APPENDIX B
Screening for Thyroid Disease: Systematic Evidence Review

Mark Helfand, M.D., M.P.H.*

INTRODUCTION

Burden of Illness

Hyperthyroidism and hypothyroidism are common conditions that have life-long effects on health. About 5 percent of U.S. adults report having thyroid disease or taking thyroid medication.1,2 In a cross-sectional study of 2,799 well-functioning adults ages 70 to 79, 9.7 percent of black women, 6 percent of white women, 3.2 percent of black men, and 2.2 percent of white men reported a history of hyperthyroidism.3 In the same study, 6.2 percent of black women, 16.5 percent of white women, 1.7 percent of black men, and 5.6 percent of white men reported a history of hypothyroidism.

Hyperthyroidism has several causes. Graves’ disease, the most common intrinsic cause, is an autoimmune disorder associated with the development of long-acting thyroid stimulating antibodies (LATS). Single or multiple thyroid nodules that produce thyroid hormones can also cause hyperthyroidism. The use of excessive doses of the thyroid hormone supplement levothyroxine is also a common cause.

*  

This evidence review was developed by the Evidence-based Practice Center, Oregon Health & Science University, for the Institute of Medicine and the U.S. Preventive Services Task Force and was reviewed and approved by both groups. This paper may differ slightly from the version that will be released by the Task Force.



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APPENDIX B Screening for Thyroid Disease: Systematic Evidence Review Mark Helfand, M.D., M.P.H.* INTRODUCTION Burden of Illness Hyperthyroidism and hypothyroidism are common conditions that have life-long effects on health. About 5 percent of U.S. adults report having thyroid disease or taking thyroid medication.1, 2 In a cross-sectional study of 2,799 well-functioning adults ages 70 to 79, 9.7 percent of black women, 6 percent of white women, 3.2 percent of black men, and 2.2 percent of white men reported a history of hyperthyroidism.3 In the same study, 6.2 percent of black women, 16.5 percent of white women, 1.7 percent of black men, and 5.6 percent of white men reported a history of hypothyroidism. Hyperthyroidism has several causes. Graves’ disease, the most common intrinsic cause, is an autoimmune disorder associated with the development of long-acting thyroid stimulating antibodies (LATS). Single or multiple thyroid nodules that produce thyroid hormones can also cause hyperthyroidism. The use of excessive doses of the thyroid hormone supplement levothyroxine is also a common cause. *   This evidence review was developed by the Evidence-based Practice Center, Oregon Health & Science University, for the Institute of Medicine and the U.S. Preventive Services Task Force and was reviewed and approved by both groups. This paper may differ slightly from the version that will be released by the Task Force.

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The most common cause of hypothyroidism is thyroiditis due to antithyroid antibodies, a condition called “Hashimoto’s thyroiditis.” Another common cause of hypothyroidism is prior treatment for Graves’ disease with surgery or radioiodine. Consequences of untreated hyperthyroidism include atrial fibrillation, congestive heart failure, osteoporosis, and neuropsychiatric disorders. Both hyperthyroidism and hypothyroidism cause symptoms that reduce functional status and quality of life. Subclinical thyroid dysfunction, which can be diagnosed by thyroid function tests before symptoms and complications occur, is viewed as a risk factor for developing these complications. The goal of screening is to identify and treat patients with subclinical thyroid dysfunction before they develop the complications of hyperthyroidism and hypothyroidism. This appendix focuses on whether it is useful to order a thyroid function test in patients who have no history of thyroid disease when they are seen by a primary care clinician for other reasons. The review is intended for use by two expert panels: the United States Preventive Services Task Force, which will make recommendations regarding screening in the general adult population, and the Institute of Medicine, which will focus on the Medicare population. Definition of Screening and Casefinding Screening can be defined as “the application of a test to detect a potential disease or condition in a person who has no known signs or symptoms of that condition at the time the test is done.”4 By this definition, screening with thyroid function tests may identify asymptomatic individuals as well as patients who have mild, nonspecific symptoms such as cold intolerance or feeling “a little tired.” The symptoms associated with thyroid dysfunction are shown in Table B-1.5, 6 When many of these symptoms and signs occur together, the clinician may have a strong suspicion that the patient has thyroid disease. However, patients who complain of one or two of the symptoms in Table B-1 may be no more likely to have abnormal thyroid function tests than those who have no complaints. In older patients7 and in pregnant women, such symptoms are so common that it becomes meaningless to try to distinguish between “asymptomatic” patients and those who have symptoms that may or may not be related to thyroid status. Studies of screening can be classified according to the setting in which the decision to screen takes place. In casefinding, testing for thyroid dysfunction is performed among patients who come to their physicians for unrelated reasons. When the screening test is abnormal, the patient is called back for a detailed thyroid-directed history. Studies of casefinding programs provide the most realistic estimates of the effects and costs of screening in clinic or office practice. Population-based studies of screening use special methods to recruit, contact, and follow patients in the context of an epidemiologic research effort. Such

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TABLE B-1 Symptoms and Signs of Thyroid Dysfunction   Hypothyroidism Hyperthyroidism Symptoms Coarse,dry skin and hair Cold intolerance Constipation Deafness Diminished sweating Physical tiredness Hoarseness Paraesthesias Periorbital puffiness Nervousness and irritability Heat intolerance Increased frequency of stools Muscle weakness Increased sweating Fatigue Blurred or double vision Erratic behavior Restlessness Heart palpitations Restless sleep Decrease in menstrual cycle Increased appetite Signs Slow cerebration Slow movement Slowing of ankle jerk Weight gain Goiter Distracted attention span Tremors Tachycardia Weight loss Goiter studies show the extent of unsuspected thyroid disease in a population sample of a particular geographic area but do not reflect the yield or costs of screening in office-based practice. Population-based studies of screening serve as a benchmark against which the yield and benefits of more practical clinic-based screening programs can be measured. Classification of Thyroid Dysfunction Thyroid dysfunction is a graded phenomenon and progresses from early to more advanced forms. As better biochemical tests have come into use, classification of the grades of thyroid dysfunction has changed dramatically. Historically, clinical, biochemical, and immunologic criteria have been used to classify patients with milder degrees of thyroid dysfunction.8, 9 Today, the most common approach is to classify patients primarily according to the results of thyroid function tests (Table B-2). In this classification, “overt hypothyroidism” refers to patients who have an elevated thyroid stimulating hormone (thyrotropin or TSH) and a low thyroxine (T4) level. “Overt hyperthyroidism” refers to patients who have a low TSH and an elevated T4 or triiodothyronine (T3). The primary rationale for screening is to diagnose and treat subclinical thyroid dysfunction.10-12 This rationale views subclinical thyroid dysfunction as a

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TABLE B-2 Classification of Thyroid Dysfunction   TSH Thyroid Hormones Overt hyperthyroidism Low or undetectable Elevated T4 or T3 Subclinical hyperthyroidism Low or undetectable Normal T4 and T3 Overt hypothyroidism >5 mU/L* Low T4 Subclinical hypothyroidism >5 mU/L* Normal T4 *Some use higher or lower values risk factor for the later development of complications and as a condition that may have symptoms that respond to treatment. Controversy centers on whether early treatment or close follow-up is warranted in apparently healthy persons in whom the only indication of a thyroid disorder is an abnormal TSH result. The terms “subclinical hypothyroidism” and “mild thyroid failure” refer to patients who have an elevated TSH and a normal thyroxine level (Table B-2).12 In some classification schemes, patients who have an elevated TSH and a normal thyroxine level are subclassified according to the degree of TSH elevation and the presence of symptoms, signs, and antithyroid antibodies.13 In the literature, the term “subclinical hypothyroidism” has been used to describe several conditions: Patients who have subclinical hypothyroidism as a result of surgery or radioiodine treatment for Graves’ disease. Patients who take inadequate doses of levothyroxine therapy for known thyroid disease. Patients who have mildly elevated TSH levels and normal T4 levels and nonspecific symptoms that could be due to hypothyroidism. Asymptomatic patients who are found by screening to have elevated TSH and normal T4. The term “subclinical hyperthyroidism” is used to describe conditions characterized by a low TSH and normal levels of circulating thyroid hormones (thyroxine and triiodothyronine). Subclinical hyperthyroidism has the same causes as overt hyperthyroidism. These include excessive doses of levothyroxine, Graves’ disease, multinodular goiter, and solitary thyroid nodule. Most studies of the course of subclinical hyperthyroidism concern patients whose history, physical examination, ultrasound, or thyroid scan suggests one of these causes. There are relatively few studies of patients found by screening to have a low TSH, normal T4 and T3 levels, and a negative thyroid evaluation, the largest group identified in a screening program.

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Accuracy of Screening Tests Screening for thyroid dysfunction can be done using a history and physical examination, antithyroid antibodies, or thyroid function tests, including various assays for TSH and T4. Today the TSH test is usually proposed as the initial test in screening because of its ability to detect abnormalities before serum thyroxine and triiodothyronine levels are abnormal. When used to confirm suspected thyroid disease in patients referred to an endocrine specialty clinic, the sensitive TSH has a sensitivity above 98 percent and a specificity greater than 92 percent for the clinical and functional diagnosis.14 The accuracy of a TSH when used to screen primary care patients has been difficult to evaluate. The greatest difficulty is in classifying a patient who has an abnormal TSH, normal T4 and T3 levels, and no evidence supporting thyroid disease on physical examination. Those who consider the TSH to be the “gold standard” determination of disease would define such a patient as a “true positive.” Others argue that patients who have an abnormal TSH but who never develop complications and never progress should be considered “false positives.” They argue that these patients happen to have TSH levels outside the 95-percent reference limits for the general population but never truly had a thyroid disorder.13 In screening programs and in the primary care clinic, many patients found to have an abnormal TSH revert to normal over time. In one randomized trial, for example, mildly elevated TSH level reverted to normal in 8 of 19 patients given placebo.15 In older subjects, only 59 percent (range 14 percent to 87 percent) of patients with an undetectable TSH on initial screening had an undetectable TSH level when the TSH was repeated.16, 17 In the Framingham cohort, screening identified 41 people with an undetectable serum TSH (= 0.1 mU/L) and a normal serum T4 level (<129 nmol/L).18 After 4 years of follow-up, when 33 of these people were retested, 29 had higher serum TSH levels (>0.1 mU/L). Nonthyroidal illness is an important cause of false-positive TSH test results. In a recent systematic review of screening patients admitted to acute care and geriatric hospitals, the positive predictive value of a low serum TSH (<0.1 mU/L) was 0.24, meaning that approximately one in four patients proved to have hyperthyroidism.19 For hypothyroidism, the predictive value of a serum TSH between 6.7 and 20 mU/L was 0.06. The predictive value of a low TSH may also be low in frail or very elderly subjects.20-22 One retrospective study reviewed the course of 40 female nursing home residents who had a low TSH and initially normal T4.21 In 10 subjects (3 with low T3 levels and 7 who died), nonthyroidal illnesses probably caused the low TSH. In 18 other women, the TSH subsequently normalized but the reason for the initially low TSH was not apparent. Only three subjects were later diagnosed to have thyroid disease as the cause of the low TSH (positive predictive value 0.075).

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Prevalence In a population that has not been screened previously, the prevalence of the disease, along with the sensitivity of the screening test and follow-up tests, determine the potential yield of screening. These factors, along with the proportion of subjects who have a screening test and comply with follow-up testing if indicated, determine the actual yield of a screening program. More than 40 studies reported the prevalence of thyroid dysfunction in defined geographic areas, in health systems, in primary care clinics, and at health fairs.1, 2, 23-33 In cross-sectional, population-based studies, a serum TSH = 4 mU/L in conjunction with a normal thyroxine level (subclinical hypothyroidism) is found in about 5 percent of women and in up to 3 percent of men. In an analysis of the third National Health and Nutrition Examination Survey (NHANES-III), a population-based survey of 17,353 people aged = 12 or more years representing the U.S. population, subclinical hypothyroidism was defined as a serum TSH level above 4.5 mU/L and a serum T4 =57.9 nmol/L.1 Among those who did not have a history of thyroid disease, the prevalence was 5.8 percent among white, non-Hispanic females; 1.2 percent among black, non-Hispanic females; and 5.3 percent among Mexican Americans. For men, the prevalence was 3.4 percent among whites, 1.8 percent among blacks, and 2.4 percent among Mexican Americans. Older age and female sex are well-documented risk factors for subclinical hypothyroidism. In the NHANES-III survey, the overall prevalence of a serum TSH= 4.5 mU/L was about 2 percent at ages 30 to 49, 6 percent at ages 50 to 59, 8 percent at ages 60 to 69, and 12 percent at ages 70 to 79. In a population-based study in Whickham, England, the prevalence (serum TSH = 6 mU/L and normal T4) was 4 percent to 5 percent in women ages 18 to 44, 8 percent to 10 percent in women ages 45 to 74, and 17.4 percent in women over age 75.34 The prevalence was 1 percent to 3 percent in men ages 18 to 65 and 6.2 percent in men over age 65. Population factors, such as iodine intake and ethnicity, affect the prevalence of subclinical hypothyroidism, but differences among studies are also due to differences in the definition of an abnormal TSH level and ascertainment of a history of thyroid disease or levothyroxine use. The prevalence of subclinical hyperthyroidism (a low TSH in conjunction with normal T4 and T3 levels) depends on how a low TSH is defined. A meta-analysis found that, when defined as an undetectable TSH level in a person with a normal free thyroxine level, the prevalence of subclinical hyperthyroidism was about 1 percent (CI, 0.4 percent to 1.7 percent) in men older than 60 years of age and 1.5 percent (CI, 0.8 percent to 2.5 percent) in women older than 60 years of age.25 Other studies defined subclinical hyperthyroidism as a TSH below the lower limit of the normal range (about 0.4 mU/L) in a person with a normal T4

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level. When defined in this way, the prevalence of subclinical hyperthyroidism in men and women 60 years and older is as high as 12 percent.35 Incidence In a population that has been screened previously, the incidence of new cases of thyroid dysfunction is the most important factor in determining the yield of a second round of screening. In a 20-year follow-up of the Whickham population, the annual incidence of overt thyroid dysfunction was 4.9 per 1,000 in women (4.1 hypothyroid and 0.8 hyperthyroid) and 0.6 per 1,000 in men (all hypothyroid).36 In most other studies, the incidence of hyperthyroidism is lower in women (0.3 to 0.4 per 1,000) and slightly higher in men (0.01 to 0.1 per 1,000).23 Within a given geographic region, older age, an elevated TSH level, antithyroid antibodies, and female sex are the strongest risk factors for developing overt hypothyroidism. In the Whickham survey, for a 50-year-old woman who has a serum TSH level of 6 mU/L and positive antithyroid antibodies, the risk of developing overt hypothyroidism over 20 years was 57 percent; for a serum TSH of 9 mU/L, the risk was 71 percent.36 A 50-year-old woman who had a normal TSH and negative antibody test had a risk of only 4 percent over 20 years. The risk of progression was not evenly distributed throughout the follow-up period. Nearly all women who developed hypothyroidism within 5 years had an initial serum TSH greater than 10 mU/L. Exposure to ionizing radiation has also received attention as a potential risk factor for thyroid dysfunction. In general, studies of populations exposed to radioactive fallout have focused primarily on screening for thyroid cancer. A large cohort study of populations exposed to radiation from the Hanford nuclear facility provides the best quality evidence about the risk of thyroid dysfunction. The study proved definitively that exposure to radioactive fallout from Hanford conferred no additional risk of hyperthyroidism or hypothyroidism compared to unexposed populations.37 Specifically, the study found that there was no dose-response relationship between exposure to radioactive fallout and the incidence of thyroid disease. It also found that the rate of thyroid dysfunction in the Hanford region was no higher than that reported in areas that had not been exposed. Evidence Regarding the Complications of Subclinical Hyperthyroidism Advocates of screening for subclinical hyperthyroidism argue that early treatment might prevent the later development of atrial fibrillation, osteoporotic fractures, and complicated overt hyperthyroidism. Other potential benefits are earlier treatment of neuropsychiatric symptoms and prevention of the long-term consequences of exposure of the heart muscle due to excessive stimulation from thyroid hormones.

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Atrial Fibrillation A good-quality cohort study in the Framingham population found that, in subjects over age 60 who did not take levothyroxine and had a low TSH, the risk of atrial fibrillation was 32 percent (CI, 14 percent to 71 percent) over 10 years.35 The risk for subjects who had a normal TSH level was 8 percent. The patients with low serum TSH values were stratified into two groups, those with serum TSH values = 0.1 mU/L and those with values of >0.1 to 0.4 mU/L; only in the former group was the risk of atrial fibrillation increased. A more recent cross-sectional study of atrial fibrillation in overt and subclinical hyperthyroidism had serious flaws and was rated as being of poor quality.38 The clinical consequences of atrial fibrillation in patients who have a low TSH have not been studied. In general, chronic atrial fibrillation is associated with stroke and other complications and with a higher risk of death.39 Mortality A population-based, 10-year cohort study of 1,191 people age 60 or over found a higher mortality rate among patients who had a low TSH initially.40 The excess mortality was due primarily to higher mortality from cardiovascular diseases. In this study, the recruitment strategy and the statistical adjustment for potential confounders were inadequate; patients who had a low TSH may have had a higher prevalence of other illnesses, but adjustment was done only for age and sex and not for co-morbidity. Such adjustment would be critical because acutely ill and chronically ill elderly patients have more falsely low TSH levels than relatively healthy elderly patients, presumably as a result of their illness.19 Thus, although it is possible that patients who had a low initial TSH had higher mortality because of their thyroid disease, it is also possible that patients who were ill to begin had a low TSH as a result of their illness. Osteoporosis and Fracture A good-quality study from the Study of Osteoporotic Fractures (SOF) cohort found similar bone loss among women with undetectable, low, and normal TSH levels.41 Two meta-analyses of older studies42, 43 suggest that women who have a low TSH because they take thyroid hormones are at higher risk of developing osteoporosis. Other studies of the risk of osteoporosis concern small numbers of subjects with nodular thyroid disease or Graves’ disease44-47 rather than patients who have no obvious clinical signs of thyroid disease. Among women in the SOF population, a history of treated hyperthyroidism is associated with an increased risk of having a hip fracture later in life.48 A more recent nested sample of cases and controls from SOF examined the relationship between fractures and a low TSH in a broader group of women who had been

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followed for 6 years.49 The sample consisted of 148 women with hip fractures, 149 with vertebral fractures, and 304 women without fracture who were selected as controls. The subjects were classified according to their initial TSH level. Among the 148 women with hip fractures, 22 had an undetectable serum TSH (<0.1 mU/L); approximately 19 of these took thyroid hormones when their initial TSH measurement was made. At baseline, the cases were significantly older, weighed less, and were less likely to be healthy by self-report than controls. They were also twice as likely to have a history of hyperthyroidism and had lower bone density at baseline. After adjustment for all of these confounding factors, the risk of hip fracture among women who had an undetectable TSH was elevated, but the value was of borderline statistical significance (adjusted relative hazard ratio 3.6; CI, 1.0-12.9). Similarly, after adjustment for confounders, the risk of vertebral fracture among women who had an undetectable TSH was significantly elevated when compared with 235 controls (odds ratio 4.5; CI, 1.3-15.6). Among women who had a borderline low serum TSH (0.1 to 0.5 mU/L), the risk for vertebral fracture (odds ratio 2.8; CI, 1.0-8.5), but not hip fracture, was elevated. The main weakness of this study is that the number of women with an undetectable TSH (14 with hip fracture and 14 with vertebral fracture versus 8 controls) was small relative to the number of confounders included in the analyses (6 to 7). Interactions could be important in this analysis because the relationship between the number of risk factors and the incidence of fracture is not linear. The number of important baseline differences between cases and controls raises the possibility that some of the women with low TSH levels had multiple factors and that other factors concomitant with age or socioeconomic status could also have been confounders. The study’s relevance to screening is limited because 86 percent of the women who had undetectable TSH levels were taking thyroid hormones. The authors state that “thyroid hormone use was not associated with increased risk for . . . fracture,” but there were not enough women with undetectable TSH levels not taking thyroid hormone to make a valid comparison. Complicated Thyrotoxicosis and Progression to Overt Hyperthyroidism Thyrotoxicosis can be complicated by severe cardiovascular or neuropsychiatric manifestations requiring hospitalization and urgent treatment. There are no data linking subclinical hyperthyroidism to the later development of complicated thyrotoxicosis. Such a link is unlikely to be made because (1) complicated thyrotoxicosis is rare, (2) one half of cases occur in patients with known hyperthyroidism, and (3) complications are associated with social factors, including insurance status, that may also affect access to screening and follow-up services.50 Progression from subclinical hyperthyroidism is well documented in patients with known thyroid disease (goiter or nodule) but not in patients found by screening to have a low TSH and no thyroid signs. Based on the sparse data from screening studies, each year 1.5 percent of women and 0 percent of men who

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have a low TSH and normal T4 and T3 levels develop an elevated T4 or T3.16, 25, 51 In one population-based study (n=2,575), 33 of 41 patients who had an initially low TSH had a serum TSH higher than 0.1 mU/L on repeat testing 4 years later.18 Two patients developed overt hyperthyroidism during the follow-up period. In another population-based study, screening in 886 85-year-olds found 6 women and 2 men who had an undetectable TSH and were not already taking levothyroxine.51 After 3 years of follow-up, two women were diagnosed to have hyperthyroidism: One was apparently healthy initially, while the other had atrial fibrillation on the initial examination. Dementia In the Rotterdam study, a population-based, longitudinal study with 2-year follow-up (to be discussed in detail), persons with reduced TSH levels at baseline had more than a threefold increase in the incidence of dementia (RR = 3.5; 95 percent CI, 1.2-10.0) and Alzheimer’s disease (RR = 3.5; 95 percent CI, 1.1-11.5), after adjustment for age and sex.52 With respect to this result, the authors stated that the results were similar “when controlling for the effects of atrial fibrillation or excluding subjects taking beta-blockers.” These results are not reported; it is unclear whether they were statistically significant. Later, after presenting several other results, they state that “adjustments for education, symptoms of depression, cigarette smoking, or apolipoprotein E4 did not alter any of these findings,” but it is not clear whether this statement pertains to the main result. Symptoms and Cardiac Effects Untreated or inadequately treated hyperthyroid patients may present with neuropsychiatric symptoms or congestive heart failure that may be responsive to treatment. In the setting of nodular thyroid disease, Graves’ disease, or long-term use of suppressive doses of levothyroxine, subclinical hyperthyroidism also has been associated with cognitive abnormalities, abnormalities in cardiac contractility, and exercise intolerance.53-58 However, the frequency of symptoms or myocardial contractility abnormalities in patients who have subclinical hyperthyroidism found by screening is not well studied, and no study has linked abnormalities in cardiac contractility or output to the development of clinically important heart failure. Evidence Regarding Complications of Subclinical Hypothyroidism The best studied potential complications of hypothyroidism are hyperlipidemia, atherosclerosis, symptoms, and (for subclinical disease) progression to overt hypothyroidism. In pregnancy, subclinical hypothyroidism confers additional risks to both mother and infant.

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Hyperlipidemia Overt hypothyroidism has long been known to be associated with elevated levels of cholesterol,59 but patients in the earliest studies had very severe hypothyroidism. In more recent studies, there is a clinically important increase in total cholesterol and LDL cholesterol among men60 and women61, 62 with overt hypothyroidism, usually with serum TSH levels higher than 20 mU/L. In women with milder forms of hypothyroidism, the relation between TSH and total cholesterol or LDL cholesterol is inconsistent. About one in four patients with subclinical hypothyroidism has a total cholesterol concentration higher than 6.2 mmol/L. The Whickham survey found no relationship between subclinical hypothyroidism and hyperlipidemia. Recent cross-sectional, population-based studies of the relation between TSH and lipid levels in women have had mixed results. In the Rotterdam study33 (discussed in detail below), lipid levels were significantly lower among women with subclinical hypothyroidism than among euthyroid women. A fair-quality study of randomly selected Medicare recipients found no differences in total cholesterol, LDL cholesterol, HDL cholesterol, or triglycerides between subjects who had a serum TSH <4.6 (n=684) and those who had a serum TSH between 4.7 and 10 (n=105). There were nonsignificant increases in LDL cholesterol and HDL cholesterol among women who had a serum TSH >10 (LDL cholesterol 143 versus 128 in euthyroid women, p=0.08; HDL cholesterol 41.6 versus 47.5, p=0.053).31 Conversely, a cross-sectional, population-based study from the Netherlands found that the prevalence of subclinical hypothyroidism was correlated with lipid levels; the prevalence was 4 percent among women with a total cholesterol level < 5 mmol/l; 8.5 percent when total cholesterol was 5 to 8 mmol/l; and 10.3 percent when total cholesterol was >8 mmol/L.63 Another recent cross-sectional study of 279 women over age 65 found a strong relationship between hyperlipidemia and serum TSH levels.64 Of the 279 women, 19 (6.8 percent) had a serum TSH >5.5 mU/L. After adjustment for age, weight, and estrogen use, women who had a serum TSH >5.5 mU/L had 13 percent higher LDL cholesterol (95 percent CI, 1 percent to 25 percent) and 13 percent lower HDL cholesterol (CI, -25 percent to 0 percent) than women with a normal serum TSH (0.1 to 5.5 mU/L). However, 2 of the 19 women who had an elevated TSH used thyroxine, suggesting they had inadequately treated overt hypothyroidism. Because T4 and T3 levels were not measured, it is possible that others in this group had overt hypothyroidism as well. Moreover, only 1 of the 19 women (6 percent) took estrogen replacement therapy, whereas 32 of 250 women in the euthyroid group used estrogen. The analysis adjusted for estrogen use but not for other factors, such as socioeconomic status, that are associated with lipid levels and are also known to be associated with estrogen use. Men with a mildly elevated TSH generally do not have an increased risk of hyperlipidemia, but data on men are sparse. Hypercholesterolemic men do not

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LT4 vs. Placebo Group Results Before/After Results Improved symptoms (-1.2 vs. +2.1) in LT4 group. 47% improved in LT4 group vs. 19% in placebo group (NNT=3.6); No difference in lipid profiles Placebo group’s TSH and symptoms rose during the year,suggesting the patients had rapidly advancing subclinical hypothyroidism Post-treatment LDLc was the same in both groups (3.7±0.2, p=0.11), and symptoms scores were not significantly different (p=.53) LDLc reduced from 4.0 to 3.7 in the LT4 group (p=0.004) and there were borderline improvements in symptom scores (p=0.02); Placebo group TSH was stable There were no significant differences between LT4 and placebo groups in any lipid parameter LT4 group: TC reduced from 5.5 to 5.0; LDLc from 3.6 to 3.1 No improvement in symptoms or lipids; improved memory in LT4 group (mean difference of .58 on z score scale,described as “small and of questionable clinical importance”) Placebo group’s TSH rose from 9.42 to 10.32 over 6 months No improvement in symptoms or lipids Placebo group’s TSH dropped from 7.3 to 5.6 over 6 months No difference in lipids; in before/after comparisons, symptom scores improved by the equivalent of 1 symptom per subject (p<0.001), and 4 patients felt better with LT4 than with placebo   LDL reduced from 6.2 to 6.1 in 25 mg group and from 6.8 to 5.9 in 50 mg group LDLc reduction was significant in 50 mg group Among symptomatic patients (n=22), there were no important differences between LT4 and placebo groups in any SF-36, memory, or cognitive measures Placebo significantly improved SF-36 general health and physical health scores reduce serum cholesterol by 8 percent in selected patients who have both a serum TSH >10 mU/L and an elevated total cholesterol (>6.2 mmol/L). About 7 percent of individuals with subclinical hypothyroidism meet these criteria. Most of the studies on which these analyses are based have important limitations.13, 25, 104 Many of these studies were before/after studies in which reductions in serum lipids could have been due to regression toward the mean. In most,

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samples were small, selection of patients was poorly described, clinicians and patients were aware of the treatment and of the need to lower lipid levels, and outcome assessment may have been biased. That is, the problem is not that these studies are observational but that many of them are poor-quality observational studies. The hazards of relying on observational studies of the effect of drug therapy is illustrated by a large (n=139) open study of levothyroxine to treat symptoms of hypothyroidism in patients who had normal thyroid function tests. This study found that the mean number of signs and symptoms of hypothyroidism decreased from 13 to 3 following 6 months or more of treatment; 76 percent of patients had improvement or disappearance of more than 12 findings.105 Whether or not these effects are real,* they illustrate that only well-controlled trials can determine the effects of thyroxine therapy in patients with subclinical hypothyroidism. In summary, treatment of subclinical hypothyroidism appears to reduce symptoms in the subset of patients who have a history of Graves’ disease and a serum TSH >10 mU/L. In other subgroups of patients with subclinical hypothyroidism, there is insufficient evidence to determine whether or not treatment is effective in reducing symptoms. Most trials found tno effect on lipid levels but, because of the number of subjects and the limited quality of the trials, the evidence from randomized trials is insufficient to determine whether treatment has a clinically important effect. No trials of treatment for subclinical hypothyroidism in pregnant patients were identified. Other Benefits One randomized trial of levothyroxine versus placebo used Doppler echocardiography and videodensitometric analysis to assess myocardial structure and parameters of myocardial contractility in 20 patients followed for 1 year.98 We excluded this trial because it did not report any clinical outcome measures. Another benefit of treating subclinical hypothyroidism is to prevent the spontaneous development of overt hypothyroidism, diagnosed when a patient with subclinical hypothyroidism develops a low free thyroxine (FT4) level (see Table B-2). This potential benefit has not been studied in randomized trials, so it is necessary to estimate it based on data from observational studies. Based on data from the Whickham study, a previous analysis estimated that if 1,000 women age 35 and over are screened, 80 will be diagnosed to have subclinical hypothyroidism; 43 of these will have a mildly elevated TSH and positive antithyroid antibodies. If these 43 individuals were treated with levothyroxine, by 5 years overt hypothyroidism would be prevented in 3 women (NNT=14.3), while 40 *   A subsequent randomized trial was negative (see Table B-3), but it was too small to exclude a clinically significant effect.

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will have taken medication for 5 years without a clear benefit. By 20 years, overt hypothyroidism would be prevented in 29 (67 percent) of the 43 women, but 14 otherwise healthy women will have taken medication for 20 years. In assessing the balance of benefits and harms, the key uncertainties are the following questions: (1) Without screening or prophylaxis, how long would overt hypothyroidism be undetected? (2) How much morbidity would undiagnosed overt hypothyroidism cause while undetected? (3) What are the harms of treatment in those who do not progress? No studies have measured the severity of symptoms or degree of disability in newly hypothyroid patients or the length of time spent in that state. There are no published data on the effect of careful follow-up on health outcomes in patients with subclinical hypothyroidism. The case for treatment to prevent progression of subclinical hypothyroidism would be greatly strengthened by data showing that this progression is associated with significant burden of illness that could be prevented by earlier treatment. Adverse Effects of Levothyroxine Adverse effects of replacement doses of levothyroxine include nervousness, palpitations, atrial fibrillation, and exacerbation of angina pectoris. Adverse effects were not assessed carefully in the randomized trials listed in Table B-4A, although some studies reported them incidentally. In one of the trials, 2 of 20 (10 percent) patients taking levothyroxine quit the protocol because of nervousness and a sense of palpitations.74 In another, 2 of the 18 (11 percent) patients assigned to levothyroxine withdrew because of complications: one because of an increase in angina, and one because of new-onset atrial fibrillation.15 In a third, anxiety scores were higher in the levothyroxine group.103 A systematic review of observational studies published from 1966 to 1997 found that replacement doses of levothyroxine have not been associated with osteoporosis or with any other serious long-term adverse effects.106 A short-term randomized trial of levothyroxine for subclinical hypothyroidism confirms this view.97 By contrast, thyroid hormone to suppress TSH because of thyroid cancer, goiters, or nodules contributed to osteoporosis in postmenopausal women.106 Overtreatment with levothyroxine, indicated by an undetectable TSH, is another potential risk. About one-fourth of patients receiving levothyroxine for primary hypothyroidism are maintained unintentionally on doses sufficient to cause the TSH to be below normal.2, 35 Data from the Framingham cohort suggest that one excess case of atrial fibrillation might occur for every 114 patients treated with doses of levothyroxine sufficient to suppress the TSH.35 As mentioned above, two meta-analyses of older studies and a recent nested case control study from SOF suggest that, in patients taking levothyroxine, a low TSH is associated with an increased risk of osteoporosis42, 43 and of osteoporotic fractures.49 Another potential risk of overtreatment is left ventricular hypertrophy

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and abnormalities of cardiac output,54, 58 but there is insufficient evidence for these effects in patients inadvertently overtreated for hypothyroidism. SUMMARY The results of this review are summarized in Table B-5. The ability of screening programs to detect subclinical thyroid dysfunction has been demonstrated in TABLE B-5 Summary of Findings of Systematic Review Arrow in Figure 1 Question Level and Type of Evidence Overall Evidence for the Link 1 Is there direct evidence from controlled studies linking screening to improved health outcomes? None N/A 2 What is the yield of screening with a TSH test? II-2. Well-designed cohort studies Good 3 What are the adverse effects of screening (false positives)? II-2. Well-designed cohort studies (for frequency of false-positive results) Poor for consequences of false-positive screening test results 4a Is treatment effective for subclinical hypothyroidism found by screening? Small, poor-to-fair-quality Poor trials, most of limited relevance to screening, and 1 good-quality trial in a population not relevant to screening Poor 4b Is treatment effective for subclinical hyperthyroidism found by screening? None Poor 5 What are the adverse effects of treatment? II-3. Cross-sectional studies (for osteoporosis and overtreatment). For short-term complications and long-term cardiac effects, there are only incidental findings from randomized trials. Good (for osteoporosis and overtreatment) Poor (for other complications)

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good-quality cohort studies, and some of the complications of subclinical thyroid dysfunction are well documented. The main gap in the evidence is the lack of convincing data from controlled trials that early treatment improves outcomes for patients with subclinical hypothyroidism and subclinical hyperthyroidism detected by screening. Findings No controlled studies link screening directly to health outcomes. Screening detects symptomatic, overt thyroid dysfunction in 4-8 per 1,000 adult women, up to 14 per 1,000 elderly women, and 0-4 per 1,000 adult men. It also detects unsuspected subclinical hyperthyroidism in 5 to 20 per 10,000 adults. Subclinical hypothyroidism is found in 5% of women and 3% of men; the yield varies with age and is highest in elderly women. Some consider positive TSH test results in patients who never develop complications to be “false positives.” A false-positive TSH test result can be harmful if it leads to anxiety or labeling or if it leads to a treatment that has adverse effects. The efficacy of treatment for reducing lipids or improving symptoms is inconsistent. A good-quality trial found treatment improved symptoms and had no effect on lipid levels in patients with a history of treatment for Graves’ disease. In an overview of observational studies, thyroxine reduced total cholesterol by 0.14 mmol/L (5.6 mg/dL) in previously untreated patients, but the quality of the observational studies was generally poor. Subclinical hyperthyroidism is a risk factor for developing atrial fibrillation, but no studies have been done to determine whether screening and early treatment are effective in reducing the risk. Replacement doses of levothyroxine have not been shown to have any serious long-term adverse effects. Cross-sectional studies consistently find no adverse effect of replacement doses on bone mineralization. Overtreatment with levothyroxine is present in about one-fourth of patients, but the duration and long-term consequences of inadvertent overtreatment have not been established. Evidence regarding the incidence of serious short-term complications of levothyroxine therapy (atrial fibrillation, angina, myocardial infarction) is poor.

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