperthyroxinemia. Propranolol, when given in high dosages [>160 mg/day (19)], and amiodarone (20) impair T4 clearance, causing euthyroid hyperthyroxinemia (see section on Effects of Pharmacologic Agents on Thyroid Hormone Metabolism in Chapter 11). Even though they have no clinical evidence of thyrotoxicosis, some patients receiving T4 therapy have modest hyperthyroxinemia. Finally, patients with generalized thyroid hormone resistance typically have elevated serum total and free T4 and T3 concentrations and normal or slightly increased TSH concentrations (21) (see Chapter 81).
Therefore, hyperthyroxinemia is not a pathognomonic manifestation of thyrotoxicosis. Differentiating thyrotoxicosis from euthyroid hyperthyroxinemia is often straightforward, based on clinical information (i.e., symptoms and signs of thyrotoxicosis or the other conditions associated with hyperthyroxinemia). Serum TSH measurement is invaluable in distinguishing euthyroid hyperthyroxinemia, in which serum TSH usually is normal, from all common forms of thyrotoxicosis, in which serum TSH is low.
SERUM TRIIODOTHYRONINE DETERMINATIONS
Serum total and free T3 concentrations are high in most patients with thyrotoxicosis. This is attributable to both increased thyroidal T3 production and increased extrathyroidal conversion of T4 to T3. About 2% of thyrotoxic patients in the United States have T3 thyrotoxicosis; that is, they have high serum T3but normal T4 concentrations. The diagnostic sensitivity of serum T3 determinations alone is limited because some thyrotoxic patients have T4 thyrotoxicosis (22). T4 toxicosis occurs primarily in patients with iodine-induced hyperthyroidism, inflammatory forms of thyroiditis, and intercurrent severe nonthyroidal illness in which extrathyroidal T3 production from T4 is inhibited. Although serum T3 concentrations are high in patients who have elevated serum TBG concentrations, the lower affinity of TBG for T3 leads to a lesser increase in serum T3 than T4. Serum T3 concentrations may be spuriously elevated in rare patients with T3-binding antibodies (14). A kindred has been reported with familial dysalbuminemic hypertriiodothyroninemia, in which a mutant albumin bound T3, but not T4 with higher affinity (23). Consequently, an elevated serum total T3 concentration is only relatively specific for thyrotoxicosis. With the availability of sensitive serum TSH assays, the diagnostic utility of serum T3 measurements—never great—has declined further. However, they are occasionally useful in monitoring treatment in patients with thyrotoxicosis, in whom antithyroid drug or radioactive iodine therapy may have discordant effects on serum T4and T3 concentrations; for example, the serum T3 concentration may remain elevated despite a normal or low serum T4 (24).
SERUM THYROTROPIN DETERMINATIONS
The sensitivity of TSH secretion to inhibition by thyroid hormone makes serum TSH measurement a remarkably accurate test for diagnosis of all common forms of thyrotoxicosis. TSH assays with detection limits of 0.1 mU/L or lower readily differentiate between these patients and normal subjects (25). The recent authoritative National Association of Clinical Biochemistry guideline for laboratory diagnosis of thyroid disease specifies that TSH assay methods should have functional sensitivity of less than 0.02 mU/L, as defined by the assay's 20% between-run coefficient of variation (25a). These assays have rendered thyrotropin-releasing hormone (TRH) stimulation tests obsolete, except possibly in the investigation of very sick hospitalized patients, who may have very low serum TSH concentrations (26,27) (see the section on Nonthyroidal Illness in Chapter 11). Although a sensitive indicator of thyrotoxicosis in general, serum TSH concentrations are normal or even elevated in the rare patients with TSH-induced thyrotoxicosis due to TSH-secreting pituitary adenoma (28) or isolated pituitary resistance to thyroid hormone (See Chapters 24 and 81). Spurious elevation of the measured TSH level, potentially masking thyrotoxicosis, also may be the result of rare analytical problems, such as the presence of circulating anti-TSH immunoglobulins or human antimouse monoclonal immunoglobulins when these antibodies are used as an assay reagent (29).
SCREENING, CASE FINDING, AND DIAGNOSIS
Based on the infrequency of thyrotoxicosis, and the relative ease with which it can be recognized clinically, biochemical screening for thyrotoxicosis among healthy persons is unjustified. Case finding, that is, the identification of thyrotoxicosis in patients with vague symptoms or signs that could indicate the presence of thyrotoxicosis or in persons with special risk of thyrotoxicosis (e.g., amiodarone-treated patients), can best be done by measurement of the serum TSH concentration (30).
Virtually all patients with thyrotoxicosis have low or undetectable serum TSH concentrations; only the rare patient with TSH-induced thyrotoxicosis will be missed by this approach. Therefore, a normal serum TSH concentration is strong evidence that the patient is euthyroid. However, low (i.e., 0.1–0.5 mU/L) or even very low (0.1 mU/L or less) serum TSH values are not pathognomonic of thyrotoxicosis. Other causes of a low serum TSH concentration are subclinical thyrotoxicosis, nonthyroidal illness, central hypothyroidism, and early pregnancy. Among older outpatients, a low TSH level is common, occurring in about 5% (31,32,33) (see Chapter 79). Patients with nonthyroidal illness who have low serum TSH values are usually acutely ill and in the hospital (27,34) (see section on Nonthyroidal Illness in Chapter 11). Central hypothyroidism is unlikely to be encountered in case finding for thyrotoxicosis because it is rare, and most patients have clinical manifestations of hypothalamic or pituitary disease that are distinct from those of thyrotoxicosis. During the first trimester of pregnancy, particularly when complicated by hyperemesis gravidarum, the serum TSH concentration may be suppressed due to the relatively weak thyroid stimulatory effects of human chorionic gonadotropin, which circulates in high concentration at this time (35).
Alternatively, the serum free T4 by immunoassay or free thyroxine index can be used, particularly if the level for excluding the diagnosis is arbitrarily set at a value somewhat below the upper limit of the normal reference range; for example, a free T4 concentration of 1.4 ng/dL for an assay with a normal range of 0.6 to 1.6 ng/dL. Using this approach, only thyrotoxic patients with small increases in serum T3 concentrations would be overlooked. Falsely elevated serum free T4 index values may be encountered in patients with familial dysalbuminemic hyperthyroxinemia and those with certain nonthyroidal illnesses or in those receiving several drugs, as noted previously.
Whether TSH or free thyroxine testing is conducted for case finding, any patient having an abnormal result should have the other test performed before any conclusion is drawn or any sustained intervention is undertaken.
Among patients with substantial clinical suspicion of thyrotoxicosis, serum TSH and free T4 should both be measured (Fig. 44.1). If the serum TSH value is low and the serum free T4 value is high, the diagnosis is confirmed. If the serum TSH value is low and the serum free T4 value is normal, the patient has either T3thyrotoxicosis, subclinical thyrotoxicosis, pregnancy, or nonthyroidal illness. Patients in the first three groups tend to have serum free T4 values in the upper portion of the normal range and can be distinguished biochemically from one another by measurement of the serum T3 concentration. If the serum TSH value is normal or high and the serum free T4 value is high, then the patient should be evaluated for TSH-induced thyrotoxicosis. Other explanations for these results are generalized resistance to thyroid hormone, or, if serum free T4 was determined by an analogue free T4 assay or THBR method, familial dysalbuminemic hyperthyroxinemia. Patients with severe nonthyroidal illness often have low-normal or low serum free T4 values and also can usually be identified by the context in which they are encountered.
FIGURE 44.1. Diagnostic scheme for evaluating patients suspected of having thyrotoxicosis subdivided according to combinations of normal or low serum thyroid-stimulating hormone (TSH) concentrations and normal or high serum free thyroxine (T4) values. Serum free T4 can be measured either directly or indirectly as the serum free T4 index (only the serum free T4 index is high in patients with familial dysalbuminemic hyperthyroxinemia).
DIAGNOSIS OF THE CAUSE OF THYROTOXICOSIS
Because the various causes of thyrotoxicosis require different therapies, it is essential that diagnosis of thyroid hormone excess be followed by definition of the underlying cause. In many patients, the history and physical examination alone are sufficient. Examples include the thyrotoxic woman with diffuse goiter and exophthalmos, indicating Graves' disease, or a thyrotoxic patient with neck pain and tenderness, suggesting subacute thyroiditis. In other patients, additional laboratory or in vivo radionuclide studies may be needed to establish the cause and guide therapeutic decision making. For example, a woman with postpartum thyrotoxicosis could have painless (postpartum) thyroiditis, Graves' disease, or even factitious thyrotoxicosis.
The relative elevations of serum T3 and T4 concentrations may provide a clue to the cause of thyrotoxicosis. Exuberant T3 production is common in Graves' hyperthyroidism and toxic nodular goiter [i.e., a serum T3:T4 (ng/dL:µg/dL) ratio of >20]. T4-predominant thyrotoxicosis (i.e., a serum T3:T4 ratio of < 15) suggests that thyroiditis (subacute or silent), iodine-induced thyrotoxicosis, or exogenous T4 ingestion may be the cause. Measurements of thyroidal uptake of radioactive iodine or pertechnetate and thyroid imaging are only needed for differential diagnosis in some patients (Table 44.2). Thyrotoxicosis caused by excessive thyroid hormone synthesis and secretion is typically accompanied by increased uptake in functioning tissue, whereas thyroid inflammation and exogenous T4 ingestion are associated with low thyroidal uptake (36). Radionuclide imaging often permits differentiation of Graves' disease from toxic nodular goiter, which have homogeneous and focal patterns of tracer distribution, respectively.
TABLE 44.2. THYROIDAL RADIOIODINE UPTAKE AND IMAGING IN THE DIFFERENTIAL DIAGNOSIS OF CAUSES OF THYROTOXICOSIS
Cause of Thyrotoxicosis
Fractional Uptake in 24 Hours (%)
Pattern of Distribution of Radionuclide in Thyroid
Graves' disease
35–95
Homogeneous
Toxic nodular goiter (uni- or multinodular)
20–60
Restricted to regions of autonomy
Subacute thyroiditis
0–2
Little or no uptake
Silent thyroiditis
0–2
Little or no uptake
Iodine-induced thyrotoxicosis
0–2
Little or no uptake
Factitious or iatrogenic thyrotoxicosis
0–2
Little or no uptake
Struma ovariia
0–2
Uptake in ovary
Follicular carcinoma
0–5
Uptake in tumor metastases
TSH-induced thyrotoxicosis
30–80
Homogeneous
a Autonomously functioning thyroid tissue in an ovarian teratoma.
The clinical utility of assays for antibodies directed against the TSH receptor in Graves' disease is limited (37). These assays measure the ability of the patient's serum (or immunoglobulin fraction) either to inhibit the binding of TSH to its receptor (TSH receptor-binding inhibitory immunoglobulins) or to stimulate thyroid tissue in some way [e.g., adenylyl cyclase activity (thyroid-stimulating immunoglobulins)] (see Chapter 15). Tests for these antibodies may be used to diagnose Graves' disease in clinically and biochemically euthyroid patients with ophthalmopathy, and in unusual cases when differentiation of Graves' disease from toxic multinodular goiter is otherwise difficult and therapeutically important. In pregnant women with current or previously treated Graves' disease, the presence and level of thyroid-stimulating immunoglobulin activity can help predict the occurrence of fetal and neonatal thyrotoxicosis (37a).
Certain tests are useful in the diagnosis of other forms of thyrotoxicosis. Most patients with subacute thyroiditis have an elevated erythrocyte sedimentation rate and C-reactive protein (37b), but those with silent thyroiditis do not. Serum thyroglobulin concentrations are high in patients with thyrotoxicosis caused by thyroid hypersecretion or inflammation, but not in those with factitious or iatrogenic thyrotoxicosis. Measurements of the serum glycoprotein hormone α subunit concentration may be of value in confirming a diagnosis of TSH-secreting pituitary adenoma (see Chapter 24).
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