Mechanisms of Liver Fibrosis

Liver fibrosis is characterized by excessive deposition of extracellular matrix, such as collagen. This condition has many causes including those of known etiology, such as chronic alcohol consumption, hepatitis virus, nonalcoholic steatohepatitis, and genetic disorders, and those of unknown etiology, such as primary biliary cirrhosis, sclerosing cholangitis, and others. Currently, treatment of fibrosis is limited to removal of the causative agent, such as cessation of alcohol consumption, or liver transplantation. Liver fibrosis is initiated when chronic liver injury stimulates production of mediators by numerous cells types, including hepatocytes, bile duct epithelial cells, platelets, Kupffer cells, and other inflammatory cells that cause cells in the liver to differentiate into myofibroblasts. The cellular sources of these myofibroblasts include hepatic stellate cells, peribiliary fibroblasts, hepatocytes, bile duct epithelial cells, and bone marrow-derived cells. Growth factors are produced during the genesis of this disease that stimulate myofibroblast proliferation, and chemokines are produced that stimulate these cells to migrate to injured regions of the liver. Once the myofibroblasts accumulate in these regions, they are stimulated to produce collagen and other components of extracellular matrix causing fibrosis. Although our understanding of the underlying mechanisms of this disease has increased substantially, there are no therapies currently available that directly prevent or reverse fibrosis. Therefore, further studies are needed to identify new and effective therapeutic targets to treat this disease.