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

Nicolas Ochs, MD; Reto Auer, MD; Douglas C. Bauer, MD; David Nanchen, MD; Jacobijn Gussekloo, MD, MPH; Jacques Cornuz, MD, MPH; and Nicolas Rodondi, MD, MAS
[+] Article and Author Information

From University of Lausanne, Lausanne, Switzerland; University of California, San Francisco, San Francisco, California; and Leiden University Medical Center, Leiden, the Netherlands.


Acknowledgment: The authors thank Professor Jayne A. Franklyn (University of Birmingham, Birmingham, United Kingdom), Professor Anne R. Cappola (University of Pennsylvania, Philadelphia, Pennsylvania), Dr. Alice M. Arnold (University of Washington, Seattle, Washington), Dr. Patrick Maisonneuve (European Institute of Oncology, Milan, Italy), Dr. Mark Vanderpump (Royal Free Hampstead NHS Trust, Hampstead, United Kingdom), Professor Mike Tunbridge (Oxford Radcliffe Hospitals, Oxford, United Kingdom), Dr. Iervasi (Clinical Physiology Institute, Pisa, Italy) and Dr. Hak (Erasmus MC University Medical Center, Rotterdam, the Netherlands) for their assistance and for supplying additional data from their studies.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Nicolas Rodondi, MD, MAS, Department of Ambulatory Care and Community Medicine, University of Lausanne, Bugnon 44, 1011 Lausanne, Switzerland; e-mail, nicolas.rodondi@hospvd.ch.

Current Author Addresses: Drs. Ochs, Nanchen, Cornuz, and Rodondi: Department of Ambulatory Care and Community Medicine, University of Lausanne, Bugnon 44, 1011 Lausanne, Switzerland.

Dr. Auer: Department of Medicine, University of Lausanne, Bugnon 46, 1011 Lausanne, Switzerland.

Dr. Bauer: University of California, San Francisco, 185 Berry Street,

Suite 5700, San Francisco, CA 94107.

Dr. Gussekloo: Department of Public Health and Primary Care, Leiden University Medical Center, V06-P, Postbus 9600, 2300 RC Leiden, the Netherlands.


Ann Intern Med. 2008;148(11):832-845. doi:10.7326/0003-4819-148-11-200806030-00225
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Background: Data on the association between subclinical thyroid dysfunction and coronary heart disease (CHD) and mortality are conflicting.

Purpose: To summarize prospective evidence about the relationship between subclinical thyroid dysfunction and CHD and mortality.

Data Sources: MEDLINE (1950 to January 2008) without language restrictions and reference lists of retrieved articles were searched.

Study Selection: Two reviewers screened and selected cohort studies that measured thyroid function and then followed persons prospectively to assess CHD or mortality.

Data Extraction: By using a standardized protocol and forms, 2 reviewers independently abstracted and assessed studies.

Data Synthesis: Ten of 12 identified studies involved population-based cohorts that included 14 449 participants. All 10 population-based cohort studies examined risks associated with subclinical hypothyroidism (2134 CHD events and 2822 deaths), whereas only 5 examined risks associated with subclinical hyperthyroidism (1392 CHD events and 1993 deaths). In a random-effects model, the relative risk (RR) for subclinical hypothyroidism for CHD was 1.20 (95% CI, 0.97 to 1.49; P for heterogeneity = 0.14; I2 = 33.4%). Risk estimates were lower when higher-quality studies were pooled (RR, 1.02 to 1.08) and were higher among participants younger than 65 years (RR, 1.51 [CI, 1.09 to 2.09] for studies with mean participant age <65 years and 1.05 [CI, 0.90 to 1.22] for studies with mean participant age ≥65 years). The RR was 1.18 (CI, 0.98 to 1.42) for cardiovascular mortality and 1.12 (CI, 0.99 to 1.26) for total mortality. For subclinical hyperthyroidism, the RR was 1.21 (CI, 0.88 to 1.68) for CHD, 1.19 (CI, 0.81 to 1.76) for cardiovascular mortality, and 1.12 (CI, 0.89 to 1.42) for total mortality (P for heterogeneity >0.50; I2 = 0% for all studies).

Limitations: Individual studies adjusted for different potential confounders, and 1 study provided only unadjusted data. Publication bias or selective reporting of outcomes could not be excluded.

Conclusion: Subclinical hypothyroidism and hyperthyroidism may be associated with a modest increased risk for CHD and mortality, with lower risk estimates when pooling higher-quality studies and larger CIs for subclinical hyperthyroidism.

Editors' Notes
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 (1213). 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 case–control studies and only 5 small prospective studies. Recently, 3 large prospective studies on this issue have been published (14, 1617), 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, 1920).

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.

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 (2324). 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 (2526) 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; κ = 0.79) and 100% for the full-text screen (κ = 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, 1415, 19, 26, 3031) 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 I2 statistic, which describes the total variation across studies attributable to heterogeneity rather than chance; an I2 value greater than 50% indicated at least moderate statistical heterogeneity (38). To explore sources of heterogeneity, we did several predefined sensitivity and subgroup analyses, all with a random-effects model. Given the recent findings of a possible protective effect of subclinical hypothyroidism in very elderly persons (19, 39), we conducted stratified analyses by mean age of the studied populations by using various cutoff values (age <65 years or ≥65 years, and age <60 years, 60 to 79.9 years, or ≥80 years). We also repeated the meta-analysis after limiting the analysis to multiply adjusted studies, studies with a TSH cutoff value of 4.5 mU/L or greater or 10.0 mU/L or greater (5), studies using formal adjudication procedures, and studies that excluded thyroid hormone or antithyroid drug recipients. Finally, we did an influence analysis to assess the effect of individual studies on the summary estimates (4041).

We used the Egger test (42) and funnel plots to help assess the possibility of publication bias. We conducted all statistical analyses by using STATA software, version 9.2 (Stata, College Station, Texas).

Role of the Funding Source

The Department of Ambulatory Care and Community Medicine and the Institute of Social and Preventive Medicine of the University of Lausanne, Lausanne, Switzerland, funded this study. The funding source had no role in defining questions, abstracting data, synthesizing results, preparing the manuscript, or deciding to submit the manuscript for publication.

Study Selection

Of the 2109 reports identified, we excluded 2077 studies that were unrelated to the association between subclinical thyroid dysfunction and CHD or mortality and 20 after detailed evaluation. Figure 1 shows details of the study selection. When similar data were published twice (19, 62), we included the original article with the most definitive and extractable form (19). Twelve prospective studies met eligibility criteria. Ten studies were population-based studies and included 14 449 community-living adults without substantive comorbid conditions. Two were convenience samples of patients with specific diseases: cardiac patients (31) or patients with a history of stroke or hip replacement (32). Given the clinical heterogeneity between these 2 types of studies, we pooled the 10 population-based studies as the core of this analysis and examined the addition of the 2 convenience samples in subsidiary analyses. All 10 of the population-based studies examined subclinical hypothyroidism, and 5 also examined subclinical hyperthyroidism.

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Figure 1.
Study flow diagram.

TSH = thyroid-stimulating hormone.

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Description and Quality of Studies

Table 1 shows the study characteristics and the effect of subclinical hypothyroidism and hyperthyroidism on the risk for CHD and cardiovascular and total mortality. Participants were mostly middle-aged or older men and women. Follow-up ranged from 2 to 20 years. All studies used standard assays for thyroid function (63), with TSH cutoff values of 4.0 to 6.0 mU/L for subclinical hypothyroidism and 0.3 to 0.5 mU/L for subclinical hyperthyroidism. Only the 2 convenience samples of patients were specifically designed to evaluate associations between thyroid function and CHD or mortality (3132). Three studies repeated assessments of thyroid function before the end of the follow-up (15, 19, 31), and 7 excluded persons treated with thyroid hormone.

Table Jump PlaceholderTable 1.  Population-Based Studies of Subclinical Thyroid Dysfunction and Risk for CHD and Mortality*

Study quality was heterogeneous. Five studies reported formal adjudication procedures, and 8 adjudicated outcomes without knowledge of thyroid status (Appendix Table 1). If an article did not clearly mention 1 of these characteristics, we considered it not to have been done. When reported, 5% or fewer participants in most studies were lost to follow-up. Only 4 studies adjusted for most cardiovascular risk factors, and several studies adjusted for only a few confounding factors.

Table Jump PlaceholderAppendix Table 1.  Quality Assessment of Included Studies
Subclinical Hypothyroidism and CHD

Several studies suggested that subclinical hypothyroidism was associated with a small increased risk for CHD; only 1 of these (17) had statistically significant findings (Figure 2). In a random-effects model, the summary RR of CHD associated with subclinical hypothyroidism was 1.20 (CI, 0.97 to 1.49) for 2134 CHD events, with weak evidence of heterogeneity (P for heterogeneity = 0.14; I= 33.4%) (Table 2). Studies that adjusted for cardiovascular risk factors yielded similar results. The summary RR was 1.02 for the 5 studies that used formal adjudication procedures and 1.08 for the 8 studies that adjudicated outcomes without knowledge of thyroid status. The 3 studies (14, 16, 19) that met most of our quality criteria (Appendix Table 1)—all conducted in older adults—had point estimates less than or close to 1.0 (1.07 in the study by Cappola and colleagues [14]). In subgroup analysis by age, the summary RR was 1.51 for studies whose samples had mean age younger than 65 years and 1.05 for studies whose samples had a mean age 65 years or older. Compared with the overall random-effects model, these subgroup analyses had lower heterogeneity (P for heterogeneity = 0.32 to 0.42; I= 0.0% to 15.4%). Using other age cutoff levels revealed a similar pattern.

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Figure 2.
Forest plots for subclinical hypothyroidism.

The diamonds represent relative risks and the horizontal lines represent 95% CIs of the effect of subclinical hypothyroidism. CHD = coronary heart disease; CV = cardiovascular.

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Table Jump PlaceholderTable 2.  Stratified Analysis of the Association of Subclinical Hypothyroidism with Risk for CHD

Excluding 2 studies that did not report T4 measurement (with the possible inclusion of some participants with overt hypothyroidism), those that included thyroid hormone recipients, or those that included cardiovascular death instead of CHD as outcomes yielded similar results (data not shown). The RR of the pooled estimates from the 2 studies that gave data for a TSH cutoff value of 10.0 mU/L or higher was 1.69 (CI, 0.64 to 4.45). Because data specific to subclinical hypothyroidism were available only for a subgroup in the study by Vanderpump and colleagues (30), we did a sensitivity analysis including all participants that showed a pooled RR of 1.18 (CI, 0.96 to 1.46).

Subclinical Hypothyroidism and Total and Cardiovascular Mortality

Several studies demonstrated a pattern of increased risk for total or cardiovascular mortality associated with subclinical hypothyroidism (Figure 2). For 2822 deaths, the summary RR was 1.12 (CI, 0.99 to 1.26) for total mortality and 1.18 (CI, 0.98 to 1.42; P for heterogeneity >0.50 for both; I= 0%) for 1167 cardiovascular deaths. Most sensitivity analyses yielded similar results (Appendix Tables 2 and 3). For cardiovascular mortality, pooling studies in which the mean age of participants was less than 65 years yielded an RR of 1.50; the RR was 1.12 if participants were 65 years or older. However, this analysis should be considered with caution because of the small number of studies.

Table Jump PlaceholderAppendix Table 2.  Stratified Analysis of the Association of Subclinical Hypothyroidism with Risk for Total Mortality
Table Jump PlaceholderAppendix Table 3.  Stratified Analysis of the Association of Subclinical Hypothyroidism with Risk for Cardiovascular Mortality
Subclinical Hyperthyroidism and CHD

Several studies demonstrated a pattern of an increased risk for CHD associated with subclinical hyperthyroidism (Figure 3), with a summary RR of 1.21 (CI, 0.88 to 1.68; P for heterogeneity = 0.85; I= 0%) for 1392 CHD events. Most sensitivity analyses yielded similar results (Table 3), except for lower point estimates when 2 studies with adjustment for most cardiovascular risk factors (RR, 1.10) and 3 studies with formal adjudication procedures (RR, 1.06) were pooled. We found no differences by mean age.

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Figure 3.
Forest plots for subclinical hyperthyroidism.

The diamonds represent relative risks and the horizontal lines represent 95% CIs of the effect of subclinical hyperthyroidism. CHD = coronary heart disease; CV = cardiovascular.

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Table Jump PlaceholderTable 3.  Stratified Analysis of the Association of Subclinical Hyperthyroidism with Risk for CHD
Subclinical Hyperthyroidism and Total and Cardiovascular Mortality

The RR for total mortality was 1.12 (CI, 0.89 to 1.42) for 1993 deaths and 1.19 (CI, 0.81 to 1.76) for 913 cardiovascular deaths (P for heterogeneity >0.80 for both; I= 0%) (Figure 3). Most sensitivity analysis yielded similar results (Appendix Tables 4 and 5), except for an RR of 0.95 for cardiovascular mortality (when 2 studies adjusted for most cardiovascular risk factors were pooled) and 1.01 for 3 studies with formal adjudication procedures.

Table Jump PlaceholderAppendix Table 4.  Stratified Analysis of the Association of Subclinical Hyperthyroidism with Risk for Total Mortality
Table Jump PlaceholderAppendix Table 5.  Stratified Analysis of the Association of Subclinical Hyperthyroidism with Risk for Cardiovascular Mortality
Additional Studies Not Included in the Primary Analyses

For both subclinical hypothyroidism and hyperthyroidism, addition of the convenience samples of patients with specific diseases (3132) increased the point estimates for CHD and mortality (summary RRs, 1.18 to 1.55 [Tables 2 and 3; Appendix Tables 2, 3, 4, and 5]). These summary RRs reached or were close to statistical significance but had increased statistical heterogeneity for all associations.

Publication Bias Evaluation

We found no evidence of publication bias, either with visual assessment of funnel plots (data not shown) or with the Egger test (P >0.30 for all associations). Because small negative studies are most subject to publication bias and some might be missing, we excluded studies with fewer than 500 participants and obtained similar estimates for all associations. Influence analysis indicated that the exclusion of single studies did not substantially alter any estimates (data not shown).

In the meta-analysis of 10 population-based prospective cohort studies, we found that subclinical thyroid dysfunction was associated with a pattern of modest increased risk for CHD and mortality (summary RRs, 1.12 to 1.21). Estimates about subclinical hyperthyroidism, which were derived from only 5 studies, had wider CIs than estimates for subclinical hypothyroidism. In general, we found lower risk estimates (RR, 1.01 to 1.21), when we pooled higher-quality studies, such as those that used formal adjudication procedures for outcomes although the upper bound of the CIs for these estimates was still consistent with overall summary RRs of increased risk. The relationship between subclinical hypothyroidism and CHD seemed to differ among studies that involved middle-aged versus elderly participants, with studies whose samples had a mean age younger than 65 years showing increased risk for CHD. Subclinical hypothyroid participants with a TSH 10.0 mU/L or greater might also have an increased CHD risk, but only 2 studies reported such stratified data. Risk estimates were higher when the 2 convenience samples of patients with specific diseases were added.

For the association between subclinical hypothyroidism and CHD, several population-based studies yielded conflicting results. Two individual prospective studies found a statistically significant association between subclinical hypothyroidism and CHD: the Busselton Health Study (HR, 1.8) (17) and a sample of cardiac patients (HR, 2.58) (31). However, 2 large prospective cohort studies of older adults found no increased risk for CHD (14, 16). These 2 studies adjusted their results for most cardiovascular risk factors and met most of our quality criteria, whereas the 2 studies with substantial associations (17, 31) did not formally adjudicate cardiovascular outcomes or report whether adjudication was done without knowledge of thyroid status. A meta-analysis pooled only 3 recent studies (14, 1617) and obtained a summary RR of 1.19 (CI, 1.02 to 1.38) (64), driven in part by the use of the unadjusted RR of 2.5 from the Busselton Health Study (adjusted HR, 1.8) (65). In our previous meta-analysis (18), we found a statistically significant association between subclinical hypothyroidism and CHD (summary odds ratio, 1.65 [CI, 1.28 to 2.12]), but that analysis included 3 case–control and 6 cross-sectional studies. When our previous meta-analysis of subclinical hypothyroidism and CHD was limited to the 5 older prospective cohort studies (12, 15, 20, 25, 30) that were of lower quality than the more recent ones, the summary RR was 1.42 (CI, 0.91 to 2.21).

Our analyses showed a pattern of higher mortality rates in participants with subclinical hypothyroidism, consistent with 2 previous meta-analyses that found slightly higher risks (summary RRs, 1.25 and 1.21 [66] and 1.12 and 1.28 [64] for total and cardiovascular mortality, respectively). However, these older meta-analyses included only 4 studies with mortality outcomes (14, 1617, 20) and had some limitations, such as data extraction errors (6465) and lack of assessment of statistical heterogeneity or sensitivity analyses (66). Our results might not apply to all ages, because 1 study found an even lower risk for total mortality (HR, 0.55) in adults age 85 years with subclinical hypothyroidism than in euthyroid participants (19).

Similar to a previous meta-analysis (66), we found a pattern of modestly increased risk for CHD and mortality associated with subclinical hyperthyroidism, with wider CIs than those for subclinical hypothyroidism, given the more limited data, and lower risk estimates when higher-quality studies were pooled. Further large studies are needed to better assess these risks. The higher risks found in the 2 convenience samples of patients with specific diseases, particularly for subclinical hyperthyroidism, increase the likelihood that subclinical thyroid dysfunction associated with other diseases might be a different, potentially more harmful entity than subclinical thyroid dysfunction among healthier individuals or that sick patients might be less tolerant to abnormal levels of TSH. We previously found that associations between subclinical hypothyroidism and heart failure were stronger for recurrent than for incident events (16). However, these differences are based on only 2 prospective cohorts of patients with specific diseases and should be confirmed in other studies.

We found weak evidence for statistical heterogeneity among individual study findings, and age explained part of the heterogeneity for the association between subclinical hypothyroidism and CHD, with an increased risk for CHD only in cohorts with a younger mean age. These potential age differences should be interpreted with caution, given the possibility of ecological fallacy without individual patient data (28). One cross-sectional study did subgroup analyses by age and found that the risk for CHD associated with subclinical hypothyroidism was higher in younger participants (67); however, no prospective study presented stratified analyses by age. Although this finding should be confirmed by stratified analyses in future prospective cohort studies with a wide age range, potential explanations for these age differences might be competing mortality among older adults (for example, due to cancer) or more competing risk factors for CHD among older adults (for example, age or sex). If the risk for CHD with subclinical hypothyroidism was mainly mediated by increased cholesterol levels, it might weaken with age because levels of total and low-density lipoprotein cholesterol are strong cardiovascular risk factors in middle-age but not older adults (68). Other potential explanations could be related to thyroid physiology in older adults (decreased thyroid hormone action at the tissue level, decreased thyroid hormone metabolism) (39). High TSH levels in elderly persons might also be a compensatory mechanism for other perturbations, whereas in younger adults it is caused by thyroid dysfunction.

Our study has several limitations. First, a meta-analysis of observational studies should be interpreted with caution (69), even though it can provide useful information when only data from observational studies are available (21). To our knowledge, no randomized, controlled trial has studied the benefits of treating adults with subclinical thyroid dysfunction with regard to CHD or mortality (5,8). We found only weak evidence for statistical heterogeneity among studies, but some clinical heterogeneity with slightly different TSH cutoff levels (4.0 to 6.0 mU/L for subclinical hypothyroidism and 0.3 to 0.5 mU/L for subclinical hyperthyroidism), varying CHD definitions, or different confounding factors included for adjustment. We could not assess the risk for specific CHD outcomes, such as MI or “hard” CHD (MI, coronary death) outcomes, because such subgroup analysis was lacking in most original studies. However, sensitivity analyses pooling more homogeneous studies yielded similar risk estimates, although such estimates were lower when higher-quality studies were pooled. Alternative explanations for observed results are bias in the selection of included studies, bias and quality problems in the original studies, publication bias, heterogeneity, and confounding (21).

To limit bias in the selection of included studies, we used broad inclusion criteria for studies that provided quantitative data on the risk for CHD or mortality associated with subclinical thyroid dysfunction and then did sensitivity analyses according to differences between the studies and methodological study quality, as recommended (21, 70). We could not exclude all participants with inadequately treated overt thyroid dysfunction or nonthyroidal illness (71) because these subgroup data were lacking in the original studies. Subgroup analyses should be interpreted with caution given the limited number of studies. Although our graphical and statistical analyses showed that publication bias was unlikely, it cannot be excluded because the capacity to detect publication bias is reduced when meta-analyses are based on a limited number of studies (42, 72). Selective reporting of the outcomes in the cohorts cannot be excluded, either.

In summary, our data suggest that subclinical thyroid dysfunction might represent a potentially modifiable—albeit modest—risk factor for CHD and mortality. Assuming that treatment is effective, given the high prevalence of thyroid disease even a small increase in CHD or mortality rates among persons with subclinical dysfunction (such as the 10% to 20% increased RR in our study) would have public health implications. From a health policy perspective, it would be premature to recommend screening for thyroid dysfunction in the general population. Given the pattern of modestly increased risk for CHD and mortality associated with subclinical thyroid dysfunction, lower risk estimates in higher-quality studies, and the remaining uncertainty, treatment of subclinical thyroid dysfunction with CHD as an end point should be studied in randomized, placebo-controlled trials to assess the efficacy of T4 replacement or antithyroid medications before current recommendations are updated (1, 5).

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Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL. et al.  Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006; 295:1033-41. PubMed
 
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; 358:861-5. PubMed
 
Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB. et al.  Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005; 165:2460-6. PubMed
 
Walsh JP, Bremner AP, Bulsara MK, O'Leary P, Leedman PJ, Feddema P. et al.  Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med. 2005; 165:2467-72. PubMed
 
Rodondi N, Aujesky D, Vittinghoff E, Cornuz J, Bauer DC.  Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis. Am J Med. 2006; 119:541-51. PubMed
 
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; 292:2591-9. PubMed
 
Imaizumi M, Akahoshi M, Ichimaru S, Nakashima E, Hida A, Soda M. et al.  Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab. 2004; 89:3365-70. PubMed
 
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D. et al.  Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000; 283:2008-12. PubMed
 
Medline cohort study filter. Search filters; 2007. Filter designed by knowledge information specialists from British Medical Journal. Accessed athttp://www.clinicalevidence.com/ceweb/about/search_filters.jspon13 February 2008.
 
Haugen B.  When Isn't the TSH Normal and Why? Clinical Implications and Causes [Presented paper]. 12th Annual Meeting of the American Association of Clinical Endocrinologists, 14–18 May 2003, San Diego, California.
 
Lee S.  When Is the TSH Normal? New Criteria for Diagnosis and Management [Presented paper]. 12th Annual Meeting of the American Association of Clinical Endocrinologists, 14–18 May 2003, San Diego, California.
 
Aho K, Gordin A, Palosuo T, Punsar S, Valkeila E, Karvonen M. et al.  Thyroid autoimmunity and cardiovascular diseases. Eur Heart J. 1984; 5:43-6. PubMed
 
Bauer DC, Rodondi N, Stone KL, Hillier TA, Study of Osteoporotic Fractures Research Group: Universities of California (San Francisco), Pittsburgh, Minnesota (Minneapolis), Kaiser Permanente Center for Health Research, Portland.  Thyroid hormone use, hyperthyroidism and mortality in older women. Am J Med. 2007; 120:343-9. PubMed
 
Smith SC Jr, Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, et al. American College of Cardiology, American Heart Association Task Force on Practice Guidelines, Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty.  ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines)—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty). J Am Coll Cardiol. 2001; 37:2215-39. PubMed
 
Egger M, Davey Smith G, Altman DG.  Systematic Reviews in Health Care: Meta-analysis in Context. 2nd ed. London: BMJ; 2001.
 
Hulley SB, Cummings SR, Browner WS, Grady D, Hearst N, Newman TB.  Designing Clinical Research: An Epidemiologic Approach. Philadelphia: Lippincott Williams & Wilkins; 2001.
 
Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F. 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; 6:155-60. PubMed
 
Iervasi G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F. et al.  Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med. 2007; 167:1526-32. PubMed
 
Radácsi A, Kovács G, Bernard W, Feldkamp J, Horster FA, Szabolcs I.  Mortality rate of chronically ill geriatric patients with subnormal serum thyrotropin concentration: a 2-yr follow-up study. Endocrine. 2003; 21:133-6. PubMed
 
Ernst E, Resch KL.  Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med. 1993; 118:956-63. PubMed
 
Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M. et al.  Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. Am J Prev Med. 2007; 32:210-6. PubMed
 
Woolf B.  On estimating the relation between blood group and disease. Ann Hum Genet. 1955; 19:251-3. PubMed
 
DerSimonian R, Laird N.  Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88. PubMed
 
Petitti DB.  Approaches to heterogeneity in meta-analysis. Stat Med. 2001; 20:3625-33. PubMed
 
Higgins JP, Thompson SG, Deeks JJ, Altman DG.  Measuring inconsistency in meta-analyses. BMJ. 2003; 327:557-60. PubMed
 
Cooper DS.  Thyroid disease in the oldest old: the exception to the rule [Editorial]. JAMA. 2004; 292:2651-4. PubMed
 
Sazawal S, Black RE, Pneumonia Case Management Trials Group.  Effect of pneumonia case management on mortality in neonates, infants, and preschool children: a meta-analysis of community-based trials. Lancet Infect Dis. 2003; 3:547-56. PubMed
 
Tobias A.  Assessing the influence of a single study in meta-analysis. Stata Tech Bull. 1999; 47:15-17.
 
Egger M, Davey Smith G, Schneider M, Minder C.  Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629-34. PubMed
 
Goldman MB, Monson RR, Maloof F.  Cancer mortality in women with thyroid disease. Cancer Res. 1990; 50:2283-9. PubMed
 
van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW.  Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab. 2005; 90:6403-9. PubMed
 
Bossoni S, Cossi S, Marengoni A, De Martinis M, Calabrese P, Leonardi R. et al.  The negative role of subclinical thyrotoxicosis on the outcome of hospitalized geriatric patients. J Endocrinol Invest. 2002; 25:64-5. PubMed
 
Davis PJ, Davis FB.  Hyperthyroidism in patients over the age of 60 years. Clinical features in 85 patients. Medicine (Baltimore). 1974; 53:161-81. PubMed
 
Friberg L, Drvota V, Bjelak AH, Eggertsen G, Ahnve S.  Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction. Am J Med. 2001; 111:699-703. PubMed
 
Kaptein EM, Weiner JM, Robinson WJ, Wheeler WS, Nicoloff JT.  Relationship of altered thyroid hormone indices to survival in nonthyroidal illnesses. Clin Endocrinol (Oxf). 1982; 16:565-74. PubMed
 
Nyirenda MJ, Clark DN, Finlayson AR, Read J, Elders A, Bain M. et al.  Thyroid disease and increased cardiovascular risk. Thyroid. 2005; 15:718-24. PubMed
 
Peters A, Ehlers M, Blank B, Exler D, Falk C, Kohlmann T. et al.  Excess triiodothyronine as a risk factor of coronary events. Arch Intern Med. 2000; 160:1993-9. PubMed
 
Alevizaki M, Synetou M, Xynos K, Pappa T, Vemmos KN.  Low triiodothyronine: a strong predictor of outcome in acute stroke patients. Eur J Clin Invest. 2007; 37:651-7. PubMed
 
Enia G, Panuccio V, Cutrupi S, Pizzini P, Tripepi G, Mallamaci F. et al.  Subclinical hypothyroidism is linked to micro-inflammation and predicts death in continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant. 2007; 22:538-44. PubMed
 
Carrero JJ, Qureshi AR, Axelsson J, Yilmaz MI, Rehnmark S, Witt MR. et al.  Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med. 2007; 262:690-701. PubMed
 
Bastenie PA.  Hypothyroidism and coronary heart disease. Acta Cardiol. 1982; 37:365-73. PubMed
 
Kent S.  Hormones and heart disease. Geriatrics. 1979; 34:97-102. PubMed
 
Popovici D.  The thyroid and the cardio-vascular system. Major physiopathologic aspects with clinical and therapeutic implications. Endocrinologie. 1980; 18:293-4. PubMed
 
Osman F, Franklyn JA, Holder RL, Sheppard MC, Gammage MD.  Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study. J Am Coll Cardiol. 2007; 49:71-81. PubMed
 
Waterhouse DF, McLaughlin AM, Walsh CD, Sheehan F, O'Shea D.  An examination of the relationship between normal range thyrotropin and cardiovascular risk parameters: a study in healthy women. Thyroid. 2007; 17:243-8. PubMed
 
Bell RJ, Rivera-Woll L, Davison SL, Topliss DJ, Donath S, Davis SR.  Well-being, health-related quality of life and cardiovascular disease risk profile in women with subclinical thyroid disease - a community-based study. Clin Endocrinol (Oxf). 2007; 66:548-56. PubMed
 
Kaji H, Iida K, Takahashi Y, Okimura Y, Chihara K.  Hormone replacement therapy and vascular risk disorders in adult hypopituitarism. Endocr J. 2007; 54:239-45. PubMed
 
Flynn RW, Macdonald TM, Jung RT, Morris AD, Leese GP.  Mortality and vascular outcomes in patients treated for thyroid dysfunction. J Clin Endocrinol Metab. 2006; 91:2159-64. PubMed
 
Singer RB.  Mortality in a complete 4-year follow up of 85-year-old residents of Leiden, classified by serum level of thyrotropin and thyroxine. J Insur Med. 2006; 38:14-9. PubMed
 
Demers LM, Spencer CA.  Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease. Laboratory Medicine Practice Guidelines. Washington, DC: National Academy of Clinical Biochemistry; 2002. Accessed athttp://www.aacc.orgon 13 February 2008.
 
Singh S, Duggal J, Molnar J, Maldonado F, Barsano CP, Arora R.  Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality: a meta-analysis. Int J Cardiol. 2008; 125:41-8. PubMed
 
Rodondi N, Newman AB, Cappola AR, Bauer DC.  Association between subclinical hypothyroidism and coronary heart disease in 2006. Int J Cardiol. 2007. PubMed
 
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; 92:2421-9. PubMed
 
Kvetny J, Heldgaard PE, Bladbjerg EM, Gram J.  Subclinical hypothyroidism is associated with a low-grade inflammation, increased triglyceride levels and predicts cardiovascular disease in males below 50 years. Clin Endocrinol (Oxf). 2004; 61:232-8. PubMed
 
Psaty BM, Anderson M, Kronmal RA, Tracy RP, Orchard T, Fried LP. et al.  The association between lipid levels and the risks of incident myocardial infarction, stroke, and total mortality: The Cardiovascular Health Study. J Am Geriatr Soc. 2004; 52:1639-47. PubMed
 
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Ross DS.  Serum thyroid-stimulating hormone measurement for assessment of thyroid function and disease. Endocrinol Metab Clin North Am. 2001; 30:245-64, vii. PubMed
 
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Hunt JR, White E.  Retaining and tracking cohort study members. Epidemiol Rev. 1998; 20:57-70. PubMed
 

Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

TSH = thyroid-stimulating hormone.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Forest plots for subclinical hypothyroidism.

The diamonds represent relative risks and the horizontal lines represent 95% CIs of the effect of subclinical hypothyroidism. CHD = coronary heart disease; CV = cardiovascular.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Forest plots for subclinical hyperthyroidism.

The diamonds represent relative risks and the horizontal lines represent 95% CIs of the effect of subclinical hyperthyroidism. CHD = coronary heart disease; CV = cardiovascular.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1.  Population-Based Studies of Subclinical Thyroid Dysfunction and Risk for CHD and Mortality*
Table Jump PlaceholderAppendix Table 1.  Quality Assessment of Included Studies
Table Jump PlaceholderTable 2.  Stratified Analysis of the Association of Subclinical Hypothyroidism with Risk for CHD
Table Jump PlaceholderAppendix Table 2.  Stratified Analysis of the Association of Subclinical Hypothyroidism with Risk for Total Mortality
Table Jump PlaceholderAppendix Table 3.  Stratified Analysis of the Association of Subclinical Hypothyroidism with Risk for Cardiovascular Mortality
Table Jump PlaceholderTable 3.  Stratified Analysis of the Association of Subclinical Hyperthyroidism with Risk for CHD
Table Jump PlaceholderAppendix Table 4.  Stratified Analysis of the Association of Subclinical Hyperthyroidism with Risk for Total Mortality
Table Jump PlaceholderAppendix Table 5.  Stratified Analysis of the Association of Subclinical Hyperthyroidism with Risk for Cardiovascular Mortality

References

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. PubMed
 
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
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Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC.  Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991; 34:77-83. PubMed
 
Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P.  The aging thyroid. Thyroid deficiency in the Framingham Study. Arch Intern Med. 1985; 145:1386-8. PubMed
 
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
 
Cooper DS.  Clinical practice. Subclinical hypothyroidism. N Engl J Med. 2001; 345:260-5. PubMed
 
Ladenson PW, Singer PA, Ain KB, Bagchi N, Bigos ST, Levy EG. et al.  American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med. 2000; 160:1573-5. PubMed
 
Villar H, Saconato H, Valente O, Atallah A.  Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007; (3) CD003419. PubMed
 
Althaus BU, Staub JJ, Ryff-De Lèche A, Oberhänsli A, Stähelin HB.  LDL/HDL-changes in subclinical hypothyroidism: possible risk factors for coronary heart disease. Clin Endocrinol (Oxf). 1988; 28:157-63. PubMed
 
Canaris GJ, Manowitz NR, Mayor G, Ridgway EC.  The Colorado thyroid disease prevalence study. Arch Intern Med. 2000; 160:526-34. PubMed
 
Kanaya AM, Harris F, Volpato S, Pérez-Stable EJ, Harris T, Bauer DC.  Association between thyroid dysfunction and total cholesterol level in an older biracial population: the health, aging and body composition study. Arch Intern Med. 2002; 162:773-9. PubMed
 
Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC.  Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med. 2000; 132:270-8. PubMed
 
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
 
Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL. et al.  Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006; 295:1033-41. PubMed
 
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; 358:861-5. PubMed
 
Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB. et al.  Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005; 165:2460-6. PubMed
 
Walsh JP, Bremner AP, Bulsara MK, O'Leary P, Leedman PJ, Feddema P. et al.  Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med. 2005; 165:2467-72. PubMed
 
Rodondi N, Aujesky D, Vittinghoff E, Cornuz J, Bauer DC.  Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis. Am J Med. 2006; 119:541-51. PubMed
 
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; 292:2591-9. PubMed
 
Imaizumi M, Akahoshi M, Ichimaru S, Nakashima E, Hida A, Soda M. et al.  Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab. 2004; 89:3365-70. PubMed
 
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D. et al.  Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000; 283:2008-12. PubMed
 
Medline cohort study filter. Search filters; 2007. Filter designed by knowledge information specialists from British Medical Journal. Accessed athttp://www.clinicalevidence.com/ceweb/about/search_filters.jspon13 February 2008.
 
Haugen B.  When Isn't the TSH Normal and Why? Clinical Implications and Causes [Presented paper]. 12th Annual Meeting of the American Association of Clinical Endocrinologists, 14–18 May 2003, San Diego, California.
 
Lee S.  When Is the TSH Normal? New Criteria for Diagnosis and Management [Presented paper]. 12th Annual Meeting of the American Association of Clinical Endocrinologists, 14–18 May 2003, San Diego, California.
 
Aho K, Gordin A, Palosuo T, Punsar S, Valkeila E, Karvonen M. et al.  Thyroid autoimmunity and cardiovascular diseases. Eur Heart J. 1984; 5:43-6. PubMed
 
Bauer DC, Rodondi N, Stone KL, Hillier TA, Study of Osteoporotic Fractures Research Group: Universities of California (San Francisco), Pittsburgh, Minnesota (Minneapolis), Kaiser Permanente Center for Health Research, Portland.  Thyroid hormone use, hyperthyroidism and mortality in older women. Am J Med. 2007; 120:343-9. PubMed
 
Smith SC Jr, Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, et al. American College of Cardiology, American Heart Association Task Force on Practice Guidelines, Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty.  ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines)—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty). J Am Coll Cardiol. 2001; 37:2215-39. PubMed
 
Egger M, Davey Smith G, Altman DG.  Systematic Reviews in Health Care: Meta-analysis in Context. 2nd ed. London: BMJ; 2001.
 
Hulley SB, Cummings SR, Browner WS, Grady D, Hearst N, Newman TB.  Designing Clinical Research: An Epidemiologic Approach. Philadelphia: Lippincott Williams & Wilkins; 2001.
 
Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F. 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; 6:155-60. PubMed
 
Iervasi G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F. et al.  Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med. 2007; 167:1526-32. PubMed
 
Radácsi A, Kovács G, Bernard W, Feldkamp J, Horster FA, Szabolcs I.  Mortality rate of chronically ill geriatric patients with subnormal serum thyrotropin concentration: a 2-yr follow-up study. Endocrine. 2003; 21:133-6. PubMed
 
Ernst E, Resch KL.  Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med. 1993; 118:956-63. PubMed
 
Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M. et al.  Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. Am J Prev Med. 2007; 32:210-6. PubMed
 
Woolf B.  On estimating the relation between blood group and disease. Ann Hum Genet. 1955; 19:251-3. PubMed
 
DerSimonian R, Laird N.  Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88. PubMed
 
Petitti DB.  Approaches to heterogeneity in meta-analysis. Stat Med. 2001; 20:3625-33. PubMed
 
Higgins JP, Thompson SG, Deeks JJ, Altman DG.  Measuring inconsistency in meta-analyses. BMJ. 2003; 327:557-60. PubMed
 
Cooper DS.  Thyroid disease in the oldest old: the exception to the rule [Editorial]. JAMA. 2004; 292:2651-4. PubMed
 
Sazawal S, Black RE, Pneumonia Case Management Trials Group.  Effect of pneumonia case management on mortality in neonates, infants, and preschool children: a meta-analysis of community-based trials. Lancet Infect Dis. 2003; 3:547-56. PubMed
 
Tobias A.  Assessing the influence of a single study in meta-analysis. Stata Tech Bull. 1999; 47:15-17.
 
Egger M, Davey Smith G, Schneider M, Minder C.  Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629-34. PubMed
 
Goldman MB, Monson RR, Maloof F.  Cancer mortality in women with thyroid disease. Cancer Res. 1990; 50:2283-9. PubMed
 
van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW.  Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab. 2005; 90:6403-9. PubMed
 
Bossoni S, Cossi S, Marengoni A, De Martinis M, Calabrese P, Leonardi R. et al.  The negative role of subclinical thyrotoxicosis on the outcome of hospitalized geriatric patients. J Endocrinol Invest. 2002; 25:64-5. PubMed
 
Davis PJ, Davis FB.  Hyperthyroidism in patients over the age of 60 years. Clinical features in 85 patients. Medicine (Baltimore). 1974; 53:161-81. PubMed
 
Friberg L, Drvota V, Bjelak AH, Eggertsen G, Ahnve S.  Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction. Am J Med. 2001; 111:699-703. PubMed
 
Kaptein EM, Weiner JM, Robinson WJ, Wheeler WS, Nicoloff JT.  Relationship of altered thyroid hormone indices to survival in nonthyroidal illnesses. Clin Endocrinol (Oxf). 1982; 16:565-74. PubMed
 
Nyirenda MJ, Clark DN, Finlayson AR, Read J, Elders A, Bain M. et al.  Thyroid disease and increased cardiovascular risk. Thyroid. 2005; 15:718-24. PubMed
 
Peters A, Ehlers M, Blank B, Exler D, Falk C, Kohlmann T. et al.  Excess triiodothyronine as a risk factor of coronary events. Arch Intern Med. 2000; 160:1993-9. PubMed
 
Alevizaki M, Synetou M, Xynos K, Pappa T, Vemmos KN.  Low triiodothyronine: a strong predictor of outcome in acute stroke patients. Eur J Clin Invest. 2007; 37:651-7. PubMed
 
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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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