Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies

Abstract

Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury as well as persistent activation of inflammatory response and of fibrogenesis. Liver fibrosis is a major determinant for chronic liver disease (CLD) progression and in the last two decades our understanding on the major molecular and cellular mechanisms underlying the fibrogenic progression of CLD has dramatically improved, boosting pre-clinical studies and clinical trials designed to find novel therapeutic approaches. From these studies several critical concepts have emerged, starting to reveal the complexity of the pro-fibrotic microenvironment which involves very complex, dynamic and interrelated interactions between different hepatic and extrahepatic cell populations. This review will offer first a recapitulation of established and novel pathophysiological basic principles and concepts by intentionally focus the attention on NAFLD/NASH, a metabolic-related form of CLD with a high impact on the general population and emerging as a leading cause of CLD worldwide. NAFLD/NASH-related pro-inflammatory and profibrogenic mechanisms will be analysed as well as novel information on cells, mediators and signalling pathways which have taken advantage from novel methodological approaches and techniques (single cell genomics, imaging mass cytometry, novel in vitro two- and three-dimensional models, etc.). We will next offer an overview on recent advancement in diagnostic and prognostic tools, including serum biomarkers and polygenic scores, to support the analysis of liver biopsies. Finally, this review will provide an analysis of current and emerging therapies for the treatment of NAFLD/NASH patients.

Keywords: Emerging therapies; Immune cells; Liver fibrosis; Myofibroblasts; NASH; diagnostic advancement.