Dyslipidemia, Insulin Resistance, Ectopic Lipid Accumulation, and Vascular Function in Resistance to Thyroid Hormone β

Purpose In resistance to thyroid hormone due to mutations in thyroid hormone receptor beta, peripheral tissues are variably refractory to the action of circulating thyroid hormones. We evaluated parameters contributing to atherosclerotic risk in this disorder.Methods We measured low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), nonesterified fatty acids (NEFA), intrahepatic lipid (IHL) and intramyocellular lipid (IMCL), Homeostasis-model assessment of insulin resistance (HOMA-IR), augmentation index (AIx) and pulse wave velocity (PWV), flow-mediated dilatation, and carotid intima-media thickness (cIMT) in an unselected, genetically confirmed cohort of adult RTH beta patients (n = 27-77) and compared these with measurements in healthy subjects (up to n = 100) and thyrotoxic patients (n = 40).Results Resistance to thyroid hormone beta (RTH beta) patients exhibited higher LDL-C (P = 0.008) and TG (P = 0.002) and lower HDL-C concentrations (P = 0.015 x 10-2) than control subjects, with LDL-C being higher than in thyrotoxic patients with comparable hyperthyroxinemia. Proprotein convertase subtilisin/kexin 9 (P = 0.002) and apolipoprotein B (P = 0.0009) levels were reduced in thyrotoxic patients but not lower in RTH beta patients or control subjects. Intrahepatic lipid (P = 0.02 x 10-4), IMCL (P = 0.002), HOMA-IR (P = 0.01 x 10-2), and NEFA (P = 0.04 x 10-6) were significantly higher in RTH beta patients than control subjects. Flow-mediated dilatation was increased (P = 0.04) but cIMT (P = 0.71), PWV P = 0.81), and AIx (P = 0.95) were unaltered in RTH beta patients.Conclusions We have documented mixed dyslipidemia with hepatic and IMCL accumulation in RTH beta, suggesting that surveillance for these metabolic abnormalities is warranted. How they combine with enhanced endothelial function and unaltered vessel wall thickness and compliance to determine overall cardiometabolic risk in this disorder remains to be defined.