Emerging Role of NF-κB in the Pathogenesis of Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a common clinical complication in patients with severe liver disease. While the pathogenesis of HE is incompletely understood, ammonia has been strongly implicated as an important etiological factor, and astrocytes appear to be the primary target of its neurotoxicity. In addition to ammonia, infection and inflammation have increasingly been implicated in the pathogenesis of HE. Nuclear factor-kappa B (NF-kappa B), a major signaling molecule involved in inflammation and immune responses, is activated in cultured astrocytes treated with ammonia, as well as in brains of experimental animals with HE. Such activation may be a consequence of systemic inflammatory events, or as a result of hyperammonemia-induced central nervous system inflammation. Once activated, NF-kappa B stimulates the transcription of genes involved in immune responses and inflammation, that produce factors which may contribute to cellular dysfunction such as astrocyte swelling and glutamate transport impairment as occurs in HE. This review summarizes the evidence for NF-kappa B activation in HE, the signaling pathways involved in its activation, and consequences of such activation.