Ratziu Vlad, Scanlan Thomas S, Bruinstroop Eveline
Sorbonne Université, ICAN Institute for Cardiometabolism and Nutrition, INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Assistance Publique-Hôpitaux de Paris, Paris, France.
Department of Chemical Physiology & Biochemistry, Oregon Health and Science University, Portland, OR 97239, USA.
J Hepatol. 2025 Feb;82(2):375-387. doi: 10.1016/j.jhep.2024.10.018. Epub 2024 Oct 19.
The association between suboptimal thyroid function ((sub)clinical hypothyroidism or low-normal thyroid function) and the metabolic syndrome and MASLD (metabolic dysfunction-associated steatotic liver disease) has been clearly established. Furthermore, in MASLD, intracellular thyroid hormone concentrations are low and the activation of the thyroid hormone receptor (THR) is reduced. Administration of thyroid hormone has been shown to reduce liver triglycerides by stimulating fatty acid disposal through lipophagy and beta-oxidation, and to lower LDL-cholesterol. As thyroid hormone exerts its effects in many different organs, including the heart and bone, several drug candidates have been developed as selective thyromimetics for the THR-β nuclear receptor with potent and liver-targeted activity. Importantly, these compounds have reduced affinity for the THR-α nuclear receptor and tissue distribution profiles that differ from endogenous thyroid hormones, thereby reducing unwanted cardiovascular side effects. The most advanced compound, resmetirom, is an oral drug that demonstrated, in a large phase III trial in patients with MASH (metabolic dysfunction-associated steatohepatitis), the ability to reduce liver fat, decrease aminotransferase levels and improve atherogenic dyslipidaemia with a good tolerability profile. This translated into histological improvement that led to accelerated approval of this drug for active fibrotic steatohepatitis, a milestone achievement as a first MASH drug.
甲状腺功能欠佳（亚临床甲状腺功能减退或甲状腺功能略低于正常水平）与代谢综合征及代谢功能障碍相关脂肪性肝病（MASLD）之间的关联已得到明确证实。此外，在MASLD中，细胞内甲状腺激素浓度较低，甲状腺激素受体（THR）的激活减少。甲状腺激素给药已显示可通过自噬性脂肪降解和β-氧化刺激脂肪酸代谢，从而降低肝脏甘油三酯，并降低低密度脂蛋白胆固醇。由于甲状腺激素在包括心脏和骨骼在内的许多不同器官中发挥作用，因此已开发出几种候选药物作为具有强效肝脏靶向活性的THR-β核受体选择性甲状腺模拟物。重要的是，这些化合物对THR-α核受体的亲和力降低，且组织分布情况与内源性甲状腺激素不同，从而减少了不必要的心血管副作用。最先进的化合物resmetirom是一种口服药物，在一项针对代谢功能障碍相关脂肪性肝炎（MASH）患者的大型III期试验中，它显示出能够减少肝脏脂肪、降低转氨酶水平并改善致动脉粥样硬化血脂异常，且耐受性良好。这转化为组织学改善，使得该药物因对活动性纤维化脂肪性肝炎的加速批准成为首个用于MASH的药物，这是一个具有里程碑意义的成就。
