medwireNews: Researchers have defined the optimal healthy ranges for thyroid function based on cardiovascular disease (CVD) risk and mortality, finding the thresholds are lower than those currently applied for the treatment of subclinical thyroid dysfunction.
Moreover, the results suggest that the healthy ranges differ according to age and sex, note Layal Chaker, from the Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues in The Lancet Diabetes & Endocrinology.
Their systematic review and individual patient data meta-analysis included 26 cohorts of 134,346 individuals with a median age of 59 years from Europe, Brazil, USA, Japan, and Iran. Measures of free thyroxine (FT4), thyroid-stimulating hormone (TSH) and cardiovascular outcomes or mortality showed that the optimal healthy ranges for free thyroxine (FT4) and thyroid-stimulating hormone (TSH) considering cardiovascular risk and mortality range between the 20th and 40th percentiles, and 60th and 80th percentiles, respectively.
This compares with current reference intervals for FT4 and TSH that are statistically defined by the 2.5th and 97.5th percentiles and “do not account for potential risk of clinical outcomes,” say the researchers, adding that “current reference intervals might not identify individuals with a higher risk of thyroid disease who could potentially benefit from intervention.”
They report that for FT4 levels there was a J-shaped association with the risk for a composite outcome comprising CVD events (coronary heart disease, stroke, and heart failure) and all-cause mortality, based on data for 14,904 events in 51,081 individuals.
Above the 20th and 40th percentiles, FT4 levels were associated with a largely linear increase in the risk for the composite outcome. Individuals with levels in the 80–100th percentiles were at greatest risk, at a significant hazard ratio (HR) of 1.20, compared with those with levels in the 20–40th percentiles (median 13.5–14.8 pmol/L). The findings were similar for CVD events and all-cause mortality when considered separately, as well as for CV mortality, with significant HRs of 1.22, 1.34, and 1.57, respectively.
Moreover, outside of the healthy thresholds, the increased risk for the composite outcome changed according to age and sex, with stronger associations, lower optimal healthy ranges, and greater absolute risk among those older than 70 years of age. For example, for this age group, the absolute 10-year risk for the composite outcome increased by more than 5% among women with FT4 levels above the 85th percentile (median 17.6 pmol/L) and by more than 5% and 10% among men with FT4 levels greater than the 75th (16.7 pmol/L) and 90th percentile (18.4 pmol/L), respectively.
Chaker et al comment that these thresholds are “lower than the currently applied threshold for diagnosis and treatment of subclinical thyroid dysfunction,” and suggest that “age-specific and sex-specific strategies for thyroid disease could be necessary.”
This was corroborated by Elizabeth Pearce, from Boston University Chobanian & Avedisian School of Medicine in Massachusetts, USA, in a comment accompanying the study. She says that “optimal thyroid function reference ranges are not one-size-fits-all but should differ by age and sex,” adding that the current findings “provide compelling evidence for working toward a more risk-focused approach to defining normal thyroid function.”
For TSH, there was a nonlinear association with the composite outcome, all-cause mortality, and cardiovascular mortality, whereby lower levels conveyed an increased risk, albeit less pronounced than that seen with FT4, the investigators note. Compared with TSH levels in the 40–60th percentiles, levels in the 0–20th percentiles were associated with HRs of 1.07, 1.09, and 1.07, respectively.
Pearce comments that although FT4 is more strongly associated with outcomes, “TSH is more sensitive to subtle shifts in thyroid status,” and so whether “both values would optimally be factored into reference ranges for risk-based clinical decision making needs to be determined,” as does the effect of exogenous thyroid hormone on outcome risk, she notes.
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Lancet Diabetes Endocrinol 2023; doi:10.1016/S2213-8587(23)00227-9
Lancet Diabetes Endocrinol 2023; doi:10.1016/S2213-8587(23)00257-7
