Objective: Thyroid hormones are essential for maintaining metabolic balance and particularly influence lipid synthesis and degradation. Metabolomics and in-depth lipid profiling may enable us to assess for differential effects of thyroid hormones and provide insight into tissue thyroid status, that cannot be captured by levels of serum free thyroid hormones alone.
Methods: 4,347 children from the Avon Longitudinal Study of Parents and Children who had thyroid function and plasma NMR metabolomics measured at age 7 were studied. Linear regression was performed to assess the association between thyrotropin (TSH), free tri-iodothyronine (FT3) or free thyroxine (FT4) and lipid metabolite levels. Analyses were adjusted for sex and BMI. We then studied 542 individuals from the WATTS trial where individuals were randomised to receive combination thyroid hormone replacement (liothyronine and levothyroxine(LT3 + LT4)) or standard levothyroxine(LT4) to compare selected metabolites and response to treatment as assessed by quality of life measures including general health questionnaire (GHQ).
Results: Multiple associations after correction for multiple testing were observed between TSH, FT3 and FT4 and lipidmetabolites (P<0.001). The classic inverse association between TSH and free thyroid hormones was often not observed. Most robust and consistent associations were observed for FT3. The strongest lipid associations for FT3:FT4 ratio were were taken forwards as markers of tissue T3 status and studied in the WATTS trial. After correction for multiple testing, 9 metabolomic markers of tissue T3 status were associated with improved GHQ in patients randomised to combination thyroid hormone replacement (LT3 + LT4) but not to standard treatment (LT4).
Conclusion: Our analysis has shown the broad and substantial impact of thyroid hormones, especially FT3, on lipid metabolomics and shown how each hormone has a different metabolomic signature, with TSH alone being unable to capture this. Metabolomic markers may reflect individuals who might benefit from combination thyroid hormone replacement. This work has key implications for monitoring treatment response in hypothyroidism and thyroid hormone replacement.
10 Sep 2022 - 13 Sep 2022