First Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Second Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Eur J Pharmacol. 2019 Nov 15;863:172661. doi: 10.1016/j.ejphar.2019.172661. Epub 2019 Sep 16.
Nonalcoholic fatty liver disease (NAFLD) affects 20-40% of the general population. Despite significant disease burden and mortality associated with advanced disease, i.e., nonalcoholic steatohepatitis (NASH), there is currently no approved medication for NASH. Farnesoid X receptor agonists have been investigated as candidates for the treatment of NASH. Obeticholic acid, approved for the treatment of primary biliary cholangitis, has gained significant attention after showing promising results in patients with NASH and fibrosis. Three trials investigating the effect of obeticholic acid in patients with NASH have been completed and the preliminary results of an ongoing one have also been made public. Generally, treatment with obeticholic acid improved hepatic histology, including inflammation and fibrosis, the latter being the main histological predictor of advanced disease. Nonetheless, there were adverse effects, the most common being pruritus and unfavorable changes in the lipid profile. Pruritus led to discontinuation of treatment in some patients. Obeticholic acid, however, is not the only farnesoid X receptor agonist currently investigated for the treatment of NASH. Another farnesoid X receptor agonist, cilofexor, in combination with firsocostat, an acetyl-CoA carboxylase inhibitor, improved hepatic steatosis, liver stiffness, liver function tests and serum fibrosis markers, without causing pruritus after 12 weeks of treatment. In conclusion, current evidence regarding the effect of farnesoid X receptor agonists on hepatic histology in patients with NASH is promising, but several safety issues need further evaluation.
非酒精性脂肪性肝病 (NAFLD) 影响 20-40%的普通人群。尽管与晚期疾病（即非酒精性脂肪性肝炎 (NASH)）相关的疾病负担和死亡率很高，但目前尚无针对 NASH 的批准药物。法尼醇 X 受体激动剂已被研究作为治疗 NASH 的候选药物。奥贝胆酸已被批准用于原发性胆汁性胆管炎的治疗，在显示出对 NASH 和纤维化患者有良好疗效后引起了广泛关注。已经完成了三项研究奥贝胆酸在 NASH 患者中的疗效的试验，并且正在进行的一项试验的初步结果也已公布。一般来说，奥贝胆酸治疗可改善肝脏组织学，包括炎症和纤维化，后者是晚期疾病的主要组织学预测因素。尽管如此，仍有不良反应，最常见的是瘙痒和血脂谱的不利变化。瘙痒导致一些患者停止治疗。然而，奥贝胆酸并不是目前正在研究用于治疗 NASH 的唯一法尼醇 X 受体激动剂。另一种法尼醇 X 受体激动剂西利福昔联合乙酰辅酶 A 羧化酶抑制剂 firsocostat，在治疗 12 周后可改善肝脂肪变性、肝硬度、肝功能试验和血清纤维化标志物，而不会引起瘙痒。总之，目前关于法尼醇 X 受体激动剂对 NASH 患者肝组织学影响的证据很有前景，但一些安全性问题需要进一步评估。
