Cirrhosis has become the major liver-related clinical endpoint in non-alcoholic steatohepatitis (NASH). However, progression to cirrhosis is less predictable in NASH than in other chronic liver diseases. This is due to the complex and multifactorial aetiology of NASH, which is determined by lifestyle and nutrition, multiple genetic and epigenetic factors, and a prominent role of hepatic and extrahepatic comorbidities. Thus, modest changes in these cofactors can also induce fibrosis regression, at least in patients with precirrhotic liver disease. Fibrogenesis in NASH correlates with, but is indirectly coupled to, classical inflammation, since fibrosis progression is driven by repetitive periods of repair. While hepatocyte lipoapoptosis is a key driving force of fibrosis progression, activated hepatic stellate cells, myofibroblasts, cholangiocytes, macrophages and components of the pathological extracellular matrix are major fibrogenic effectors and thus pharmacological targets for therapies aimed at inhibition of fibrosis progression or induction of fibrosis reversal. The advent of novel, highly sensitive and specific serum biomarkers and imaging methods to assess the dynamics of liver fibrosis in NASH will improve detection, stratification and follow-up of patients with progressive NASH . These non-invasive tools will also promote the clinical development of antifibrotic drugs, by permitting the design of lean proof-of-concept studies, and enabling development of a personalised antifibrotic therapy for patients with rapid fibrosis progression or advanced disease.

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NASH 中纤维化进展和消退的决定因素

肝硬化已成为非酒精性脂肪性肝炎 (NASH) 的主要肝脏相关临床终点。然而，与其他慢性肝病相比，NASH 进展为肝硬化的可预测性较差。这是由于 NASH 的病因复杂且多因素，这由生活方式和营养、多种遗传和表观遗传因素以及肝和肝外合并症的突出作用决定。因此，这些辅因子的适度变化也可以诱导纤维化消退，至少在肝硬化患者中是如此。NASH 中的纤维化与经典炎症相关但间接耦合，因为纤维化进展是由重复的修复期驱动的。虽然肝细胞脂肪细胞凋亡是纤维化进展的关键驱动力，但活化的肝星状细胞、肌成纤维细胞、胆管细胞、巨噬细胞和病理性细胞外基质的成分是主要的纤维化效应物，因此是旨在抑制纤维化进展或诱导纤维化逆转的治疗的药理学靶点。用于评估 NASH 中肝纤维化动态的新型、高度敏感和特异的血清生物标志物和成像方法的出现将改善进展性 NASH 患者的检测、分层和随访。这些非侵入性工具还将促进抗纤维化药物的临床开发，允许设计精益的概念验证研究，并为纤维化快速进展或晚期疾病的患者开发个性化的抗纤维化治疗。