Pathogenesis and Treatment of Non-alcoholic Steatohepatitis and Its Fibrosis: A Systematic Review

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a slowly progressive liver disease characterized by hepatic steatosis, inflammation, and fibrosis. Despite multiple therapeutic approaches under investigation, no globally approved standard pharmacotherapy currently exists. This systematic review aims to inform and enhance critical care and hepatology practice by synthesizing the most recent evidence on the pathogenesis and treatment of MASH and associated fibrosis. The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was performed using both text words and controlled vocabulary, incorporating Boolean operators ("AND," "OR") across PubMed, Embase, and the Cochrane Library. The inclusion criteria encompassed open-access, full-text English-language randomized controlled trials (RCTs) published between 2014 and 2024. Study quality was assessed using the RoB 2.0 tool, and the strength of evidence was evaluated using the GRADE framework. Fourteen RCTs were included. Of these, two were rated as high risk of bias (RoB) and consequently downgraded to "low-quality" evidence. Two RCTs with low RoB were classified as "high-quality" evidence, while the remaining 10 trials had unclear RoB, leading to a "moderate-quality" rating due to imprecision. This review discusses clinical trials evaluating therapies such as GLP-1 receptor agonists, THR-β agonists, pan-PPAR agonists, FGF21 analogues, and bariatric surgery. GLP-1 agonists and resmetirom (a THR-β agonist) demonstrated substantial reductions in liver fat content, while lanifibranor (a pan-PPAR agonist) also significantly improved fibrosis. Bariatric surgery showed MASH resolution in 56-70% of cases, though challenges remain regarding incomplete fibrosis reversal and the lack of long-term outcome data. Future research should prioritize combination therapies, explore novel antifibrotic agents, and investigate genetically based therapeutic strategies to better address the multifactorial nature of MASH.