Mark Helfand, M.D., M.P.H.a
The author of this article is responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Address correspondence to: Mark Helfand, M.D., M.P.H.; Oregon Health & Science University; Evidence-based Practice Center, Portland, OR, 97239.
This article originally appeared in Annals of Internal Medicine. Select for copyright and source information. The USPSTF recommendations based on this review are online.
The summaries of the evidence briefly present evidence of effectiveness for preventive health services used in primary care clinical settings, including screening tests, counseling, and chemoprevention. They summarize the more detailed Systematic Evidence Reviews, which are used by the U.S. Preventive Services Task Force (USPSTF) to make recommendations.
Abstract
Introduction
Methods
Results
Discussion
Acknowledgments
Grant Support
References
Notes
Background: Subclinical thyroid dysfunction is a risk factor for developing symptomatic thyroid disease. Advocates of screening argue that early treatment can prevent serious morbidity in individuals who are found to have laboratory evidence or subclinical thyroid dysfunction.
Purpose: This article focuses on whether it is useful to order a thyroid function test for patients who have no history of thyroid disease and have few or no signs or symptoms of thyroid dysfunction.
Data Sources: A MEDLINE® search, supplemented by searches of EMBASE and the Cochrane Library, reference lists, and a local database of thyroid-related articles.
Study Selection: I selected controlled studies of treatment that used thyroid-stimulating hormone (TSH) levels as an inclusion criterion and reported quality of life, symptoms, or lipid level outcomes. I also reviewed observational studies of the prevalence, progression, and consequences of subclinical thyroid dysfunction.
Data Extraction: Using preset criteria, I assessed the quality of each trial and abstracted information about its setting, patients, interventions, and outcomes.
Data Synthesis: The prevalence of unsuspected thyroid disease is lowest in men and highest in older women. Evidence regarding the efficacy of treatment in patients found by screening to have subclinical thyroid dysfunction is inconclusive. No trials of treatment for subclinical hyperthyroidism have been done. Several small, randomized trials of treatment for subclinical hypothyroidism have been done, but the results are inconclusive except in patients who have a history of treatment for Graves' disease, a subgroup that is not a target of screening in the general population. Data on the adverse effects of broader use of levothyroxine are sparse.
Conclusion: It is uncertain whether treatment will improve quality of life in otherwise healthy patients who have abnormal TSH levels and normal free-thyroxine levels.
Hyperthyroidism and hypothyroidism are common conditions that have lifelong effects on health.1,2 About 5 percent of U.S. adults report having thyroid disease or taking thyroid medication.1,2 Consequences of untreated hyperthyroidism include atrial fibrillation, congestive heart failure, osteoporosis, and neuropsychiatric disorders. Hypothyroidism causes symptoms that reduce functional status and quality of life.3
Subclinical thyroid dysfunction, which can be diagnosed by thyroid function tests before symptoms and complications occur, is viewed as a risk factor for developing hyperthyroidism and hypothyroidism complications. The goal of screening is to identify and treat patients with subclinical thyroid dysfunction before they develop these complications.4-6
The term subclinical hyperthyroidism describes 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 who are found by screening to have an undetectable TSH, normal free thyroxine (FT4) and normal free triiodothyronine (FT3) levels, and a negative thyroid evaluation, the largest group identified in a screening program. The prevalence of subclinical hyperthyroidism is about 1 percent (95 percent confidence interval [CI], 0.4 percent-1.7 percent) in men older than 60 and 1.5 percent (CI, 0.8 percent-2.5 percent) in women older than 60.7
The terms subclinical hypothyroidism and mild thyroid failure refer to patients who have an elevated TSH and a normal FT4 level (Table 1).6 Subclinical hypothyroidism is common, especially in older women.1,2,7-16 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 older representing the U.S. population, the prevalence of subclinical hypothyroidism was 5.8 percent among white, non-Hispanic females, 1.2 percent among black, non-Hispanic females, and 5.3 percent among Mexican-American females.1 The prevalence of subclinical hypothyroidism was 3.4 percent among white men, 1.8 percent among black men, and 2.4 percent among Mexican-American men. In the Whickham survey, a large, good-quality, population-based study with 20-year followup, prevalence was 4 percent to 5 percent among women age 18 to 44, 8 percent to 10 percent among women age 45 to 74, and 17.4 percent among women older than age 75.17 The prevalence was 1 percent to 3 percent among men age 18 to 65 and 6.2 percent among men over age 65.
In this paper, I 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. I focus on whether screening should be aimed at detection of subclinical thyroid dysfunction and whether individuals who have mildly abnormal TSH values can benefit.
In consultation with members of the U.S. Preventive Services Task Force (USPSTF) and an Institute of Medicine expert panel, I defined the population, interventions, and outcomes of interest and developed key questions to guide the literature review.18 The population of interest was asymptomatic, non-pregnant adults who do not have a goiter, nodule, proptosis, tremor, profound physical tiredness, or a past history of thyroid disease.19 I also included elderly patients who complained of 1 or 2 nonspecific or mild symptoms, such as cold intolerance, fatigue, weight gain, or constipation, because they are no more likely to have abnormal thyroid function tests than those who have no complaints.20
Previous systematic reviews have established that subclinical thyroid function is common and can be diagnosed easily using a TSH test.7,8,21 In this article, I focus on the following questions:
To find articles published before 1998, I searched the reference lists of previous reviews6,8,9,21-29 and our own files of over 1,600 full-text articles from 1910 to 1998 (available online at www.ohsu.edu/epc/endnote/thyroidscreening). I then searched MEDLINE® and EMBASE from 1996 to February 2002, PREMEDLINE® in March 2002, and the Cochrane Library (2002, Issue 2) to identify recent articles relevant to each question.
For question 1, I searched for studies of the causal relationship between subclinical thyroid dysfunction and any potential complication. I included studies if they were conducted in the general adult population, a demographic segment of the adult population, or among patients seen in the general clinic setting. I excluded studies of screening for congenital or familial thyroid disorders and studies of screening in pregnant women, inpatients, institutionalized patients, and series of patients seen in specialized referral clinics for depression or obesity.
To examine the benefits and harms of treatment (questions 2 and 3), I included any controlled trial of oral levothyroxine or triiodothyronine that used TSH levels as a criterion for entry, in any population, including patients with known thyroid disease. I also included recent observational (pre/post treatment and time series) studies that had not been included in previous meta-analyses.7,9,21,30
I reviewed abstracts and articles to identify studies that met the eligibility criteria and abstracted information about the setting, patients, interventions, and outcomes of each included trial using a standard template. I used predefined criteria from the USPSTF to assess the internal validity of included studies18 and rated the applicability of each study to screening.
This article is based on a larger evidence report that was funded by the Agency for Healthcare Research and Quality (AHRQ) and the Institute of Medicine (available at www.preventiveservices.ahrq.gov). Staff of both funding agencies, members of the USPSTF, and members of an Institute of Medicine expert panel reviewed the draft of the larger report and made editing suggestions.
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 to excessive stimulation from thyroid hormones.
A good-quality cohort study in the Framingham population found that, in patients older than age 60 who did not take levothyroxine and had a serum TSH level of 0.1 mU/L or less, the risk for atrial fibrillation was 32 percent (CI, 14 percent-71 percent) over 10 years.31 The risk for patients who had a normal TSH level was 8 percent. 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.32 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 for death.33
A population-based, 10-year cohort study of 1,191 people age 60 or older found a higher mortality rate among patients who had a low TSH initially.34 The excess mortality was due primarily to 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, not for comorbidity. Comorbidity adjustment would be critical because acutely ill and chronically ill elderly patients often have falsely low TSH levels, presumably because of their illness.35 Thus, while 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 with had a low TSH as a result of their illness.
Most data about the risk for osteoporosis and fracture come from women who take thyroid hormones rather than from untreated women found by screening to have a low TSH. Two meta-analyses of older studies36,37 suggest that women who have a low TSH because they take thyroid hormones are at higher risk for developing osteoporosis. However, 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, but markers of bone turnover were higher in women with a low TSH.38 In a more recent nested sample of cases and controls from SOF, the risk for hip fracture among women who had an undetectable TSH was elevated, but of borderline statistical significance (adjusted hazard ratio, 3.6; CI, 1.0-12.9).39 The risk for vertebral fracture among women who had an undetectable TSH was significantly elevated when compared with 235 controls (odds ratio [OR], 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 (OR, 2.8; CI, 1.0-8.5), but not hip fracture, was elevated.
This analysis has limited relevance to screening because the investigators were not able to obtain serum FT4 or FT3 tests, which could have distinguished between overt and subclinical hyperthyroidism. Also, among the 148 women with hip fractures, 22 had an undetectable serum TSH (< 0.1 mU/L), and of these, approximately 19 (86 percent) were taking thyroid hormones when their initial TSH measurement was obtained. Bauer and colleagues stated 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.39 Finally, at baseline, the hip fracture cases were significantly older, weighed less, had lower bone density, were less healthy by self-report, and were twice as likely to have a history of hyperthyroidism than controls. The analysis could not exclude the possibility that some of the women with low TSH levels had several interacting risk factors and that other factors concomitant with age or socioeconomic status could have been confounders.
Other studies of the risk for osteoporosis among patients not taking levothyroxine concern small numbers of patients with nodular thyroid disease or Graves' disease40-43 rather than patients who have no obvious clinical signs of thyroid disease.
Overt 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:
Progression from subclinical to overt 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, a previous meta-analysis estimated that each year, 1.5 percent of women and 0 percent of men who have a low TSH and normal FT4 and FT3 levels develop an elevated FT4 or FT3.7,45-46
In the setting of nodular thyroid disease, Graves' disease, or long-term use of suppressive doses of levothyroxine, subclinical hyperthyroidism has been associated with cognitive abnormalities, abnormalities in cardiac contractility, and exercise intolerance.47-52 However, the frequency of symptoms or myocardial contractility abnormalities in patients who have subclinical hyperthyroidism found by screening has not been studied; no study has linked abnormalities in cardiac contractility or output to the development of clinically important heart disease.
No controlled trials of treatment for subclinical hyperthyroidism have been done. Small observational studies in patients with nodular thyroid disease not detected by screening have shown improvements in bone metabolism and hemodynamic measures after treatment.53-56