Meta-analysis: Subclinical Thyroid Dysfunction and the Risk for Coronary Heart Disease and Mortality

Context Is subclinical thyroid dysfunction associated with increased risk for coronary heart disease and mortality? Contribution This systematic review of 12 prospective cohort studies found that both subclinical hypothyroidism and hyperthyroidism were possibly associated with a small increased risk for coronary heart disease and mortality. Caution Data were uncertain. Confidence intervals around risk estimates were wide, particularly for those related to subclinical hyperthyroidism. Higher-quality studies showed lower estimates of risk than lower-quality studies. Implication Randomized trials testing the efficacy of thyroxine replacement and antithyroid medications for subclinical hypothyroidism and subclinical hyperthyroidism are needed. The Editors Subclinical thyroid dysfunction refers to patients who have an abnormal thyrotropin (thyroid-stimulating hormone [TSH]) level and a normal free thyroxine (T4) level (1). The prevalence of subclinical hypothyroidism is about 4.3% in adults (0.7% for subclinical hyperthyroidism), and prevalence is higher in older adults and women (25). Controversy persists about whether screening and treating subclinical thyroid dysfunction is warranted (1, 57) because current evidence about the risks is limited (1, 5) and randomized, controlled trials on relevant clinical outcomes have not been done (5, 8). Subclinical hypothyroidism has been associated with elevated cholesterol levels (911) and increased risk for atherosclerosis (12, 13). Yet, data on the relationship between subclinical hypothyroidism and coronary heart disease (CHD) events are conflicting (12, 1417). In a previous meta-analysis (18), we found that subclinical hypothyroidism was associated with a 1.65-fold increased risk (CI, 1.28 to 2.12) for CHD. However, that meta-analysis included several cross-sectional and casecontrol studies and only 5 small prospective studies. Recently, 3 large prospective studies on this issue have been published (14, 16, 17), with somewhat inconsistent results. Because these new data include many additional CHD events, data are now sufficient to do a meta-analysis that includes only prospective studies, which provide greater validity. Data on the association between subclinical hypothyroidism and mortality are also conflicting (14, 17, 19, 20). The consequences of subclinical hyperthyroidism have been less frequently studied than those of subclinical hypothyroidism. Subclinical hyperthyroidism has been associated with cardiovascular and total mortality (15), but with conflicting data (14, 17). Two of the 3 recent, large prospective studies (14, 17) also examined CHD and mortality in subclinical hyperthyroid participants. To summarize prospective evidence about the relationship between subclinical thyroid dysfunction and CHD and mortality, we did a systematic review of prospective cohort studies. Methods We followed a standardized protocol and conducted and reported this analysis according to the guidelines of the Meta-analysis Of Observational Studies in Epidemiology group (21). Data Sources and Searches We conducted a systematic literature search of MEDLINE for articles in any language on the association between subclinical thyroid dysfunction (both subclinical hypothyroidism and hyperthyroidism) and CHD or mortality (cardiovascular and total) published from 1950 to January 2008. To avoid missing any relevant study, we also searched the bibliographies of key articles in the field and those included in this review. We did our search on an Ovid (MEDLINE) server by using broadly defined Medical Subject Headings, such as thyroid diseases, hypothyroidism, hyperthyroidism, thyroid hormones, thyrotropin, mortality, myocardial ischemia, survival, and cardiovascular diseases and such keywords as subclinical hypothyroidism, subclinical hyperthyroidism, subclinical dysthyroidism, and subclinical thyroid, combined with the filter designed by knowledge information specialists from BMJ to select prospective studies (MEDLINE cohort-study filter) (22) but without their year limitation. Study Selection Two reviewers independently screened the abstracts and titles of the search results and eliminated articles only if they did not clearly study the association between subclinical thyroid dysfunction and CHD or mortality (cardiovascular or total) in a prospective design. The same 2 reviewers independently evaluated the remaining full-text articles for eligibility on the basis of a predefined set of eligibility criteria. Disagreements were resolved by consensus. We included only full-text, published, longitudinal cohort studies that measured thyroid function and followed persons prospectively, assessed CHD or mortality, and provided risk estimates or sufficient data to calculate risk estimates associated with subclinical thyroid dysfunction compared with normal thyroid function. Subclinical hypothyroidism was defined as elevated TSH levels and normal T4 levels (1). Several reviews suggest a TSH upper limit cutoff of 4.5 to 5.0 mU/L (1, 5), but others suggest decreasing the upper limit of the TSH range to 2.5 to 3.0 mU/L (23, 24). In the absence of consensus, we did not prespecify a TSH cutoff value to define subclinical hypothyroidism and did a sensitivity analysis by limiting the analysis to studies with a TSH cutoff of 4.5 mU/L or greater (5). Because most adults with elevated TSH levels have subclinical and not overt hypothyroidism (2), we included 2 studies with participants who had elevated TSH levels without a T4 measurement report (25, 26) and did a sensitivity analysis excluding those studies. For subclinical hyperthyroidism, we did not specify a TSH cutoff value (in the absence of consensus), but all studies had a cutoff value close to 0.3 to 0.5 mU/L. We included 1 study with participants who had low TSH levels without a reported T4 measurement (26) and did a sensitivity analysis excluding this study. For CHD, we considered myocardial infarction, angina, the acute coronary syndrome, revascularization (coronary artery surgery, percutaneous transluminal coronary angioplasty), and significant coronary stenosis (defined as 50%) (27). We also considered death due to CHD or cardiovascular disease and did a sensitivity analysis excluding studies that only included the latter. We assessed methods and criteria used for adjudication of those outcomes. The agreement between the 2 reviewers was 99.5% for the first screen (titles and abstracts; = 0.79) and 100% for the full-text screen (= 1.00). Data Extraction and Quality Assessment Two reviewers independently abstracted data on participant characteristics, criteria used to define subclinical thyroid dysfunction, CHD and mortality data, and study results with adjustment factors by using a standardized data collection form. Discrepancies in data extraction between reviewers were resolved by consensus. We systematically assessed key indicators of study quality (28): methods of outcome adjudication and ascertainment that account for confounders and completeness of follow-up ascertainment. Similar to our previous meta-analysis (18), study populations were considered either a convenience or a population-based sample (defined as a random sample of the general population) (29). Methods of outcome adjudication were categorized as use of formal adjudication procedures and adjudication without knowledge of thyroid status. A formal adjudication procedure was defined as having clear criteria for the outcomes that were reviewed by experts for each potential case (29) (for example, specific electrocardiogram or cardiac enzyme modifications for CHD). We did not consider CHD adjudication based only on death certificates as a formal adjudication procedure. If an article did not clearly mention 1 of these criteria, we considered that it had not been done. We contacted the authors of 7 studies (12, 14, 15, 19, 26, 30, 31) that met inclusion criteria but did not provide specific data on the associations between subclinical thyroid dysfunction and CHD or mortality. We obtained risk estimates and CIs for cardiovascular and total mortality from cohort studies in the United Kingdom (15) and the Netherlands (19), as well as specific data for CHD mortality from a cohort of cardiac patients in Italy (31). Authors of a cohort study that published data about the relationship between autoimmune thyroid disease and CHD (30) provided us with data specific to subclinical hypothyroidism that were available for a subgroup of the participants. Three studies provided us with specific numbers of outcomes in each thyroid group (12, 14, 26). We used the most adjusted risk estimates available (the model containing the greatest number of covariates), unless a separate model further adjusted for thyroid antibodies, because thyroid autoimmunity has been hypothesized to be a mediator in the association between subclinical hypothyroidism and CHD (20). We did a sensitivity analysis without the studies that adjusted for cholesterol because high cholesterol might be on the causal pathway. When risk estimates and CIs were not provided but raw data were available (25, 30, 32), we calculated relative risks (RRs) and CIs by using the Woolf method (3335). Data Synthesis and Analysis We first qualitatively synthesized data, paying particular attention to which definitions of subclinical thyroid dysfunction were used and which outcomes were measured. To calculate summary estimates and CIs of the risk for subclinical thyroid dysfunction, we pooled both RRs and hazard ratios (HRs) by using random-effects models based on the variance model developed by DerSimonian and Laird (36). Analyses were repeated by using fixed-effects models for comparison. The presence of heterogeneity across studies was evaluated by using the Q statistic with a conservative P value of 0.10 (37). We also calculated the I 2 statistic, which describes the total variation across studies attributable to heterogeneity rather than chance; an I