Thyroid function and risk of all-cause and cardiovascular mortality: a prospective population-based cohort study

Abstract

Purpose: Although thyroid hormones are irrefutably implicated in cardiovascular physiology, the impact of within-reference range variations of thyroid function on cardiovascular disease (CVD) remains unclear. Elucidating this is important, since it could foster preventive treatment and reduce global CVD burden. We therefore investigated the impact of within-reference range variations of thyroid function on all-cause and cardiovascular mortality.

Methods: We included community-dwelling individuals aged 28-75 years from a prospective cohort study, without known use of thyroid-affecting therapy and with thyrotropin within reference range. Associations of thyroid function with mortality were quantified using Cox models and adjusted for sociodemographic and cardiovascular risk factors.

Results: Mean (SD) age of the 6,054 participants (52.0% male) was 53.3 (12.0) years. During 47,594 person-years of follow-up, we observed 380 deaths from all causes and 103 from CVDs. Although higher thyrotropin was not associated with all-cause mortality (adjusted HR 1.02, 95% CI 0.92-1.14), point estimates for cardiovascular mortality diverged toward increased risk in younger (<72 years) participants (1.31, 1.00-1.72) and decreased risk in elderly (≥72 years) (0.77, 0.56-1.06). Higher free thyroxine (FT₄) was associated with all-cause mortality (1.18, 1.07-1.30) and with cardiovascular mortality only in elderly (1.61, 1.19-2.18), but not in younger participants (1.03, 0.78-1.34). Higher free triiodothyronine (FT₃) was associated with all-cause mortality in females only (1.18, 1.02-1.35). FT₃ was not associated with cardiovascular mortality (0.91, 0.70-1.18).

Conclusions: Community-dwelling elderly individuals with high-normal thyroid function are at increased risk of all-cause and cardiovascular mortality, reinforcing the need of redefining the current reference ranges of thyroid function.

Keywords: Biomarker; Cohort study; Euthyroid; General population; Mortality risk; Thyroid function.

Fig. 1

Flow of the participants through the study. *Size of the random sample was arbitrarily set at 3,395 (out of the 22,350 eligible participants) to obtain a total cohort size of ~10,000, taking into account a 15% nonparticipation rate

Fig. 2

Graphical representation of the survival estimates of thyrotropin and thyroxine for cardiovascular mortality stratified by age. a shows the impact of thyrotropin on the risk of cardiovascular mortality in participants younger than 72 years and b in participants aged 72 years or older. c shows the impact of FT₄ on the risk of cardiovascular mortality in participants younger than 72 years and d in participants aged 72 years or older. The lines represent the risk of cardiovascular mortality. The areas about the lines represent the 95% confidence interval associated with the line. The median thyrotropin and FT₄ concentration was chosen as a reference in the upper two and lower two panels, respectively. The distribution of thyrotropin and FT₄ in both age strata is depicted by the histogram in the background. Cutoff values for the age strata were established through dichotomization of the cohort by the median age in participants who had succumbed to cardiovascular disease, to obtain an equal amount of events per stratum. FT₄ thyroxine, TSH thyrotropin