Effects of subclinical hypothyroidism on bone mineral density and cardiometabolic risk: genetic and immune influences

Effects of subclinical hypothyroidism on bone mineral density and cardiometabolic-risk: genetic and immune influences Subclinical hypothyroidism (SH) affects 3-8% of the population and is associated with hypertension, dyslipidaemia and altered bone mineral density (BMD). Metabolic anomalies in thyroid disease have been attributed to thyroid hormone variation but mice deficient in thyrotropin (TSH) receptor (TSHR) have low BMD, despite normal thyroid hormones, suggesting that TSH/TSHR function in bone is important. SH has several aetiologies including thyroid autoimmunity characterised by thyroid peroxidase autoantibodies (TPO-Ab), inactivating TSHR mutations (TSHR-M) and FOXE1 polyalanine tract length (FOXE1-PTL) polymorphisms. I hypothesise differential bone effects in SH relating to these causes. Similarly the effects of SH on metabolic outcomes is unclear and may also depend on SH aetiology. Principle aims - 1. To determine the prevalence of heterozygous TSHR-Ms in SH. 2. To evaluate body composition and metabolic parameters according to i) TSH, T4 and T3; ii) TPO-Ab; iii) TSHR-M or polymorphism; iv) FOXE1-PTL polymorphism. 156 women and 52 men, mean age 51 with primary untreated SH were recruited. Blood samples were obtained for biochemistry (thyroid & lipid profiles, TPO-Ab, HOMA-IR) and blood pressure (BP) and anthropometric data collected. TSHR and FOXE1 were genotyped. Dual-energy X-ray absorptiometry generated Z-scores. Stepwise multivariate regression analyses were performed. Half of the cohort had TPO-Ab; 6% had TSHR-Ms (essentially TPO-Ab negative) and 60% expressed FOXE114/14-PTL. TSH and TPO-Ab associated negatively with BMD-Z at lumbar spine but not hip whereas free-T3 and male gender associated negatively at both sites. TSHR-M status did not influence BMD-Z despite lower free-T3 relative to TSH. Free-T3 associated positively with BP and HOMA-IR. FOXE1-PTL14/14 associated positively with free-T3 and negatively with BP. TSH, TSHR-M and TPO-Ab status showed no metabolic associations but unexpectedly TSH showed a positive association with T3. SH is considered homogenous but my results illustrate its heterogeneity and highlight the need for studies accounting for aetiology in order to optimise clinical managemen