An update on the recent advances in antifibrotic therapy

Expert Rev Gastroenterol Hepatol. 2018 Nov;12(11):1143-1152. doi: 10.1080/17474124.2018.1530110. Epub 2018 Oct 3.

Abstract

Chronic injury to the liver, such as viral hepatitis, alcoholism, non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), promotes extracellular matrix deposition and organ scarring, termed hepatic fibrosis. Fibrosis might progress to cirrhosis and predisposes to hepatocellular carcinoma (HCC), but is also associated with extrahepatic morbidity and mortality in NAFLD/NASH. The improved understanding of pathogenic mechanisms underlying chronic inflammation and fibrogenesis in the liver prompted recent advances in antifibrotic therapies. Areas covered: We review recent advances in antifibrotic therapy, of which most are currently tested in clinical trials for NAFLD or NASH. This explains the manifold metabolic pathways as antifibrotic targets, including farnesoid X receptor (FXR) agonism (obeticholic acid, nonsteroidal FXR agonists), acetyl-CoA carboxylase inhibition, peroxisome proliferator-activator receptor agonism (elafibranor, lanifibranor, saroglitazar), and fibroblast growth factor (FGF)-21 or FGF-19 activation. Other antifibrotic drug candidates target cell death or inflammation, such as caspase (emricasan) or ASK1 inhibitors (selonsertib), galectin-3 inhibitors and reducing inflammatory macrophage recruitment by blocking chemokine receptors CCR2/CCR5 (cenicriviroc). Expert commentary: The tremendous advances in translational and clinical research fuels the hope for efficacious antifibrotic therapies within the next 5 years. Very likely, a combination of etiology-specific, metabolic, anti-inflammatory, and direct antifibrotic interventions will be most effective.

Keywords: Liver fibrosis; NAFLD/NASH; chemokine; gut-liver axis; hepatic stellate cell; macrophages; matrix; microbiome; myofibroblast; regression; translational medicine.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / therapeutic use*
  • Humans
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / diagnosis
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / metabolism
  • Molecular Targeted Therapy / methods*
  • Signal Transduction / drug effects
  • Treatment Outcome

Substances

  • Anti-Inflammatory Agents