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Original Investigation |

Subclinical Hyperthyroidism and the Risk of Coronary Heart Disease and Mortality FREE

Tinh-Hai Collet, MD; Jacobijn Gussekloo, MD, PhD; Douglas C. Bauer, MD; Wendy P. J. den Elzen, PhD; Anne R. Cappola, MD, ScM; Philippe Balmer, BSc; Giorgio Iervasi, MD; Bjørn O. Åsvold, MD, PhD; José A. Sgarbi, MD; Henry Völzke, MD; Bariş Gencer, MD; Rui M. B. Maciel, MD; Sabrina Molinaro, PhD; Alexandra Bremner, PhD; Robert N. Luben, PhD; Patrick Maisonneuve, Ing; Jacques Cornuz, MD, MPH; Anne B. Newman, MD, MPH; Kay-Tee Khaw, MD; Rudi G. J. Westendorp, MD, PhD; Jayne A. Franklyn, MD, PhD, FRCP, FMedSci; Eric Vittinghoff, PhD; John P. Walsh, MBBS, FRACP, PhD; Nicolas Rodondi, MD, MAS; for the Thyroid Studies Collaboration
[+] Author Affiliations

Author Affiliations: Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland (Drs Collet, Gencer, and Cornuz and Mr Balmer); Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands (Drs Gussekloo and den Elzen); Departments of Medicine (Dr Bauer) and Epidemiology and Biostatistics (Drs Bauer and Vittinghoff), University of California, San Francisco; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia (Dr Cappola); National Council Research Institute of Clinical Physiology/Tuscany Region G. Monasterio Foundation, Pisa, Italy (Drs Iervasi and Molinaro); Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway (Dr Åsvold); Division of Endocrinology, Department of Medicine, Federal University of São Paulo, Brazil (Drs Sgarbi and Maciel); Division of Endocrinology, Faculdade de Medicina de Marília, Marília, Brazil (Dr Sgarbi); Institute for Community Medicine, Clinical-Epidemiological Research, University of Greifswald, Greifswald, Germany (Dr Völzke); Schools of Population Health (Dr Bremner) and Medicine and Pharmacology (Dr Walsh), The University of Western Australia, Crawley, Australia; Department of Public Health and Primary Care, University of Cambridge, Cambridge, England (Drs Luben and Khaw); Division of Epidemiology and Biostatistics, European Institute of Oncology, Milano, Italy (Dr Maisonneuve); Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Newman); Department of Gerontology and Geriatrics, Leiden University Medical Center, and Netherlands Consortium for Healthy Ageing, Leiden (Dr Westendorp); School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, England (Dr Franklyn); Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia (Dr Walsh); and Department of General Internal Medicine, Inselspital, University of Bern, Bern, Switzerland (Dr Rodondi).


Arch Intern Med. 2012;172(10):799-809. doi:10.1001/archinternmed.2012.402.
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Published online

Background Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting. We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.

Methods Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.

Results Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio [HR], 1.24, 95% CI, 1.06-1.46), CHD mortality (HR, 1.29; 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95% CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43). Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% for AF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L (for both, P value for trend, ≤.03).

Conclusion Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

Figures in this Article

Subclinical hyperthyroidism, defined by low thyrotropin level with normal concentrations of free thyroxine (FT4) and triiodothyronine (T3),14 has been associated with several biological effects on cardiovascular system, such as increased heart rate, left ventricular mass, carotid intima-media thickness, and plasma fibrinogen levels.3,5 Observational studies have reported an association between subclinical hyperthyroidism and coronary heart disease (CHD),68 incident atrial fibrillation (AF),912 and cardiac dysfunction.13,14 Results from prospective cohort studies are conflicting,6,10 and study-level meta-analyses have reached contradictory conclusions, for example, regarding the association between subclinical hyperthyroidism and cardiovascular mortality.1517 In fact, interpretation of these studies is hampered by several methodological factors: population heterogeneity, different thyrotropin cutoff levels for subclinical hyperthyroidism definition, different use of covariates, and different CHD definitions.16 Although no large randomized controlled trials have examined the effects of treating subclinical hyperthyroidism on clinically relevant outcomes, a consensus statement2 and recent guidelines4 advocate treatment of subclinical hyperthyroidism, particularly when thyrotropin level is lower than 0.10 mIU/L, to avoid long-term complications.

Individual participant data analysis from large cohort studies may help reconcile these conflicting results; allow exploration of the influence of age, sex, thyrotropin levels, and preexisting cardiovascular disease (CVD); and allows the use of a uniform thyrotropin cutoff level and outcome definitions for all participants. This approach is considered optimal for synthesizing evidence across cohorts because it is not subject to potential bias from study-level meta-analyses (ecological fallacy)18 and allows performance of time-to-event analyses.19

On the basis of data from the Thyroid Studies Collaboration,20 we aimed to assess the risks of total mortality, CHD mortality, CHD events, and AF associated with endogenous subclinical hyperthyroidism.

Similar to our previous study,20 we conducted a systematic literature search in MEDLINE and EMBASE databases from 1950 to June 30, 2011, without language restriction (eAppendix, and screened bibliographies from retrieved articles. We used a priori criteria for greater comparability and quality of the studies. We included only full-text published longitudinal cohorts reporting baseline thyroid function test results (both thyrotropin and FT4), with a control euthyroid group and prospective follow-up of mortality and CHD outcomes. We excluded studies that included only participants taking thyroid-altering medications (antithyroid drugs, thyroxine, or amiodarone) or participants with overt hyperthyroidism (low thyrotropin and high FT4 levels). We performed an additional systematic literature review for articles reporting incident AF events and updated our previous search20 to June 2011. Reviews were performed independently by 2 authors (P.B. and B.G.), and discrepancies were resolved by discussion with a third author (N.R.). Agreement between reviewers was 99.9% for first screen (titles and abstracts, κ = 0.66; 95% CI, 0.62-0.72) and 100% for full-text screen (κ = 1.00).

Data were collected from original studies that joined the Thyroid Studies Collaboration20 and included individual demographic characteristics; thyrotropin, FT4, and total T3 or free T3 levels; baseline cardiovascular risk factors (eg, blood pressure, cigarette smoking, total cholesterol level, diabetes mellitus); preexisting CVD; and cardiovascular and thyroid-altering medication use at baseline and during follow-up. Data on mortality, CHD events, AF, stroke, and cancer outcomes were requested.

Similar to our previous analysis,20 we used a uniform thyrotropin cutoff level for subclinical hyperthyroidism definition, based on an expert consensus meeting of our collaboration20 (International Thyroid Conference, Paris, France, 2010), expert reviews,1,21 and previous large cohorts.10,22,23 Subclinical hyperthyroidism was defined as a thyrotropin level lower than 0.45 mIU/L with normal FT4 levels, and euthyroidism as a thyrotropin level between 0.45 and 4.49 mIU/L. Subclinical hyperthyroidism was further categorized as suppressed thyrotropin level (<0.10 mIU/L) and low but not suppressed thyrotropin level (0.10-0.44 mIU/L) according to current guidelines.1,4 Data from cohorts using first-generation thyrotropin assays (functional sensitivity, 1-2 mIU/L) were excluded9,24,25 because subclinical hyperthyroidism cannot be diagnosed using these methods.26 For FT4 and total and free T3, we used study-specific cutoff values because these measurements show greater intermethod variation than thyrotropin assays. For participants with missing values of FT4 and total or free T3 (measured in 5 of 10 cohorts [ eTable]), we performed sensitivity analyses excluding (1) participants with missing FT4 values and (2) those with abnormal total or free T3 levels.14,21

Outcomes were total mortality, CHD mortality, CHD events, and incident AF. Stroke and cancer mortality were available for all cohorts except one.27 As in our previous analysis,20 we used homogenous definitions to reduce the heterogeneity in outcomes.15,16 Similar to the Framingham risk score,28 we limited cardiovascular mortality to CHD mortality or sudden death (eTable). We defined CHD events as nonfatal myocardial infarction or CHD death (equivalent to hard events28) or hospitalization for angina or coronary revascularization.10 We performed a sensitivity analysis with hard CHD events only (ie, CHD death, nonfatal myocardial infarction). For AF analyses, participants with baseline AF were excluded (eTable).

To assess the risks of endogenous subclinical hyperthyroidism, we excluded participants using thyroxine or antithyroid drugs at baseline. To explore the possible heterogeneity between exogenous (using thyroid-altering medications) and endogenous subclinical hyperthyroidism, we performed sensitivity analyses by adding participants using thyroxine or antithyroid drugs at baseline.

We conducted a study quality evaluation using previous criteria16 after collecting the following additional information from study authors: methods of outcome adjudication and ascertainment, accounting for confounders, and completeness of follow-up.

The association between subclinical hyperthyroidism and each outcome was analyzed using separate Cox proportional hazard models for each cohort (SAS 9.2 [SAS Institute Inc]; Stata 11.2 [StataCorp]). Pooled estimates for each outcome were calculated using random-effects models based on inverse variance model29 as recommended.19,30,31 Results were summarized using forest plots (Review Manager 5.1.2, Nordic Cochrane Centre). To assess heterogeneity across studies, we used the I2 statistic, which measures the inconsistency across studies attributable to heterogeneity instead of chance alone.32

Primary analyses were adjusted for age and sex (some traditional cardiovascular risk factors being potential mediators3), then further adjusted for traditional cardiovascular risk factors (systolic blood pressure, current or former smoking, total cholesterol, and diabetes). As missing data rates were lower than 3% and unlikely to substantially bias the multivariate model estimates,33 complete case analysis was used.

To explore potential sources of heterogeneity, we performed predefined subgroup and sensitivity analyses, as in our previous analysis.20 We conducted stratified analyses by age, sex, race, thyrotropin categories, and preexisting CVD. For strata with participants but no event in some subgroup analyses, we used penalized likelihood methods34 to calculate hazard ratios (HRs) and 95% confidence intervals. To calculate age- and sex-adjusted event rates/1000 person-years, we used Poisson models.35 We checked the proportional hazard assumption using graphical methods and the Schoenfeld test.36 For publication bias, we used age- and sex-adjusted funnel plots and the Egger test.37

Among identified reports, 13 prospective cohorts met all inclusion criteria (eFigure). We excluded 3 cohorts9,24,25 using first-generation thyrotropin assays,26which were insufficiently sensitive for the diagnosis of subclinical hyperthyroidism. After the exclusion of users of thyroxine and antithyroid drugs, the final sample comprised 10 prospective cohorts with a total of 52 674 participants (median age, 59 years, 58.5% women), with median follow-up 8.8 years and total follow-up 501 922 persons-years. Of the participants, 50 486 were euthyroid and 2188 (4.2%) had endogenous subclinical hyperthyroidism (Table 1), including 1884 participants (3.6%) with low but not suppressed thyrotropin (0.10-0.44 mIU/L) and 304 (0.6%) with suppressed thyrotropin (<0.10 mIU/L). The loss to follow-up rate was lower than 5% in all included studies. Total and CHD mortality were reported in all cohorts. Coronary heart disease event data were available for 22 437 participants from 6 cohorts (3.2% with subclinical hyperthyroidism), and were formally adjudicated for 4 of these 6 studies.7,8,10,38 After excluding those with AF at baseline, data for incident AF events were available in 8711 participants from 5 cohorts (9.3% with subclinical hyperthyroidism).

Table Graphic Jump LocationTable 1. Baseline Characteristics of Individuals in Included Studies

During follow-up, 8527 participants died (including 1896 from CHD), 3653 had CHD events, and 785 had incident AF. In age- and sex-adjusted analyses, the overall HR for participants with subclinical hyperthyroidism compared with euthyroidism was 1.24 (95% CI, 1.06-1.46; 23.5 vs 19.9/1000 person-years for euthyroidism) for total mortality, 1.29 (95% CI, 1.02-1.62; 5.1 vs 4.5/1000 person-years) for CHD mortality, 1.21 (95% CI, 0.99-1.46; 24.1 vs 20.9/1000 person-years) for CHD events, and 1.68 (95% CI, 1.16-2.43; 17.1 vs 12.5/1000 person-years) for incident AF (Figure). Stroke and cancer mortality were not higher with subclinical hyperthyroidism. Heterogeneity was present across studies for total mortality (I 2 = 49%), but not for CHD mortality, CHD events or incident AF (all I 2 = 0%). Among subclinical hyperthyroid and euthyroid groups, there was a trend for more late events than early events for total mortality, CHD mortality, CHD events, and AF events (for all, P value for trend, ≤.02). We subsequently examined whether heterogeneity was related to differences in risks by degree of subclinical hyperthyroidism and age.

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Total mortality, coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation in endogenous subclinical hyperthyroidism vs euthyroidism. Age and sex-adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) are represented by squares or diamonds, those to the right of the solid line indicate increased risk. The sizes of data markers are proportional to the inverse of the variance of the HRs. *Forty-one participants were excluded from the analyses of CHD mortality because of missing cause of death. †The Birmingham Study,6 HUNT (Nord-Trøndelag Health Study),27 SHIP (Study of Health in Pomerania),39 and Brazilian Thyroid Study40 were not included because follow-up data were only available for death. EPIC indicates European Prospective Investigation of Cancer.

Table 2 presents stratified analyses for total mortality, CHD mortality, CHD events, and incident AF. In age- and sex-adjusted analyses, CHD mortality and incident AF (but not other outcomes) were significantly greater in participants with lower thyrotropin levels: HRs, 1.24 (95% CI, 0.96-1.61) and 1.63 (95% CI, 1.10-2.41) for thyrotropin levels 0.10-0.44 mIU/L, respectively, vs HRs, 1.84 (95% CI, 1.12-3.00) and 2.54 (95% CI, 1.08-5.99) for thyrotropin levels lower than 0.10 mIU/L, respectively (for both, P value for trend, ≤.03 for each outcome). Men had a slightly greater risk for total mortality, CHD mortality and incident AF, without statistical significance for interaction (all P ≥ .30). Risks for Asian participants were greater for total mortality (HR, 2.73; 95% CI, 1.53-4.88) and CHD mortality (HR, 2.35; 95% CI, 0.50-11.14), with nonsignificant interaction test results (all P ≥ .40), but data on Asian participants were available from only 1 cohort.40 Risks did not differ significantly by age or preexisting CVD. All risks were similar after further adjustment for cardiovascular risk factors, with an attributable risk of 14.5% for total mortality to 41.5% for AF in those with subclinical hyperthyroidism and a population attributable risk of 0.7% for total mortality to 6.2% for AF, given the relatively low prevalence of subclinical hyperthyroidism.

Table Graphic Jump LocationTable 2. Stratified Analyses for the Association Between Endogenous Subclinical Hyperthyroidism and the Risk of Total Mortality, CHD Mortality, CHD Events, and Atrial Fibrillation

Sensitivity analyses yielded similar results (Table 3). Excluding users of thyroxine and antithyroid drugs during follow-up or adding participants taking these medications at baseline to the overall sample yielded similar HRs. The risk of CHD mortality was higher (HR, 1.50; 95% CI, 1.00-2.27) after limiting the analyses to 4 studies with formal adjudication procedures.7,8,13,38 Risks of total mortality, CHD mortality and incident AF increased slightly after excluding a study with previous iodine supplementation.39 Risks were similar after further adjustment of multivariate models with lipid-lowering and antihypertensive medication use or body mass index.

Table Graphic Jump LocationTable 3. Sensitivity Analyses of the Association Between Subclinical Hyperthyroidism and the Risk of Total Mortality, CHD Mortality, CHD Events, and Atrial Fibrillation

The proportional hazard assumption was consistent across studies, except for the Birmingham Study6 (P = .009), which was excluded in a sensitivity analysis giving similar results. We found limited evidence of publication bias with visual assessment of age- and sex-adjusted funnel plots and the Egger test for total mortality (P = .17), but not the other outcomes (all P ≥ .20). For total mortality, the Brazilian Thyroid Study40 might be an outlier with no corresponding study of similar size with reduced risk associated with subclinical hyperthyroidism: a sensitivity analysis excluding this study yielded similar results.

In this analysis of all available prospective cohorts, endogenous subclinical hyperthyroidism was associated with an increased risk of total mortality, CHD mortality, and incident AF. Coronary heart disease mortality and incident AF (but not other outcomes) were significantly greater in participants with thyrotropin levels lower than 0.10 mIU/L than those with thyrotropin levels between 0.10 and 0.44 mIU/L (for both, P value for trend, ≤.03). Risks did not differ significantly by age, sex, or preexisting CVD and were similar after further adjustment for cardiovascular risk factors.

Previous study-level meta-analyses produced conflicting results regarding the association between subclinical hyperthyroidism and cardiovascular mortality.1517 Our results, based on individual participant data, demonstrate that there is indeed an increased risk of total and CHD mortality associated with subclinical hyperthyroidism,15,16 and add new information on subgroups at increased risk and the risk of incident AF. Previous meta-analyses could not accurately assess the differences in risk according to thyrotropin level, because of potential ecological fallacy without individual participant data analysis18 and they pooled individual studies using varying thyrotropin cutoff levels, outcome definitions, and confounding factors for adjustment.15,16 Only a few individual studies reported stratified risks according to thyrotropin levels. Our results are consistent with those recently reported by Vadiveloo et al,41 who found an increased risk of nonfatal CVD, increasing with lower thyrotropin levels (HR, 1.67 [95% CI, 1.45-1.92] for thyrotropin level 0.10-0.40 mIU/L, vs HR, 1.74 [95% CI, 1.36-2.21] for thyrotropin level <0.10 mIU/L); this study was not included in our analysis because of its retrospective case-control design.

To our knowledge, no meta-analysis has been conducted on the association of AF with subclinical hyperthyroidism. Similar to our data, some individual studies showed increased risk of AF associated with subclinical hyperthyroidism.9,10 Sawin et al9 reported an increased risk of incident AF in persons older than 60 years with thyrotropin levels lower than 0.1 mIU/L (HR, 3.8; 95% CI, 1.7-8.3) and among those with thyrotropin levels between 0.1 and 0.4 mIU/L (HR, 1.6; 95% CI, 1.0-2.5); this study was excluded from our analysis because of its first-generation thyrotropin assay.26 Cappola et al10 showed a relationship between low thyrotropin levels and AF incidence in individuals 65 years or older with endogenous subclinical hyperthyroidism, which was also significant in those with thyrotropin levels between 0.10 and 0.44 mIU/L (HR, 1.85; 95% CI, 1.14-3.00). In a population with a mean age of 65.5 years, Vadiveloo et al41 found an increased risk of cardiac arrhythmia for participants with endogenous subclinical hyperthyroidism, especially in those with thyrotropin levels lower than 0.10 mIU/L. Taken together, these previous studies and our data suggest that the risk of AF in individuals with endogenous subclinical hyperthyroidism is higher with lower thyrotropin levels and is mostly pronounced in those with thyrotropin levels lower than 0.10 mIU/L.

The increased risks of AF events and total and CHD mortality associated with subclinical hyperthyroidism have been postulated to be caused by systemic effects of thyroid hormones, such as a change in cardiac function1,3 or cardiac arrhythmia.3,42 These hypotheses are favored by the fact that adjustment for cardiovascular risk factors did not alter risks of subclinical hyperthyroidism. An alternative explanation for the results could be publication bias, selection bias or quality issues in the included cohorts, or unmeasured confounders.43 Sensitivity analyses (1) excluding a small study40 with no corresponding study of similar size with reduced risk associated with subclinical hyperthyroidism and (2) pooling only higher-quality cohorts yielded similar results.

Among the strengths of our study, an individual participant data analysis is considered the best way for synthesizing evidence across several studies because it is not subject to potential bias from study-level meta-analyses (ecological fallacy)18 and allows performance of time-to-event analyses and use of standardized definitions of predictors, outcomes, and adjustment for confounding factors.19 We included all available international published data after conducting a systematic review.

Among the limitations of our study, our analysis included predominantly white populations, except for one cohort including Brazilians of Japanese descent.40 Although we included all available data, our results may not be generalized to all other populations. Second, thyroid function tests were performed only at baseline, and we have no data to assess how many participants with subclinical hyperthyroidism progressed to overt hyperthyroidism or normalized to euthyroidism over time, which is a limitation of most published large cohorts.10,23,27,38 Third, subclinical hyperthyroidism was defined as a thyrotropin level lower than 0.45 mIU/L and normal FT4 levels, since T3 was not measured in all included cohorts; sensitivity analyses excluding participants with abnormal total or free T3 levels yielded similar results. Fourth, the high prevalence of subclinical hyperthyroidism in the Study of Health in Pomerania (SHIP, Northern Germany, 24.1%) may be explained by the iodine supplementation that was introduced in the area 4 years before the start of SHIP in the late 1990s.44 Excluding SHIP yielded similar risk estimates. Fifth, we did not have information on the etiology of subclinical hyperthyroidism, while cardiovascular complications may be related to the etiology of the condition.45 Sixth, up to 2.6% of participants started thyroxine or antithyroid drugs during follow-up; sensitivity analyses excluding users of these medications during follow-up yielded similar results. However, we did not have complete data from all cohorts on use of other medications that could alter thyrotropin and/or FT4 levels, such as steroids or amiodarone; sensitivity analyses excluding other medications users (0%-2.8% when available) yielded similar results. Seventh, only mortality and cardiovascular outcomes were assessed. Other conditions such as osteoporosis and cognition were not analyzed and could partly account for increased total mortality, particularly among elderly persons, although data on the associations between subclinical hyperthyroidism and osteoporosis and cognition are conflicting.1 Eighth, 4 of 6 studies7,8,10,38 formally adjudicated CHD outcomes. Sensitivity analyses limited to these 4 studies yielded similar risk estimates. As most included cohorts used self-reported preexisting CVD, stratified analyses according to preexisting CVD should be interpreted with caution.

Recent guidelines4 recommend that “treatment of SH [subclinical hyperthyroidism] should be strongly considered in all individuals ≥65 years of age” with thyrotropin level lower than 0.10 mIU/L (recommendation 65) and “treatment of SH should be considered in individuals ≥65 years of age” with low thyrotropin levels but 0.1 mIU/L or higher (recommendation 66). Based on all available prospective cohort studies, our findings of increased risks of total mortality, CHD mortality, and incident AF associated with subclinical hyperthyroidism, with greater risks of CHD mortality and AF among those with thyrotropin levels lower than 0.10 mIU/L, are consistent with these recent guidelines.4 However, findings based on observational data should be interpreted with great caution for clinical practice, since they are subject to several aforementioned limitations. No clinical trials have assessed whether treating subclinical hyperthyroidism results in improved cardiovascular outcomes. Because our data included only a limited sample of young men and premenopausal women, generalization of our findings to younger adults is limited.

In conclusion, pooling individual data from all available prospective cohorts suggests that endogenous subclinical hyperthyroidism is associated with an increased risk of total mortality, CHD mortality, and incident AF, with higher risks of CHD mortality and AF with thyrotropin levels below 0.10 mIU/L. Our study is observational, and as such cannot address whether the risks associated with subclinical hyperthyroidism are lowered by treatment. A large randomized controlled trial with relevant clinical outcomes will be required to demonstrate whether these risks are altered by therapy; such a trial will be challenging to conduct given the large sample size required and the lower prevalence of adults with subclinical hyperthyroidism compared with subclinical hypothyroidism. If conducted, such a trial should examine prevention of AF and surrogate outcome measures, such as carotid intima-media thickness.46

Correspondence: Nicolas Rodondi, MD, MAS, Department of General Internal Medicine, Inselspital, University of Bern, 3010 Bern, Switzerland (Nicolas.Rodondi@insel.ch).

Accepted for Publication: January 27, 2012.

Published Online: April 23, 2012. doi:10.1001/archinternmed.2012.402

Author Contributions: Drs Collet and Rodondi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Gussekloo, Newman, Westendorp, Franklyn, and Rodondi. Acquisition of data: Gussekloo, den Elzen, Iervasi, Åsvold, Sgarbi, Völzke, Gencer, Maciel, Molinaro, Luben, Newman, Khaw, Westendorp, Franklyn, Walsh, and Rodondi. Analysis and interpretation of data: Collet, Gussekloo, Bauer, den Elzen, Cappola, Balmer, Iervasi, Åsvold, Sgarbi, Völzke, Gencer, Maciel, Bremner, Maisonneuve, Cornuz, Westendorp, Franklyn, Vittinghoff, and Rodondi. Drafting of the manuscript: Collet, Balmer, Maciel, Westendorp, and Franklyn. Critical revision of the manuscript for important intellectual content: Collet, Gussekloo, Bauer, Cappola, Balmer, Iervasi, Åsvold, Sgarbi, Völzke, Gencer, Molinaro, Bremner, Luben, Maisonneuve, Cornuz, Newman, Khaw, Westendorp, Franklyn, Vittinghoff, Walsh, and Rodondi. Statistical analysis: Collet, Gussekloo, Balmer, Gencer, Franklyn, Vittinghoff, and Rodondi. Obtained funding: Sgarbi, Völzke, Maciel, Newman, Khaw, Westendorp, Walsh, and Rodondi. Administrative, technical, and material support: Collet, den Elzen, Gencer, Maciel, Luben, Newman, Khaw, Franklyn, and Rodondi. Study supervision: Gussekloo, Iervasi, Molinaro, Westendorp, and Rodondi. Dr Vittinghoff reviewed the statistical analyses of the manuscript.

Financial Disclosure: None reported.

Funding/Support: This study was supported by a grant SNSF 320030-138267 from the Swiss National Science Foundation (principal investigator, Dr Rodondi). The Cardiovascular Health Study and the research reported in this article were supported by contracts N01-HC-80007, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and grant U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through grants R01 AG-15928, R01 AG-20098, AG-027058, and AG-032317 from the National Institute on Aging; grant R01 HL-075366 from the National Heart, Lung, and Blood Institute; and the University of Pittsburgh Claude. D. Pepper Older Americans Independence Center grant P30-AG-024827. The thyroid measurements in the Cardiovascular Health Study were supported by an American Heart Association Grant-in-Aid (to Linda Fried, MD). A full list of principal Cardiovascular Health Study investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. The Health, Aging, and Body Composition Study was supported by National Institute on Aging (NIA) contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; NIA grant R01-AG028050; and National Institute of Nursing Research grant R01-NR012459. The NIA funded the Health, Aging, and Body Composition Study, reviewed the manuscript, and approved its publication. The EPIC-Norfolk study was supported by research grants from the Medical Research Council UK and Cancer Research UK. The Nord-Trøndelag Health Study (HUNT Study) is a collaborative effort of HUNT Research Center, Faculty of Medicine, Norwegian University of Science and Technology; Nord-Trøndelag County Council; Central Norway Health Authority; and the Norwegian Institute of Public Health. The thyroid function testing in the HUNT Study was financially supported by Wallac Oy (Turku, Finland). The Leiden 85-Plus Study was partly funded by the Dutch Ministry of Health, Welfare, and Sports. The Study of Health in Pomerania (SHIP) is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research, the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg–West Pomerania. Analyses were further supported by a grant of the German Research Foundation (DFG Vo 955/5-2). The Brazilian Thyroid Study was supported by an unrestricted grant from the Sao Paulo State Research Foundation (Fundacão de Amparo a’ Pesquisa do Estado de Sao Paulo, FAPESP, grant 6/59737-9 to Dr Maciel). Dr Newman is supported by grant AG-023629 from the NIA. Dr Westendorp is supported by the Netherlands Organization for Scientific Research (NGI/NWO 911-03-016).

Role of the Sponsor: None of the sponsors had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript; except for the NIA, which funded the Health, Aging, and Body Composition Study, reviewed the manuscript, and approved its publication.

Participating Studies of the Thyroid Studies Collaboration:United States: Cardiovascular Health Study; Health, Aging, and Body Composition Study; United Kingdom: Birmingham Study and EPIC-Norfolk Study; Norway: Nord-Trøndelag Health Study (HUNT Study); the Netherlands: Leiden 85-Plus Study; Italy: Pisa Cohort; Germany: Study of Health in Pomerania; Australia: Busselton Health Study; and Brazil: Brazilian Thyroid Study.

Online-Only Material: Visit http://www.archinternmed.com to listen to an author podcast about this article.

Surks MI, Ortiz E, Daniels GH,  et al.  Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.  JAMA. 2004;291(2):228-238
PubMed   |  Link to Article
Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society.  J Clin Endocrinol Metab. 2005;90(1):581-587
PubMed   |  Link to Article
Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction.  Endocr Rev. 2008;29(1):76-131
PubMed   |  Link to Article
Bahn RS, Burch HB, Cooper DS,  et al; American Thyroid Association; American Association of Clinical Endocrinologists.  Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists.  Thyroid. 2011;21(6):593-646
PubMed   |  Link to Article
Biondi B. Endogenous subclinical hyperthyroidism: who, when and why to treat.  Expert Rev Endocrinol Metab. 2011;6(6):785-792
Link to Article
Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study.  Lancet. 2001;358(9285):861-865
PubMed   |  Link to Article
Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age.  JAMA. 2004;292(21):2591-2599
PubMed   |  Link to Article
Iervasi G, Molinaro S, Landi P,  et al.  Association between increased mortality and mild thyroid dysfunction in cardiac patients.  Arch Intern Med. 2007;167(14):1526-1532
PubMed   |  Link to Article
Sawin CT, Geller A, Wolf PA,  et al.  Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons.  N Engl J Med. 1994;331(19):1249-1252
PubMed   |  Link to Article
Cappola AR, Fried LP, Arnold AM,  et al.  Thyroid status, cardiovascular risk, and mortality in older adults.  JAMA. 2006;295(9):1033-1041
PubMed   |  Link to Article
Auer J, Scheibner P, Mische T, Langsteger W, Eber O, Eber B. Subclinical hyperthyroidism as a risk factor for atrial fibrillation.  Am Heart J. 2001;142(5):838-842
PubMed   |  Link to Article
Gammage MD, Parle JV, Holder RL,  et al.  Association between serum free thyroxine concentration and atrial fibrillation.  Arch Intern Med. 2007;167(9):928-934
PubMed   |  Link to Article
Rodondi N, Bauer DC, Cappola AR,  et al.  Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure: the Cardiovascular Health study.  J Am Coll Cardiol. 2008;52(14):1152-1159
PubMed   |  Link to Article
Biondi B, Palmieri EA, Fazio S,  et al.  Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients.  J Clin Endocrinol Metab. 2000;85(12):4701-4705
PubMed   |  Link to Article
Völzke H, Schwahn C, Wallaschofski H, Dörr M. Review: the association of thyroid dysfunction with all-cause and circulatory mortality: is there a causal relationship?  J Clin Endocrinol Metab. 2007;92(7):2421-2429
PubMed   |  Link to Article
Ochs N, Auer R, Bauer DC,  et al.  Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality.  Ann Intern Med. 2008;148(11):832-845
PubMed
Haentjens P, Van Meerhaeghe A, Poppe K, Velkeniers B. Subclinical thyroid dysfunction and mortality: an estimate of relative and absolute excess all-cause mortality based on time-to-event data from cohort studies.  Eur J Endocrinol. 2008;159(3):329-341
PubMed   |  Link to Article
Egger M, Davey Smith G, Altman D. Systematic Reviews in Health Care: Meta-analysis in Context. 2nd ed. London, England: BMJ Publishing Group; 2001
Simmonds MC, Higgins JP, Stewart LA, Tierney JF, Clarke MJ, Thompson SG. Meta-analysis of individual patient data from randomized trials: a review of methods used in practice.  Clin Trials. 2005;2(3):209-217
PubMed   |  Link to Article
Rodondi N, den Elzen WP, Bauer DC,  et al; Thyroid Studies Collaboration.  Subclinical hypothyroidism and the risk of coronary heart disease and mortality.  JAMA. 2010;304(12):1365-1374
PubMed   |  Link to Article
Helfand M.US Preventive Services Task Force.  Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the US Preventive Services Task Force.  Ann Intern Med. 2004;140(2):128-141
PubMed
Walsh JP, Bremner AP, Bulsara MK,  et al.  Subclinical thyroid dysfunction as a risk factor for cardiovascular disease.  Arch Intern Med. 2005;165(21):2467-2472
PubMed   |  Link to Article
Boekholdt SM, Titan SM, Wiersinga WM,  et al.  Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study.  Clin Endocrinol (Oxf). 2010;72(3):404-410
PubMed   |  Link to Article
Imaizumi M, Akahoshi M, Ichimaru S,  et al.  Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism.  J Clin Endocrinol Metab. 2004;89(7):3365-3370
PubMed   |  Link to Article
Vanderpump MP, Tunbridge WM, French JM,  et al.  The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community.  Thyroid. 1996;6(3):155-160
PubMed
Goichot B, Sapin R, Schlienger JL. Subclinical hyperthyroidism: considerations in defining the lower limit of the thyrotropin reference interval.  Clin Chem. 2009;55(3):420-424
PubMed   |  Link to Article
Åsvold BO, Bjøro T, Nilsen TI, Gunnell D, Vatten LJ. Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study.  Arch Intern Med. 2008;168(8):855-860
PubMed   |  Link to Article
Grundy SM.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.  Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).  JAMA. 2001;285(19):2486-2497
PubMed   |  Link to Article
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188
PubMed   |  Link to Article
Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting.  BMJ. 2010;340:c221
PubMed   |  Link to Article
Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of InterventionsHoboken, NJ: John Wiley & Sons Ltd; 2008
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Schafer JL. Multiple imputation: a primer.  Stat Methods Med Res. 1999;8(1):3-15
PubMed   |  Link to Article
Heinze G, Schemper M. A solution to the problem of monotone likelihood in Cox regression.  Biometrics. 2001;57(1):114-119
PubMed   |  Link to Article
Vittinghoff E, Glidden DV, Shiboski S, McCulloch CE. Regression Methods in Biostatistics: Linear, Logistic, Survival, and Repeated Measures Models. New York, NY: Springer; 2005
Schoenfeld D. Chi-squared goodness-of-fit tests for the proportional hazards regression model.  Biometrika. 1980;67(1):145-153
Link to Article
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634
PubMed   |  Link to Article
Rodondi N, Newman AB, Vittinghoff E,  et al.  Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death.  Arch Intern Med. 2005;165(21):2460-2466
PubMed   |  Link to Article
Ittermann T, Haring R, Sauer S,  et al.  Decreased serum TSH levels are not associated with mortality in the adult northeast German population.  Eur J Endocrinol. 2010;162(3):579-585
PubMed   |  Link to Article
Sgarbi JA, Matsumura LK, Kasamatsu TS, Ferreira SR, Maciel RM. Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5-year follow-up: the Japanese Brazilian Thyroid Study.  Eur J Endocrinol. 2010;162(3):569-577
PubMed   |  Link to Article
Vadiveloo T, Donnan PT, Cochrane L, Leese GP. The Thyroid Epidemiology, Audit, and Research Study (TEARS): morbidity in patients with endogenous subclinical hyperthyroidism.  J Clin Endocrinol Metab. 2011;96(5):1344-1351
PubMed   |  Link to Article
Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart.  Ann Intern Med. 2002;137(11):904-914
PubMed
Moher D, Liberati A, Tetzlaff J, Altman DG.PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement.  Ann Intern Med. 2009;151(4):264-269, W64
PubMed
Völzke H, Lüdemann J, Robinson DM,  et al.  The prevalence of undiagnosed thyroid disorders in a previously iodine-deficient area.  Thyroid. 2003;13(8):803-810
PubMed   |  Link to Article
Biondi B, Kahaly GJ. Cardiovascular involvement in patients with different causes of hyperthyroidism.  Nat Rev Endocrinol. 2010;6(8):431-443
PubMed   |  Link to Article
Taylor AJ, Villines TC, Stanek EJ,  et al.  Extended-release niacin or ezetimibe and carotid intima-media thickness.  N Engl J Med. 2009;361(22):2113-2122
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Total mortality, coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation in endogenous subclinical hyperthyroidism vs euthyroidism. Age and sex-adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) are represented by squares or diamonds, those to the right of the solid line indicate increased risk. The sizes of data markers are proportional to the inverse of the variance of the HRs. *Forty-one participants were excluded from the analyses of CHD mortality because of missing cause of death. †The Birmingham Study,6 HUNT (Nord-Trøndelag Health Study),27 SHIP (Study of Health in Pomerania),39 and Brazilian Thyroid Study40 were not included because follow-up data were only available for death. EPIC indicates European Prospective Investigation of Cancer.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of Individuals in Included Studies
Table Graphic Jump LocationTable 2. Stratified Analyses for the Association Between Endogenous Subclinical Hyperthyroidism and the Risk of Total Mortality, CHD Mortality, CHD Events, and Atrial Fibrillation
Table Graphic Jump LocationTable 3. Sensitivity Analyses of the Association Between Subclinical Hyperthyroidism and the Risk of Total Mortality, CHD Mortality, CHD Events, and Atrial Fibrillation

References

Surks MI, Ortiz E, Daniels GH,  et al.  Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.  JAMA. 2004;291(2):228-238
PubMed   |  Link to Article
Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society.  J Clin Endocrinol Metab. 2005;90(1):581-587
PubMed   |  Link to Article
Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction.  Endocr Rev. 2008;29(1):76-131
PubMed   |  Link to Article
Bahn RS, Burch HB, Cooper DS,  et al; American Thyroid Association; American Association of Clinical Endocrinologists.  Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists.  Thyroid. 2011;21(6):593-646
PubMed   |  Link to Article
Biondi B. Endogenous subclinical hyperthyroidism: who, when and why to treat.  Expert Rev Endocrinol Metab. 2011;6(6):785-792
Link to Article
Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study.  Lancet. 2001;358(9285):861-865
PubMed   |  Link to Article
Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age.  JAMA. 2004;292(21):2591-2599
PubMed   |  Link to Article
Iervasi G, Molinaro S, Landi P,  et al.  Association between increased mortality and mild thyroid dysfunction in cardiac patients.  Arch Intern Med. 2007;167(14):1526-1532
PubMed   |  Link to Article
Sawin CT, Geller A, Wolf PA,  et al.  Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons.  N Engl J Med. 1994;331(19):1249-1252
PubMed   |  Link to Article
Cappola AR, Fried LP, Arnold AM,  et al.  Thyroid status, cardiovascular risk, and mortality in older adults.  JAMA. 2006;295(9):1033-1041
PubMed   |  Link to Article
Auer J, Scheibner P, Mische T, Langsteger W, Eber O, Eber B. Subclinical hyperthyroidism as a risk factor for atrial fibrillation.  Am Heart J. 2001;142(5):838-842
PubMed   |  Link to Article
Gammage MD, Parle JV, Holder RL,  et al.  Association between serum free thyroxine concentration and atrial fibrillation.  Arch Intern Med. 2007;167(9):928-934
PubMed   |  Link to Article
Rodondi N, Bauer DC, Cappola AR,  et al.  Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure: the Cardiovascular Health study.  J Am Coll Cardiol. 2008;52(14):1152-1159
PubMed   |  Link to Article
Biondi B, Palmieri EA, Fazio S,  et al.  Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients.  J Clin Endocrinol Metab. 2000;85(12):4701-4705
PubMed   |  Link to Article
Völzke H, Schwahn C, Wallaschofski H, Dörr M. Review: the association of thyroid dysfunction with all-cause and circulatory mortality: is there a causal relationship?  J Clin Endocrinol Metab. 2007;92(7):2421-2429
PubMed   |  Link to Article
Ochs N, Auer R, Bauer DC,  et al.  Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality.  Ann Intern Med. 2008;148(11):832-845
PubMed
Haentjens P, Van Meerhaeghe A, Poppe K, Velkeniers B. Subclinical thyroid dysfunction and mortality: an estimate of relative and absolute excess all-cause mortality based on time-to-event data from cohort studies.  Eur J Endocrinol. 2008;159(3):329-341
PubMed   |  Link to Article
Egger M, Davey Smith G, Altman D. Systematic Reviews in Health Care: Meta-analysis in Context. 2nd ed. London, England: BMJ Publishing Group; 2001
Simmonds MC, Higgins JP, Stewart LA, Tierney JF, Clarke MJ, Thompson SG. Meta-analysis of individual patient data from randomized trials: a review of methods used in practice.  Clin Trials. 2005;2(3):209-217
PubMed   |  Link to Article
Rodondi N, den Elzen WP, Bauer DC,  et al; Thyroid Studies Collaboration.  Subclinical hypothyroidism and the risk of coronary heart disease and mortality.  JAMA. 2010;304(12):1365-1374
PubMed   |  Link to Article
Helfand M.US Preventive Services Task Force.  Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the US Preventive Services Task Force.  Ann Intern Med. 2004;140(2):128-141
PubMed
Walsh JP, Bremner AP, Bulsara MK,  et al.  Subclinical thyroid dysfunction as a risk factor for cardiovascular disease.  Arch Intern Med. 2005;165(21):2467-2472
PubMed   |  Link to Article
Boekholdt SM, Titan SM, Wiersinga WM,  et al.  Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study.  Clin Endocrinol (Oxf). 2010;72(3):404-410
PubMed   |  Link to Article
Imaizumi M, Akahoshi M, Ichimaru S,  et al.  Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism.  J Clin Endocrinol Metab. 2004;89(7):3365-3370
PubMed   |  Link to Article
Vanderpump MP, Tunbridge WM, French JM,  et al.  The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community.  Thyroid. 1996;6(3):155-160
PubMed
Goichot B, Sapin R, Schlienger JL. Subclinical hyperthyroidism: considerations in defining the lower limit of the thyrotropin reference interval.  Clin Chem. 2009;55(3):420-424
PubMed   |  Link to Article
Åsvold BO, Bjøro T, Nilsen TI, Gunnell D, Vatten LJ. Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study.  Arch Intern Med. 2008;168(8):855-860
PubMed   |  Link to Article
Grundy SM.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.  Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).  JAMA. 2001;285(19):2486-2497
PubMed   |  Link to Article
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188
PubMed   |  Link to Article
Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting.  BMJ. 2010;340:c221
PubMed   |  Link to Article
Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of InterventionsHoboken, NJ: John Wiley & Sons Ltd; 2008
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Schafer JL. Multiple imputation: a primer.  Stat Methods Med Res. 1999;8(1):3-15
PubMed   |  Link to Article
Heinze G, Schemper M. A solution to the problem of monotone likelihood in Cox regression.  Biometrics. 2001;57(1):114-119
PubMed   |  Link to Article
Vittinghoff E, Glidden DV, Shiboski S, McCulloch CE. Regression Methods in Biostatistics: Linear, Logistic, Survival, and Repeated Measures Models. New York, NY: Springer; 2005
Schoenfeld D. Chi-squared goodness-of-fit tests for the proportional hazards regression model.  Biometrika. 1980;67(1):145-153
Link to Article
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634
PubMed   |  Link to Article
Rodondi N, Newman AB, Vittinghoff E,  et al.  Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death.  Arch Intern Med. 2005;165(21):2460-2466
PubMed   |  Link to Article
Ittermann T, Haring R, Sauer S,  et al.  Decreased serum TSH levels are not associated with mortality in the adult northeast German population.  Eur J Endocrinol. 2010;162(3):579-585
PubMed   |  Link to Article
Sgarbi JA, Matsumura LK, Kasamatsu TS, Ferreira SR, Maciel RM. Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5-year follow-up: the Japanese Brazilian Thyroid Study.  Eur J Endocrinol. 2010;162(3):569-577
PubMed   |  Link to Article
Vadiveloo T, Donnan PT, Cochrane L, Leese GP. The Thyroid Epidemiology, Audit, and Research Study (TEARS): morbidity in patients with endogenous subclinical hyperthyroidism.  J Clin Endocrinol Metab. 2011;96(5):1344-1351
PubMed   |  Link to Article
Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart.  Ann Intern Med. 2002;137(11):904-914
PubMed
Moher D, Liberati A, Tetzlaff J, Altman DG.PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement.  Ann Intern Med. 2009;151(4):264-269, W64
PubMed
Völzke H, Lüdemann J, Robinson DM,  et al.  The prevalence of undiagnosed thyroid disorders in a previously iodine-deficient area.  Thyroid. 2003;13(8):803-810
PubMed   |  Link to Article
Biondi B, Kahaly GJ. Cardiovascular involvement in patients with different causes of hyperthyroidism.  Nat Rev Endocrinol. 2010;6(8):431-443
PubMed   |  Link to Article
Taylor AJ, Villines TC, Stanek EJ,  et al.  Extended-release niacin or ezetimibe and carotid intima-media thickness.  N Engl J Med. 2009;361(22):2113-2122
PubMed   |  Link to Article

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