Understanding the molecular mechanisms underlying liver fibrogenesis is fundamentally relevant to developing new treatments that are independent of the underlying etiology. The increasing success of antiviral treatments in blocking or reversing the fibrogenic progression of chronic liver disease has unearthed vital information about the natural history of fibrosis regression, and has established important principles and targets for antifibrotic drugs. Although antifibrotic activity has been demonstrated for many compounds in vitro and in animal models, none has been thoroughly validated in the clinic or commercialized as a therapy for fibrosis. In addition, it is likely that combination therapies that affect two or more key pathogenic targets and/or pathways will be needed. To accelerate the preclinical development of these combination therapies, reliable single target validation is necessary, followed by the rational selection and systematic testing of combination approaches. Improved noninvasive tools for the assessment of fibrosis content, fibrogenesis and fibrolysis must accompany in vivo validation in experimental fibrosis models, and especially in clinical trials. The rapidly changing landscape of clinical trial design for liver disease is recognized by regulatory agencies in the United States (FDA) and Western Europe (EMA), who are working together with the broad range of stakeholders to standardize approaches to testing antifibrotic drugs in cohorts of patients with chronic liver diseases.

Little is known about outcomes of liver transplantation for patients with non-alcoholic steatohepatitis (NASH). We aimed to determine the frequency and outcomes of liver transplantation for patients with NASH in Europe and identify prognostic factors. We analysed data from patients transplanted for end-stage liver disease between January 2002 and December 2016 using the European Liver Transplant Registry database. We compared data between patients with NASH versus other aetiologies. The principle endpoints were patient and overall allograft survival. Among 68,950 adults undergoing first liver transplantation, 4.0% were transplanted for NASH - an increase from 1.2% in 2002 to 8.4% in 2016. A greater proportion of patients transplanted for NASH (39.1%) had hepatocellular carcinoma (HCC) than non-NASH patients (28.9%, p 65: HR 1.72, p = 0.017), elevated model for end-stage liver disease score (>23: HR 1.48, p = 0.048) and low (40 kg/m2: HR 1.96, p = 0.012) recipient body mass index independently predicted death in patients transplanted for NASH without HCC. Data must be interpreted in the context of absent recognised confounders, such as pre-morbid metabolic risk factors. The number and proportion of liver transplants performed for NASH in Europe has increased from 2002 through 2016. HCC was more common in patients transplanted with NASH. Survival of patients and grafts in patients with NASH is comparable to that of other disease indications. The prevalence of non-alcoholic fatty liver disease has increased dramatically in parallel with the worldwide increase in obesity and diabetes. Its progressive form, non-alcoholic steatohepatitis, is a growing indication for liver transplantation in Europe, with good overall outcomes reported. However, careful risk factor assessment is required to maintain favourable post-transplant outcomes in patients with non-alcoholic steatohepatitis.

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.