Virus-related liver cirrhosis: Molecular basis and therapeutic options

Abstract

Chronic infections with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) are the major causes of cirrhosis globally. It takes 10-20 years to progress from viral hepatitis to cirrhosis. Intermediately active hepatic inflammation caused by the infections contributes to the inflammation-necrosis-regeneration process, ultimately cirrhosis. CD8⁺ T cells and NK cells cause liver damage via targeting the infected hepatocytes directly and releasing pro-inflammatory cytokine/chemokines. Hepatic stellate cells play an active role in fibrogenesis via secreting fibrosis-related factors. Under the inflammatory microenvironment, the viruses experience mutation-selection-adaptation to evade immune clearance. However, immune selection of some HBV mutations in the evolution towards cirrhosis seems different from that towards hepatocellular carcinoma. As viral replication is an important driving force of cirrhosis pathogenesis, antiviral treatment with nucleos(t)ide analogs is generally effective in halting the progression of cirrhosis, improving liver function and reducing the morbidity of decompensated cirrhosis caused by chronic HBV infection. Interferon-α plus ribavirin and/or the direct acting antivirals such as Vaniprevir are effective for compensated cirrhosis caused by chronic HCV infection. The standard of care for the treatment of HCV-related cirrhosis with interferon-α plus ribavirin should consider the genotypes of IL-28B. Understanding the mechanism of fibrogenesis and hepatocyte regeneration will facilitate the development of novel therapies for decompensated cirrhosis.

Keywords: Liver cirrhosis, Hepatitis B virus, Hepatitis C virus, Evolution, Immune cells, Signaling pathway, Hepatic stellate cells, Antiviral therapy

Core tip: Hepatic inflammation caused by viral infections contributes to the inflammation-necrosis-regeneration process, ultimately cirrhosis. Immune selection of some hepatitis B virus mutations in the evolution towards cirrhosis seems different from that towards hepatocellular carcinoma. Hepatic stellate cells and macrophages are important for the fibrogenesis. Antiviral treatment is generally effective in reducing the morbidity of decompensated cirrhosis. The standard of care for the treatment of hepatitis C virus-related cirrhosis with pegylated interferon-α and ribavirin should consider the genotypes of IL-28B. Stem cell-based therapy can be an option for the treatment of decompensated cirrhosis patients who fail to respond to antiviral treatment.