Antifibrotic therapy in chronic liver disease

Abstract

The response to injury is one of wound healing and, subsequently, fibrosis. This response is generalized, occurring in diverse organ systems. Injury and wounding in the liver ultimately lead to cirrhosis in many patients (although not all patients), and are the result of many different diseases. The fact that various diseases result in cirrhosis suggests a common pathogenesis. Study over the past 2 decades has shed considerable light on the pathogenesis of fibrosis and cirrhosis. A growing body of literature indicates that the hepatic stellate cell is a central component in the fibrogenic process. Stellate cells undergo a transformation during injury that has been termed activation. Activation is complex and multifaceted, but one of its most prominent features is the synthesis of large amounts of extracellular matrix, resulting in deposition of scar or fibrous tissue. The fibrogenic process is dynamic; it is noteworthy that even advanced fibrosis (or cirrhosis) is reversible. The best antifibrotic therapy is treatment of the underlying disease. For example, eradication of hepatitis B or C virus can lead to the reversal of fibrosis. In situations in which treating the underlying process is not possible, specific antifibrotic therapy is desirable. A number of specific antifibrotic therapies have been tried, but have been met with poor or mediocre success. However, elucidation of the mechanisms responsible for fibrogenesis, with particular emphasis on stellate cell biology, has highlighted many putative novel therapies. This article emphasizes mechanisms underlying fibrogenesis, and reviews current antifibrotic therapies as well as potential future approaches.