Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis

Layal Chaker¹, Christine Baumgartner¹, Wendy P J den Elzen¹, Tinh-Hai Collet¹, M Arfan Ikram¹, Manuel R Blum¹, Abbas Dehghan¹, Christiane Drechsler¹, Robert N Luben¹, Marileen L P Portegies¹, Giorgio Iervasi¹, Marco Medici¹, David J Stott¹, Robin P Dullaart¹, Ian Ford¹, Alexandra Bremner¹, Anne B Newman¹, Christoph Wanner¹, José A Sgarbi¹, Marcus Dörr¹, W T Longstreth Jr¹, Bruce M Psaty¹, Luigi Ferrucci¹, Rui M B Maciel¹, Rudi G Westendorp¹, J Wouter Jukema¹, Graziano Ceresini¹, Misa Imaizumi¹, Albert Hofman¹, Stephan J L Bakker¹, Jayne A Franklyn¹, Kay-Tee Khaw¹, Douglas C Bauer¹, John P Walsh¹, Salman Razvi¹, Jacobijn Gussekloo¹, Henry Völzke¹, Oscar H Franco¹, Anne R Cappola¹, Nicolas Rodondi¹, Robin P Peeters¹; Thyroid Studies Collaboration¹

Affiliations

Affiliation

¹ Departments of Internal Medicine (R.P.P., L.C., M.M.) and Epidemiology (R.P.P., O.H.F., A.D., A.H., A.I., L.C., M.L.P.P.), Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands; Rotterdam Thyroid Center (R.P.P., L.C., M.M.) and Department of Radiology and Neurology (M.A.I.), Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands; Department of General Internal Medicine (N.R., C.B., M.R.B.), Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Service of Endocrinology, Diabetes, and Metabolism (T.-H.C.), University Hospital of Lausanne, 1011 Lausanne, Switzerland; Departments of Clinical Chemistry and Laboratory Medicine (W.P.J.d.E.), Public Health and Primary Care (J.G.), and Cardiology (W.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Departments of Medicine and Epidemiology and Biostatistics (D.C.B.), University of California, San Francisco, San Francisco, California 94143; Division of Endocrinology, Diabetes, and Metabolism (A.R.C.), Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; Department of Epidemiology (A.H.), Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115; Department of Endocrinology (S.R.), Gateshead Health Foundation National Health Service Trust, Gateshead, SE18 4QH, United Kingdom; Department of Endocrinology and Diabetes (J.P.W.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Schools of Medicine and Pharmacology (J.P.W.) and Population Health (A.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; National Council Research Institute of Clinical Physiology (G.I.), 56124 Pisa, Italy; Robertson Centre for Biostatistics (I.F.) and Institute of Cardiovascular and Medical Sciences (D.J.S.), Faculty of Medicine, University of Glasgow, Glasgow G12 8TA, United Kingdom; Department of Epidemiology (A.B.N.), University of Pittsburgh, Pittsburgh, Pennsylvania 15260; Department of Internal Medicine (S.J.L.B., R.P.D.), University Medical Center, University of Groningen, 9700 AB Groningen, The Netherlands; Department of Medicine (C.W., C.D.), Division of Nephrology, University Hospital of Würzburg, and Comprehensive Heart Failure Centre (C.W., C.D.), 97070 Würzburg, Germany; Department of Clinical Studies (M.I.), Radiation Effects Research Foundation, Nagasaki 850-8555, Japan; Department of Clinical and Experimental Medicine (G.C.), University of Parma, 143100 Parma, Italy; National Institute on Aging (L.F.), Baltimore, Maryland 21225; Institute for Community Medicine (H.V.), Clinical-Epidemiological Research/Study of Health in Pomerania, University Medicine, German Centre of Cardiovascular Research, Partner Site, Department of Internal Medicine (M.D.), and University Medicine (M.D.), German Centre of Cardiovascular Research, Partner Site, 17487 Greifswald, Germany; Departments of Neurology and Epidemiology (W.T.L.), and Cardiovascular Health Research Unit (W.T.L.), Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington 98108; Group Health Research Institute (B.M.P.), Group Health Cooperative, Seattle, Washington 98101; Division of Endocrinology (R.M.B.M., J.A.S.), Department of Medicine, Federal University of Sao Paulo, 05508-900 São Paulo, Brazil; Division of Endocrinology (J.A.S.), Faculdade de Medicina de Marília, Marília, Brazil; Department of Public Health and Primary Care (R.N.L., K.-T.K.), University of Cambridge, Cambridge CB2 1TN, United Kingdom; Interuniversity Cardiology Institute of The Netherlands (W.J.), 3508 GA Utrecht, The Netherlands; School of Clinical and Experimental Medicine (J.A.F.), College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and Department of Public Health and Center for Healthy Ageing (R.G.W.), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2400 Copenhagen, Denmark.

PMID: 27603906
PMCID: PMC5095234
DOI: 10.1210/jc.2016-2255

Meta-Analysis

Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis

Layal Chaker et al. J Clin Endocrinol Metab. 2016 Nov.

. 2016 Nov;101(11):4270-4282.

doi: 10.1210/jc.2016-2255. Epub 2016 Sep 7.

Authors

Affiliation

¹ Departments of Internal Medicine (R.P.P., L.C., M.M.) and Epidemiology (R.P.P., O.H.F., A.D., A.H., A.I., L.C., M.L.P.P.), Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands; Rotterdam Thyroid Center (R.P.P., L.C., M.M.) and Department of Radiology and Neurology (M.A.I.), Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands; Department of General Internal Medicine (N.R., C.B., M.R.B.), Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Service of Endocrinology, Diabetes, and Metabolism (T.-H.C.), University Hospital of Lausanne, 1011 Lausanne, Switzerland; Departments of Clinical Chemistry and Laboratory Medicine (W.P.J.d.E.), Public Health and Primary Care (J.G.), and Cardiology (W.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Departments of Medicine and Epidemiology and Biostatistics (D.C.B.), University of California, San Francisco, San Francisco, California 94143; Division of Endocrinology, Diabetes, and Metabolism (A.R.C.), Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; Department of Epidemiology (A.H.), Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115; Department of Endocrinology (S.R.), Gateshead Health Foundation National Health Service Trust, Gateshead, SE18 4QH, United Kingdom; Department of Endocrinology and Diabetes (J.P.W.), Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia; Schools of Medicine and Pharmacology (J.P.W.) and Population Health (A.B.), University of Western Australia, Crawley, Western Australia 6009, Australia; National Council Research Institute of Clinical Physiology (G.I.), 56124 Pisa, Italy; Robertson Centre for Biostatistics (I.F.) and Institute of Cardiovascular and Medical Sciences (D.J.S.), Faculty of Medicine, University of Glasgow, Glasgow G12 8TA, United Kingdom; Department of Epidemiology (A.B.N.), University of Pittsburgh, Pittsburgh, Pennsylvania 15260; Department of Internal Medicine (S.J.L.B., R.P.D.), University Medical Center, University of Groningen, 9700 AB Groningen, The Netherlands; Department of Medicine (C.W., C.D.), Division of Nephrology, University Hospital of Würzburg, and Comprehensive Heart Failure Centre (C.W., C.D.), 97070 Würzburg, Germany; Department of Clinical Studies (M.I.), Radiation Effects Research Foundation, Nagasaki 850-8555, Japan; Department of Clinical and Experimental Medicine (G.C.), University of Parma, 143100 Parma, Italy; National Institute on Aging (L.F.), Baltimore, Maryland 21225; Institute for Community Medicine (H.V.), Clinical-Epidemiological Research/Study of Health in Pomerania, University Medicine, German Centre of Cardiovascular Research, Partner Site, Department of Internal Medicine (M.D.), and University Medicine (M.D.), German Centre of Cardiovascular Research, Partner Site, 17487 Greifswald, Germany; Departments of Neurology and Epidemiology (W.T.L.), and Cardiovascular Health Research Unit (W.T.L.), Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington 98108; Group Health Research Institute (B.M.P.), Group Health Cooperative, Seattle, Washington 98101; Division of Endocrinology (R.M.B.M., J.A.S.), Department of Medicine, Federal University of Sao Paulo, 05508-900 São Paulo, Brazil; Division of Endocrinology (J.A.S.), Faculdade de Medicina de Marília, Marília, Brazil; Department of Public Health and Primary Care (R.N.L., K.-T.K.), University of Cambridge, Cambridge CB2 1TN, United Kingdom; Interuniversity Cardiology Institute of The Netherlands (W.J.), 3508 GA Utrecht, The Netherlands; School of Clinical and Experimental Medicine (J.A.F.), College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and Department of Public Health and Center for Healthy Ageing (R.G.W.), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2400 Copenhagen, Denmark.

PMID: 27603906
PMCID: PMC5095234
DOI: 10.1210/jc.2016-2255

Abstract

Context: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously.

Design and setting: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T₄, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L.

Results: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T₄ analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes.

Conclusion: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.

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Figures

**Figure 1.**
The association between TSH and risk of all stroke (A) and fatal stroke (B). HRs and their 95% CIs are represented by squares and are across the range of TSH (0.45 and 4.49 mIU/L). Sizes of data markers are proportional to the inverse of the variance of the HRs. Data for all stroke were available in 12 studies. Three hundred ninety-three participants were excluded from the analysis of all stroke due to missing follow-up data. Data for fatal stroke were available in 17 studies. Two hundred sixty-five participants were excluded from the analysis of fatal stroke due to missing cause of death.

**Figure 2.**
The association between standardized FT4 and risk of all stroke (A) and fatal stroke (B). HRs and their 95% CIs are represented by squares and are per one increase of 1 SD of FT4. Sizes of data markers are proportional to the inverse of the variance of the HRs. Data for all stroke were available in nine studies. Three hundred eighty-seven participants were excluded from the analysis of all stroke due to missing follow-up data. Data for fatal stroke were available in 13 studies. Twenty-seven participants were excluded from the analysis of fatal stroke due to missing cause of death.

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Comment in

Letter to the Editor: Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis.
Choy KW. Choy KW. J Clin Endocrinol Metab. 2017 Apr 1;102(4):1407-1408. doi: 10.1210/jc.2016-3338. J Clin Endocrinol Metab. 2017. PMID: 28388728 No abstract available.
Response to the Letter by Choy.
Chaker L, Cappola AR, Rodondi N, Peeters RP; Thyroid Studies Collaboration. Chaker L, et al. J Clin Endocrinol Metab. 2017 Apr 1;102(4):1409-1410. doi: 10.1210/jc.2016-3502. J Clin Endocrinol Metab. 2017. PMID: 28388731 No abstract available.

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1. Bauer DC, Ettinger B, Browner WS. Thyroid functions and serum lipids in older women: a population-based study. Am J Med. 1998;104:546–551. - PubMed
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Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis

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Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis

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