Mechanisms of Liver Injury

The death of constituent cell populations of the liver is a central component of liver injury cascades. Hepatocytes are targeted by most injurious stimuli, though other cells types are affected as well. Cell death in the liver can occur via apoptosis or necrosis. Apoptosis can be initiated via death receptor-mediated pathways, the extrinsic pathway, or from intracellular perturbations, the intrinsic pathway. Mitochondrial permeabilization is required for hepatocyte apoptosis, and both intrinsic and extrinsic pathways converge on mitochondria. Effector caspases are activated downstream of mitochondria, and cleave several cellular targets to result in the characteristic apoptotic morphology. Dead cells release damage-associated molecular patterns that activate the innate immune system and downstream inflammatory cascades. Ongoing apoptosis in the liver stimulates Kupffer cells, and activates hepatic stellate cell-stimulating fibrosis. Therapies aimed at preventing hepatocyte apoptosis show promise in experimental and clinical settings.