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Medicare Coverage of Routine Screening for Thyroid Dysfunction (2003)

Chapter: Appendix B: Screening for Thyroid Disease: Systematic Evidence Review

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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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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.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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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

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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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

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

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:

  1. Patients who have subclinical hypothyroidism as a result of surgery or radioiodine treatment for Graves’ disease.

  2. Patients who take inadequate doses of levothyroxine therapy for known thyroid disease.

  3. Patients who have mildly elevated TSH levels and normal T4 levels and nonspecific symptoms that could be due to hypothyroidism.

  4. 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.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

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).

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

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

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

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.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×
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

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

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

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

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.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×
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

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

have a higher prevalence of subclinical hypothyroidism than men with low lipid levels.63

Another cross-sectional study of 2,799 adults ages 70 to 79 illustrates some of the difficulties in determining whether subclinical hypothyroidism is associated with hypercholesterolemia, especially in men.3 For the entire group, a serum TSH >5.5 mU/L was associated with a 9 mg/dL (0.23 mmol/L) higher total cholesterol after adjustment for age, sex, race, body mass index, current smoking, alcohol use, estrogen use, and diabetes. Among men, the association was statistically significant for a cutoff serum TSH = 7.0 mU/L but not for a serum TSH = 5.5 mU/L. About 23 percent of white subjects and 14 percent of black subjects took lipid-lowering medication and a substantial proportion took thyroid hormones (e.g., 18 percent of white women, 6.1 percent of white men). Among subjects taking thyroid hormones but not lipid-lowering medication, a serum TSH =5.5 mU/L was associated with a 15 mg/dL higher total cholesterol. However, the results for subjects not taking either medication were not reported.

Atherosclerosis

The relationship of subclinical hypothyroidism to the later development of atherosclerosis is unclear.31,33,65 The Whickham survey found no relationship between initial TSH levels and the subsequent development of ischemic heart disease over 20 years of follow-up.65

A widely publicized population-based study of 1,149 women age 55 or older from Rotterdam came to a different conclusion.33 The main analysis in the paper was cross-sectional. In that analysis, after adjustment for age, body mass index, cholesterol level, blood pressure, and smoking status, a serum TSH >4.0 mU/L was associated with a history of myocardial infarction (odds ratio 2.3; CI, 1.3 to 4.2) and with atherosclerosis of the abdominal aorta, diagnosed by blinded review of a lateral radiograph of the lumbar spine (odds ratio 1.9; CI, 1.2 to 3.1). An analysis of incident myocardial infarction over 3 to 6 years of follow-up found a statistically nonsignificant increased risk in women with a serum TSH >4.0 mU/L (adjusted relative risk 2.5; CI, 0.7 to 9.1).

The strengths of the Rotterdam study are the relatively large sample size, adjustment for some potential confounders, and validated, blinded assessment of outcomes. Because the study was primarily cross-sectional, however, the findings do not prove that an elevated TSH precedes the development of atherosclerosis. The prospective part of the study adds little because, at baseline, the women who had an elevated TSH had a higher prevalence of atherosclerotic disease; they would be expected to have a higher incidence of myocardial infarction over 3 to 6 years in any case. The prospective analysis would have been more consequential if subjects who had atherosclerosis at baseline were excluded. In contrast, the long follow-up period in the Whickham study reduces the chance that baseline differences in the prevalence of coronary disease affected the results. None of the

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

cross-sectional studies adequately adjusted for several factors that may influence rates of cardiovascular disease, such as socioeconomic status, diet, diabetes, estrogen use, and other health practices. The relation of these factors to the development of subclinical hypothyroidism has not been well studied, so it is possible one or more of them are confounders.

In the Rotterdam study, women with subclinical hypothyroidism had lower lipid levels than euthyroid women; this might be an artifact of higher use of diet or other lipid-lowering therapy in women with known cardiovascular risk factors, but it also might suggest that atherosclerosis developed by another mechanism. One hypothesis is that elevations in both homocysteine and cholesterol may contribute to the elevated risk of atherosclerosis in overt hypothyroidism. In cross-sectional studies, including an analysis of the second National Health and Nutrition Examination Survey (NHANES-II) sample, patients who had overt hypothyroidism had higher homocysteine levels than euthyroid subjects.66,67 Although no single study has adjusted statistically for all potential confounders, the association of elevated homocysteine and hypothyroidism appears to persist after controlling for serum folate levels, which are decreased in hypothyroidism.66-70 In overtly hypothyroid patients, homocysteine levels decreased after treatment with levothyroxine in small, observational studies.69-73 The association of homocysteine levels with subclinical hypothyroidism has not yet been established.

Symptoms, Mood, and Quality of Life

In its 1998 review and guideline, the American College of Physicians concluded that, in the general population, it was not clear that the prevalence and severity of symptoms and the quality of life differs for individuals who have mildly elevated TSH levels.7,74 Since then, two cross-sectional studies in volunteers have addressed this question, with mixed results. A cross-sectional interview survey of 825 Medicare enrollees in New Mexico found no differences in the age-adjusted frequency of self-reported symptoms between participants with serum TSH elevations from 4.7 to 10 mU/L and those with normal TSH concentrations.31 A larger survey from Colorado (n=25,862) is less pertinent because it included subjects who took levothyroxine in the analysis of symptoms. It also found no difference between euthyroid subjects and those with subclinical hypothyroidism in current symptoms but found a higher percentage of “changed symptoms” in the subclinical hypothyroid group (13.4 percent versus 15.4 percent).2

Patients who have subclinical hypothyroidism and a history of antithyroid treatment for Graves’ disease or nodular thyroid disease have a higher prevalence of symptoms than healthy controls.75,76 This observation is likely to be valid, but an important limitation of the evidence should be noted: The appropriate comparison group is not healthy volunteers but patients who have a normal TSH and a history of antithyroid treatment. The reason is that euthyroid patients who have

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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a history of treatment for hyperthyroidism also have a higher prevalence of anxiety, depression, and psychosocial dysfunction than healthy controls.77

Prior Recommendations

In 1996 the United States Preventive Services Task Force recommended against routine screening for thyroid disease in asymptomatic adults (D recommendation).81 They found insufficient evidence to recommend for or against routine screening with thyroid function tests in the elderly but recommended screening based on the higher prevalence of disease and the increased likelihood that symptoms of thyroid disease will be overlooked (C recommendation). At that time, two randomized trials of treatment for subclinical hypothyroidism had been done. The Task Force found that one of them75 was not relevant to screening because the subjects had a known history of thyroid disease. They found the other trial to be methodologically flawed.74 There were no trials of treatment for subclinical hyperthyroidism.

Analytic Framework and Key Questions

In this appendix we address whether the primary care physician should screen for thyroid function in patients seen in general medical practice who have no specific indication for thyroid testing and who come to the physician for other reasons. We focus on whether screening should be aimed at detection of subclinical thyroid dysfunction and whether individuals who have mildly abnormal TSH values can benefit.

We used the analytic framework shown in Figure B-1 to guide the literature review. The population of interest was adults who are seeing a primary care clinician, have no history of thyroid disease, and have no or few signs or symptoms of thyroid dysfunction.

Arrows 2 and 3 represent the ability of screening to detect unsuspected thyroid dysfunction, the false-positive rate of the screening tests, and the symptom status of the patients diagnosed by screening. These issues, summarized above, were reviewed in detail elsewhere.14,25 In this appendix, we address key questions related to Arrows 4 and 5, focusing primarily on evidence about the benefits and harms of treating early thyroid dysfunction. Specifically, we addressed

Arrow 4. What are the benefits of earlier treatment of subclinical hyperthyroidism and hypothyroidism?

Arrow 5. What are the adverse effects of treatment?

A thorough review of the adverse effects of antithyroid drugs, radioiodine therapy, thyroid surgery, and thyroid replacement therapy was beyond the scope of this review. Instead, we emphasize the frequency of adverse effects in trials of levothyroxine therapy for subclinical hypothyroidism and the potential adverse effects of long-term treatment with levothyroxine.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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FIGURE B-1 Screening with thyroid function tests analytic framework

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

METHODS

Search Strategy

We identified articles published before 1998 from the reference lists of previous reviews9,12,13,23,24,76,82-87 and by searching our own files of more than 1,600 full-text articles from the period 1910 to 1998. We then searched MEDLINE and EMBASE from 1996 to February 2002, PREMEDLINE for March 2002, and the Cochrane Library (2002, Issue 2) to identify additional articles. In a MEDLINE search, the medical subject headings (MeSH) thyroid function tests and thyroid diseases were combined with the term mass screening and the text words screening or casefinding. We conducted a separate search for controlled studies of the effect of thyroid-directed treatments on potential complications of subclinical thyroid disease, using the word levothyroxine in title, abstract, or keywords combined with terms for clinical trials. We also searched MEDLINE from 1966 to May 2002 for articles about the adverse effects of thyroid hormone replacement. Periodic hand searching of endocrinologic and major medical journals, review of the reference lists of retrieved articles, and suggestions from peer reviewers of earlier versions of this appendix supplemented the electronic searches.

Inclusion Criteria

We selected controlled trials of treatment of thyroid dysfunction that reported at least one health outcome (symptoms, cognitive function, or quality of life) or lipid levels. Broad inclusion criteria were used to get a picture of the benefits and adverse effects of treatment on patients with different degrees of thyroid dysfunction. Specifically, we included any trial that used TSH levels as a criterion for entry, in any population, including patients with known thyroid disease. We also identified observational studies of treatment for subclinical thyroid dysfunction; we included recent ones that had not been included in previous metaanalyses.13,24,25,88

To assess the prevalence of thyroid disease and the causal relationships between thyroid dysfunction and potential complications, we used the following sources:

  • Previous meta-analyses and systematic reviews.

  • More recent cross-sectional, cohort, and case control studies of the prevalence of overt or subclinical thyroid dysfunction.

  • Cross-sectional and longitudinal studies of the relationship between an elevated or low TSH to potential complications of subclinical hypothyroidism or subclinical hyperthyroidism.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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For these categories of studies, we included studies in the general adult population, in a demographic segment of the adult population, or among patients seen in the general clinic setting. We excluded studies of screening for congenital or familial thyroid disorders and studies of screening in inpatients, institutionalized patients, and series of patients seen in specialized referral clinics for depression or obesity.

Finally, we identified observational studies of the long-term adverse effects of levothyroxine therapy. We excluded studies of suppressive doses of thyroxine; to be included, the study had to include at least some patients taking replacement doses of thyroxine.

Data Extraction

We used predefined criteria from the Task Force to assess the internal validity of trials, which we rated as “good,” “fair,” or “poor.” We also rated the applicability of each study to screening. The rating system is described in detail elsewhere.89 (The criteria are listed as column headings in Table B-3.) We also abstracted information about its setting, patients, interventions, and outcomes. When possible we recorded the difference between the probability of a response in the treatment and control groups for each complication studied.

RESULTS

Efficacy of Treatment for Subclinical Hyperthyroidism

No controlled trials of treatment for subclinical hyperthyroidism have been done. Small observational studies of patients with nodular thyroid disease not detected by screening have shown improvements in bone metabolism and hemodynamic measures after treatment.53,90-92

Efficacy of Treatment for Subclinical Hypothyroidism

We identified 14 randomized trials of levothyroxine therapy. We excluded two trials that compared levothyroxine to levothyroxine plus triiodothyronine in patients with overt hypothyroidism,93,94 one trial of different levothyroxine preparations,95 and one of levothyroxine suppressive therapy for solitary nodules.96 Two trials of levothyroxine treatment in patients with subclinical hypothyroidism reported no clinical outcomes or lipid results; one of these concerned bone density97 and the other, cardiac function parameters from Doppler echocardiography and videodensitometric analysis.98 These trials are not included in evidence tables but are discussed briefly.

Of the eight included trials,15,74,75,99-103 six concerned patients with elevated TSH levels. One concerned hyperlipidemic patients with high-normal TSH levels,99

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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TABLE B-3 Quality of Randomized Trials of Thyroxine Replacement Therapy

Study and Year

Random Assignment?

Allocation Concealed?

Groups Similar at Baseline?

Eligibility Criteria Specified?

Outcome Assessors Blinded?

Care Provider Blinded?

Cooper, 1984

Yes, by individual

Not stated

LT4 subjects were older (58.2 vs.50.2) and had fewer symptoms (2.1 vs.2.4), but otherwise similar

Yes

Probably; one investigator was not blinded; article states “patients were questioned in a blinded manner by one of the investigators,” but doesn’t say which investigator.

 

Meier, 2001

Sequential assignment using a predefined list; randomized by matched pairs

No

LT4 subjects had higher TSH (14.4±1.7 vs. 11.3±1.0)and LDLc (4.1 vs. 3.7), but groups were otherwise similar for the whole groups (n=66); comparisons were not presented for the analyzed group (n=63).

Yes

Not Started

Yes

Caraccio, 2002

Yes, by individual

Not Started

Generally yes, but mean TSH (6 vs.4.9)and LDLc (3.6 vs. 3.3)were higher in LT4 group.

Yes

No

No

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

Patient Unaware of Treatment?

Intention-to-Treat Analysis?

Maintenance of Comparable Groups?

Reporting of Attrition, Crossovers, Adherence, and Contamination?

Differential Loss to Follow-up or Overall High Loss to Follow-up?

Statistical Analysis Appropriate?

Score (Good/Fair/Poor)

Yes-not verified

No

The number of patients randomized appears to be 41; 33 patients were analyzed; it is not clear to which group the other 8 belonged.

Partially

Unclear, probably not

Yes, except it did not address dropouts.

Good

Yes—not verified

No

Yes

No

No

No— analyzed as RCT,but reported primarily as a before/after study

Poor

Probably were aware because dosing and length of follow-up differed; not clear whether patients were informed of their lipid levels

Yes, assuming that completion of study was not a criterion for inclusion

 

No

No

Yes (when analyzed as an RCT)

Poor

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

Study and Year

Random Assignment?

Allocation Concealed?

Groups Similar at Baseline?

Eligibility Criteria Specified?

Outcome Assessors Blinded?

Care Provider Blinded?

Jaeschke, 1996

Yes, by individual

Not stated

LT4 subjects had higher TSH (12.1 vs.9.4) and slightly more symptoms (14 vs.13), but similar in age.

Yes

Yes; one investigator was not blinded but was not involved in assessment or care.

 

Kong, 2002

Yes, in blocks of 6

Yes

LT4 subjects were older (53 vs.45 years), had lower FT 4 (.9 vs.1), and higher TSH (8 vs.7.3).

Yes

Yes; one investigator was not blinded, but was not involved in assessment or care.

 

Nystrom, 1988

Not stated

Not stated

No baseline data were given for the groups initially assigned LT4 and placebo.

Yes

Yes

Yes

Michal -opoulou, 1998

Yes, method not stated

Not stated

Inadequately described; LDL was higher in 50 mg group (6.8 vs.6.2).

Yes

Not stated

Not stated

Pollack, 2001

Yes, by coin toss in blocks of 4

No

No baseline data were given for the groups initially assigned LT4 and placebo.

Yes

Not stated

Yes

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

Patient Unaware of Treatment?

Intention-to-Treat Analysis?

Maintenance of Comparable Groups?

Reporting of Attrition, Crossovers, Adherence, and Contamination?

Differential Loss to Follow-up or Overall High Loss to Follow-up?

Statistical Analysis Appropriate?

Score (Good/Fair/Poor)

Yes—not verified

No

Probably, 3 dropouts in each group

Partially

Overall 6 out of 40 dropped out

Yes, except it did not address dropouts.

Fair

Yes—not verified

No

Unknown

Yes

Yes, especially for lipid comparison

Yes, except it did not address dropouts.

Poor

Probably aware—verified

No

Yes

No

No

No—no baseline comparisons or results provided about the first assignment

Poor

Not stated

Probably yes

Yes

No

No

No— analyzed as before/after

Poor

Yes— verified

No

Probably, but all 3 dropouts were from the LT4 group

No

No

Yes

Fair

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

and the last trial concerned patients with a normal TSH who had symptoms of hypothyroidism.101

Randomized trials of levothyroxine treatment in subclinical hypothyroidism and in symptomatic patients who have a normal TSH are described in Table B-3 (quality ratings) and in Tables B-4A through B-4C (description and results). The first two trials listed in the tables concerned patients followed in thyroid specialty clinics. In both trials subjects had a mean serum TSH above 10 mU/L. The first trial (Cooper) concerned patients who had been treated for Graves’ disease in whom TSH was rising relatively quickly.75 Symptoms were rated on the “Cooper Questionnaire,” a 24-point scale that records how six symptoms of hypothyroidism change over time. After 1 year, patients taking levothyroxine improved by 2.1 points, while patients taking placebo deteriorated by 1.2 points (p=0.037). The difference (3.3 points) is roughly equivalent to complete relief of one symptom and partial relief of a second symptom per patient. Eight (47 percent) of 17 treated patients reported reduced or milder symptoms; 4 felt worse; and 5 reported no change in symptoms. In the placebo group, 3 (19 percent) of 16 patients felt better, 6 felt worse, and 7 reported no change. The difference between the proportion of patients who felt better in each group was 0.28 (CI, -0.09 to 0.65), indicating that the Number Needed to Treat to benefit one patient is 3.5.75 Treatment had no effect on lipid levels. The internal validity of this trial was rated “good quality”; it was the highest quality trial of the group.

The second trial (Meier) concerned patients with thyroiditis or a history of Graves’ disease.100 In this trial, treatment with levothyroxine had no effect on symptoms. In reporting results, the authors emphasized that there was a significant reduction in LDL cholesterol in the levothyroxine-treated group, from 4.0 to 3.7 mmol/L (p=0.004), and no significant reduction in the placebo group. The difference appears to be related to an imbalance in the groups at baseline: pre-treatment LDL cholesterol was 4.0 mmol/L in the treatment group versus 3.7 mmol/L in the placebo group. In fact, posttreatment LDL cholesterol was the same in both groups (3.7±0.2, p=0.11). When analyzed as a randomized trial, the difference between the treatment and control groups in lipid levels was not significant. The discrepancy suggests that randomization may have been flawed.

We rated the relevance of these two studies to screening to be “low.” The Cooper study supports treatment in patients with a history of treated Graves’ disease, especially if the serum TSH is above 10 mU/L, but it has little relevance to screening because the natural history of treated Graves’ disease differs from the natural history of spontaneous hypothyroidism in the general population.

The third trial, in patients known to have Hashimoto’s thyroiditis and positive antithyroid antibodies who had mildly elevated TSH levels, had a similar flaw.102 When analyzed as a randomized trial, there were no significant differences between levothyroxine-treated and placebo groups in any lipid parameter. When analyzed as a pre-/post-treatment study, there was a statistically significant reduction in LDL cholesterol levels (3.6 to 3.1 mmol/L) in the levothyroxine

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

treated group but not in the control group. The study appeared to be unblinded; this could be a major flaw because differential attention to lipid levels in the treatment and control groups could lead to different behavioral approaches to reducing lipid levels. If the results are valid, they would be fairly relevant to screening; the mean TSH was only slightly elevated, and patients who have antithyroid antibodies and a modestly elevated TSH are found commonly in screening programs.

The next three studies may have had more relevance to screening or primary care. They generally concerned patients, mostly women, with subclinical hypothyroidism who were not previously treated for Graves’ disease or nodular thyroid disease. However, two of the three studies had poor internal validity. In the fair-quality trial by Jaeschke and colleagues, 37 patients with subclinical hypothyroidism were recruited from the outpatient clinics of a community hospital and randomized to levothyroxine treatment or placebo.15 Patients given placebo did as well as or better than those given levothyroxine. After 6 months, in the levothyroxine group, eight patients improved, three were worse, and five were the same according to the “Cooper Questionnaire.” In the placebo group, 11 patients improved, 1 was worse, and 4 were the same. After 11 months, patients treated with levothyroxine had a small but statistically significant improvement in short-term memory, but treatment did not improve general health status as measured by a standardized questionnaire, the Sickness Impact Profile (SIP). In that study, the mean SIP score in patients with subclinical hypothyroidism recruited from a general medical clinic was initially 3.1 out of 100. On this scale, a score of 3.0 is usually interpreted as the border between no disability and mild disability. A random sample of healthy older adults had a similar mean SIP of 3.4.

The other negative trial was too small to achieve balance in the compared groups and had high loss to follow-up.103

A small crossover trial74 concerned women identified by screening in the general population. The 20 subjects were women over age 50 who had an initial serum TSH between 4 and 15 mU/L. After 6 months of treatment, the mean symptom score improved by 1.81 units, equivalent to complete relief of one symptom per patient. As judged by subjective improvement and cognitive measures, 4 (24 percent) of the 19 patients who received levothyroxine improved, while 2 (12 percent) felt worse with treatment.

The last two studies listed in Table B-4 concern patients who have TSH levels in the normal range. In one of these, 50 micrograms of levothyroxine therapy reduced LDL cholesterol levels from 6.8 to 5.9 mmol/L in patients with elevated total cholesterol levels (>7.5 mmol/L) and normal TSH levels.99 In the other trial, levothyroxine was ineffective in patients who had symptoms of hypothyroidism but normal TSH and T4 levels.101 The latter trial, designed as a crossover study, found that levothyroxine significantly reduced SF-36 vitality score compared to placebo, whereas placebo improved SF-36 general health and physical well-being scores significantly.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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TABLE B-4A Description and Results of Randomized Trials of Thyroxine Replacement Therapy

Study and Year

Study Design

Patients

Setting

Known history of thyroid disease

Cooper, 1984

Randomized, double-blind, placebo-controlled trial

Previously treated Graves’ disease, stage c subclinical hypothyroidism

Thyroid specialty clinic, Boston

Meier, 2001

Double-blind, placebo-controlled trial

Autoimmune thyroiditis (n=33), previously treated Graves’ disease (n=22), previously treated goiter (7)

Thyroid specialty clinic, Switzerland

Caraccio, 2002

Unblinded, placebo-controlled, randomized trial

Hashimoto’s thyroiditis (48) or Graves’ disease (1)

Medical school internal medicine clinic, Italy

No known history or not stated

Jaeschke, 1996

Randomized, double-blind, placebo-controlled trial

Diagnosis of subclinical hypothyroidism

Unclear setting, Ontario

Kong 2002

Randomized, double-blind placebo-controlled trial

Women with a diagnosis of subclinical hypothyroidism

Referrals from GPs for thyroid function tests, London

Nystrom 1988

Randomized, double-blind placebo controlled crossover trial

Women identified by screening

Population-based screening study, Gothenburg

Biochemically euthyroid patients

Michalopoulou, 1998

Randomized trial with active control group

Patients referred for lipid assessment

Preventive medicine (lipid) hospital-based clinic, Greece

Pollack, 2001

Double-blind, placebo-controlled, randomized crossover trial

Symptomatic patients with normal TSH and T4

Referrals from GPs, hospital clinic,and response to newspaper ad, Glasgow

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Age and Gender

Eligibility Criteria

Other Population Characteristics

32 women and 1 man, mean age 55 years

TSH >3.5 mU/L on 2 occasions

History of Graves’ disease

63 women, mean age 58.5±1.3 years

Women 18-75 years; TSH >6.0 mU/L on 2 occasions; exaggerated TSH response to TRH; good general health

History of autoimmune thyroiditis (n=33), Graves’ disease (n=22), goiter (n=7); only 4 had idiopathic subclinical hypothyroidism.

42 premenopausal women, 7 men

TSH >3.6 mU/L for >6 months, + atP and anti-Tg, good general health

SCH patients had higher TC, LDL, and ApoB levels than healthy controls.

28 women and 9 men over age 55, mean age 68 years

TSH >6 mU/L on 2 occasions

 

45 women, mean age ~49 years

Women over 18 years; 5<TSH<10 mU/L

Most patients were referred because of symptoms.

20 women, aged 51-73

Women over 18 years; 4<TSH<15 mU/L, exaggerated TSH response to TRH

Symptoms did not differ between subjects and healthy controls.

Not stated

TC >7.5 mmol/L and TSH 0.4-4.0 mU/L

 

25 symptomatic and 19 asymptomatic subjects, sex and age not given

a) at least 3 symptoms of hypothyroidism (tiredness, lethargy, weight gain, or 3 others) or

(b) no symptoms

Symptomatic subjects weighed more and had worse memory and psychological function than healthy controls.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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TABLE B-4B Description and Results of Randomized Trials of Thyroxine Replacement Therapy

Study and Year

Exclusion Criteria

Funding Sources and Role of Funder

Interventions (Dose, Duration)

Known history of thyroid disease

Cooper, 1984

None stated

U.S.PHS (Armour supplied LT4)

LT4 50 micrograms then titrated up

Meier, 2001

Coronary heart disease, lipid-lowering drugs, history of poor compliance (estrogen therapy allowed)

Swiss Research Foundation, Henning Berlin, Sandoz, Roche

LT4 titrated over 6 months (mean final dose 85.5±4.3), with similar visits and changes in control group. Total follow-up 50 weeks

Caraccio 2002

Diabetes, renal or liver disease, TC>7.8 mmol/L

Grant from university

LT4 25 then titrated up

No known history or not stated

Jaeschke, 1996

Medications that interfere with TFTs; serious medical conditions

Ontario Ministry of Health, Boots Pharmaceuticals

LT4 25 then titrated up (mean final dose 68±21)

Kong, 2002

History of thyroid disease, psychiatric disorder, anticipated pregnancy

Medical Research Council

LT4 50 then titrated up to 100 if TSH >6 mU/L

Nystrom, 1988

History or signs of thyroid disease, history of cardiovascular disease

Nonindustry grants (Nyegaard supplied LT4)

LT4 50 for 2 weeks, then 100 mg for 2 wks, then 150 daily

Biochemically euthyroid patients

Michalopoulou, 1998

Conditions and medications that affect lipid profiles

 

LT4 50

Pollack, 2001

Current medical disorders

Association of Clinical Biochemists

LT4 100

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Control

Baseline TSH

Number Screened/ Eligible/Enrolled

Number Withdrawn/Analyzed

Placebo

11 (mean);

3.6-55 (range);

mean TSH in control group increased to ~15 by the end of the study

656/91/41

8/33

Placebo

12.8 (mean);

5-50 (range)

NR/NR/66

3/63

Placebo

5.43 (mean)

3.65-15 (range)

NR/NR/49

0/49

Placebo

9.4 (mean);

6-32 (range)

NR/NR/37

6/31

Placebo

~7.7 (mean)

NR/52/45

10/34 (for quality of life);

18/27 for lipids

Placebo

~7.7 (mean);

2.9-16.3 (range)

1,192/22/20

3/17

LT4 25 mg

stratified 1.0 (mean) or ~2.6 (mean)

NR/NR/110

0/110

Placebo

1.9 (mean)

NR/NR/25*

3/22

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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TABLE B-4C Description and Results of Randomized Trials of Thyroxine Replacement Therapy

Study and Year

Outcomes Assessed/When Assessed

How Outcomes Assessed (e.g., Scales Used)

Known history of thyroid disease

Cooper, 1984

Symptoms, lipid profile at 1 year

Symptom change scores (“Cooper questionnaire”)

Meier, 2001

Symptoms, lipid profile at 1 year

Thyroid symptom questionnaire

Caraccio, 2002

Lipid profile at 6 months for placebo group vs.about 11 months for LT4 group

Biochemical tests

No known history or not stated

Jaeschke, 1996

Quality of life, symptoms, lipid profile at 6 months

Chronic Thyroid Questionnaire, Cooper questionnaire, SIP, cognitive tests

Kong, 2002

Quality of life, symptoms, lipid profile at 6 months

Thyroid symptom questionnaire, GHQ-30, HADS

Nystrom, 1988

Quality of life, symptoms, psychometric tests, vital signs, ECG, lipid profile at 6 months

Thyroid symptom questionnaire, reaction time, Bingley’s memory test

Biochemically euthyroid patients

Michalopoulou, 1998

Lipid profile

 

Pollack, 2001

Symptoms, vital signs, biochemical tests after 14 weeks

SF-36 plus validated cognitive/ memory testing

Many observational studies have examined the effects of treatment in patients with subclinical hypothyroidism. One meta-analysis of these observational studies found that treatment reduced LDL cholesterol levels by 0.4 mmol/L and a more recent meta-analysis of both observational and randomized studies found that, in previously untreated patients, total cholesterol was reduced by 0.14 mmol/L (-5.6 mg/dL).104 Another review concluded that levothyroxine treatment might

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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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,

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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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.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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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

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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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)

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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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.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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ACKNOWLEDGMENTS

The author thanks Robert Utiger, Marc Stone, and David Atkins for their comments on an earlier draft of this appendix.

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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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97. Ross DS. 1993. Bone density is not reduced during the short-term administration of levothyroxine to postmenopausal women with subclinical hypothyroidism: A randomized, prospective study. Am J Med 95:385–388.

98. Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C, et al. 2001. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: A double blind, placebo-controlled study. J Clin Endocrinol Metab 86:1110–1115.

99. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P, et al. 1998. High serum cholesterol levels in persons with “high-normal” TSH levels: Should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol 138:141–145.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
×

100. Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR, et al. 2001. TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: A double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab 86:4860–4866.

101. Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJ, McMahon AD, et al. 2001. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: Randomised double blind placebo controlled crossover trial. BMJ 323:891–895.

102. Caraccio N, Ferrannini E, Monzani F. 2002. Lipoprotein profile in subclinical hypothyroidism: Response to levothyroxine replacement, a randomized placebo-controlled trial. J Clin Endocrinol Metab 87:1533–1538.

103. Kong WM, Sheikh MH, Lumb PJ. 2002. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med 112:348–354.

104. Danese MD, Ladenson PW, Meinert CL, Powe NR. 2000. Clinical review 115: Effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: A quantitative review of the literature. J Clin Endocrinol Metab 85:2993–3001.

105. Skinner GRB, Holmes D, Ahmad A, Davies A, Benitez J. 2000. Clinical response to thyroxine sodium in clinically hypothyroid but biochemically euthyroid patients. J Nutr Environ Med 10:115–124.

106. Greenspan SL, Greenspan FS. 1999. The effect of thyroid hormone on skeletal integrity. Ann Intern Med 130:750–758.

Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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Suggested Citation:"Appendix B: Screening for Thyroid Disease: Systematic Evidence Review." Institute of Medicine. 2003. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: The National Academies Press. doi: 10.17226/10682.
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When the Medicare program was established in 1965, it was viewed as a form of financial protection for the elderly against catastrophic medical expenses, primarily those related to hospitalization for unexpected illnesses. The first expansions to the program increased the eligible population from the retired to the disabled and to persons receiving chronic renal dialysis. It was not until 1980 that an expansion of services beyond those required "for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member" was included in Medicare. These services, known as preventive services, are intended either to prevent disease (by vaccination) or to detect disease (by diagnostic test) before the symptoms of illness appear. A Committee was formed "to conduct a study on the addition of coverage of routine thyroid screening using a thyroid stimulating hormone test as a preventive benefit provided to Medicare beneficiaries under Title XVIII of the Social Security Act for some or all Medicare beneficiaries."

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