title: Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation.
abstract: The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review.
authors.affiliation: Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
authors.forename: Dominic R
authors.initials: DR
authors.lastname: Aldridge
authors.affiliation: Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Tranah
authors.affiliation: Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
authors.forename: Debbie L
authors.initials: DL
authors.lastname: Shawcross
keywords: ATP, adenosine triphosphate; AoCLF, acute-on-chronic liver failure; BBB, blood–brain barrier; CBF, cerebral blood flow; CNS, central nervous system; GS, glutamine synthetase; HE, hepatic encephalopathy; ICH, intracranial hypertension; MHE, minimal hepatic encephalopathy; MPT, mitochondrial permeability transition; PAG, phosphate-activated glutaminase; PTP, permeability transition pore; TLR, toll-like receptor; ammonia; hepatic encephalopathy; iNOS, inducible nitric oxide synthase; infection; inflammation; systemic inflammatory response syndrome