Progress and challenges in hepatic fibrosis

The field of hepatic fibrosis has exploded with exciting new information and progress in clinical trials based on years of basic and translational research. Several key concepts characterize the current 'state of the art':1. Effective antiviral therapies can reverse fibrosis, and recent successes with new all-oral HCV antiviral regimens promise to attenuate of the prevalence cirrhosis in this disease over time. 2. Despite this progress, the NASH epidemic will overtake HCV as the dominant etiology of advanced liver disease and HCC in the US and Europe. HBV and HCV remain significant causes of advanced liver disease in other regions.3. NAFLD is a more challenging therapeutic target than viral hepatitis because of its multiple causative pathways and more marked disease heterogeneity.4. New advances in understanding the pathophysiology of hepatic injury, inflammation and fibrosis provide an expanding framework for identifying potential anti-inflammatory and antifibrotic targets.5. The framework for therapies includes: a) Eliminate the cause of injury and their mediators; b) Reduce inflammation and the immune response; c) Antagonize receptor-ligand interactions, intracellular signaling; d) Reduce fibrogenesis by antagonizing TGFbeta1 activation, inhibit matrix synthesis; e) Resolve fibrosis by increasing scar matrix degradation, stimulating apoptosis of stellate cells or antagonizing matrix cross-linking.6. Endpoints of anti-fibrotic clinical trials are rapidly evolving to incorporate non-invasive methods that complement liver biopsy as well as more quantitative methods to assess collagen content when biopsy is performed. Strategies for clinical trial design will need to incorporate surrogate endpoints when performed in patients with low risk of clinical decompensation.7. The key challenges in the field are: a) to optimize animal models that have maximal relevance to human disease; b) to improve non-invasive diagnostic methods that will eliminate the need for liver biopsy; c) to improve predictions of drug efficacy and safety prior to initiating human trials; d) to accelerate drug discovery, successful clinical testing, and availability to patients.