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Screening and Treatment of Thyroid Dysfunction: An Evidence Review for the U.S. Preventive Services Task ForceScreening and Treatment of Thyroid Dysfunction FREE

J. Bruin Rugge, MD, MPH; Christina Bougatsos, MPH; and Roger Chou, MD
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This article was published online first at www.annals.org on 28 October 2014.


From Oregon Health & Science University, Portland, Oregon.

Disclaimer: The authors of this article are responsible for its content. Statements in the article should not be construed as endorsement by the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services.

Acknowledgment: The authors thank Agency for Healthcare Research and Quality Medical Officer Jennifer Croswell, MD, MPH. They also thank the U.S. Preventive Services Task Force Lead Work Group, including Jessica Herzstein, MD, MPH; Wanda Nicholson, MD, MPH, MBA; Timothy Wilt, MD, MPH; and Virginia A. Moyer, MD, MPH. In addition, the authors thank Raj Sehgal, MD; Paul N. Gorman, MD; Howard Balshem, MS; and Rose Relevo, MLS, who were coauthors of a comparative effectiveness review on this same topic, on which this article builds.

Grant Support: By the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services (contract HHSA-290-2007-10057-I-EPC3).

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1456.

Requests for Single Reprints: J. Bruin Rugge, MD, MPH, Oregon Health & Science University, Mail Code FM, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239; e-mail, ruggeb@ohsu.edu.

Current Author Addresses: Dr. Rugge: Oregon Health & Science University, Mail Code FM, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239.

Ms. Bougatsos and Dr. Chou: Oregon Health & Science University, Mail Code BICC, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239.

Author Contributions: Conception and design: J.B. Rugge, C. Bougatsos, R. Chou.

Analysis and interpretation of the data: J.B. Rugge, C. Bougatsos, R. Chou.

Drafting of the article: J.B. Rugge, C. Bougatsos, R. Chou.

Critical revision of the article for important intellectual content: J.B. Rugge, R. Chou.

Final approval of the article: J.B. Rugge, C. Bougatsos, R. Chou.

Statistical expertise: R. Chou.

Obtaining of funding: R. Chou.

Administrative, technical, or logistic support: C. Bougatsos.

Collection and assembly of data: J.B. Rugge, C. Bougatsos, R. Chou.


Ann Intern Med. 2015;162(1):35-45. doi:10.7326/M14-1456
Text Size: A A A

Background: In 2004, the U.S. Preventive Services Task Force found insufficient evidence to recommend thyroid screening.

Purpose: To update the 2004 U.S. Preventive Services Task Force review on the benefits and harms of screening and treatment of subclinical and undiagnosed overt hypothyroidism and hyperthyroidism in adults without goiter or thyroid nodules.

Data Sources: MEDLINE and Cochrane databases through July 2014.

Study Selection: Randomized, controlled trials and observational studies of screening and treatment.

Data Extraction: One investigator abstracted data, and a second investigator confirmed; 2 investigators independently assessed study quality.

Data Synthesis: No study directly assessed benefits and harms of screening versus no screening. For subclinical hypothyroidism (based on thyroid-stimulating hormone levels of 4.1 to 11.0 mIU/L), 1 fair-quality cohort study found that treatment of subclinical hypothyroidism was associated with decreased risk for coronary heart disease events versus no treatment. No study found that treatment was associated with improved quality of life, cognitive function, blood pressure, or body mass index versus no treatment. Effects of treatment versus no treatment showed potential beneficial effects on lipid levels, but effects were inconsistent, not statistically significant in most studies, and of uncertain clinical significance (difference, −0.7 to 0 mmol/L [−28 to 0 mg/dL] for total cholesterol levels and −0.6 to 0.1 mmol/L [−22 to 2 mg/dL] for low-density lipoprotein cholesterol levels). Treatment harms were poorly studied and sparsely reported. Two poor-quality studies evaluated treatment of subclinical hyperthyroidism but examined intermediate outcomes. No study evaluated treatment versus no treatment of screen-detected, undiagnosed overt thyroid dysfunction.

Limitation: English-language articles only, no treatment study performed in the United States, and small trials with short duration that used different dosage protocols.

Conclusion: More research is needed to determine the clinical benefits associated with thyroid screening.

Primary Funding Source: Agency for Healthcare Research and Quality.


An estimated 5% of women and 3% of men in the United States have subclinical thyroid dysfunction (1), and approximately 0.5% of the population may have undiagnosed overt thyroid disease (23). Subclinical thyroid dysfunction is defined as elevated or low results on a thyroid-stimulating hormone (TSH) test (reference range, 0.45 to 4.50 mIU/L) in the setting of normal thyroid hormone levels. Overt thyroid disease is defined by the presence of abnormal thyroid hormone (free thyroxine, with or without triiodothyronine) levels (45) (Table 1). In some studies, subclinical hypothyroidism is associated with increased risk for coronary artery disease (67); congestive heart failure (8); and subclinical hyperthyroidism with increased risk for all-cause and coronary heart disease mortality, atrial fibrillation (9), and decreased bone density (5). Overt thyroid disease is associated with negative cardiovascular, musculoskeletal, dermatologic, gastrointestinal, and other effects, but clinical manifestations are highly variable and depend on the severity of thyroid abnormalities. Thyroid screening could identify persons with subclinical as well as undiagnosed overt thyroid dysfunction who could potentially benefit from treatment to reduce the risk for adverse health outcomes.

Table Jump PlaceholderTable 1. Classification of Thyroid Dysfunction: Biochemical Definition 

In 2004, the U.S. Preventive Services Task Force (USPSTF) found insufficient evidence to recommend for or against thyroid screening in asymptomatic, nonpregnant adults. Although the USPSTF concluded that subclinical hypothyroidism is a risk factor for overt thyroid disease, it found insufficient data to estimate effects of early treatment on clinical outcomes. A contemporaneous systematic review conducted for the American Thyroid Association, the American Association of Clinical Endocrinologists, and the Endocrine Society reached similar conclusions (5). Nonetheless, prescribing rates for thyroid medication in the United States have increased dramatically, from an estimated 49.8 million in 2006 to 70.5 million in 2010 (10). Among community-dwelling persons who are older than 65 years with subclinical hypothyroidism, the proportion receiving thyroid hormone has more than doubled, from 8.1% to 20.0%, between 1989 and 2005 (11).

This report was commissioned by the USPSTF to update its 2004 recommendation on thyroid screening. It builds on a 2011 comparative-effectiveness review funded by the Agency for Healthcare Research and Quality (12) and previous USPSTF reviews on identification and treatment of subclinical thyroid dysfunction (1, 13). Before updating its 2004 recommendation, the USPSTF determined that in addition to subclinical thyroid dysfunction, screening could also identify undiagnosed overt thyroid disease (23); therefore, the decision to screen should also consider the potential benefits and harms of identifying and treating undiagnosed overt disease. Therefore, this update differs from previous USPSTF reviews and the 2011 review in that it also addresses identification and treatment of undiagnosed overt thyroid disease.

Key Questions and Analytic Framework

We developed a review protocol and analytic framework (Supplement 1) that included the following key questions:

1. Does screening for thyroid dysfunction reduce morbidity and mortality?

2. What are the harms of screening?

3. Does treating screen-detected overt or subclinical thyroid dysfunction improve: a) mortality and morbidity? or b) intermediate outcomes?

4. What are the harms of treating thyroid dysfunction detected by screening?

Detailed methods and data for this review, including search strategies, inclusion criteria, abstraction and quality rating tables, and evidence on benefits and harms of treatment of subclinical hyperthyroidism, are in the full report (14). The protocol was developed using a standardized process with input from the USPSTF, experts, and the public. The analytic framework addresses direct evidence on benefits and harms of thyroid screening, as well as benefits and harms of treatment of subclinical or overt thyroid dysfunction.

Data Sources and Searches

A research librarian searched MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from 2002 to mid-July 2014 for subclinical hypothyroidism and hyperthyroidism and without a previous date limitation for overt hypothyroidism and hyperthyroidism (Supplement 2). Additional studies were identified from a review of reference lists of relevant articles and peer-review suggestions.

Study Selection

Two investigators independently evaluated each study at the title or abstract and full-text article stages to determine eligibility for inclusion. We included randomized trials and observational studies of thyroid screening versus no screening in adults (excluding pregnant women) without a history of thyroid dysfunction or obvious goiter, nodules, or symptoms, following the protocol. We also included studies of treatment versus no treatment in adults with subclinical or overt thyroid dysfunction. Screening was based on TSH testing, with follow-up testing of thyroid hormone levels (free thyroxine, with or without triiodothyronine). Studies of patients with subclinical hypothyroidism due to Hashimoto thyroiditis (based on antibody testing) were included if they did not describe enrollment of symptomatic patients. Clinical outcomes were cardiovascular end points (cardiovascular disease, coronary artery disease or congestive heart failure, and atrial fibrillation); fractures; measures of quality of life or cognitive function; and harms, including those related to overreplacement (such as negative effects on bone mineral density or atrial fibrillation). Intermediate outcomes were effects on lipid levels, blood pressure, weight change, and bone mineral density.

We restricted inclusion to English-language articles and excluded studies published only as abstracts. The literature flow diagram is shown in Supplement 3.

Data Abstraction and Quality Assessment

One investigator abstracted details about the study design, patient population, setting, screening method, interventions, data analysis, and results, and another investigator verified data abstraction for accuracy. Two investigators independently applied criteria developed by the USPSTF to rate the quality of each study as good, fair, or poor (1516). Discrepancies were resolved through a consensus process. For all studies, we evaluated applicability to populations likely to be encountered in primary care screening settings.

Data Synthesis and Analysis

We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) using methods developed by the USPSTF, on the basis of aggregate study quality, precision of estimates, consistency of results among studies, and directness of evidence (1516). A meta-analysis was not performed because of the methodological and clinical diversity among the included studies.

Role of the Funding Source

This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions. The funding source had no role in study selection, quality assessment, or data synthesis. Agency for Healthcare Research and Quality staff provided project oversight; reviewed the report to ensure that the analysis met methodological standards; and distributed the draft for peer review, including representatives of professional societies and federal agencies. The investigators are solely responsible for the content and the decision to submit the manuscript for publication.

No study compared clinical benefits or harms in persons screened versus not screened for thyroid dysfunction (the first 2 key questions). We identified 11 trials (in 14 publications) and 1 retrospective cohort study on treatment of subclinical hypothyroidism (1731). Two studies examined treatment of subclinical hyperthyroidism but were poor-quality and evaluated intermediate outcomes (3233); they are discussed in the full report (14). No study addressed treatment versus no treatment of screen-detected, undiagnosed overt hypothyroidism.

Three trials were rated good-quality (22, 2728), 6 trials (reported in 7 publications) were rated fair-quality (1821, 2324, 26), and 4 trials (in 5 publications) were rated poor-quality (17, 3031, 33). The retrospective cohort study was rated fair-quality (29). Most of the poor-quality studies were characterized by poor reporting of methods (such as methods of randomization, allocation concealment, blinding, and reporting of attrition) rather than clearly inadequate methods.

None of the trials were conducted in the United States. The TSH values used to diagnose subclinical thyroid dysfunction at baseline ranged from 4.1 to 11.0 mIU/L. Mean patient ages ranged from 32 years to older than 70 years. Treatment of subclinical hypothyroidism was levothyroxine using different dosing regimens. Study duration ranged from 4 to 12 months, except for the cohort study, which analyzed data with up to a 7.6-year follow-up (29). Sample sizes in the trials ranged from 14 to 120 patients; the cohort study analyzed 4735 patients (29). Whereas most studies evaluated a placebo comparator, 3 used a no-treatment comparison (1819, 29).

Three trials (in 4 publications) specifically evaluated screen-detected populations (17, 2021, 27). Most other trials did not clearly report how patients were identified, other than that they were recruited from outpatient clinics. Trials generally reported that patients were newly diagnosed and excluded those with previous thyroid dysfunction or previous receipt of antithyroid medications.

Effectiveness of Treatment of Subclinical Hypothyroidism on Clinical Outcomes
Cardiovascular Events and Mortality

The 2004 USPSTF review (1, 13) included no study on the effects of treatment of subclinical hypothyroidism on risk for cardiac events or death. We identified 1 fair-quality, retrospective cohort study published since the 2004 USPSTF review on the effects of treatment of subclinical hypothyroidism (based on a single TSH level of >5.01 to 10.00 mIU/L) in 4735 persons aged 40 years or older in the United Kingdom on risk for cardiac events (mean follow-up, 7.6 years) (29) (Table 2). On the basis of an a priori categorization, analyses were stratified by age (40 to 70 years vs. >70 years), and analyses of the entire cohort were not reported. Approximately one half of the persons were treated with levothyroxine (mean dose, 75 µg/day).

Table Jump PlaceholderTable 2. Subclinical Hypothyroidism Cardiovascular Events and Mortality 

After adjustment for age, sex, body mass index, socioeconomic status, total cholesterol level, smoking status, history of diabetes mellitus, index serum TSH level, and blood pressure, levothyroxine use versus no treatment was associated with lower risk for fatal or nonfatal ischemic heart disease events (4.2% vs. 6.6%; hazard ratio [HR], 0.61 [95% CI, 0.39 to 0.95]), all-cause mortality (3.4% vs. 6.4%; HR, 0.36 [CI, 0.19 to 0.66]), death due to circulatory diseases (1.4% vs. 2.4%; HR, 0.54 [CI, 0.37 to 0.92]), and cancer mortality (1.2% vs 2.2%; HR, 0.59 [CI, 0.21 to 0.88]) in the younger age group (40 to 70 years) (29). In patients older than 70 years, there was no association between use of levothyroxine versus nonuse and risk for ischemic heart disease events (HR, 0.99 [CI, 0.59 to 1.33]), all-cause mortality (35.2% vs. 40.5%; HR, 0.71 [CI, 0.56 to 1.08]), or cancer mortality (4.6% vs. 6.5%; HR, 0.51 [CI, 0.24 to 1.09]). Potential limitations include the lack of adjustment for medications to reduce risk for cardiovascular disease, although baseline data suggested no differences between treatment groups.

Quality of Life

The 2004 USPSTF review (1, 13) included 5 trials on the association between treatment of subclinical thyroid dysfunction and quality of life (22, 3437). One trial found treatment of subclinical hypothyroidism associated with better quality of life in patients with recent Graves disease (34). The other 4 trials found no effects of treatment (22, 3537). However, 3 of these trials would have been excluded from this update because patients were previously treated for thyroid dysfunction (34, 36) or because it enrolled mostly patients who were euthyroid (37).

We identified 5 trials (3 good-quality [22, 2728], 1 fair-quality [21], and 1 poor-quality [17]) published since the 2004 USPSTF review on effects of treatment of subclinical hypothyroidism (TSH thresholds varied from >3.5 to >5.5 mIU/L) using various doses of levothyroxine (mean, 50.0 to 109.7 µg/day) on measures of quality of life (Short Form-36 Health Survey, the General Health Questionnaire-30, the Beck Depression Inventory, the Hospital Anxiety and Depression Scale, and the Underactive Thyroid-Dependent Quality of Life Questionnaire) (Table 3). Sample sizes were less than 100 in all trials, mean age ranged from 45 to 74 years, and follow-up ranged from 4 to 12 months. No differences were found between treatment and placebo in any study. Three trials evaluated screen-detected populations (17, 21, 27).

Table Jump PlaceholderTable 3. Subclinical Hyperthyroidism Quality of Life and Cognitive Function 
Cognitive Function

Two trials included in the previous USPSTF review evaluated effects of treatment of subclinical hypothyroidism on cognitive function (35, 37). One trial that also included patients who were euthyroid (37) found no effect, and the second trial found a statistically significant but clinically small improvement in memory using a composite outcome in persons older than 55 years (35).

We identified 1 good-quality (27) and 1 fair-quality (21) trial published since the last USPSTF review that found no association between treatment with levothyroxine for subclinical hypothyroidism (defined as TSH levels >3.5 and <10 mIU/L [21] or TSH levels >5.5 mIU/L [27]) versus placebo and various measures of cognitive function after 12 months (Table 3). Both studies seemed to evaluate screen-detected populations. Mean ages were 62 to 63 years in 1 study (69 patients) (21) and 74 years in the other (94 patients) (27). The good-quality study (27) found no effects on cognitive skills and performance (Middlesex Elderly Assessment of Mental State score, 11.67 vs. 11.60; P = 0.57), cognitive status (Mini-Mental State Examination score, 28.24 vs. 28.22; P = 0.18), speed of cognitive processing and accounting (Speed and Capacity of Language Processing Test score, 1.29 vs. 0.84; P = 0.59), or psychomotor tests of executive function (Trail Making Test, Part A or B).

Effectiveness of Treatment of Subclinical Hypothyroidism on Intermediate Outcomes
Blood Pressure

The 2004 USPSTF review (1, 13) included no study on the effect of treatment of subclinical hypothyroidism on blood pressure.

We identified 1 good-quality (28) and 2 fair-quality (24, 26) trials that found no effects on blood pressure between treatment versus no treatment of subclinical hypothyroidism (defined as TSH levels >3.6 mIU/L [24] or >4.0 mIU/L [28], or TSH levels greater than the normal limit [26]). Differences between treatment and placebo groups in mean systolic blood pressure ranged from −3 to −2 mm Hg and in mean diastolic blood pressure ranged from −3 to 0 mm Hg (Supplement 4).

Lipids

The previous USPSTF review included 7 trials on the effect of treatment of subclinical hypothyroidism and effects on lipid profiles (22, 25, 3436, 3839). Six trials found no improvement in lipid variables (22, 25, 3436, 39), with 1 poor-quality trial in euthyroid patients reporting approximately a 5% improvement in low-density lipoprotein (LDL) cholesterol levels with 50 µg/day versus 25 µg/day of levothyroxine (38).

Total Cholesterol

We identified 2 good-quality trials (22, 28), 6 fair-quality trials (1819, 2324, 26), and 1 poor-quality (3031) trial published since the 2004 USPSTF review on the effects of treatment of subclinical hypothyroidism on total cholesterol levels. Thyroid-stimulating hormone thresholds varied from greater than 3.6 to greater than 5 mIU/L, or “greater than the upper limit of normal” (26) (Supplement 4). In the 8 good- and fair-quality trials, differences between treatment and no treatment in mean total cholesterol levels ranged from −0.7 to 0 mmol/L (−28 to 0 mg/dL). Three of the trials (45, 100, and 120 patients) reported statistically significant differences in mean total cholesterol levels of −0.3 mmol/L (−12 mg/dL) (P < 0.03) (23), −0.7 mmol/L (−28 mg/dL) (P = 0.03) (24), and −0.3 mmol/L (−12 mg/dL) (P < 0.001) (28). The poor-quality trial found treatment associated with slightly lower total cholesterol levels (difference in means, −0.2 mmol/L [−6 mg/dL], P = 0.03) (3031).

Low-Density Lipoprotein Cholesterol

Two good-quality trials (22, 28), 6 fair-quality trials (1820, 2324, 26), and 1 poor-quality (3031) trial published since the previous USPSTF review evaluated the effect of treatment of subclinical hypothyroidism on LDL cholesterol levels (Supplement 4). In the 8 good- and fair-quality trials, differences between treatment and no treatment in mean LDL cholesterol levels ranged from −0.6 to 0.1 mmol/L (−22 to 2 mg/dL). Three of the trials (45, 100, and 120 patients) reported statistically significant differences in mean LDL cholesterol levels of −0.2 mmol/L (−8 mg/dL) (P < 0.001) (23), −0.6 mmol/L (−22 mg/dL) (P = 0.03) (24), and −0.3 mmol/L (−12 mg/dL) (P < 0.001) (28). The poor-quality trial found treatment associated with slightly lower LDL cholesterol levels (difference in means, −0.3 mmol/L [−12 mg/dL], P = 0.02) (3031).

High-Density Lipoprotein Cholesterol

We identified 2 good-quality trials (22, 28), 6 fair-quality trials (1820, 2324, 26), and 1 poor-quality (3031) trial published since the previous USPSTF review on the effect of treatment of subclinical hypothyroidism on high-density lipoprotein cholesterol levels (Supplement 4). In the 8 good- and fair-quality trials, differences between treatment and no treatment in mean high-density lipoprotein cholesterol levels ranged from −0.1 to 0.1 mmol/L (−4 to 4 mg/dL). None of the trials found a significant difference between treatment and control groups in high-density lipoprotein cholesterol levels.

Triglycerides

We identified 2 good-quality trials (22, 28), 6 fair-quality trials (1820, 2324, 26), and 1 poor-quality (3031) trial on the effect of treatment of subclinical hypothyroidism on triglyceride levels (Supplement 4). In the 8 good- and fair-quality trials, differences in means ranged from −0.4 to 0.1 mmol/L (−32 to 11 mg/dL). None of the trials found a significant difference between treatment and control in triglyceride values.

Body Mass Index or Weight

No study in the 2004 USPSTF review assessed effects of treatment of subclinical thyroid dysfunction on body mass index or weight.

We identified 2 good-quality (22, 28) and 4 fair-quality (1920, 24, 26) trials published since the 2004 USPSTF review on the effect of treatment of subclinical hypothyroidism (TSH thresholds varied from >3.5 to >5 mIU/L, or “greater than the normal range” [26]) on body mass index or weight (Supplement 4). None of the trials found a significant difference between treatment and control groups in body mass index or weight. Of 5 trials reporting body mass index, differences between treatment and placebo groups ranged from −1 to 1 kg/m2. Of the 2 trials reporting weight, 1 found a difference in means of −1 kg (28) and 1 found a 0.1% difference in lean body weight (22).

Harms of Treatment of Subclinical Hypothyroidism

The 2004 USPSTF report found very limited evidence on harms related to treatment of subclinical hypothyroidism. One good-quality trial of patients who developed subclinical hypothyroidism after treatment of Graves disease found that 4 of 17 persons randomly assigned to levothyroxine felt worse than 6 of 15 persons given placebo (P = 0.33) (34). Other studies reported 1 case of angina (35), 1 case of atrial fibrillation (35), decreased anxiety scores (22), decreased Short Form-36 Health Survey vitality scores (37), and 2 withdrawals due to adverse events (39).

Five trials (in 6 publications) published since the 2004 USPSTF review reported harms, but they were poorly assessed and reported, precluding reliable conclusions (17, 2628, 3031). In addition, the studies were not designed or powered to assess long-term or serious harms, or harms related to overtreatment. One study reported “no indication of harms” (17), and another study stated that none of the patients reported adverse events requiring withdrawal or dose reduction (26). One study reported no difference between treatment versus placebo in risk for withdrawal due to adverse events after 12 months (9.6% vs. 14.3%; P = 0.49) (27). Two other trials (100 and 60 patients) reported 0 (28) or 2 (3031) withdrawals due to adverse events in patients with subclinical hypothyroidism.

The evidence we reviewed is summarized in Table 4.As in the 2004 USPSTF review, we found no direct evidence on effects of thyroid screening versus no screening on clinical outcomes. The scope of this update was expanded to include detection and treatment of screen-detected, undiagnosed overt thyroid disease, but we found no studies of treatment versus no treatment, probably because treatment is considered the standard of care for this condition.

Evidence on benefits and harms of treatment was largely restricted to patients with subclinical hypothyroidism. Despite the potential association between subclinical hypothyroidism and cardiovascular disease and congestive heart failure (68), there is no clear evidence that treatment improves clinical outcomes. Although 1 fair-quality retrospective cohort study found treatment of subclinical hypothyroidism associated with decreased risk for cardiac events, cancer, and all-cause mortality in adults aged 40 to 70 years (29), it was an observational study with potential methodological limitations, including a lack of adjustment for some important confounders. As in the 2004 USPSTF review, evidence from newer trials found that treatment of subclinical hypothyroidism was not associated with clear improvement in quality of life or measures of cognitive function (17, 2122, 2728). Findings about intermediate outcomes were also consistent with the 2004 USPSTF review. Trials found no clear benefits of treatment of subclinical hypothyroidism on blood pressure, bone mineral density, or body mass index. Although treatment of subclinical hypothyroidism may have some beneficial effects on total cholesterol and LDL cholesterol levels, differences were small and of uncertain clinical significance (range, −0.7 to 0 mmol/L [−28 to 0 mg/dL] for total cholesterol levels and −0.6 to 0.1 mmol/L [−22 to 2 mg/dL] for LDL cholesterol levels) and were not statistically significant in most studies (1820, 2226, 28, 3031). No study evaluated treatment of subclinical hypothyroidism with greater TSH levels, which may be associated with increased risk for adverse clinical outcomes.

As detailed in the full report (14), only 2 poor-quality trials evaluated effects of treatment of subclinical hyperthyroidism on intermediate outcomes (3233). Although a recent systematic review of observational studies found that subclinical hyperthyroidism may be associated with an increased risk for fractures, it only found trends, not statistically significant effects (40).

The harms of screening remain poorly studied and sparsely reported. Potential harms of screening for subclinical hypothyroidism include false-positive test results, anxiety related to test results, and harms of treatment (including overreplacement or overtreatment), but evidence is too limited to estimate effects on any of these outcomes. Two prospective cohort studies suggest that approximately 40% of persons with subclinical hypothyroidism were biochemically euthyroid after 3 years of watchful waiting, suggesting that overdiagnosis and subsequent overtreatment could be an issue (4142).

Our review has several limitations. We did not include non–English-language articles, and we could not assess for publication bias using graphical or statistical methods because of small numbers of studies (43). Limitations of the evidence include methodological shortcomings in most studies, the lack of studies conducted in the United States, small sample sizes, relatively brief duration of follow-up (4 to 12 months), and variability in criteria used to define thyroid dysfunction and in the treatment regimens. The applicability of the evidence on treatment is also uncertain because few trials clearly evaluated screen-detected populations or described how patients were identified (17, 2021, 27).

Additional research may help clarify the benefits and harms of thyroid screening. To better understand potential benefits and harms of thyroid screening, research is needed on the prevalence of unrecognized overt thyroid disease and on effects of treatment in such patients. Trials that evaluate clinical outcomes associated with thyroid screening versus no screening would provide the most direct evidence but may require large samples and long duration of follow-up to evaluate cardiovascular outcomes and mortality rates. Therefore, it may be prudent to first conduct well-designed trials of treatment of subclinical hypothyroidism versus placebo or no treatment in screen-detected populations because determining treatment efficiency is a prerequisite for effective screening interventions. Observational studies could help provide important information on effects of screening and treatment but should be conducted in well-defined populations and account for important confounders (such as patient demographic characteristics, medical and psychiatric comorbid conditions, risk factors for cardiovascular disease, and concomitant medication use) in their design and analysis. Another emerging area with implications for screening is research suggesting that subclinical hypothyroidism may be protective in older persons (41, 4445) and that the reference ranges for TSH should be adjusted upward in older adults (4647). Additional research to clarify criteria for abnormal thyroid function would have important implications for defining the target populations and understanding the effect of screening.

In conclusion, screening can identify patients with subclinical thyroid dysfunction or undiagnosed overt thyroid disease, but direct evidence on benefits and harms of screening versus no screening remains unavailable. Trials of treatment of subclinical hypothyroidism suggest potential beneficial effects on total cholesterol and LDL cholesterol levels, but results were inconsistent and the magnitude of effect was of uncertain clinical significance. The only study showing a beneficial effect of treatment on cardiovascular events was observational and susceptible to residual confounding. Trials on the effects of treatment of subclinical hypothyroidism on other clinical and intermediate outcomes showed no clear beneficial effects, and data on harms were poor. More research is needed to understand effects of treatment of subclinical thyroid dysfunction and screen-detected, undiagnosed overt thyroid disease.

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PubMed
CrossRef
 
Rugge B, Balshem H, Sehgal R, Relevo R, Gorman P, Helfand M.  Screening and Treatment of Subclinical Hypothyroidism or Hyperthyroidism. Comparative Effectiveness Review no. 24. (Prepared by the Oregon Evidence-based Practice Center under contract no. 290-2007-10057-I.) AHRQ Publication no. 11(12)-EHC033-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2011. Accessed at http://effectivehealthcare.ahrq.gov/ehc/products/129/750/Hypo-Hyper-Thyroid_CER24_20111114.pdf on 15 August 2014.
 
Helfand M, U.S. Preventive Services Task Force. Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2004; 140:128-41.
CrossRef
 
Rugge JB, Bougatsos C, Chou R.  Screening and Treatment for Thyroid Dysfunction: An Evidence Review for the U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality. 2014.
 
Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al, Methods Work Group, Third U.S. Preventive Services Task Force. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001; 20:21-35.
PubMed
CrossRef
 
U.S. Preventive Services Task Force.  Procedure Manual. Accessed at www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanual.htm on 15 August 2014.
 
Abu-Helalah M, Law MR, Bestwick JP, Monson JP, Wald NJ. A randomized double-blind crossover trial to investigate the efficacy of screening for adult hypothyroidism. J Med Screen. 2010; 17:164-9.
PubMed
CrossRef
 
Cabral MD, Teixeira P, Soares D, Leite S, Salles E, Waisman M. Effects of thyroxine replacement on endothelial function and carotid artery intima-media thickness in female patients with mild subclinical hypothyroidism. Clinics (Sao Paulo). 2011; 66:1321-8.
PubMed
 
Duman D, Sahin S, Esertas K, Demirtunc R. Simvastatin improves endothelial function in patents with subclinical hypothyroidism. Heart Vessels. 2007; 22:88-93.
PubMed
CrossRef
 
Iqbal A, Jorde R, Figenschau Y. Serum lipid levels in relation to serum thyroid-stimulating hormone and the effect of thyroxine treatment on serum lipid levels in subjects with subclinical hypothyroidism: the Tromsø Study. J Intern Med. 2006; 260:53-61.
PubMed
CrossRef
 
Jorde R, Waterloo K, Storhaug H, Nyrnes A, Sundsfjord J, Jenssen TG. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab. 2006; 91:145-53.
PubMed
CrossRef
 
Kong WM, Sheikh MH, Lumb PJ, Naoumova RP, Freedman DB, Crook M, et al. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med. 2002; 112:348-54.
PubMed
CrossRef
 
Mikhail GS, Alshammari SM, Alenezi MY, Mansour M, Khalil NA. Increased atherogenic low-density lipoprotein cholesterol in untreated subclinical hypothyroidism. Endocr Pract. 2008; 14:570-5.
PubMed
CrossRef
 
Monzani F, Caraccio N, Kozàkowà M, Dardano A, Vittone F, Virdis A, et al. Effect of levothyroxine replacement on lipid profile and intima–media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2004; 89:2099-106.
PubMed
CrossRef
 
Caraccio N, Ferrannini E, Monzani F. Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled study. J Clin Endocrinol Metab. 2002; 87:1533-8.
PubMed
CrossRef
 
Nagasaki T, Inaba M, Yamada S, Shirakawa K, Nagata Y, Kumeda Y, et al. Decrease of brachial-ankle pulse wave velocity in female subclinical hypothyroid patients during normalization of thyroid function: a double-blind, placebo-controlled study. Eur J Endocrinol. 2009; 160:409-15.
PubMed
CrossRef
 
Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, et al. A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study. J Clin Endocrinol Metab. 2010; 95:3623-32.
PubMed
CrossRef
 
Razvi S, Ingoe L, Keeka G, Oates C, McMillan C, Weaver JU. The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial. J Clin Endocrinol Metab. 2007; 92:1715-23.
PubMed
CrossRef
 
Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med. 2012; 172:811-7.
PubMed
 
Teixeira Pde F, Reuters VS, Ferreira MM, Almeida CP, Reis FA, Buescu A, et al. Lipid profile in different degrees of hypothyroidism and effects of levothyroxine replacement in mild thyroid failure. Transl Res. 2008; 151:224-31.
PubMed
CrossRef
 
Teixeira PF, Reuters VS, Ferreira MM, Almeida CP, Reis FA, Melo BA, et al. Treatment of subclinical hypothyroidism reduces atherogenic lipid levels in a placebo-controlled double-blind clinical trial. Horm Metab Res. 2008; 40:50-5.
PubMed
CrossRef
 
Buscemi S, Verga S, Cottone S, Andronico G, D'Orio L, Mannino V, et al. Favorable clinical heart and bone effects of anti-thyroid drug therapy in endogenous subclinical hyperthyroidism. J Endocrinol Invest. 2007; 30:230-5.
PubMed
CrossRef
 
Yönem O, Dökmetas HS, Aslan SM, Erselcan T. Is antithyroid treatment really relevant for young patients with subclinical hyperthyroidism? Endocr J. 2002; 49:307-14.
PubMed
CrossRef
 
Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-Thyroxine therapy in subclinical hypothyroidism. A double-blind, placebo-controlled trial. Ann Intern Med. 1984; 101:18-24.
CrossRef
 
Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D, et al. Does treatment with L-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J Gen Intern Med. 1996; 11:744-9.
PubMed
CrossRef
 
Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR, et al. 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. 2001; 86:4860-6.
PubMed
CrossRef
 
Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJ, McMahon AD, et al. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ. 2001; 323:891-5.
PubMed
CrossRef
 
Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P, et al. High serum cholesterol levels in persons with 'high-normal' TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998; 138:141-5.
PubMed
CrossRef
 
Nyström E, Caidahl K, Fager G, Wikkelsö C, Lundberg PA, Lindstedt G. A double-blind cross-over 12-month study of L-thyroxine treatment of women with 'subclinical' hypothyroidism. Clin Endocrinol (Oxf). 1988; 29:63-75.
PubMed
CrossRef
 
Wirth CD, Blum MR, daCosta BR, Baumgartner C, Collet TH, Medici M, et al. Subclinical thyroid dysfunction and the risk for fractures: a systematic review and meta-analysis. Ann Intern Med. 2014; 161:189-99.
CrossRef
 
Gussekloo J, vanExel E, deCraen AJ, Meinders AE, Frölich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004; 292:2591-9.
PubMed
CrossRef
 
Díiez JJ, Iglesias P. Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab. 2004; 89:4890-7.
PubMed
CrossRef
 
Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011; 343:d4002.
PubMed
CrossRef
 
Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab. 2009; 94:1251-4.
PubMed
CrossRef
 
Simonsick EM, Newman AB, Ferrucci L, Satterfield S, Harris TB, Rodondi N, et al, Health ABC Study. Subclinical hypothyroidism and functional mobility in older adults. Arch Intern Med. 2009; 169:2011-7.
PubMed
CrossRef
 
Surks MI, Boucai L. Age- and race-based serum thyrotropin reference limits. J Clin Endocrinol Metab. 2010; 95:496-502.
PubMed
CrossRef
 
Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the U.S. population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007; 92:4575-82.
PubMed
CrossRef
 

Figures

Tables

Table Jump PlaceholderTable 1. Classification of Thyroid Dysfunction: Biochemical Definition 
Table Jump PlaceholderTable 2. Subclinical Hypothyroidism Cardiovascular Events and Mortality 
Table Jump PlaceholderTable 3. Subclinical Hyperthyroidism Quality of Life and Cognitive Function 

References

Helfand M.  Screening for Thyroid Disease. Systematic Evidence Review no. 23. (Prepared by the Oregon Health & Science Evidence-based Practice Center under contract no. 290-97-0018.) Rockville, MD: Agency for Healthcare Research and Quality; 2004. Accessed at www.ahrq.gov/downloads/pub/prevent/pdfser/thyrser.pdf on 15 August 2014.
 
Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002; 87:489-99.
PubMed
CrossRef
 
Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000; 160:526-34.
PubMed
CrossRef
 
Jameson J. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008.
 
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004; 291:228-38.
PubMed
CrossRef
 
Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, et al, Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010; 304:1365-74.
PubMed
CrossRef
 
Ochs N, Auer R, Bauer DC, Nanchen D, Gussekloo J, Cornuz J, et al. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med. 2008; 148:832-45.
CrossRef
 
Gencer B, Collet TH, Virgini V, Bauer DC, Gussekloo J, Cappola AR, et al, Thyroid Studies Collaboration. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation. 2012; 126:1040-9.
PubMed
CrossRef
 
Collet TH, Gussekloo J, Bauer DC, den Elzen WP, Cappola AR, Balmer P, et al, Thyroid Studies Collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. 2012; 172:799-809.
PubMed
CrossRef
 
IMS Institute for Healthcare Informatics.  The Use of Medicines in the United States: Review of 2010. 2011. Accessed at www.imshealth.com/deployedfiles/imshealth/Global/Content/IMS%20Institute/Static%20File/IHII_UseOfMed_report.pdf on 15 August 2014.
 
Somwaru LL, Arnold AM, Cappola AR. Predictors of thyroid hormone initiation in older adults: results from the cardiovascular health study. J Gerontol A Biol Sci Med Sci. 2011; 66:809-14.
PubMed
CrossRef
 
Rugge B, Balshem H, Sehgal R, Relevo R, Gorman P, Helfand M.  Screening and Treatment of Subclinical Hypothyroidism or Hyperthyroidism. Comparative Effectiveness Review no. 24. (Prepared by the Oregon Evidence-based Practice Center under contract no. 290-2007-10057-I.) AHRQ Publication no. 11(12)-EHC033-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2011. Accessed at http://effectivehealthcare.ahrq.gov/ehc/products/129/750/Hypo-Hyper-Thyroid_CER24_20111114.pdf on 15 August 2014.
 
Helfand M, U.S. Preventive Services Task Force. Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2004; 140:128-41.
CrossRef
 
Rugge JB, Bougatsos C, Chou R.  Screening and Treatment for Thyroid Dysfunction: An Evidence Review for the U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality. 2014.
 
Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al, Methods Work Group, Third U.S. Preventive Services Task Force. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001; 20:21-35.
PubMed
CrossRef
 
U.S. Preventive Services Task Force.  Procedure Manual. Accessed at www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanual.htm on 15 August 2014.
 
Abu-Helalah M, Law MR, Bestwick JP, Monson JP, Wald NJ. A randomized double-blind crossover trial to investigate the efficacy of screening for adult hypothyroidism. J Med Screen. 2010; 17:164-9.
PubMed
CrossRef
 
Cabral MD, Teixeira P, Soares D, Leite S, Salles E, Waisman M. Effects of thyroxine replacement on endothelial function and carotid artery intima-media thickness in female patients with mild subclinical hypothyroidism. Clinics (Sao Paulo). 2011; 66:1321-8.
PubMed
 
Duman D, Sahin S, Esertas K, Demirtunc R. Simvastatin improves endothelial function in patents with subclinical hypothyroidism. Heart Vessels. 2007; 22:88-93.
PubMed
CrossRef
 
Iqbal A, Jorde R, Figenschau Y. Serum lipid levels in relation to serum thyroid-stimulating hormone and the effect of thyroxine treatment on serum lipid levels in subjects with subclinical hypothyroidism: the Tromsø Study. J Intern Med. 2006; 260:53-61.
PubMed
CrossRef
 
Jorde R, Waterloo K, Storhaug H, Nyrnes A, Sundsfjord J, Jenssen TG. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab. 2006; 91:145-53.
PubMed
CrossRef
 
Kong WM, Sheikh MH, Lumb PJ, Naoumova RP, Freedman DB, Crook M, et al. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med. 2002; 112:348-54.
PubMed
CrossRef
 
Mikhail GS, Alshammari SM, Alenezi MY, Mansour M, Khalil NA. Increased atherogenic low-density lipoprotein cholesterol in untreated subclinical hypothyroidism. Endocr Pract. 2008; 14:570-5.
PubMed
CrossRef
 
Monzani F, Caraccio N, Kozàkowà M, Dardano A, Vittone F, Virdis A, et al. Effect of levothyroxine replacement on lipid profile and intima–media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2004; 89:2099-106.
PubMed
CrossRef
 
Caraccio N, Ferrannini E, Monzani F. Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled study. J Clin Endocrinol Metab. 2002; 87:1533-8.
PubMed
CrossRef
 
Nagasaki T, Inaba M, Yamada S, Shirakawa K, Nagata Y, Kumeda Y, et al. Decrease of brachial-ankle pulse wave velocity in female subclinical hypothyroid patients during normalization of thyroid function: a double-blind, placebo-controlled study. Eur J Endocrinol. 2009; 160:409-15.
PubMed
CrossRef
 
Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, et al. A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study. J Clin Endocrinol Metab. 2010; 95:3623-32.
PubMed
CrossRef
 
Razvi S, Ingoe L, Keeka G, Oates C, McMillan C, Weaver JU. The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial. J Clin Endocrinol Metab. 2007; 92:1715-23.
PubMed
CrossRef
 
Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med. 2012; 172:811-7.
PubMed
 
Teixeira Pde F, Reuters VS, Ferreira MM, Almeida CP, Reis FA, Buescu A, et al. Lipid profile in different degrees of hypothyroidism and effects of levothyroxine replacement in mild thyroid failure. Transl Res. 2008; 151:224-31.
PubMed
CrossRef
 
Teixeira PF, Reuters VS, Ferreira MM, Almeida CP, Reis FA, Melo BA, et al. Treatment of subclinical hypothyroidism reduces atherogenic lipid levels in a placebo-controlled double-blind clinical trial. Horm Metab Res. 2008; 40:50-5.
PubMed
CrossRef
 
Buscemi S, Verga S, Cottone S, Andronico G, D'Orio L, Mannino V, et al. Favorable clinical heart and bone effects of anti-thyroid drug therapy in endogenous subclinical hyperthyroidism. J Endocrinol Invest. 2007; 30:230-5.
PubMed
CrossRef
 
Yönem O, Dökmetas HS, Aslan SM, Erselcan T. Is antithyroid treatment really relevant for young patients with subclinical hyperthyroidism? Endocr J. 2002; 49:307-14.
PubMed
CrossRef
 
Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-Thyroxine therapy in subclinical hypothyroidism. A double-blind, placebo-controlled trial. Ann Intern Med. 1984; 101:18-24.
CrossRef
 
Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D, et al. Does treatment with L-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J Gen Intern Med. 1996; 11:744-9.
PubMed
CrossRef
 
Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR, et al. 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. 2001; 86:4860-6.
PubMed
CrossRef
 
Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJ, McMahon AD, et al. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ. 2001; 323:891-5.
PubMed
CrossRef
 
Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P, et al. High serum cholesterol levels in persons with 'high-normal' TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998; 138:141-5.
PubMed
CrossRef
 
Nyström E, Caidahl K, Fager G, Wikkelsö C, Lundberg PA, Lindstedt G. A double-blind cross-over 12-month study of L-thyroxine treatment of women with 'subclinical' hypothyroidism. Clin Endocrinol (Oxf). 1988; 29:63-75.
PubMed
CrossRef
 
Wirth CD, Blum MR, daCosta BR, Baumgartner C, Collet TH, Medici M, et al. Subclinical thyroid dysfunction and the risk for fractures: a systematic review and meta-analysis. Ann Intern Med. 2014; 161:189-99.
CrossRef
 
Gussekloo J, vanExel E, deCraen AJ, Meinders AE, Frölich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004; 292:2591-9.
PubMed
CrossRef
 
Díiez JJ, Iglesias P. Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab. 2004; 89:4890-7.
PubMed
CrossRef
 
Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011; 343:d4002.
PubMed
CrossRef
 
Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab. 2009; 94:1251-4.
PubMed
CrossRef
 
Simonsick EM, Newman AB, Ferrucci L, Satterfield S, Harris TB, Rodondi N, et al, Health ABC Study. Subclinical hypothyroidism and functional mobility in older adults. Arch Intern Med. 2009; 169:2011-7.
PubMed
CrossRef
 
Surks MI, Boucai L. Age- and race-based serum thyrotropin reference limits. J Clin Endocrinol Metab. 2010; 95:496-502.
PubMed
CrossRef
 
Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the U.S. population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007; 92:4575-82.
PubMed
CrossRef
 

Letters

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Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

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Supplements

Supplemental Content
Supplement 1. Analytic Framework
Supplemental Content
Supplement 2. Search Strategies
Supplemental Content
Supplement 3. Literature Flow Diagram
Supplemental Content
Supplement 4. Subclinical Hypothyroidism Intermediate Outcomes

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