[Pathogenetic mechanisms of acute liver failure]

Mechanistic investigations into the pathophysiology of acute liver failure after hepatic ischemia and reperfusion revealed that reactive oxygen species are generated intracellularly only after prolonged periods of ischemia. Parenchymal cell injury during ischemia seems to be a prerequisite for a significant intracellular oxidant stress. However, after shorter periods of ischemia without significant ischemic injury, reactive oxygen is formed predominantly in the extracellular (vascular) space with Kupffer cells and later also with neutrophils as the main sources. Both cell types generate a variety of inflammatory and cytotoxic mediators and are involved in a complex, self-aggravating injury mechanism leading to massive liver cell necrosis and a systemic inflammatory reaction, which may also affect other organs. Integrins and cellular adhesion molecules are critical for neutrophil accumulation and formation of reactive oxygen. An important aspect of the pathogenesis is the manifestation of a "priming" effect for enhanced reactive oxygen formation, but not cytokine generation by Kupffer cells and neutrophils. Priming of phagocytes means that even after short periods of hepatic ischemia (20-30 min) with only moderate reperfusion injury, secondary stimuli, e.g. as generated during sepsis, can cause a potentiation of the postischemic oxidant stress and liver injury and may eventually lead to acute liver failure.