Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Department of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan.
Clin Mol Hepatol. 2023 Jan;29(1):77-98. doi: 10.3350/cmh.2022.0237. Epub 2022 Oct 13.
The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. The dysfunction of lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes lipid accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress would further contribute to hepatocyte injury and death, leading to inflammation and immune dysfunction in the liver. During the healing process, the accumulation of an excessive amount of fibrosis might occur while healing. During the development of NASH and liver fibrosis, the gut-liver axis, adipose-liver axis, and renin-angiotensin system (RAS) may be dysregulated and impaired. Translocation of bacteria or its end-products entering the liver could activate hepatocytes, Kupffer cells, and hepatic stellate cells, exacerbating hepatic steatosis, inflammation, and fibrosis. Bile acids regulate glucose and lipid metabolism through Farnesoid X receptors in the liver and intestine. Increased adipose tissue-derived non-esterified fatty acids would aggravate hepatic steatosis. Increased leptin also plays a role in hepatic fibrogenesis, and decreased adiponectin may contribute to hepatic insulin resistance. Moreover, dysregulation of peroxisome proliferator-activated receptors in the liver, adipose, and muscle tissues may impair lipid metabolism. In addition, the RAS may contribute to hepatic fatty acid metabolism, inflammation, and fibrosis. The treatment includes lifestyle modification, pharmacological therapy, and non-pharmacological therapy. Currently, weight reduction by lifestyle modification or surgery is the most effective therapy. However, vitamin E, pioglitazone, and obeticholic acid have also been suggested. In this review, we will introduce some new clinical trials and experimental therapies for the treatment of NASH and related fibrosis.
非酒精性脂肪性肝炎（NASH）的初始表现为肝脂肪变性。肝细胞内脂质代谢的遗传因素、饮食和胰岛素抵抗功能障碍导致脂质堆积。脂毒性、氧化应激、线粒体功能障碍和内质网应激会进一步导致肝细胞损伤和死亡，导致肝脏炎症和免疫功能障碍。在修复过程中，可能会在修复过程中发生过多的纤维化积累。在 NASH 和肝纤维化的发展过程中，肠道-肝脏轴、脂肪-肝脏轴和肾素-血管紧张素系统（RAS）可能会失调和受损。细菌或其终产物易位进入肝脏会激活肝细胞、枯否细胞和肝星状细胞，加剧肝脂肪变性、炎症和纤维化。胆汁酸通过肝脏和肠道中的法尼醇 X 受体调节葡萄糖和脂质代谢。增加的脂肪组织衍生的非酯化脂肪酸会加重肝脂肪变性。增加的瘦素也在肝纤维化中起作用，而减少的脂联素可能导致肝胰岛素抵抗。此外，肝脏、脂肪和肌肉组织中过氧化物酶体增殖物激活受体的失调可能会损害脂质代谢。此外，RAS 可能有助于肝脂肪酸代谢、炎症和纤维化。治疗包括生活方式改变、药物治疗和非药物治疗。目前，通过生活方式改变或手术减轻体重是最有效的治疗方法。然而，也有人提出维生素 E、吡格列酮和奥贝胆酸。在这篇综述中，我们将介绍一些治疗 NASH 和相关纤维化的新临床试验和实验性治疗方法。
