Douglas S. Ross
The introduction of serum thyrotropin (TSH) measurements into clinical practice during the early 1970s provided the necessary tool for defining subclinical hypothyroidism, although it took several years for our present understanding and an accepted definition of this entity to evolve (see Chapter 78). Similarly, the introduction in the 1980s of sensitive immunometric TSH assays allowed detection of subnormal serum TSH values in patients with no symptoms or signs of thyrotoxicosis. Subclinical thyrotoxicosis is best defined as a low serum TSH concentration and normal serum free thyroxine (T4) and triiodothyronine (T3) concentrations associated with few or no symptoms or signs of thyrotoxicosis. Patients with low serum TSH concentrations who have high serum free thyroid hormone concentrations are defined as having overt thyrotoxicosis. Before the introduction of sensitive assays for serum TSH, subclinical thyrotoxicosis could be demonstrated by the finding of blunted responses of serum TSH after administration of thyrotropin-releasing hormone (TRH). Now, however, TRH testing is not necessary because serum TSH responses to TRH are usually proportional to basal serum TSH concentrations. The studies reviewed in this chapter document the biologic importance of subclinical thyrotoxicosis; however, no consensus has been reached regarding the indications for treatment.
ETIOLOGY
The major causes of subclinical thyrotoxicosis are similar to those of overt thyrotoxicosis (Table 79.1). Conceptually, there are two groups of patients: those who have subclinical thyrotoxicosis caused by exogenous thyroid hormone therapy and those in whom it is caused by slight endogenous overproduction of T4and T3.
TABLE 79.1. COMMON CAUSES OF SUBCLINICAL THYROTOXICOSIS
Exogenous subclinical thyrotoxicosis
Overzealous thyroid hormone repalcement therapy
Thyroid hormone suppressive therapy
Endogenous subclinical thyrotoxicosis
Thyroid gland autonomy
Autonomously functioning thyroid adenomas
Multinodular goiter
Grave's disease
After radioidine or surgical treatment
During remission after antithyroid drug therapy
Euthyroid (ophthalmic)Grave's disease
TSH suppression not associated with subclinical thyrotoxicosis
Central thypothyroidism
Severe nonthyroidal illness, glucocorticoid or dopamine therapy
After treatment of thyrotoxicosis, before recovery of the pituitary-thyroid axis
Interference of high serum human chorinic gonadotropin concentrations in immunometric assays for TSH
Laboratory error
TSH, thyrotropin
Exogenous Subclinical Thyrotoxicosis
As many as 10 million people in the United States, and perhaps as many as 200 million people worldwide, are taking thyroid hormone and are therefore at risk for subclinical thyrotoxicosis because of either overzealous replacement therapy or intentional suppressive therapy. When sensitive methods for measuring serum TSH first became available, an estimated 40% to 50% of patients taking T4 replacement therapy had subnormal serum TSH concentrations (1), but the proportion has diminished as a result of the use of these assays to monitor therapy and recognition of the potential dangers of overreplacement. Patients with thyroid cancer, thyroid nodules, or multinodular or diffuse goiter who are treated with T4 to suppress TSH secretion to below normal have subclinical (if not overt) thyrotoxicosis. In these patients, the benefits of TSH suppression are considered to exceed the potential risks of subclinical thyrotoxicosis.
Endogenous Subclinical Thyrotoxicosis
The most common causes of endogenous subclinical thyrotoxicosis include multinodular goiter, autonomously functioning thyroid adenomas, Graves' disease, and subacute lymphocytic and subacute granulomatous thyroiditis (2). In one study, 6 of 15 patients had “patchy or irregular” uptake on thyroid radionuclide imaging, suggesting multinodular goiter and the possibility of autonomous thyroid secretion (3). Low serum TSH concentrations also have been found in apparently healthy people who had no evidence of thyroid disease.
The prevalence of autonomously functioning adenomas and multinodular goiter varies considerably from one region of the world to another. This variation is the result of differences in dietary iodine intake and perhaps also genetic differences. For example, in a U.S. study, the ratio of patients with thyrotoxicosis caused by an autonomously functioning adenoma to those with thyrotoxicosis caused by Graves' disease was 1:50 (4), whereas in Switzerland it was 1:2 (5); the ratios for subclinical thyrotoxicosis are probably similar. In Europe, 22% of patients with nontoxic multinodular goiter had blunted serum TSH responses to TRH consistent with subclinical thyrotoxicosis, and 28% had autonomous areas on thyroid radionuclide imaging (6). Subclinical thyrotoxicosis also occurs in patients with Graves' disease; they include patients who had overt thyrotoxicosis and are asymptomatic after radioiodine or surgical treatment, patients who remain asymptomatic (are in remission) after a course of antithyroid drug therapy, and those with only ophthalmic manifestations of Graves' disease. For example, 64% of a group of Japanese patients with Graves' ophthalmopathy but no symptoms of thyrotoxicosis had subnormal serum TSH responses to TRH (7), and in another study 4% of patients with Graves' thyrotoxicosis in apparent remission were found to have subclinical thyrotoxicosis (by TRH testing) (8). It is likely that Graves' disease is the cause of subclinical thyrotoxicosis in some patients who have no history of thyroid disease and little or no thyroid enlargement (2). Patients with subacute lymphocytic thyroiditis (painless or silent thyroiditis and postpartum thyroiditis) may present with subclinical thyrotoxicosis (2), and it also occurs in patients with subacute granulomatous thyroiditis. The thyrotropic activity of high serum chorionic gonadotropin concentrations during early pregnancy also may cause a transient increase in serum free T
4 and T3 concentrations within the normal range and low serum TSH concentrations (9).
Differential Diagnosis
There are other causes of low serum TSH concentrations, but many of the patients have abnormal serum T4 and T3 concentrations (Table 79.1). Patients with pituitary or hypothalamic disease who have hypothyroidism may have low serum TSH concentrations, and the concentrations are often low in patients with severe nonthyroidal illness, especially those receiving glucocorticoid or dopamine therapy (10). Low serum TSH concentrations may be associated with low or normal serum T4 and T3 concentrations shortly after treatment or spontaneous resolution of overt thyrotoxicosis because of persistent suppression of TSH secretion.
EPIDEMIOLOGY AND NATURAL HISTORY
In the United States, among 13,344 people with no known thyroid disease in the National Health and Nutrition Examination Survey (NHANES III), 0.7% had subclinical thyrotoxicosis (11). In a Swedish community-based study of 2000 people attending a medical clinic, 3.3% had low serum TSH concentrations without overt thyrotoxicosis (12); only 9% of the subjects with subclinical thyrotoxicosis had thyroid abnormalities (e.g., multinodular goiter, thyroiditis), and 40% had a normal serum TSH concentration on recall a few weeks later. In a U.S. study of 968 subjects over 55 years of age, 0.7% had endogenous subclinical thyrotoxicosis (13). In another U.S. study, 46 of 2411 subjects (1.9%) over 60 years of age had subclinical thyrotoxicosis, with serum TSH values less than 0.1 mU/L (14); during a 4-year follow-up period, only two developed overt thyrotoxicosis, and serum TSH concentrations became normal in most of the remainder. In a similar study from England, 6.3% of women and 5.5% of men had low serum TSH concentrations (< 0.5 mU/L); a year later, the serum TSH values were normal in 60% of these subjects, and only one (1.5) had overt thyrotoxicosis (15). In Sweden, 1.8% of 886 subjects 85 years of age or older had subclinical thyrotoxicosis (16). Thus, the prevalence of subclinical thyrotoxicosis in the community has varied from 0.7% to 6.0%, depending on the criteria used and the age of the population. More than half of these subjects, especially those with slightly low serum TSH values, had normal values when retested during follow-up, and few developed thyrotoxicosis (see Chapter 19).
Although no long-term studies of the natural history of subclinical thyrotoxicosis have been reported, data are available regarding the natural history of autonomously functioning thyroid adenomas. In a U.S. study, 8.8% of initially euthyroid patients with these tumors developed overt thyrotoxicosis during a 6-year follow-up period (4); in a European study, 18% of patients developed overt thyrotoxicosis during a 7-year follow-up period (17).
BIOLOGIC IMPORTANCE
Although suppression of TSH secretion defines subclinical thyrotoxicosis, the increases in serum free thyroid hormone concentrations that cause the suppression may also cause symptoms suggestive of thyrotoxicosis and may have effects on other tissues similar to but less marked than those of overt thyrotoxicosis. Both the pituitary and the systemic effects of the increases are considered here.
PHYSIOLOGY OF SUPPRESSION OF TSH SECRETION
The negative feedback relationship between serum TSH and free T4 (and T3) concentrations is log-linear. Therefore, very small increases in endogenous thyroid hormone production, or only slightly excessive doses of the exogenous thyroid hormone, decrease serum TSH concentrations to below the normal range (18) (see Regulation of Thyrotropin Secretion, Chapter 10D). Groups of patients with low serum TSH concentrations who receive slightly excessive doses of T4 have serum T4 and T3 concentrations greater than the mean values for normal subjects but within the respective normal ranges. Presently, most clinicians accept serum TSH measurements as the most sensitive indicator of thyroid hormone status (in the absence of pituitary or hypothalamic disease). Several findings, however, raise the question of whether this is always the case. In laboratory animals, intrapituitary deiodination of T4 to T3, a reaction that is catalyzed primarily by type 2 T4-5′-deiodinase (see Chapter 7), contributes more of the T3 bound to the T3 nuclear receptors, and serum T3 contributes less, compared with most other organs (19). Hence, the extent of T3-induced inhibition, or lack thereof, of TSH secretion, may vary somewhat independently of the serum T3concentration. In addition, the concentrations of the different isoforms of the T3 nuclear receptor are different in the pituitary and peripheral organs (see Chapter 8), and these concentrations are altered discordantly in states of thyroid hormone excess or deficiency (20). Some euthyroid elderly patients with low serum T4 and normal serum TSH concentrations appear to have a decreased set point for T4- and T3-mediated feedback inhibition of TSH secretion (21). Finally, some patients with hypothyroidism feel better subjectively when they are given a slightly higher dose of T4 than that needed to normalize their TSH secretion (18).
BONE AND MINERAL METABOLISM
Thyroid hormone has a direct resorptive effect on bone, and overt thyrotoxicosis is associated with increased bone resorption and, to a lesser extent, increased bone formation and an increase in fracture rate (22) (Table 79.2). Cortical bone is affected more than trabecular bone. In two studies patients with nodular goiter and subclinical thyrotoxicosis had lower bone density than comparable normal subjects (23,24), although in one study significant reductions in bone density occurred only in sites rich in cortical bone in postmenopausal women (24), and in a study of 15 premenopausal women bone density was not reduced (25). In two nonrandomized trials, postmenopausal women with nodular goiter and subclinical thyrotoxicosis treated with an antithyroid drug (26) or radioiodine (27) had higher bone density after 2 years than similar women who were not treated. Serum concentrations of osteocalcin, a marker of bone formation, are high in patients with subclinical thyrotoxicosis and are inversely correlated with serum TSH concentrations (28).
TABLE 79.2. BIOLOGIC EFFECTS OF SUBCLINICAL THYROTOXICOSIS
Measurements Reported to Be Abnormal
Change
References
Skeletal effects
Bone density
↓
23,30,31
Biochemical markers of bone mineral metabolism
Serum osteocalcin
↑
28,38
Urinary excretion of bone collagen–derived pyridinoline cross-links
↑
33
Urinary excretion of hydroxyproline
↑
34
Serum carboxyl-terminal-1-telopeptide
↑
35
Cardic effects
Heart rate
↑
48,49
Premature atrial contractions
↑
49
Risk of atrial fibrillation
↑
43,44,45
Cardiac contractility
↑
49
Systolic time intervals
Preejection period divided by LV ejection time
↓
51,52
Isovolumetric contraction time
↓
49,50
Isovolumetric relaxation time
↑
56
Left ventricular mass index, intraventricular septal, and posteriour wall thickness
↑
49,56
Left ventricular diastolic filling
↓
54
Exercise tolerance and maximal oxygen uptake
↓
56
Mortality from circulatory disease
↑
59
Other effects
Serum total and low-density lipoprotein cholesterol
↓
60
Erythrocyte ouabain-binding capacity
↓
61
Serum alanine aminotransferase, glutathione
↑
62
S-transferase, and γ-glutamyl transferase
Serum creatine kinase
↓
62
Rations of uranary sodium excretion and urine flow during the day to those in the nighta
↓
48
Serum sex hormone–binding globulin
↑
28,30
Time asleep at night
↓
64
Hyperthyroid symptoms (Short Form 36 Health Survey)
↑
65
Mood (using multidimensional scale for state of well-being)
↑
64
Dementia
↑
66
aUrine sodium excretion and flow rate are increased at night in patients with overt thyrotoxicosis.
Whether T4 therapy in doses that result in subclinical thyrotoxicosis causes low bone density is controversial. Bone density may be low in premenopausal women receiving suppressive or overzealous replacement doses, but women receiving lower but still suppressive or slightly excessive replacement doses have normal bone density (22, 29). As in endogenous subclinical thyrotoxicosis, bone density more often is reduced at sites rich in cortical bone (e.g., wrist and hip) than sites rich in trabecular bone (e.g., lumbar spine), and postmenopausal women are more likely to be affected than premenopausal women (22). A metaanalysis concluded that low bone density occurs only in postmenopausal women (30). The adverse effect of T4 on bone density is associated with doses in excess of 1.6 µg/kg (31). Estrogen therapy appears to protect against T4-induced bone loss in postmenopausal women (31). In a study of postmenopausal women taking T4 who had subclinical thyrotoxicosis, bone density increased when the T4 dose was reduced and serum TSH concentrations increased to normal (32).
Other measures of bone turnover, in addition to serum osteocalcin, are abnormal in patients who have subclinical thyrotoxicosis. Urinary excretion of bone collagen–derived pyridinoline cross-links and hydroxyproline (33,34) and serum concentrations of carboxyl-terminal-1-telopeptide, markers of bone resorption, are increased (35). In women with thyroid cancer receiving T4 suppression therapy, serum C-terminal telopeptide and osteocalcin concentrations and urinary excretion of N-terminal telopeptide of type I collagen were high in those who were postmenopausal, but not those who were premenopausal (36). Among patients with Graves' thyrotoxicosis treated with an antithyroid drug who had normal serum T4 and T3 concentrations, those who had persistently low serum TSH concentrations had higher serum alkaline phosphatase concentrations and urinary excretion of pyridinoline cross-links as compared with those who had normal serum TSH concentrations (37). Serum osteocalcin and TSH concentrations are also inversely correlated in patients with exogenous subclinical thyrotoxicosis (38).
Data regarding the risk for fracture in patients with subclinical thyrotoxicosis are still preliminary. In one study of women over 65 years of age, the overall fracture rate was 0.9% in those with normal serum TSH values, and it was 2.5% in those with low values; this difference was not statistically significant (39). An interview-based study did not find an increased fracture risk in women taking T4 (40). In a third study, the risk for hip fracture was increased 1.6 times in women taking thyroid hormone; serum TSH values were not reported (41). Finally, in a study of postmenopausal women with serum TSH concentrations of 0.1 mU/L or lower, there was an increased risk for both hip and vertebral fracture; however, serum T
4 was not measured, so the proportion of patients with overt thyrotoxicosis is unknown (42).
CARDIAC FUNCTION
The risk for atrial fibrillation is increased in patients with subclinical thyrotoxicosis (Table 79.2). In a community-based study of 2007 subjects 60 years of age or older followed for 10 years, the cumulative incidence of atrial fibrillation was 28% among those with serum TSH concentrations of 0.1 mU/L or less, 16% among those with serum TSH concentrations greater than 0.1 to 0.4 mU/L, and 11% among those with normal serum TSH concentrations (43); the relative risk for atrial fibrillation was threefold higher in the group with the lowest serum TSH concentrations. In a study of hospitalized patients, 13% of 613 patients with subclinical thyrotoxicosis, 14% of 725 patients with overt thyrotoxicosis, and 2% of 22,300 euthyroid patients had atrial fibrillation (44). In a study of 80 patients, the prevalence of atrial fibrillation was two times higher in those with subclinical thyrotoxicosis, as compared with matched control patients with normal serum TSH concentrations (45), and during a 2-year follow-up period, 9% of the patients with subclinical thyrotoxicosis developed atrial fibrillation, as compared with none of the control group.
Patients presenting with atrial fibrillation may prove to have subclinical thyrotoxicosis. Of 126 consecutive patients presenting to a hospital with atrial fibrillation, 2 had overt thyrotoxicosis, and 13 (10%) had subclinical thyrotoxicosis (46). The arrhythmia may remit with antithyroid therapy (47). Subclinical thyrotoxicosis is also associated with an increase in heart rate and an increase in atrial premature beats (48,49).
Both cardiac contractility and left ventricular hypertrophy may be increased in patients with exogenous subclinical thyrotoxicosis. Echocardiography reveals higher values for the percentage of fractional shortening and the rate-adjusted mean velocity of shortening, and a reduction in the isovolumetric contraction time (the time between mitral value closure and aortic value opening) (49,50). Systolic time intervals, measured as the ratio of the preejection period to the left ventricular ejection time (PEP:LVET ratio), also are reduced in patients with subclinical thyrotoxicosis (51,52). Left ventricular mass index, the thickness of the intraventricular septum, and left ventricular posterior wall thickness are all increased in patients with subclinical thyrotoxicosis (49). The increase in left ventricular mass index is proportional to the duration of subclinical thyrotoxicosis (49), and it is prevented by β-adrenergic blocking drugs (53). Impaired left ventricular diastolic filling, which is associated with reduced exercise capacity, is found in some patients with subclinical thyrotoxicosis and also is prevented by β-adrenergic blocking drugs (54). These results suggest that subclinical thyrotoxicosis could aggravate angina pectoris or congestive heart failure, although there are no data that address these possibilities. These measurements of cardiac function have not been abnormal in all studies (55), and most of the studies in which abnormalities were found were conducted in patients who had serum TSH concentrations well below 0.1 mU/L. In one study (56), significant abnormalities in left ventricular mass index, end-diastolic dimension, exercise tolerance, and maximal oxygen uptake at peak exercise became normal after the dose of T4 was reduced and serum TSH concentrations increased to approximately 0.1 mU/L.
In two small studies in patients with endogenous subclinical thyrotoxicosis, cardiac function improved after antithyroid treatment (57,58). In one study, 10 patients treated with methimazole had a lower heart rate, fewer atrial premature beats, and a reduction of left ventricular mass index, interventricular septum thickness, and left ventricular posterior wall thickness when their serum TSH concentrations increased to normal (57). In the other study, six patients treated with radioiodine had a decrease in heart rate and cardiac output and an increase in systemic vascular resistance when their serum TSH concentrations returned to normal (58).
Subclinical thyrotoxicosis may be associated with increased mortality. In a population-based study of 1191 subjects 60 years of age or older who were not taking T4, 10-year mortality was increased among those with low serum TSH concentrations, primarily due to a twofold increase in the standardized mortality ratio from cardiovascular diseases (59) (see Chapter 77). Thyroid hormone therapy was associated with an increased risk for ischemic heart disease in patients under 65 years of age, but this did not correlate with their serum TSH concentrations (39). This observation may reflect undertreatment or poor compliance with thyroid hormone therapy, because subclinical hypothyroidism is associated with high serum lipid concentrations (see Chapter 78), whereas patients with subclinical thyrotoxicosis tend to have low serum lipid concentrations (60).
OTHER MEASUREMENTS
Other clinical, biochemical, and physiologic measurements that are often abnormal in patients with overt thyrotoxicosis may be abnormal in patients with subclinical thyrotoxicosis. The numbers of sodium pump sites on erythrocytes, estimated by measuring ouabain-binding capacity, were reduced by 15% in patients with exogenous subclinical thyrotoxicosis (61). Serum alanine aminotransferase, glutathione S-transferase, and γ-glutamyl transferase values may be high (62). Serum creatine kinase concentrations may be low (62). The ratios of urinary sodium excretion and urine flow during the day to those during the night are decreased (48). Serum sex hormone–binding globulin concentrations may be high in patients with either endogenous or exogenous subclinical thyrotoxicosis (28,63). Patients with subclinical thyrotoxicosis sleep less than normal subjects and have a better mood (64). In the standardized Short Form 36 Health Survey, patients with exogenous subclinical thyrotoxicosis had more symptoms consistent with thyroid hormone excess (65). Finally, in a population-based study of 1843 elderly Dutch subjects, subclinical thyrotoxicosis was associated with a threefold increased risk for dementia (66).
PREVENTION AND TREATMENT
Both low bone density and an increased risk for atrial fibrillation may result in substantial morbidity in older patients with subclinical thyrotoxicosis. These and other adverse effects of exogenous subclinical thyrotoxicosis can and should be avoided or minimized by careful titration of thyroid hormone therapy using serum TSH measurements. Patients who are receiving T4 replacement therapy should have the dose adjusted to maintain a normal serum TSH concentration. Subclinical thyrotoxicosis cannot be avoided in patients treated with T4 to decrease goiter size, prevent recurrent goiter, or prevent recurrence or minimize growth of thyroid carcinoma. The efficacy of suppressive therapy of goiter or thyroid nodules is controversial (see Chapter 73) (67), and data that support specific goals for serum TSH concentrations are contradictory. In one study of patients with a nodular goiter, the nodules were more likely to regress if serum TSH concentrations were reduced to less than 0.1 mU/L (68), while in another study the response to T4 was similar in patients whose serum TSH concentrations were reduced to 0.4 to 0.6 mU/L and those whose concentrations were reduced to less than 0.01 mU/L (69). Many thyroidologists suggest giving sufficient T4to lower serum TSH concentrations to slightly low values in patients with benign thyroid diseases and to lower values (e.g., < 0.05 mU/L) only in patients with thyroid cancer who have recurrent local or metastatic disease.
Few data are available to guide clinical decisions regarding the treatment of patients with endogenous subclinical thyrotoxicosis. However, the studies reviewed previously demonstrate that antithyroid drug or radioiodine therapy increases bone density in postmenopausal women with subclinical thyrotoxicosis (26,27), and it improves several measures of cardiac function in most patients with subclinical thyrotoxicosis (57,58). These results suggest that cardiac status and skeletal integrity should be carefully assessed, and the possible coexistence of other risk factors for cardiac disease and osteoporosis should be determined in patients with subclinical thyrotoxicosis. Treatment should be seriously considered in those patients considered at risk, especially those whose serum TSH concentrations are very low (e.g., < 0.1 mU/L).
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