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Figure.
Hazard Ratios (HRs) of Coronary Heart Disease (CHD) Mortality, a First-Time CHD Event, and a First-Time Hard CHD Event per 1-mIU/L Higher Thyrotropin Level at Baseline, Adjusted for Age, Sex, and Smoking at Baseline
Hazard Ratios (HRs) of Coronary Heart Disease (CHD) Mortality, a First-Time CHD Event, and a First-Time Hard CHD Event per 1-mIU/L Higher Thyrotropin Level at Baseline, Adjusted for Age, Sex, and Smoking at Baseline

The squares represent HRs from each cohort, and the lines represent 95% CIs. The diamonds represent pooled HRs (with 95% CIs) from random-effects (DerSimonian and Laird39 [D+L] Overall) and fixed-effect (inverse variance [I-V] Overall) meta-analysis. EPIC-Norfolk indicates European Prospective Investigation of Cancer–Norfolk; HUNT, Nord-Trøndelag Health Study; InCHIANTI, Invecchiare in Chianti; and PROSPER, Prospective Study of Pravastatin in the Elderly at Risk.

aWeights are from random-effects analysis.

Table 1.  
Characteristics of the 14 Cohorts
Characteristics of the 14 Cohorts
Table 2.  
HRs of CHD Outcomes per 1-mIU/L Higher Thyrotropin Level at Baseline, Overall, and by Sex and Agea
HRs of CHD Outcomes per 1-mIU/L Higher Thyrotropin Level at Baseline, Overall, and by Sex and Agea
Table 3.  
HRs of CHD Outcomes by Categories of Thyrotropin Levels at Baseline, Overall, and by Sex and Age at Baselinea
HRs of CHD Outcomes by Categories of Thyrotropin Levels at Baseline, Overall, and by Sex and Age at Baselinea
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Original Investigation
Less Is More
June 2015

Thyroid Function Within the Normal Range and Risk of Coronary Heart DiseaseAn Individual Participant Data Analysis of 14 Cohorts

Author Affiliations
  • 1Department of Public Health, Norwegian University of Science and Technology, Trondheim
  • 2Department of Endocrinology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
  • 3Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, Massachusetts
  • 4Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
  • 5Faculty of Medicine, University of Oslo, Oslo, Norway
  • 6Department of Medicine, University of California, San Francisco
  • 7Department of Epidemiology and Biostatistics, University of California, San Francisco
  • 8School of Population Health, The University of Western Australia, Crawley
  • 9Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia
  • 10Department of Clinical and Experimental Medicine, Geriatric Endocrine Unit, University Hospital of Parma, Parma, Italy
  • 11Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
  • 12National Institute on Aging, Baltimore, Maryland
  • 13Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
  • 14School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, England
  • 15National Council Research Institute of Clinical Physiology/Tuscany Region G. Monasterio Foundation, Pisa, Italy
  • 16Department of Clinical Studies, Radiation Effects Research Foundation, Nagasaki, Japan
  • 17Department of Epidemiology and Public Health, University College Cork, Cork, Ireland
  • 18Department of Public Health and Primary Care, University of Cambridge, Cambridge, England
  • 19Division of Endocrinology, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil
  • 20Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 21Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
  • 22Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle
  • 23Group Health Research Institute, Group Health Cooperative, Seattle, Washington
  • 24Department of Endocrinology, Gateshead Health Foundation National Health Service Trust, Gateshead, England
  • 25Division of Endocrinology, Faculdade de Medicina de Marília, Marília, Brazil
  • 26Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland
  • 27Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
  • 28Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
  • 29Department of Endocrinology, Royal Free Hospital, London, England
  • 30Institute for Community Medicine, Study of Health in Pomerania/Clinical-Epidemiological Research and German Centre of Cardiovascular Research, University of Greifswald, Greifswald, Germany
  • 31Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia
  • 32School of Medicine and Pharmacology, The University of Western Australia, Crawley
  • 33Netherlands Consortium for Healthy Aging, Leiden, the Netherlands
  • 34Department of Public Health, University of Copenhagen, Copenhagen, Denmark
  • 35Department of General Internal Medicine, Inselspital, University of Bern, Bern, Switzerland
JAMA Intern Med. 2015;175(6):1037-1047. doi:10.1001/jamainternmed.2015.0930
Abstract

Importance  Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD).

Objective  To assess the association between differences in thyroid function within the reference range and CHD risk.

Design, Setting, and Participants  Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55 412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline.

Exposures  Thyroid function as expressed by serum thyrotropin levels at baseline.

Main Outcomes and Measures  Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status.

Results  Among 55 412 individuals, 1813 people (3.3%) died of CHD during 643 183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48 875 individuals (9.5%) experienced a first-time CHD event during 533 408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results.

Conclusions and Relevance  Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.

Introduction

Hypothyroidism has been associated with atherosclerosis,1 and evidence from large observational studies suggests that individuals with hypothyroidism may be at increased risk of coronary heart disease (CHD) events and CHD mortality.2 Among people with apparently normal thyroid function, thyrotropin levels in the upper part of the reference range may indicate an early stage of hypothyroidism.36 In addition, such thyrotropin levels have been associated with an adverse cardiovascular risk profile that includes high levels of non–high-density lipoprotein cholesterol, triglycerides, blood pressure, and body mass index, as well as low levels of high-density lipoprotein cholesterol.711 Therefore, it seems plausible that differences in thyroid function within the population reference range may be differentially associated with CHD risk. In support of this hypothesis, the results of one cohort study suggested that thyrotropin levels within the reference range may be positively associated with CHD mortality in women, but not in men.12,13 In contrast, the results of other studies do not suggest any association between thyrotropin levels within the reference range and the risk of CHD events,14 vascular mortality,15 or need for coronary revascularization.16

The definition of the clinically normal range for thyroid function is controversial. Some experts have suggested that the upper thyrotropin reference limit should be lowered from approximately 4.5 to 2.5 or 3.0 mIU/L since higher thyrotropin levels may indicate early-stage hypothyroidism.17 Others disagree,1821 because many people with a healthy thyroid gland would thereby be classified with abnormal thyroid function, and there is no firm evidence that thyrotropin levels in the upper part of the reference range are associated with health consequences that would benefit from early recognition and treatment of hypothyroidism. Most research on such potential consequences has focused on CHD and its risk factors,11 and a recent review concluded that there was good evidence for associations between higher thyrotropin levels within the reference range and cardiovascular risk factors and events.11 However, most of this evidence comes from cross-sectional studies, which are inferior to prospective studies for causal inference. To clarify whether people with thyrotropin levels in the upper part of the reference range may be at increased risk of CHD, we performed a meta-analysis of individual participant data in 14 cohort studies included in the Thyroid Studies Collaboration consortium.2,22,23

Methods
Cohorts

The Thyroid Studies Collaboration consists of cohorts with thyroid function measurements at baseline and prospective follow-up of CHD outcomes. Its original purpose was to examine CHD risk among people with subclinical thyroid dysfunction, and suitable cohorts for that purpose were identified through systematic literature searches of the MEDLINE and EMBASE databases from January 1, 1950, to June 30, 2011, as previously described.2,22 Among 13 cohorts identified in the searches, 2 were excluded from the present study either because all participants had cardiovascular disease at baseline24 or owing to a lack of information on cardiovascular disease and smoking habits at baseline.15 Data from the remaining 11 cohorts1214,2534 were included, as well as from 3 additional cohorts3537 that have recently joined the collaboration. The individual cohort studies were approved by their appropriate ethics boards, and the present study was approved by the Central Norway Regional Committee for Medical and Health Research Ethics. Participants provided written or, in one cohort,29 oral informed consent. In some cohorts, participants received minor financial compensation to cover expenses related to participation.

Each cohort provided individual-level information on thyroid function measurements, cardiovascular risk factors, and history of thyroid and cardiovascular disease and diabetes mellitus, as well as prospectively recorded information on CHD outcomes during follow-up. From all cohorts, we included participants with thyrotropin levels within the reference range and with no previously known thyroid disease (or use of thyroid medication) or cardiovascular disease at baseline. As previously explained2,22 and based on expert reviews21,38 and a 2010 consensus meeting within our consortium, we applied a common thyrotropin reference range of 0.45 to 4.49 mIU/L for all cohorts except for the Whickham Survey.31,34 In that cohort, we used a reference range of 0.5 to 5.9 mIU/L because the first-generation thyrotropin assay used in that study yields consistently higher levels than measurements of current assays.2 Among 55 935 individuals who fulfilled the criteria for inclusion, we excluded 523 people (0.9%) without information on smoking habits or follow-up information, leaving a total of 55 412 participants for analysis.

We examined the risk of CHD mortality in all cohorts. In cohorts with information on both nonfatal and fatal CHD events, we also examined risks of a first-time CHD event (combined end point of CHD mortality, myocardial infarction, coronary artery revascularization, incident angina pectoris, or hospital diagnosis of CHD) and a first-time hard CHD event (combined end point of CHD mortality or myocardial infarction). Types of CHD event data available in each cohort are described in eTable 1 in the Supplement.

Statistical Analysis

For each cohort, we used separate Cox proportional hazard models to estimate the associations of thyrotropin levels with each CHD outcome. We then calculated pooled estimates across cohorts using random-effects models based on the variance model described by DerSimonian and Laird.39,40 Heterogeneity across cohorts was assessed by the I2 statistic, which describes the proportion of the total variation across studies attributable to heterogeneity rather than to chance. We adjusted for age (by using attained age as the time scale), sex, and smoking status41 (never, former, or current smokers or, in one cohort,29 ever- or never-smokers) at baseline as these characteristics may influence both thyroid function test results and CHD risk. We also analyzed women and men separately because in women, more often than in men, thyrotropin levels in the upper part of the reference range may indicate an early stage of hypothyroidism.3,4,6 Some evidence suggests that the association of hypothyroidism with CHD risk may be relatively stronger at younger ages2; therefore, we examined whether the associations differed by age at baseline (<65, 65-79, or ≥80 years). We analyzed thyrotropin both as a continuous variable and by categories, using equal width categories (0.45-1.49, 1.50-2.49, 2.50-3.49, and 3.50-4.49 mIU/L). For the Whickham Survey, analogous categories were considered to be 0.5 to 1.8, 1.9 to 3.2, 3.3 to 4.6, and 4.7 to 5.9 mIU/L. As reference, we used the lowest thyrotropin category, which is likely to have the lowest prevalence of preclinical autoimmune thyroid disease indicated by presence of thyroid peroxidase (TPO) antibodies.4

High thyrotropin levels may be more likely to indicate low thyroid function in people with TPO antibodies in serum.5,6 Among cohorts with TPO antibody measurements at baseline, we therefore estimated the risk of CHD by combinations of thyrotropin level (0.45-2.49 or 2.50-4.49 mIU/L) and TPO antibody status (positive or negative using study-specific cutoff points as reported in eTable 1 in the Supplement).

In addition, we examined risks of CHD outcomes by free thyroxine (FT4) levels at baseline, analyzing FT4 both as a continuous variable and by categories. Because the different FT4 assays are not standardized and yield different reference limits,42 we used quartile categories based on the quartile distributions within each cohort. As reference, we used the highest quartile, which suggests relatively high thyroid function. After observing an association between FT4 categories and CHD risk, we examined whether there was statistical evidence for a U-shaped association between FT4 and CHD risk as expressed by the P value for the squared value of FT4 levels.

We performed a set of sensitivity analyses to evaluate the robustness of the findings. First, because nonthyroidal illness may influence thyroid function test results,43 we repeated the analyses after excluding the first 2 years of follow-up to reduce the influence that preclinical CHD at baseline could have on the results. Second, we repeated the analyses with statistical adjustment for body mass index at baseline (expressed by restricted cubic spline) because adiposity, in addition to being a possible mediator between thyroid function and CHD,10 may be a common cause of high thyrotropin levels and CHD.44 Third, we excluded participants with diabetes mellitus at baseline since diabetes may be associated with thyroid dysfunction45,46 and silent CHD.47 Fourth, we restricted the analyses to never-smokers to avoid residual confounding from smoking.41 Fifth, in cohorts with information on use of thyroid medication during follow-up, we examined whether hazard ratios (HRs) for CHD outcomes changed after exclusion of participants who began therapy with thyroid medication during follow-up. Sixth, we restricted the analyses to the 11 cohorts that were identified through the systematic literature searches. Seventh, we repeated the analyses after excluding the Study of Health in Pomerania cohort, which was formerly iodine deficient and had a substantially different study-specific reference range for thyrotropin (0.25-2.12 mIU/L).30 Eighth, we repeated the analyses after excluding the Whickham Survey31,34 (which started follow-up in the 1970s) and the Leiden 85-Plus Study27 (which only included participants aged 85 years). Ninth, we repeated the analysis of FT4 and CHD risk after excluding participants with FT4 levels outside the study-specific reference ranges reported in eTable 1 in the Supplement. Because thyroid function could influence the risk of CHD through thyroid hormone effects on blood pressure and cholesterol levels,1 whenever associations with CHD outcomes were observed, we examined whether the HRs were altered by statistical adjustment for systolic blood pressure and total serum cholesterol levels at baseline. All analyses were performed using Stata, version 13.1 for Windows (StataCorp LP).

Results

Characteristics of the 14 cohorts are given in Table 1 and eTable 1 in the Supplement. Baseline characteristics by thyrotropin category are given in eTable 2 in the Supplement. Among 55 412 individuals, 1813 people (3.3%) died of CHD during 643 183 person-years of follow-up. In one cohort of 763 individuals,33 only 5 CHD deaths occurred; this cohort was excluded from further analyses. There was no association between thyrotropin levels and risk of CHD mortality. For each 1-mIU/L higher thyrotropin level at baseline, the HR for CHD mortality was 0.97 (95% CI, 0.90-1.04), with little heterogeneity across studies (I2, 36%) (Figure). The association did not differ by sex or age (Table 2).

Ten cohorts had information on both fatal and nonfatal CHD events. Among 48 875 individuals in these cohorts, 4666 people (9.5%) experienced a first-time CHD event during 533 408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level at baseline, the HR for a first-time CHD event was 1.00 (95% CI, 0.97-1.03). The association was homogeneous across studies (I2, 0%) (Figure) and did not differ by sex or age (Table 2).

In 7 cohorts, the risk of hard CHD events (CHD mortality or myocardial infarction) could be examined, and 2488 (7.3%) of 34 256 individuals in these cohorts experienced a first-time hard CHD event during 356 400 person-years of follow-up. There was no association between thyrotropin levels and the risk of a first-time hard CHD event, and the HRs did not substantially differ from those of any CHD event (Table 2 and Figure).

The sensitivity analyses of thyrotropin levels and CHD risk yielded results similar to the main analysis (eTable 3 in the Supplement). We also examined CHD risk by categories of thyrotropin at baseline but found no associations with risk of CHD mortality or CHD events (Table 3).

Among cohorts with TPO antibody measurement at baseline, we examined the combined association of thyrotropin level and TPO antibody status with the risk of CHD mortality (4 cohorts), a first-time CHD event (3 cohorts), and a first-time hard CHD event (2 cohorts). There was no evidence that high (2.50-4.49 mIU/L) thyrotropin levels combined with TPO antibodies were associated with increased CHD risk compared with low (0.45-2.49 mIU/L) thyrotropin levels and no TPO antibodies (eTable 4 in the Supplement).

In addition, we examined associations of FT4 levels at baseline with risk of CHD. We observed no linear associations of FT4 levels with risk of CHD mortality (9 cohorts) or a first-time CHD event (6 cohorts) (eFigure in the Supplement), and the associations did not convincingly differ by sex or age (eTable 5 in the Supplement). In analyses by FT4 categories, the risk of CHD mortality and CHD events did not substantially differ between participants with low (lowest quartile) and high (highest quartile) FT4 levels (eTable 6 in the Supplement). However, the results suggested a U-shaped association between FT4 level and CHD risk since participants with FT4 levels in the second quartile had lower risks of CHD mortality (HR, 0.76 [95% CI, 0.57-0.99]) and CHD events (HR, 0.73 [95% CI, 0.58-0.94]) compared with participants with high (highest quartile) FT4 levels. Nonetheless, the P value for squared FT4 levels did not show statistically significant evidence of a U-shaped association of FT4 level with CHD risk (P = .48 for CHD mortality and P = .22 for CHD events). Associations between FT4 level and risk of hard CHD events could be examined only in 4 cohorts of elderly participants, but estimates were similar to those of any CHD event (eTable 5, eTable 6, and eFigure in the Supplement).

Sensitivity analyses of FT4 levels and CHD risk yielded results similar to the main analysis (eTable 7 and eTable 8 in the Supplement), except that when the analysis was restricted to participants with FT4 levels within the reference range, there was statistically significant evidence to suggest a U-shaped association between FT4 and risk of CHD events (squared value of FT4 levels, P = .02). The association of FT4 categories with CHD risk remained essentially unchanged after adjustment for baseline levels of systolic blood pressure and total serum cholesterol levels (eTable 8 in the Supplement).

Discussion

In this individual participant data analysis of 55 412 people from 14 cohorts, differences in thyrotropin levels within the reference range were not associated with risk of CHD mortality or CHD events.

Associations between thyrotropin levels within the reference range and risk of CHD have been examined in a few cohort studies,1216 2 of which are included in the present individual participant data analysis.1214 In one of these cohorts, each 1-mIU/L higher thyrotropin level at baseline was associated with a 37% higher risk of CHD mortality in women,12 but there was no corresponding association in men and no association of thyrotropin with risk of hospitalization for myocardial infarction.12,13 In other cohorts, there were no associations of thyrotropin levels with risk of CHD events,14 vascular mortality,15 or coronary revascularizations.16

Compared with the previous cohort studies, a major strength of this individual participant data analysis is the large sample size, which enabled more precise risk estimates for both fatal and total CHD events. The use of individual-level data enabled similar classification of exposures and covariates across cohorts. In cohorts in which medication was recorded during follow-up, few participants initiated therapy with thyroid medication, and risk estimates for CHD were similar after exclusion of these individuals. Therefore, use of thyroid medication is not likely to have substantially influenced our results. The results of this meta-analysis strongly suggest that differences in thyrotropin levels within the population reference range are not associated with the risk of CHD and that the previously reported association between thyrotropin levels within the reference range and CHD mortality12,13 is likely to be a chance finding. A limitation of the present study is that only one measurement of thyroid function at baseline was available, and we could not specifically examine the risk of CHD among people whose thyrotropin level remained in the upper part of the reference range over time. Also, few cohorts included measurement of TPO antibodies, so the risk of CHD among people with thyrotropin levels in the upper part of the reference range combined with the presence of TPO antibodies could not be estimated with high precision.

Of the different measures of thyroid function, we emphasized serum thyrotropin levels in this study for 2 reasons. First, thyrotropin levels in the upper part of the reference range are sometimes a marker of early-stage hypothyroidism, as indicated by an increased prevalence of autoimmune thyroid disease and risk of future hypothyroidism.36 Second, serum thyrotropin is considered to be the most sensitive marker for change in thyroid function since pituitary thyrotropin secretion responds to even slight changes in circulating thyroid hormone levels.49 The discrepancy in our data between thyrotropin showing no association but FT4 showing a possible U-shaped association with CHD risk was therefore unexpected. It has been suggested that serum thyrotropin, although a reflection of thyroid-pituitary feedback, may not reflect thyroid status in every organ.18,50 Under this assumption, FT4 levels that are sensed as appropriate by the pituitary gland could be inappropriate for the vascular system and lead to increased risk of CHD similar to that seen in hypothyroid2 or hyperthyroid22 individuals. However, there are several reasons to suspect that the association of FT4 levels with CHD risk in our data may not be causal. First, FT4 measurements may be affected by low albumin levels,51 which have been associated with increased CHD risk,52 and use of specific cardiovascular medications, such as aspirin, heparin, and furosemide.53,54 Second, the lack of robust statistical evidence, as expressed by Pvalues for the squared value of FT4 levels, suggests that the U-shaped association of FT4 levels with CHD risk may be a chance finding. Further study of the role of FT4 in disease risk among people with clinically normal thyroid function is needed.

Controversy surrounds the definition of the reference range for thyrotropin,1721 and it has been suggested that the upper reference limit should be lowered to 2.5 to 3.0 mIU/L.17 This approach would have a large effect on the number of people classified as having abnormal thyroid function. For example, approximately 8% to 14% of US adults without known thyroid disease would be reclassified as having abnormally high thyrotropin levels20 that might necessitate follow-up and suggest a need for levothyroxine therapy. Unnecessary levothyroxine therapy is undesirable since many patients receive excessive levothyroxine doses (as indicated by low thyrotropin levels)55,56 that may increase their risk of atrial fibrillation and osteoporosis.57 A large UK study56 of new levothyroxine users between 2001 and 2009, excluding those receiving levothyroxine in association with hyperthyroidism, pituitary disease, thyroid surgery, pregnancy, or use of thyroid-altering medication, reported an increase in the use of levothyroxine for borderline elevated thyrotropin levels, and approximately 6% had a thyrotropin level of less than 4.0 mIU/L at the initiation of levothyroxine therapy. This finding suggests that levothyroxine is being prescribed to many individuals in whom its clinical benefit is uncertain.

Knowledge about health hazards associated with thyrotropin in the upper part of the reference range is important to inform a lowering of the upper thyrotropin reference limit. Cardiovascular hazards have been suggested by cross-sectional studies711 that found positive associations of thyrotropin with adverse lipid levels and higher blood pressure and body mass index. However, recent longitudinal evidence suggests that associations are very weak, if any, between thyrotropin levels within the reference range and future levels of serum lipids, blood pressure, and body mass index.58,59 In line with those findings, the present study provides prospective evidence indicating that individuals with thyrotropin levels in the upper part of the reference range are not at increased risk of CHD. The present results are also consistent with a previous Thyroid Studies Collaboration2 analysis showing similar risk of CHD between people with mildly elevated serum thyrotropin levels (4.5-6.9 mIU/L) and people with thyrotropin within the reference range.

In this study, we examined associations between thyrotropin levels and future CHD among people without previously known cardiovascular disease. Our results do not inform whether thyrotropin levels measured after the clinical onset of cardiovascular disease may have prognostic value, as suggested by some evidence.60 In addition, we did not examine whether levels of thyroid function tests within the reference ranges may be differentially associated with all-cause mortality16,61,62 or the risk of non-CHD outcomes, such as atrial fibrillation,62,63 heart failure,62 fractures,64 dementia,62,65 chronic kidney disease66 or cancer mortality,61 as suggested in some prospective studies. However, except for a modestly increased risk of chronic kidney disease,66 these studies did not show increased disease risk among people with thyrotropin levels in the upper part of the reference range and thus do not provide evidence in support of lowering the upper thyrotropin reference limit.

Conclusions

In this individual participant data analysis of 55 412 individuals from 14 cohorts, thyrotropin levels in the upper part of the reference range were not associated with an increased risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased risk of CHD does not appear to be a reason for lowering the upper thyrotropin reference limit.

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Article Information

Accepted for Publication: February 23, 2015.

Corresponding Author: Bjørn O. Åsvold, MD, PhD, Department of Public Health, Norwegian University of Science and Technology, Postboks 8905 MTFS, N-7491 Trondheim, Norway (bjorn.o.asvold@ntnu.no).

Published Online: April 20, 2015. doi:10.1001/jamainternmed.2015.0930.

Author Contributions: Dr Åsvold had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Åsvold, Bjøro, Bauer, Ferrucci, Gussekloo, Maciel, Newman, Razvi, Westendorp, Rodondi.

Acquisition, analysis, or interpretation of data: Åsvold, Bjøro, Bremner, Cappola, Ceresini, den Elzen, Franco, Franklyn, Gussekloo, Iervasi, Imaizumi, Kearney, Khaw, Maciel, Peeters, Psaty, Razvi, Sgarbi, Stott, Trompet, Vanderpump, Völzke, Walsh, Westendorp, Rodondi.

Drafting of the manuscript: Åsvold.

Critical revision of the manuscript for important intellectual content: Vatten, Bjøro, Bauer, Bremner, Cappola, Ceresini, den Elzen, Ferrucci, Franco, Franklyn, Gussekloo, Iervasi, Imaizumi, Kearney, Khaw, Maciel, Newman, Peeters, Psaty, Razvi, Sgarbi, Stott, Trompet, Vanderpump, Völzke, Walsh, Westendorp, Rodondi.

Statistical analysis: Åsvold, Rodondi.

Obtained funding: Åsvold, Ferrucci, Khaw, Maciel, Newman, Sgarbi, Völzke, Walsh, Westendorp, Rodondi.

Administrative, technical, or material support: Bjøro, Ceresini, den Elzen, Ferrucci, Franco, Gussekloo, Khaw, Newman, Peeters, Psaty, Trompet, Völzke.

Study supervision: Vatten, Bjøro, Gussekloo, Stott, Westendorp, Rodondi.

Conflict of Interest Disclosures: Dr Peeters has received lecture and consultancy fees from Genzyme Europe. No other disclosures were reported.

Funding/Support: The Thyroid Studies Collaboration was supported by grants from the Swiss National Science Foundation (SNSF 320030-138267 and 320030-150025) and partially supported by a grant from the Swiss Heart Foundation (all to Dr Rodondi). Dr Åsvold is supported by the Research Council of Norway. The Whickham Survey was supported by the UK Department of Health. The Rotterdam Study is funded by Erasmus MC and Erasmus University, Rotterdam, the Netherlands; the Netherlands Organisation for Scientific Research; the Netherlands Organisation for the Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; the European Commission; and the Municipality of Rotterdam. Maryam Kavousi, MD, PhD (Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands), is supported by the AXA Research Fund. Maarten J. G. Leening, MD, MSc, and Bruno H. Stricker, MMed, PhD (both with Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands), are supported by a grant from the Netherlands Organisation for Health Research and Development (HTA grant 80.82500.98.10208). Dr Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc, and AXA. The Leiden 85-Plus Study was partly funded by the Dutch Ministry of Health, Welfare, and Sports. The Nagasaki Adult Health Study was supported by the Radiation Effects Research Foundation, Hiroshima and Nagasaki, Japan, a private, nonprofit foundation funded by the Japanese Ministry of Health, Labor, and Welfare and the US Department of Energy, the latter in part through the National Academy of Sciences. 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 research was supported in part by the Intramural Research Program of the NHNIA. Principal investigators and staff of the Health, Aging, and Body Composition Study are Anne B. Newman, MD, MPH, and Diane Ives, MPH, University of Pittsburgh; Suzanne Satterfield, MD, DrPH, and Jan Elam, BS, University of Tennessee, Memphis; Steven R. Cummings, MD, Michael C. Nevitt, PhD, and Susan M. Rubin, MPH, University of California, San Francisco; and Tamara B. Harris, MD, and Melissa E. Garcia, MPH, National Institute on Aging. The Cardiovascular Health Study (CHS) is supported by contracts HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 as well as grant 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 AG-032317 and AG-023629 from the NIA (see also https://chs-nhlbi.org/). 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. Data were provided by the HUNT Research Center, Statistics Norway, and the Department for Research and Development, Nord-Trøndelag Hospital Trust. The thyroid function testing in the HUNT Study was financially supported by Wallac Oy (Turku, Finland). The EPIC-Norfolk Study was supported by research grants from the Medical Research Council UK and Cancer Research UK. The Brazilian Thyroid Study was supported by an unrestricted grant from the São Paulo State Research Foundation (Fundacão de Amparo à Pesquisa do Estado de São Paulo grant 6/59737-9 to Dr Maciel). The Study of Health in Pomerania 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, and 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 955/12-1). The Prospective Study of Pravastatin in the Elderly at Risk study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Dr Jukema is an established clinical investigator of the Netherlands Heart Foundation (grant 2001 D 032). The Osteoporotic Fractures in Men Study is supported by National Institutes of Health (NIH) funding. The following institutes provide support: the NIA, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Advancing Translational Sciences, and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128.

Role of the Funder/Sponsor: The National Institute on Aging, which funded the Health, Aging, and Body Composition Study, and the Radiation Effects Research Foundation, which funded the Nagasaki Adult Health Study, reviewed and approved the manuscript. The other funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The Thyroid Studies Collaboration: Participating studies of the Thyroid Studies Collaboration include the following: United States: Health, Aging, and Body Composition Study, Cardiovascular Health Study, and Osteoporotic Fractures in Men (MrOS) Study. Europe: Whickham Survey, Rotterdam Study, Birmingham Study, Leiden 85-Plus Study, Pisa cohort, HUNT Study (Nord-Trøndelag Health Study), EPIC-Norfolk Study, Study of Health in Pomerania (SHIP), PROSPER trial, and InCHIANTI. Australia: Busselton Health Study. Asia: Nagasaki Adult Health Study. South America: Brazilian Thyroid Study. Members of the Executive Committee: Nicolas Rodondi, MD, MAS (Department of General Internal Medicine, Inselspital, University of Bern, Bern, Switzerland); Jacobijn Gussekloo, MD, PhD (Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands); Douglas C. Bauer, MD (Department of Medicine and Department of Epidemiology and Biostatistics, University of California, San Francisco); Anne R. Cappola, MD, ScM (Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia); and Robin P. Peeters, MD, PhD (Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus Medical Center, and Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands). Members of the Steering Committee: Bjørn O. Åsvold, MD, PhD (Department of Public Health, Norwegian University of Science and Technology, and Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway); John P. Walsh, MBBS, FRACP, PhD (Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, and School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia); Jayne A. Franklyn, MD, PhD, FRCP, FMedSci (School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, England); Giorgio Iervasi, MD (National Council Research Institute of Clinical Physiology/Tuscany Region G. Monasterio Foundation, Pisa, Italy); Misa Imaizumi, MD, PhD (Department of Clinical Studies, Radiation Effects Research Foundation, Nagasaki, Japan); Salman Razvi, MD, FRCP (Department of Endocrinology, Gateshead Health Foundation NHS Trust, Gateshead, England); Kay-Tee Khaw, MD (Department of Public Health and Primary Care, University of Cambridge, Cambridge, England); Henry Völzke, MD (Institute for Community Medicine, Study of Health in Pomerania/Clinical-Epidemiological Research and German Centre of Cardiovascular Research, University of Greifswald, Greifswald, Germany); José A. Sgarbi, MD (Division of Endocrinology, Department of Medicine, Federal University of São Paulo, São Paulo, and Division of Endocrinology, Faculdade de Medicina de Marília, Marília, Brazil); Rudi G. J. Westendorp, MD, PhD (Department of Cardiology, Leiden University Medical Center, and Netherlands Consortium for Healthy Aging, Leiden, the Netherlands, and Department of Public Health, University of Copenhagen, Copenhagen, Denmark); and Graziano Ceresini, MD, PhD (Department of Clinical and Experimental Medicine, Geriatric Endocrine Unit, University Hospital of Parma, Parma, Italy). Members of the Data Management Group: Wendy P. J. den Elzen, PhD (Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands); Tinh-Hai Collet, MD (Service of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, Lausanne, Switzerland, and University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom); Bruno da Costa, PhD (Berner Institut für Hausarztmedizin, University of Bern, Bern, Switzerland); Christine Baumgartner, MD (Department of General Internal Medicine, Inselspital, University of Bern, Bern, Switzerland); Manuel Raphael Blum, MD (Department of General Internal Medicine, Inselspital, University of Bern, Bern, Switzerland); and Hendrika Anette van Dorland, PD, DrSc (Department of General Internal Medicine, Inselspital, University of Bern, Bern, Switzerland).

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