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The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis

Lookup NU author(s): Dr Salman Razvi



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Background Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5th-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease (CVD) and mortality. Methods This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from January 2011 to October 2022. We included cohorts that collected TSH and/or FT4, cardiovascular outcomes and/or mortality for adults.The primary outcome was a composite outcome including CVD events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes included CVD events, all-cause mortality, and CVD mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes mellitus, and total cholesterol. The study protocol was registered with PROSPERO CRD42017057576. Findings We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th- 40th percentiles of FT4 (median 13·5-14·8 pmol/L) conveying the lowest risk. Compared to the 20th- 40th percentiles, the age- and sex-adjusted HR (95% CI) for FT4 in the 80th-100th percentiles was 1·20 (1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for CVD mortality and 1·22 (1·11-1·33) for CVD events. In individuals aged ≥70 years, ten-year absolute risk of composite outcome increased over 5% for women with FT4 >85th percentile (median 17·6 pmol/L), and men with FT4 >75th percentile (16·7 pmol/L). Nonlinear associations were identified for TSH, with the 60th-80thpercentiles of TSH (median 1·90-2·90 mIU/L) associated with the lowest risk of CVD and mortality. Compared to the 60th -80th percentiles, the age- and sex-adjusted HR (95% CI) of TSH in the 0th-20th percentiles was 1·07 (1·02-1·12) for the composite outcome, 1·09 (1·05 to 1·14) for all-cause mortality, and 1·07 (0·99-1·16) for CVD mortality.Interpretation There was a J-shaped association of FT4 with CVD and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and CVD mortality. The 20th-40th percentiles of FT4 and the 60th-80thpercentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of CVD and mortality, with more than 5% increase of ten-year composite risk identified for FT4 >85th percentile in women and men aged over 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes.Funding None

Publication metadata

Author(s): Xu Y, Derakhshan A, Hysaj O, Wildisen L, Ittermann T, Pingitore A, Abolhassani N, Medici M, Kiemeney LALM, Riksen NP, Dullaart RPF, Trompet S, Dörr M, Brown SJ, Schmidt B, Führer-Sakel D, Vanderpump MPJ, Muendlein A, Drexel H, Fink HA, Ikram MK, Kavousi M, Rhee CM, Bensenor IM, Azizi F, Hankey GJ, Iacoviello M, Imaizumi M, Ceresini G, Ferrucci L, Sgarbi JA, Bauer DC, Wareham N, Boelaert K, Bakker SJL, Jukema JW, Vaes B, Iervasi G, Yeap BB, Westendorp RGJ, Korevaar TIM, Völzke H, Razvi S, Gussekloo J, Walsh JP, Cappola AR, Rodondi N, Peeters RP, Chaker L

Publication type: Article

Publication status: Published

Journal: The Lancet Diabetes and Endocrinology

Year: 2023

Pages: epub ahead of print

Online publication date: 08/09/2023

Acceptance date: 25/07/2023

Date deposited: 26/07/2023

ISSN (print): 2213-8587

ISSN (electronic): 2213-8595

Publisher: Elseiver


DOI: 10.1016/S2213-8587(23)00227-9

ePrints DOI: 10.57711/qe57-xr47


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