The role of central nervous system endothelial cell activation in the pathogenesis of hepatic encephalopathy.

I propose that central nervous system endothelial cells are directly or indirectly responsible for the brain pathology in hepatic encephalopathy, and that this damage to the central nervous system is mediated by specific cytokines and nitric oxide which activate endothelial cells and thereby alter their cell functions. Liver diseases are conditions characterized by high circulating levels of cytokines, namely interleukin-1, interleukin-6 and tumor necrosis factor. Interactions between these cytokines and central nervous system endothelial cells may trigger a cascade of events including enhanced blood-brain barrier permeability, brain edema, astrocyte alterations and gliosis. Cytokine-induced production of nitrogen reactive molecules by endothelial cells themselves may also lead to further cellular damage and neuronal dysfunction. This hypothesis may explain several characteristics of hepatic encephalopathy including reversibility, disease progression and clinical features. It also suggests potential ways of intervention.