Douglas S. Ross
The term “subclinical hypothyroidism” was first introduced in the early 1970s coincident with the introduction of serum thyrotropin (TSH) measurements. This term eventually replaced other terms, such as “preclinical myxedema,” “compensated euthyroidism,” “preclinical hypothyroidism,” and “decreased thyroid reserve.” Subclinical hypothyroidism is defined biochemically as a high serum TSH concentration and normal serum free thyroxine (T4) and triiodothyronine (T3) concentrations. Some investigators, especially those studying the neuropsychiatric aspects of hypothyroidism, also consider patients who have normal basal serum TSH concentrations and supranormal serum TSH responses to thyrotropin-releasing hormone (TRH) to have hypothyroidism. Table 78.1 defines the several grades of hypothyroidism that have been suggested (1,2). By definition, patients with subclinical hypothyroidism cannot be identified on the basis of symptoms and signs (3).
TABLE 78.1. GRADES OF HYPOTHYROIDISM
Symptoms and Signs
Serum TSH Response to TRH
None or few
T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyrotropin.
The causes of subclinical hypothyroidism are the same as the causes of overt hypothyroidism (see Chapter 46) and are listed in Table 78.2. Most patients have chronic autoimmune thyroiditis, as defined by high serum concentrations of antithyroid peroxidase (anti-TPO) antibodies. In a Michigan outpatient practice, 54% of patients with subclinical hypothyroidism had chronic autoimmune thyroiditis (4), and in a community survey in Whickham, England, 67% of women and 40% of men with high serum TSH concentrations also had high serum antibody values (5). Destructive therapy for thyrotoxicosis caused by Graves' disease is another major cause of subclinical hypothyroidism, accounting for 39% of the cases in the Michigan study (4). Among clinically euthyroid patients who have received radioiodine therapy for Graves' thyrotoxicosis, the majority have high serum TSH concentrations (6,7), and, in one survey, 65% of clinically euthyroid patients treated surgically for Graves' thyrotoxicosis had high serum TSH concentrations (8). Several drugs may cause subclinical (or overt) hypothyroidism, including lithium carbonate, iodine, iodine-containing drugs such as amiodarone, and iodine-containing radiographic contrast agents. Smoking may exacerbate subclinical hypothyroidism and its metabolic consequences (9). External radiation therapy to the neck also may cause subclinical hypothyroidism. Another important cause of subclinical hypothyroidism is inadequate thyroid hormone therapy for overt hypothyroidism. In a community-based study (in Framingham, Massachusetts), 37% of older patients taking a thyroid hormone preparation for hypothyroidism had high serum TSH concentrations (10). Inadequate thyroid therapy may have been intentional in some patients because of coexisting heart disease, but more often it is caused by poor patient compliance or inadequate monitoring of therapy.
TABLE 78.2. COMMON CAUSES OF SUBCLINICAL HYPOTHYROIDISM
Chronic autoimmune (Hashimoto's) thyroiditis
Radioiodine or surgical treatment of Graves' thyrotoxicosis
Inadequate thyroid hormone replacement therapy for overt hypothyroidism
Lithium carbonate therapy
Iodine and iodine-containing drugs and contrast agents
External radiotherapy to the neck
Serum TSH elevations not associated with subclinical hypothyroidism
Pulsatile TSH secretion, nocturnal surge in TSH secretion
TSH-secreting pituitary adenomas
Thyroid hormone resistance syndromes
Several causes of high serum TSH concentrations do not properly fit the definition of subclinical hypothyroidism (Table 78.2). One is during recovery from nonthyroidal illness, during which time serum TSH concentrations may be transiently high for a week or occasionally longer. Studies of subclinical hypothyroidism based on serum TSH measurements in hospitalized patients may be invalid because of failure to recognize this cause of high serum TSH values. An occasional serum TSH determination may exceed the normal reference range because of a robust pulse of TSH secretion, especially at night, or because of assay variability.
Therefore, slightly high serum TSH concentrations should be confirmed before the diagnosis of subclinical hypothyroidism is accepted. Artifactual increases in serum TSH values may be caused by heterophile antibodies, for example, in patients treated with monoclonal mouse antibody preparations, which interfere with TSH measurement, although this technical problem has been corrected by most manufacturers of TSH assay materials. Serum TSH concentrations also may be high in patients with adrenal insufficiency and occasionally during treatment with metoclopramide or domperidone. Rare causes of slightly high serum TSH concentrations are TSH-secreting pituitary adenomas and resistance to thyroid hormone; patients with the former have thyrotoxicosis, whereas those with the latter are euthyroid or possibly thyrotoxic.
Several population-based studies have defined the prevalence of subclinical hypothyroidism. In England (the Whickham Survey), the prevalence of serum TSH concentrations higher than 6 mU/L in the absence of overt hypothyroidism was 7.5% in women and 2.8% in men (5) (see Chapter 19). An age-dependent increase in serum TSH concentrations was found in women only when those with high serum antithyroid antibody concentrations were included in the analysis. In women over 75 years of age, the prevalence of subclinical hypothyroidism was 17.4%. In the United States, the National Health and Examination Survey (NHANES III) found a 4.3% prevalence of subclinical hypothyroidism (11); in blacks the prevalence was only 1.6%. In Detroit, the prevalence of high serum TSH concentrations was 8.5% in women and 4.4% in men over age 55 years (12). The higher prevalence of subclinical hypothyroidism in older people was confirmed by data from the Framingham Study, in which the prevalence of minor elevations in serum TSH concentrations in people over 60 years of age was 8.2% in men and 16.9% in women (13), and by a Dutch study in which the prevalence of subclinical hypothyroidism in a group of women (mean age 55 years) was 4%; the rate was 7.3% in the same women 10 years later (14). The prevalence of subclinical hypothyroidism may be lower in elderly women; in an English study, the prevalence was 13.7% in women 60 to 69 years of age and 6.2% in women over 80 years of age (15).
Subclinical hypothyroidism is more prevalent in areas of higher, as compared with lower, but not deficient, iodine intake. Among nursing home residents with a mean age of 80 years and similar prevalence of high serum anti-TPO antibody concentrations, the prevalence of subclinical hypothyroidism was 4.2% in relatively iodine-deficient northern Hungary; 10.4% in Slovakia, where iodinated salt prophylaxis had been mandated for 40 years; and 23.9% in eastern Hungary, where iodine intake is high (16).
Subclinical hypothyroidism is more prevalent in patients with Down syndrome (17), type 1 diabetes mellitus (18), and probably other autoimmune diseases. In a survey of pregnant women in the United States, 2% had subclinical hypothyroidism, 58% of whom had high anti-TPO antibody concentrations (19).
In a follow-up study of persons from the original Whickham Survey (20), women who had high serum TSH and antithyroid antibody concentrations developed overt hypothyroidism at a rate of 4.3% yearly over 20 years, whereas women who had only high serum TSH concentrations or only high antibody concentrations developed overt hypothyroidism at annual rates of 2.6% and 2.1%, respectively. In a Swiss study of women with known thyroid disease followed prospectively for 9 years, overt hypothyroidism developed in 0%, 43%, and 77% of women with serum TSH concentrations of 4 to 6 mU/L, greater than 6 to 12 mU/L, and greater than 12 mU/L, respectively, and was 2.5-fold more likely in those with high serum anti-TPO antibody concentrations (21). In a New Mexico study of asymptomatic ambulatory subjects over 60 years of age with subclinical hypothyroidism (22), one third developed overt hypothyroidism during 4 years of follow-up; among them were all those whose initial serum TSH concentrations were higher than 20 mU/L and 80% of those whose serum anti-TPO antibody titers were 1:1600 or higher, but none with lower titers. In an English study of persons with subclinical hypothyroidism followed for 1 year, 18% developed overt hypothyroidism, 6% had normal serum TSH concentrations, and 77% had persistent subclinical hypothyroidism (15).
The underlying cause of subclinical hypothyroidism also may predict progression to overt hypothyroidism. In one study, 53% of patients with subclinical hypothyroidism followed for 8 years had overt hypothyroidism, and 47% continued to have subclinical hypothyroidism (23). The former group included all patients with autoimmune thyroid disease, prior radioiodine therapy, high-dose external radiotherapy, and long-term lithium therapy, whereas the latter group included patients who had thyroid or neck surgery for indications other than thyrotoxicosis or external neck radiotherapy during childhood.
The fundamental clinical question regarding patients with subclinical hypothyroidism is whether they require treatment with thyroid hormone. Based on the natural history of subclinical hypothyroidism alone, one can argue that treatment should be started to prevent the development of overt hypothyroidism. Additionally, goiter, if present, decreases in size in some patients (24). This section summarizes several randomized trials of thyroid hormone therapy and other studies that compared various measures of tissue thyroid hormone action in patients with subclinical hypothyroidism with those in euthyroid subjects (Table 78.3).
TABLE 78.3. SUBCLINICAL HYPOTHYROIDISM: BIOLOGIC EFFECTS
Serum lipid and apoprotein concentrations
29, 31, 38, 42a, 48, 54b, 55b, 56a, 57a
24, 25, 27, 28, 36, 43, 45, 49–53
Low-density lipoprotein cholesterol
31, 34, 36, 38
41, 42, 44–47
29, 31, 42a, 48, 52, 54b, 56a, 57a
24, 28, 30, 36, 45, 50, 53
High-density lipoprotein cholesterol
37, 39, 43
31, 41, 42, 44–46
24, 28, 29–31, 43, 45, 48–50, 52, 53
13, 41, 43, 45
29, 31, 38, 43, 45, 48, 50, 52
29, 31, 36, 38, 43, 45, 48, 50, 52
Lipoprotein lipase activity
36, 37, 58
29, 31, 36, 38, 48, 58
Systolic time intervals
44, 60, 62
25a, 27c, 51c,d, 61f, 62c
Isovolumetric relaxation time
27, 32, 49
Systemic vascular resistence
25, 27, 29, 71
Psychometric test scores
27, 28, 71, 72
Achilles tendon reflex time
Amplitude of the stapedial reflex
Basal metabolic rate
Body mass or weight
31, 32, 46
25, 27, 30, 32, 50
Nerve conduction velocity
Brainstem auditory evoked potentials
Increase in serum lactate with exercise
Response to TRH
Serum insulin and glucagon
Serum sex hormone–binding globulin, and corticosteroid-binding globulin
Serum creatine kinase
Serum ionized calcium
33, 46, 81
Serum C-reactive protein
aValues improved in a subgroup of patients with abnormal baseline values.
cSome patients may have received excess doses of thyroid hormone.
dSome patients may have had mild hypothyroidism.
eValues abnormal only in postmenopausal women.
fDuring exercise only.
gUpright posture only.
TRH, thyrotropin-releasing hormone.
The first randomized trial of T4 therapy in 33 patients with subclinical hypothyroidism included patients with serum TSH values as high as 55 mU/L (25). It was a 1-year study, the T4 dose was adjusted to normalize serum TSH concentrations, and symptoms were assessed based on a standardized hypothyroidism diagnostic index (26). The T4-treated patients had no change in weight, basal metabolic rate, serum cholesterol or triglyceride concentrations, ratio of preejection period to left ventricular ejection time ratio (PEP:LVET ratio), or QKd (the interval from the Q wave on the electrocardiogram to the pulse arrival time at the brachial artery). A subgroup of patients with high PEP:LVET ratios had normal values during therapy. The major finding of this study was that half the patients with subclinical hypothyroidism had fewer symptoms during treatment.
A second randomized trial was a 1-year double-blind crossover study of 20 women with subclinical hypothyroidism (serum TSH values as high as 16 mU/L) (27). All patients received 0.15 mg of T4 daily. Because this is an above-average replacement dose, some patients probably had subclinical thyrotoxicosis during treatment, as reflected by a shortening of systolic time intervals to subnormal values (see Chapter 79). During the 6-month T4 therapy period, serum procollagen II peptide concentrations increased; but heart rate, serum cholesterol, creatine kinase, or sex hormone–binding globulin concentrations, body mass, blood pressure, or hemoglobin concentration did not change. Psychometric test scores and hypothyroid symptoms improved during T4 administration, and many patients correctly distinguished the T4 treatment period from the placebo period. Thus, the major findings in this study were improved results of psychometric testing and fewer hypothyroid symptoms when the patients were receiving T4.
A third randomized trial was a 10-month double-blind placebo-controlled study of 37 patients with serum TSH values as high as 32 mU/L (28). The T4-treated patients had a significant improvement in psychometric test scores related to memory, but no improvement in scores of several other cognitive function tests or in health-related quality of life, as assessed by several standardized questionnaires, including one used in the first trial.
In a fourth 48-month trial of 66 patients with serum TSH values as high as 50 mU/L (mean 12.8 mU/L), T4 therapy resulted in improvement in symptom scores and lower serum total and low-density lipoprotein (LDL) cholesterol concentrations, but had no effect on serum high-density lipoprotein (HDL) cholesterol, triglyceride, apoprotein A1, or lipoprotein(a) concentrations (29).
A fifth randomized trial of 40 patients who had serum TSH concentrations between 5 and 10 mU/L revealed no improvement in symptom scores, body mass index, energy expenditure, or serum lipid concentrations (30). In a randomized trial in 49 patients with serum TSH values between 3.6 and 15 mU/L in which only serum lipids were measured, serum concentrations of total and LDL cholesterol decreased, whereas those of HDL cholesterol, apoprotein A1 or B, or lipoprotein(a) did not change (31). A randomized trial using Doppler echocardiography and videodensitometric analysis found that T4 therapy normalized the low cyclic variation index and reduced the PEP: LVET ratio and isovolumetric relaxation time (32). Finally, neither T4 nor placebo given for 48 weeks altered serum homocysteine and C-reactive protein concentrations in 63 women with subclinical hypothyroidism (33).
In summary, in patients with subclinical hypothyroidism, T4 therapy resulted in improvement in psychometric test scores in both studies in which the tests were conducted, improvement of hypothyroid symptoms in three of five studies, improvement in serum lipid levels in two of six studies, and improvement in cardiac function in one study.
SERUM LIPID AND APOPROTEIN CONCENTRATIONS
The serum total cholesterol concentrations in patients with subclinical hypothyroidism were high in six studies (31,34,35,36,37,38) but not different from those in normal subjects in most other studies (1,14,39,40,41,42,43,44,45,46) (Table 78.3). In a survey of 25,862 people, the 1,799 subjects who had serum TSH concentrations of 5.1 to 10 mU/L had a mean serum cholesterol concentration of 223 mg/dL (5.8 m), as compared with 216 mg/dL (5.6 m) in the 22,842 subjects with normal serum TSH concentrations (35). Serum cholesterol concentrations decreased in response to TMM4 therapy in three studies (31,38,47,48), but not in many other studies (24,25,26,27,28,36,43,45,49,50,51,52,53). In two meta-analyses of the treatment studies, serum total cholesterol concentrations decreased by 9 to 15 mg/dL (0.2–0.4 m) during TM4 therapy (54,55).
Patients with subclinical hypothyroidism had high serum LDL cholesterol concentrations in six studies (31,34,36,37,38) and normal concentrations in six studies (41,42,44,45,46,47). The values were reduced by T4 therapy in five studies (29,31,38,48,52) but not in seven others (24,28,30,36,35,50,53). In a meta-analysis, T4 therapy reduced serum LDL cholesterol concentrations by 11 mg/dL (0.3 m) (54). TM4 therapy is more likely to lower serum total and LDL cholesterol concentrations in patients who have high values and in those with higher serum TSH concentrations (37,45,56,57).
Patients with subclinical hypothyroidism had lower serum HDL cholesterol concentrations than normal subjects in three studies (37,39,43), but the values were similar in six studies (31,41,42,44,45,46). Among the studies of the effect of T4 therapy on serum HDL cholesterol in patients with subclinical hypothyroidism (24,28,29,30,31,43,45,48,49,50,52,53), the concentrations increased in only one (43).
Serum apoprotein A1 concentrations were high in two studies (37,44) and were not different from normal subjects in four studies (14,31,43,45); there was a decrease during T4 therapy in only one (43) of eight studies (29,31,38,43,45,48,50,52). Serum apoprotein B concentrations were high in four studies (31,36,37,38) and did not differ from normal subjects in four studies (14,43,44,45); during T4 therapy, the concentrations decreased in two (38,52) of nine studies (29,31,36,38,43,45,48,50,52). Lastly, serum lipoprotein(a) concentrations were high in three (36,37,58) of five studies (31,36,37,45,58), and they decreased during T4 therapy in two (38,58) of six studies (29,31,36,38,48,58).
In a study of 1,149 Dutch women (mean age 69 years), aortic atherosclerosis and a history of myocardial infarction were increased in patients with subclinical hypothyroidism independent of other risk factors (59).
In summary, despite variable findings in multiple studies, subclinical hypothyroidism is likely associated with a small increase in serum total and LDL cholesterol concentrations that improve slightly with treatment. A response to treatment is more likely in patients with higher serum TSH concentrations (e.g., >10 mU/L), or those with initially higher serum lipid concentrations.
Patients with subclinical hypothyroidism had no differences in the duration of electromechanical systole (Q-A2), LVET, or PEP:LVET ratio, as compared with normal subjects (60). In another study, resting PEP, LVET, and QKd values decreased during T4 therapy (51); however, 25% of the patients had baseline serum TSH concentrations above 40 mU/L, and 20% were overtreated. There was no change in the PEP:LVET ratio or QKd in patients with subclinical hypothyroidism who received T4 therapy in one of the randomized trials discussed previously (25), but in another group of patients an initially high PEP:LVET ratio became normal during T4 therapy. In another study of T4 therapy, resting PEP did not change, but there was a decrease in PEP during exercise and in left ventricular diastolic dimensions at rest (61). Two of these trials are flawed because of possible overtreatment. In one trial, patients treated with 20 µg T3 twice daily had shorter systolic time intervals, but so, too, did normal subjects receiving the same regimen (62). In the randomized trial discussed previously in which all the patients received 0.15 mg of T4 daily, the mean values for Q-A2, PEP, and the PEP:LVET ratio all decreased, but some patients had subclinical thyrotoxicosis (27).
Isovolumetric relaxation time was increased in two studies (63,64) and improved with T4 therapy in one study (63). The ratio of velocity of blood flow across the mitral valve during early and late diastole was lower in patients with subclinical hypothyroidism, as compared with normal subjects, and became normal during T4 therapy (63). The time to peak ventricular filling rate was high and became normal with treatment (65). In other studies of T4 therapy, there was no change in left ventricular ejection fraction at rest or with moderate exercise, but it was higher during maximal exercise, and there also was an increase in the slope of the ratio of systolic blood pressure to end-systolic volume at maximal exercise (but not at rest), indicating improved myocardial contractility (49,66). Among 16 women with subclinical hypothyroidism (mean serum TSH 17.1 mU/L) who were treated with T4 (mean serum TSH 2.2 mU/L), cardiac output increased by 14% and systemic vascular resistance (upright) decreased by 14% (67). Diastolic blood pressure was high in one study (46) and declined with treatment in another study (67).
Thus, some patients with subclinical hypothyroidism have subtle abnormalities in systolic time intervals, diastolic function, and myocardial contractility that may improve during treatment.
Reports of an increased prevalence of subclinical hypothyroidism in patients with depression or bipolar affective disorders need careful assessment because of frequently inadequate control groups, coincident lithium therapy, and the inclusion of patients with normal serum TSH values whose thyroid abnormality is limited to either an increased response of serum TSH after TRH administration or high serum antithyroid antibody concentrations (2). Nonetheless, several studies suggest an association of subclinical hypothyroidism with neuropsychiatric abnormalities. In one study of hospitalized patients, the prevalence of hypothyroidism was 14.8% in those with neurotic depression and 2.3% in those with senile and multiinfarct dementia, as compared with 1.9% in those with no psychiatric disorder (68). Patients with depression and subclinical hypothyroidism had a higher prevalence of associated panic disorder and a poorer response to antidepressant drug therapy than depressed euthyroid patients (69). Randomly selected women with subclinical hypothyroidism who had formal psychiatric assessment before assessment of thyroid function had a higher lifetime frequency of depression than euthyroid women (70). Women found to have subclinical hypothyroidism after presenting to a clinic for assessment of goiter had increased rates of free-flowing anxiety, somatic complaints, depressive features, and hysteria, as compared with euthyroid women with goiter, and these abnormalities improved during treatment with T4 (71). Psychometric test scores in this (71) and one other study (72) were also abnormal and improved with therapy, confirming the results of two randomized trials of T4 therapy discussed above (27,28).
Patients with subclinical hypothyroidism have a normal thyroidal response to TSH stimulation and no abnormality in volume of the sella turcica (40). They may have supranormal increases in the serum concentrations of glycoprotein hormone α subunit and TSH-β subunit in response to TRH administration (40). The serum prolactin response to TRH administration was increased in one study (34) and normal in another study (73).
The Achilles tendon reflex time is prolonged (44,62), and treatment with T3 restores it to normal (62). The amplitude of the stapedial reflex is low and returns to normal with T4 therapy (74). Brainstem auditory evoked potentials are normal (75). A peripheral neuropathy is suggested by prolonged latency in distal motor nerves during electrophysiologic testing (76); however, nerve conduction velocity is normal (75) and does not change during T4 therapy (49). Serum myoglobin concentrations may be high (44), and excess lactate is released during exercise (77). More frequent neuromuscular symptoms, reduced serum ionized calcium, and repetitive discharges on surface electromyography were found in 33 patients; T4 therapy reversed all these changes (78). Intraocular pressure may be high but decreases during T4 therapy (79). Endothelium-dependent vasodilatation is impaired (80). Serum homocysteine concentrations are normal (33,46,81) and do not change during T4 therapy (33,81). Serum C-reactive protein concentrations were slightly high in one study of 63 patients but did not decrease during T4 therapy (33). Bone density was not reduced in patients with subclinical hypothyroidism after 14 months of T4 therapy (82). Subclinical hypothyroidism is not more prevalent among women with premenstrual syndrome (74). Subclinical hypothyroidism during pregnancy may be a risk factor for poor developmental outcome in offspring (see Chapter 80) (83).
Subclinical hypothyroidism is common, especially among older women. Treatment may be indicated to prevent progression to overt hypothyroidism; this seems most appropriate for patients who have serum TSH concentrations greater than 10 mU/L and high serum anti-TPO antibody concentrations. The major immediate benefit of treatment is an improvement in symptoms and memory in some patients, a small decrease in serum total and LDL cholesterol concentrations, and possible increases in cardiac systolic and diastolic function. However, patients with subclinical hypothyroidism who have symptoms suggestive of hypothyroidism should be advised that treatment may not ameliorate those symptoms. Treatment may also be indicated to reduce thyroid enlargement.
The benefit of treatment is much less certain in patients with serum TSH concentrations less than 10 mU/L. However, pregnant women with any increase in serum TSH concentration should be treated.
Arguments against treatment include the limited clinical benefit, based on the results of the therapeutic trials described above, the relatively low rate of progression, the cost of therapy and the cost of monitoring therapy, and the lifelong commitment to daily medication in patients who have few if any symptoms. Rarely, therapy may exacerbate angina pectoris or a cardiac arrhythmia (84). If treatment is given, careful monitoring to avoid the adverse effects of subclinical thyrotoxicosis is mandatory.
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