| Diabetes, older age, severe fibrosis, and PNPLA3 GG genotype are risk factors for incident HCC in NAFLD. Since hepatic fibrosis is the determinant of over-all or liver-related mortality, we should identify severe fibrosis in NAFLD. FIB-4 index is the first triaging tool for excluding severe fibrosis. Diagnostic modality as the second step includes US elastography or liver-specific fibrosis markers such as type 4 collagen 7s and ELF tests. As the third step, MRE will be alternative for liver biopsy which is “unperfect gold standard”. The efficacy of vitamin E and pioglitazone has been appreciated. GLP-1RA and SGLT2 inhibitors have shown early efficacy. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation; modulation of PPARs, medications targeting farnesoid X receptor (FXR) axis, inhibitors of de novo lipogenesis, mitochondria target of thiazolidine (mTOT) and fibroblast growth factor analogues. A second target is oxidative stress, inflammation, and apoptosis. A third target is intestinal microbiomes and metabolic endotoxemia. The final target is hepatic fibrosis. Antifibrotic agents are cenicriviroc (CVC) and galectin 3 antagonist. FXR ligand, elafibranor, thyroid hormone receptor β agonist, mTOT, and CVC are currently being evaluated in phase 3 trials for NASH. Interim results showed that FXR agonists for 72wk significantly reduced hepatic fibrosis more than 1 stage over placebo in NASH (F2/3). Milestones in NASH therapy include ALT, body weight, and HbA1c (ABC). |
