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Subclinical hypothyroidism
Author Douglas S Ross, MD Section Editor David S Cooper, MD Deputy Editors Kathryn A Martin, MD

Last literature review version 16.1: January 2008 | This Topic Last Updated: February 4, 2008 (More) INTRODUCTION Subclinical hypothyroidism is defined as a normal serum free thyroxine (T4) concentration and a slightly high serum thyrotropin (TSH) concentration [ 1] . Patients with a basal serum TSH concentration in the upper normal range and a greater than normal serum TSH response to the administration of thyrotropin- releasing hormone (TRH) are also said to have subclinical hypothyroidism by some authors [ 2] . (See "Laboratory assessment of thyroid function" ). Patients with subclinical hypothyroidism may have vague, non-specific symptoms of hypothyroidism, but attempts to identify the patients on the basis of specific, thyroid-related symptoms and signs have not been successful [ 3] . Thus, this disorder can only be diagnosed on the basis of laboratory test results. ( See "Laboratory assessment of thyroid function" ETIOLOGY The causes of subclinical hypothyroidism are the same as those of overt hypothyroidism. ( See "Disorders that cause hypothyroidism" ). Most patients have chronic autoimmune (Hashimoto's) thyroiditis with high serum concentrations of antithyroid microsomal (or antithyroid peroxidase) antibodies. In a study in the United States, for example, chronic autoimmune thyroiditis was found in 54 percent of patients with subclinical hypothyroidism [ 4] . Similarly, in an English study 67 percent of women and 40 percent of men with subclinical hypothyroidism had high serum antithyroid antibody concentrations [ 5] . The other major cause is prior ablative therapy for hyperthyroidism caused by Graves' disease, accounting for up to 40 percent of the cases in the United States [ 4] . About half of clinically euthyroid patients who received radioiodine for Graves' hyperthyroidism and up to two-thirds of those treated surgically have high serum TSH concentrations [ 6-8] . ).

Another common cause of subclinical hypothyroidism is inadequate T4 replacement therapy for overt hypothyroidism, found in 37 percent of patients in one study [ 9] . This may be intentional in patients with coexisting heart disease, due to poor patient compliance, and/or inadequate monitoring of therapy. EPIDEMIOLOGY In two population-based studies, the prevalence of subclinical hypothyroidism was 7.5 to 8.5 percent in women and 2.8 to 4.4 percent in men [ 5,10] . In the United States, National Health and Examination Survey (NHANES III), which excluded subjects with known thyroid disease, 4.3 percent of 16,533 people had subclinical hypothyroidism [11] . The prevalence is lower in blacks than in whites in the United States [12] . However, serum TSH distribution shifts towards higher values with age [ . The change is independent of the presence of antithyroid antibodies, raising uncertainty as to the upper limit of normal for serum TSH ( see "Laboratory assessment of thyroid function" ). 13]

Subclinical hypothyroidism occurs in about 15 percent of women over the age of 60 years [ 5,14] and in about 8 percent of elderly men [ 14] . The prevalence in women over age 80 years is lower (6 percent) [ overt) in the elderly are discussed in detail elsewhere. ( 15] . The clinical manifestations and consequences of hypothyroidism (subclinical and See "Clinical manifestations of hypothyroidism" , section on Hypothyroidism in the elderly). Subclinical hypothyroidism is more common in patients with type 1 diabetes mellitus [16] , and probably also in those with other autoimmune diseases, as compared with otherwise normal subjects. Two percent of pregnant women have subclinical hypothyroidism, many of whom have high serum antithyroid antibody concentrations [ 17] . In Europe, where iodine intake is variable, subclinical hypothyroidism is more prevalent in areas of iodine sufficiency. In one study, the prevalence of subclinical hypothyroidism ranged from 4.2 percent in iodine-deficient areas to 23.9 percent in an area of abundant iodine intake, despite a similar prevalence of patients with high serum concentrations of anti-thyroid peroxidase antibodies [ 18] . NATURAL HISTORY A substantial proportion of patients with subclinical hypothyroidism eventually develop overt hypothyroidism. In a study in which subjects were followed for 20 years, for example, women with both high serum TSH and high thyroid antibody concentrations developed

hypothyroidism at a rate of 4.3 percent per year [ 19] . Another study evaluated patients over age 60 years [ 20] . One-third of

those with subclinical hypothyroidism developed overt hypothyroidism in four years (8 percent per year). The risk was related in part to the initial laboratory findings. All patients with an initial serum TSH concentration >20 mU/L, 80 percent of those with serum antithyroid microsomal antibody titers of 1:1600 or higher, but no one with titers of less than 1:1600 developed overt hypothyroidism. Only 5 to 6 percent of patients had normal serum TSH concentrations during follow up [ 15] . In a prospective study of 82 women, overt hypothyroidism developed in no woman who had a serum TSH concentration <6 mU/L, 43 percent of women with serum TSH concentrations of 6 to 12 mU/L, and 77 percent of women with serum TSH concentration >12 mU/L after 10 years; overt hypothyroidism was more likely in women with high serum antithyroid peroxidase concentrations [ 21] . Another study of 107 subjects found that serum TSH concentration was the only significant predictor of progression to overt hypothyroidism: patients with serum TSH concentrations under 10, or between 15 and 19 mU/L were associated with 1.76 and 73.47 cases of overt hypothyroidism per 100 patient years, respectively [ 22] .

Spontaneous recovery has also been described in patients with subclinical hypothyroidism, although the frequency of this phenomenon is unclear [21,22] . In one study, 37 percent of patients normalized their serum TSH levels over a mean follow-up time of 31.7 months [ 22] . Normalization of serum TSH concentrations were more likely to occur in patients with negative antithyroid antibodies and serum TSH levels <10 mU/I, and within the first two years after diagnosis [ 23] . The underlying disease also may be a determinant of the risk of overt hypothyroidism [ 24] . Patients who have autoimmune thyroid disease or received radioiodine therapy or high-dose external radiotherapy are likely to progress to overt hypothyroidism. In contrast, subclinical hypothyroidism is likely to persist in those who have had thyroid surgery for indications other than hyperthyroidism, or in those who received external radiotherapy during childhood. In an analysis of a primary care network, which included 422,242 persons without known thyroid disease, 62 percent who had had a TSH measurement between 5.5 to 10 mIU/L had a normal TSH subsequently in the absence of treatment [ 25] . EFFECTS OF THYROID HORMONE REPLACEMENT The fundamental clinical question regarding patients with subclinical hypothyroidism is whether they should be treated with thyroid hormone. Based upon the

natural history alone, one might argue that treatment should be started to prevent progression to overt hypothyroidism. Many randomized trials and other studies suggest additional benefits from treatment. Hypothyroid symptoms and psychometric outcomes Thyroid hormone replacement has resulted in improved hypothyroid symptoms and psychometric outcomes in some, but not all trials. Benefit appears to be limited to patients with baseline serum TSH concentration 10 mU/L. One double-blind trial randomly assigned patients with subclinical hypothyroidism, including some patients with TSH values as high as 55 mU/L, some of whom had symptoms such as dry skin, low energy and cold intolerance, to treatment with T4 or placebo for one year [26] . The dose of T4 was adjusted to normalize the serum TSH concentration. During treatment, one-half of the patients in the T4 group, but none in the placebo group, had fewer symptoms, as assessed by a standardized hypothyroidism diagnostic index. Another trial was a double-blind cross-over study in which patients received either T4 (0.15 mg/day) or placebo, each for six months [ 27] . The T4 dose was somewhat high; as a result, some patients may have had subclinical hyperthyroidism. Hypothyroid symptom scores and psychometric test results improved during the T4-treatment period, and about one-half of the patients felt better during this period, as compared with the placebo period. A third 10-month double-blind trial found a significant improvement in psychometric test scores, but no improvement in quality of life, during treatment with T4 [ 28] ; some TSH values were as high as 32 mU/L. In an additional trial, hypothyroid symptom scores also improved [ 29] .

In a double blind randomized cross-over trial of 100 patients with serum TSH between 3.7 and 15.8 mU/L, fatigue improved with a fixed dose of levothyroxine 0.100 mg daily [30] . In a trial of hypothyroid patients receiving T4 replacement, subclinical hypothyroidism was induced by reducing the thyroxine dose (mean TSH 17 mU/L). The fatigue subscale of the Profile of Mood States, the general health subscale of the Short Form 36, and measures of working memory were impaired during the subclinical hypothyroid arm [31] . In contrast, in two trials of patients with serum TSH concentrations 10 mU/L treated with T4, no beneficial effect was seen on quality of life measures [ 32] , cognitive function, emotional function, or hypothyroid symptoms scores [ 33] .

Lastly, in a meta-analysis of 12 clinical trials, there were no differences in hypothyroid signs or symptoms, quality of life, and adverse effects between levothyroxine therapy and placebo [ 34] . Thus, improvement was seen in psychometric test scores and hypothyroid symptoms in some, but not all, trials. No benefit was seen in trials of patients whose TSH values were under 10 mU/L. Serum lipid and apoprotein concentrations Despite a few conflicting reports [ 35-37] , many cross-sectional studies have found that serum total cholesterol concentrations in patients with subclinical hypothyroidism were similar to those of normal subjects [ 1,38-46] ; these concentrations did not consistently fall during T4 treatment [ 26,27,35-37,41,45,47-51 ] . However, in the largest cross-sectional study to date (25,862 participants), subjects with modest elevations of serum TSH (between 5.1 and 10 mIU/L) had significantly higher mean total cholesterol concentrations than those who were euthyroid (223 versus 216 mg/dL [5.6 versus 5.8 mmol/L], p<0.03) [52] . It is not known whether this difference is clinically important with regard to cardiovascular risk. There are no consistent changes in serum low-density-lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and apoprotein concentrations. In some studies patients with subclinical hypothyroidism had high serum LDL-cholesterol [ 35-37,39,53 ] and low HDL-cholesterol concentrations [ 39,45] , but the values were normal in other studies [43,44,46 ] . Serum apoprotein A1 concentrations were high in one study [46] and low in another [ 53] , serum lipoprotein(a) concentrations were high in another study [ 37] , and serum apoprotein B concentrations were normal in some studies [ 38,45,46 ] and high in two studies [ 35,54] . In a randomized, controlled trial in 66 women with subclinical hypothyroidism treated with T4, serum total and LDL cholesterol, and apoprotein B-100 concentrations decreased significantly, whereas serum HDL cholesterol, triglyceride, and lipoprotein (a) concentrations did not change [ 29] . In other studies, serum total and LDL cholesterol concentrations [ 30,35,54 ] and apoprotein B [ 30,53] decreased after T4 therapy. And in two non-randomized trials serum lipoprotein (a) concentrations were reduced by T4 [ 55,56] . Further support for a mild increase in serum cholesterol in subclinical hypothyroidism comes from a pooled analysis of the published literature, which revealed that T4 therapy resulted in a small decrease in mean serum total cholesterol concentration of about 16 mg/dL (0.4 mmol/L) [ 57] . In

addition, a meta-analysis of 247 patients in 13 studies of subclinical hypothyroidism found that T4 therapy resulted in significant reductions in serum total cholesterol (8 mg/dL [0.2 mmol/L]) and serum LDL cholesterol (10 mg/dL [0.3 mmol/L]); the mean serum HDL cholesterol and triglyceride concentrations did not change [ 58] . In this metaanalysis, reductions in serum cholesterol were only seen in patients with levels >240 mg/dL at baseline. Also, only those patients who had "subclinical hypothyroidism" based on inadequately treated overt hypothyroidism had statistically significant decreases in serum cholesterol. ( See "Lipid abnormalities in thyroid disease" ). Smoking may worsen subclinical hypothyroidism and increase its peripheral effects. Among women with subclinical hypothyroidism, those who smoked two or more cigarettes per day had higher serum TSH concentrations and higher serum total and LDL cholesterol concentrations than those who did not smoke [ 59] . The effect of smoking was dose-dependent. Cardiac function Diastolic blood pressure was unchanged in one study [ 60] , increased in two

studies [ 61,62] , and mean arterial pressure fell after T4 treatment in another study [ 63] . Some patients with subclinical hypothyroidism have diastolic dysfunction and increased peripheral vascular resistance, as noted in patients with overt hypothyroidism [ 64] , and cardiac output increases and systemic vascular resistance decreases after T4 treatment [ 63] . Right ventricular systolic and diastolic function were abnormal in one study and improved with T4 treatment [ 65] . Systolic time intervals usually do not change [ 26,66] , unless they were initially prolonged [ 26] . The left ventricular ejection fraction at rest [ 47,67] or during moderate exercise does not change, but may increase during maximal exercise [ 67] . Myocardial contractility during maximal exercise also may increase [ 67] . In contrast, one observational study found no abnormalities in left ventricular mass or function in patients with serum TSH concentrations between 3.5 and 10 mU/l compared to those with normal TSH [ 68] . (See "Cardiovascular effects of hypothyroidism" ). One randomized trial assessed only myocardial structure and contractility. Isovolumetric relaxation time and preejection/ejection ratio were increased and the cyclic variation index was decreased in patients with subclinical hypothyroidism. These alterations returned to normal with T4, but not with placebo [ 69] .

Finally, one trial demonstrated an 11 percent improvement in carotid intima-media thickness with treatment of subclinical hypothyroidism [ 54] . Cardiovascular disease Overt hypothyroidism may be associated with an increased risk of cardiovascular disease. ( See "Cardiovascular effects of hypothyroidism" ). Subclinical hypothyroidism may also be associated with an increased risk of cardiovascular disease, coronary heart disease, and possibly, all-cause mortality [ 70-77] . This was illustrated by the following studies: Flow-mediated dilatation, a measure of vascular endothelial response and an early marker for atherosclerosis, was impaired in a cross-sectional study of patients with subclinical hypothyroidism (mean TSH 8.85) compared with matched euthyroid controls [ 74] , and was improved with thyroxine treatment in two trials [ 30,75] . The brachial-ankle pulse wave velocity, a parameter of arterial stiffening and a predictor of coronary atherosclerosis, was significantly increased in a cross-sectional study of patients with subclinical hypothyroidism (mean TSH 6.89) [ 62] . Central aortic pressure and arterial stiffness was increased in patients with subclinical hypothyroidism (mean TSH 8.8) and was reduced by treatment [ 78] . Serum C-reactive protein and plasma asymmetric dimethylarginine (an endogenous nitric oxide synthase inhibitor) concentrations, appear to be high in patients with subclinical hypothyroidism, and are normalized by levothyroxine administration [ 76] . Platelet-activating factor (PAF) is a proinflammatory lipid mediator that has been implicated in atherogenesis. In plasma, PAF is inactivated by platelet-activating factor acetylhydrolase (PAF-AH). HDL-associated plasma PAF-AH activity is low in patients with subclinical hypothyroidism (mean TSH 9.9), and increases to control values with levothyroxine therapy [ 79] . A number of observational studies have reported that, in general, older subjects with subclinical hypothyroidism are at increased risk for coronary heart disease [ 70-72,80 ] . In one of these reports, the increased risk was seen in men, but not women [ 72] , while in another, older subjects with subclinical hypothyroidism were at increased risk for developing heart failure, but not CHD [ 81] . A meta-analysis of 14 observational studies of subclinical hypothyroidism calculated an overall increased risk of CHD (OR 1. 65) [82] .

In summary, subclinical hypothyroidism may be associated with an increased risk of CHD. However, clinical trials are needed to assess whether thyroid hormone replacement reduces the risk of CHD in these patients. Mortality An English study of mortality in patients treated for hyperthyroidism found that patients with subclinical hypothyroidism following radioiodine treatment had a two-fold increased mortality from ischemic heart disease [ 83] . (See "Radioiodine in the treatment of hyperthyroidism" , section on Mortality). One of the observational studies noted above reported an increase in all-cause mortality in men, but not women [ 72] , while two others observed an increased risk of cardiovascular mortality [ 77,80] , one of which included 3121 cardiac patients and also found an increase in all cause mortality [ 77] .

In contrast to the studies described above, the Cardiovascular Health Study of 3233 community-dwelling subjects over age 65 years, reported that subclinical hypothyroidism was not associated with an increased risk of CHD, adverse cardiovascular outcomes, or mortality [ 84] . In addition, in a study of individuals over age 85 in the Netherlands followed for four years, those with untreated subclinical hypothyroidism actually had a lower rate of cardiovascular and all-cause mortality. ( See "Diagnosis of and screening for hypothyroidism" , section on Very elderly). Neuropsychiatric disease Many reports of an increased prevalence of subclinical hypothyroidism in patients with depression or bipolar affective disorder need critical assessment because of confounding factors such as inadequate control groups, coincident lithium therapy, inclusion of patients with normal basal serum TSH concentrations but an increased response of serum TSH to TRH administration, and/or positive tests for antithyroid microsomal antibodies. A 1998 study suggested that depression correlated with high serum anti-thyroid peroxidase antibody concentrations rather than thyroid function [ 85] . Despite these limitations, several reports suggest that subclinical hypothyroidism is associated with neuropsychiatric disease. In one study, as an example, the prevalence of hypothyroidism was 14.8 percent in patients with neurotic depression, 2.3 percent in those with senile and multi-infarct dementia, and 1.9 percent in non-psychiatric inpatients [ 86] . However, a large study of primary care patients in England failed to demonstrate an association of subclinical hypothyroidism with depression, anxiety, or cognitive function [ 87] .

The following additional findings have been noted: Patients with depression and subclinical hypothyroidism have a higher prevalence of associated panic disorder, and a poorer response to antidepressant drugs than euthyroid depressed patients [ 88] .

Patients with subclinical hypothyroidism have a higher lifetime frequency of depression than euthyroid subjects [ 89] .

Women with subclinical hypothyroidism who presented to a clinic for assessment of goiter were found to have increased rates of free-flowing anxiety, somatic complaints, depressive features, hysteria, and abnormal psychometric testing as compared with euthyroid patients with goiter [ 90] . These problems improved with T4 treatment. Pregnancy Undetected subclinical hypothyroidism in pregnancy is a risk factor for poor developmental outcome in the offspring, as shown in a study of 62 children whose mothers had high serum TSH (48 of whom were not treated) and low serum T4 concentrations during the second trimester [ 91] . At age seven to nine years, these children had slightly lower IQ scores than did 124 children of mothers whose serum TSH concentrations were normal (IQ score 103 versus 107, p=0.06); 15 percent of the former group but only 5 percent of the latter group had scores of 85 or less. Other findings The following findings have also been described in patients with subclinical hypothyroidism: In one study, serum TSH concentrations greater than 3.6 mU/I (and a normal free T4) were associated with modest weight gain when compared to those with serum TSH 0.4 to 0.99 mU/I [ 92] . However, another study in children found that obese subjects had a higher serum TSH which fell to normal levels with weight loss, suggesting that the higher TSH was a result of obesity and not the cause [ (See "Etiology and natural history of obesity" , section on Hypothyroidism) An increase in C-reactive protein [ 73] An increase in erythrocyte Na/K-ATPase [ 94] A high frequency of neuromuscular symptoms (weakness, fatigue, paresthesias, cramps), as compared with normal subjects; in one study 21 of 33 patients (64 percent) had two or more of these symptoms, as compared with 6 of 44 normal subjects (14 percent) [95] A prolonged Achilles reflex time that became normal during treatment with triiodothyronine [ 46,96] 93] .

Muscle dysfunction characterized by excessive release of lactate during exercise [ 97] Altered response to exercise in terms of tolerance and pattern of substrate utilization; one year of thyroid hormone therapy and restoration of euthyroidism did not correct this defect [ 98] Electromyographic evidence of peripheral neuropathy [ 99] Elevated basal prolactin (in 19 percent of patients), and elevated prolactin response to TRH administration, which falls with T4 treatment [100] Elevated intraocular pressure, which falls with T4 treatment [ In one study, bone density was not reduced in patients with subclinical hypothyroidism after 14 months of treatment with T4 [ 102] ; however, another study documented increased parameters of bone turnover. ( See "Bone disease with hyperthyroidism and thyroid hormone therapy" ) Patients with unprovoked deep venous thrombosis are more likely to have subclinical hypothyroidism [ 103] . Patients with subclinical hypothyroidism are more likely to have common bile duct stones, thought to be secondary to sphincter of Oddi dysfunction [ 104] . Patients with type 2 diabetes and subclinical hypothyroidism have a greater prevalence of diabetic nephropathy [ 105] . 101]

Hypothyroid symptoms with normal thyroid function tests Anecdotal reports suggest that T4 therapy may be beneficial in patients with symptoms of hypothyroidism but normal thyroid function tests. However, in a randomized, crossover trial of 22 such patients, T4 was no more effective than placebo in increasing cognitive function and psychologic well-being [106] . Thus, T4 should not be prescribed for patients with hypothyroid symptoms but normal thyroid function. SERUM TSH ELEVATIONS NOT ASSOCIATED WITH SUBCLINICAL HYPOTHYROIDISM There are several causes of high serum TSH concentrations that do not properly fit the definition of subclinical hypothyroidism. These include: During the period of recovery from nonthyroidal illness An unusually large pulse of TSH secretion, especially late in the evening Assay variability Adrenal insufficiency

During treatment with metoclopramide or domperidone TSH-producing pituitary adenomas and resistance to thyroid hormone, and rare mutations of the TSH receptor All patients who have high serum TSH concentrations due to these causes are either hyperthyroid or euthyroid. Thus, minimal elevations in serum TSH concentrations must be confirmed by repeat testing before the diagnosis of subclinical hypothyroidism can be accepted. RECOMMENDATIONS A 1998 American College of Physicians position paper questioned whether sufficient data existed to recommend treatment for patients with subclinical hypothyroidism [ 107] . However, others have recommended treatment for most patients, in large part because unrecognized symptoms may improve and correction of abnormal serum lipid concentrations may be cardioprotective [ 108-110 ] . In view of data linking subclinical hypothyroidism with atherosclerosis and myocardial infarction [70] , I recommend that most patients with subclinical hypothyroidism and TSH levels greater than 10 mU/L be treated with T4. This recommendation is consistent with that of a clinical consensus group (comprised of representatives from the Endocrine Society, American Thyroid Association, and the American Association of Clinical Endocrinologists) [ 111] . Treatment will prevent progression to overt hypothyroidism, especially in those with serum TSH concentrations greater than 10 to 15 mU/L and high serum antithyroid peroxidase antibody concentrations. Treatment in patients with lesser elevations in serum TSH concentrations will prevent growth of a goiter or possibly ameliorate nonspecific symptoms of hypothyroidism such as fatigue, constipation or depression. The major benefit of therapy, based upon two randomized studies, is an improvement in symptoms [26,27] . Goiter, if present, decreases in size in about 80 percent of patients [ 112] . Treatment may also improve cardiac contractility and serum lipid concentrations in some patients and secondarily reduce the risk of atherosclerosis. The goal of therapy should be to reduce the patient's serum TSH concentration to normal. The initial dose can be the full anticipated dose in young, healthy patients, but older patients should be started on a lower dose ( See "Treatment of hypothyroidism" ). Arguments against T4 treatment include its cost, for both the hormone and for monitoring its efficacy, the lifelong commitment to daily medication in asymptomatic patients, and the possible induction or exacerbation of angina pectoris or cardiac arrhythmia in susceptible patients [ 113] . Although these concerns are not usually sufficient to counterbalance the benefits of therapy, we do recommend a higher threshold for treating elderly patients with cardiovascular disease. If the patient is not treated, regular follow up is

indicated. Recommendations for routine screening are discussed elsewhere. ( the periodic health examination). See

"Diagnosis of and screening for hypothyroidism" , section on Screening at

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