Bjørn O Åsvold1, Lars J Vatten2, Trine Bjøro3, Douglas C Bauer4, Alexandra Bremner5, Anne R Cappola6, Graziano Ceresini7, Wendy P J den Elzen8, Luigi Ferrucci9, Oscar H Franco10, Jayne A Franklyn11, Jacobijn Gussekloo8, Giorgio Iervasi12, Misa Imaizumi13, Patricia M Kearney14, Kay-Tee Khaw15, Rui M B Maciel16, Anne B Newman17, Robin P Peeters18, Bruce M Psaty19, Salman Razvi20, José A Sgarbi21, David J Stott22, Stella Trompet23, Mark P J Vanderpump24, Henry Völzke25, John P Walsh26, Rudi G J Westendorp27, Nicolas Rodondi28. 1. Department of Public Health, Norwegian University of Science and Technology, Trondheim2Department of Endocrinology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. 2. Department of Public Health, Norwegian University of Science and Technology, Trondheim3Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, Massachusetts. 3. Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway5Faculty of Medicine, University of Oslo, Oslo, Norway. 4. Department of Medicine, University of California, San Francisco7Department of Epidemiology and Biostatistics, University of California, San Francisco. 5. School of Population Health, The University of Western Australia, Crawley. 6. Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia. 7. Department of Clinical and Experimental Medicine, Geriatric Endocrine Unit, University Hospital of Parma, Parma, Italy. 8. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands. 9. National Institute on Aging, Baltimore, Maryland. 10. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. 11. School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, England. 12. National Council Research Institute of Clinical Physiology/Tuscany Region G. Monasterio Foundation, Pisa, Italy. 13. Department of Clinical Studies, Radiation Effects Research Foundation, Nagasaki, Japan. 14. Department of Epidemiology and Public Health, University College Cork, Cork, Ireland. 15. Department of Public Health and Primary Care, University of Cambridge, Cambridge, England. 16. Division of Endocrinology, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil. 17. Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania. 18. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands21Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. 19. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle23Group Health Research Institute, Group Health Cooperative, Seattle, Washington. 20. Department of Endocrinology, Gateshead Health Foundation National Health Service Trust, Gateshead, England. 21. Division of Endocrinology, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil25Division of Endocrinology, Faculdade de Medicina de Marília, Marília, Brazil. 22. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland. 23. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands28Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. 24. Department of Endocrinology, Royal Free Hospital, London, England. 25. Institute for Community Medicine, Study of Health in Pomerania/Clinical-Epidemiological Research and German Centre of Cardiovascular Research, University of Greifswald, Greifswald, Germany. 26. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia32School of Medicine and Pharmacology, The University of Western Australia, Crawley. 27. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands33Netherlands Consortium for Healthy Aging, Leiden, the Netherlands34Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 28. Department of General Internal Medicine, Inselspital, University of Bern, Bern, Switzerland.
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.
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.
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