title: Systemic inflammation and ammonia in hepatic encephalopathy.
abstract: Infection and inflammation have been associated with the development of delirium for many centuries and there is a rapidly growing evidence base supporting the role of inflammation in exacerbating the neurological manifestations of both acute and chronic liver failure. Inflammation in the context of hepatic encephalopathy (HE) can arise directly within the brain itself resulting in astrocytic, microglial and neuronal dysfunction, impacting on the development of 'brain failure'. Inflammation may also develop systemically and indirectly influence brain function. Systemic inflammation develops following liver injury, resulting in hyperammonemia and a 'cytotoxic soup' of pro-inflammatory mediators which are released into the circulation and modulate the impact of ammonia on the brain. The aim of this review is to summarise the current evidence base supporting the synergistic role of systemic inflammation and hyperammonemia in the pathogenesis of hepatic encephalopathy. Systemic inflammation and ammonia induce neutrophil degranulation and release reactive oxygen species into the peripheral circulation that may ultimately cross the blood brain barrier. Circulating endotoxin arising from the gut (bacterial translocation), superimposed sepsis, and hyperammonemia upregulate the expression of microbial pattern recognition receptors such as Toll-like receptors. The early recognition and management of systemic inflammation may not only facilitate improved outcomes in HE but supports the development of novel therapeutic strategies that reduce circulating endotoxemia and immune cell dysfunction.
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, UK.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Tranah
authors.forename: Godhev K Manakkat
authors.initials: GK
authors.lastname: Vijay
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Ryan
authors.forename: Debbie L
authors.initials: DL
authors.lastname: Shawcross
mesh_terms: D000641:Ammonia / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000188:drug therapy / Q000209:etiology*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000150:complications*; D017093:Liver Failure / Q000276:immunology; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications
chemical_list: D000641:Ammonia