Liver Fibrosis

Overview of liver fibrosis

Liver fibrosis is the accumulation of extracellular matrix (ECM) proteins, mainly collagen, that occurs in most types of chronic liver disease. The main causes of liver fibrosis in industrialized countries include chronic hepatitis C virus (HCV) infection, alcohol abuse, and nonalcoholic steatohepatitis (NASH).

The accumulation of ECM proteins distorts the hepatic architecture by forming a fibrous scar and the subsequent development of nodules of regenerating hepatocytes defines cirrhosis. Cirrhosis produces hepatocellular dysfunction and increased intrahepatic resistance to blood flow, resulting in hepatic insufficiency and portal hypertension, respectively.

Hepatic fibrosis was historically thought to be a passive and irreversible process, due to the collapse of the hepatic parenchyma and its substitution by a collagen-rich tissue. Currently, it is considered a model of the wound healing response to chronic liver injury. Liver fibrosis received little attention until the 1980s, when the hepatic stellate cell (HSC), formerly known as the lipocyte, Ito cell or perisinusoidal cell, was identified as the main collagen-producing cell in the liver.

This cell type, first described by von Kupffer in 1876, undergoes a dramatic phenotypic activation in chronic liver diseases with the acquisition of fibrogenic properties. The molecular mechanisms leading to HSC activation and increased collagen synthesis in liver fibrosis have been identified using cultured HSCs and experimental models of chronic liver injury in rodents.

Besides HSCs, portal myofibroblasts and cells of bone marrow origin have also been shown to have fibrogenic potential. The demonstration that even advanced liver fibrosis is reversible has greatly stimulated researchers to identify antifibrotic therapies. However, the most effective therapy to treat hepatic fibrosis is still to remove the causative agent. A number of drugs are able to reduce the accumulation of scar tissue in experimental models of chronic liver injury. Renin–angiotensin system blockers and antioxidants are promising drugs, yet evidence-based therapies are not yet available.

The onset of liver fibrosis is usually insidious and most of the related morbidity and mortality occur after the development of cirrhosis. In the majority of patients, progression to cirrhosis occurs after an interval of 15 –20 years. The natural history of liver fibrosis is influenced by both genetic and environmental factors. Epidemiological studies have identified polymorphisms in a number of candidate genes that may influence the progression of liver fibrosis in humans. These genetic factors may explain the broad spectrum of responses to the same aetiological agent found in patients with chronic liver diseases. Conceptually, the process of hepatic fibrosis must, at some point, consist of the stimulation of excessive ECM molecule synthesis by one or more populations(s) of cells (or an increase in the population of ECM-producing cells), or a decrease in the rate of ECM degradation or turnover.

This article reviews our current understanding of the pathogenesis of hepatic fibrosis and highlights those elements of the process for which intervention has been attempted. The etiology and cellular and molecular mechanisms of liver fibrosis will be detailed. The mechanisms of transition of advanced fibrosis to cirrhosis are also discussed. Finally, the basis for pathophysiologically based therapies will be detailed.