Apoptosis and the liver: Relation to autoimmunity and related conditions

Apoptosis is a normal physiologic form of cell death that follows activation of either an intrinsic or extrinsic pathway. In the intrinsic, various stimuli, such as oxidative stress, lead to mitochondrial dysfunction and the release of pro-apoptotic factors. Ligand binding to cell surface death receptors, such as Fas, activates the extrinsic pathway. Due to the rapid clearance of apoptotic cells, detection and quantification of apoptotic cells is prone to underestimation. In the liver, the importance of apoptosis is evident both during development and homeostasis of the biliary tree. Apoptosis also plays a prominent role in liver pathogenesis. Induction of the extrinsic apoptotic pathway by cytotoxic lymphocytes predominates in autoimmune liver diseases, viral hepatitis, and liver allograft rejection. Biliary cell apoptosis is highly regulated by bcl-2 family members. Both the extrinsic and intrinsic pathways are active in alcohol-related liver disease. Overexpression of anti-apoptotic proteins and FasL allow liver tumor cells to evade tumor specific cytotoxic lymphocytes. Agents that modulate apoptosis may be of future therapeutic benefit in a number of liver diseases.