Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications

Abstract

Hepatic fibrosis, or scarring of the liver, is emerging as a treatable complication of advanced liver disease, following significant progress in understanding its underlying mechanisms. Efforts have focused on the hepatic stellate cell, as these cells can undergo 'activation' into proliferative and fibrogenic myofibroblast-like cells during liver injury. Stimuli driving stellate cell activation include hepatocellular necrosis due to oxidant stress, apoptosis, and soluble growth factors. Specific lymphocyte subsets can also stimulate fibrogenesis. A cascade of signaling and transcriptional events in stellate cells underlies the fibrogenic response to liver injury, with each step in the cascade being a potential target for antifibrotic therapy. Disease-specific fibrogenic mechanisms have also been uncovered: in hepatitis C, this may include direct stimulation of stellate cell activation by viral infection; in nonalcoholic steatohepatitis, elevated levels of leptin and increased leptin signaling by stellate cells increase fibrogenesis. Determinants of fibrosis progression include both environmental and genetic factors, with ongoing efforts to define specific polymorphisms correlating with fibrosis progression rates. Human studies now indicate that fibrosis and even cirrhosis could be reversible, especially if the underlying disease is eradicated. A key challenge is to establish noninvasive means of assessing fibrosis stage and progression using either serum tests and/or imaging. In addition, endpoints of antifibrotic clinical trials need to be established so that reliable evidence of benefit can be identified. We are on the cusp of a new era in which antifibrotic therapies could become important in treating chronic fibrosing liver disease.