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Update in Hepatic Encephalopathy

      In the forthcoming issues of the Journal of Clinical and Experimental Hepatology, the reader will find a series of articles that represent a consolidated effort at clarifying and simplifying our views on pathogenesis, classification and management of hepatic encephalopathy (HE). The International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) organized 17th ISHEN Symposium that took place in Gurugram, India from 9 to 11 March 2017. Global experts convened for presenting their review of current literature on various aspects of HE, from nomenclature to etiology, pathogenesis, classification, diagnosis, treatment and to outcome. After an extensive discussion by the experts, the team have now compiled a series of review articles based on their research and clinical experience in this subject. Furthermore, these articles have been rigorously peer reviewed and compiled by the editorial board. A balanced opinion coming from different viewpoints of the experts is now presented as a Special Section: Update in Hepatic Encephalopathy.
      The experts have discussed new insights in the pathogenesis of HE. Ochoa-Sanchez and Rose
      • Ochoa-Sanchez R.
      • Rose C.
      Pathogenesis of hepatic encephalopathy in chronic liver disease.
      discussed synergic interplay of pathological factors such as ammonia inflammation, oxidative stress,
      • Lemberg A.
      • Fernández M.A.
      Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress.
      bile acids,
      • Quinn M.
      • McMillin M.
      • Galindo C.
      • Frampton G.
      • Pae H.Y.
      • DeMorrow S.
      Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms.
      lactate,
      • Bosoi C.R.
      • Rose C.F.
      Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy.
      and extracellular glutamate and glutamatergic neurotransmission
      • Cauli O.
      • Rodrigo R.
      • Llansola M.
      • et al.
      Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy.
      in the progression and severity of HE is emphasized. The synergic interaction between precipitating factors may better explain the progression and severity of HE in chronic liver disease. The review by Jayakumar and Norenberg
      • Jayakumar A.R.
      • Norenberg M.D.
      Hyperammonemia in hepatic encephalopathy.
      summarizes the central role of ammonia in the pathogenesis of HE in human as well as in experimental models of acute and chronic liver failure.
      • Ott P.
      • Vilstrup H.
      Cerebral effects of ammonia in liver disease: current hypotheses.
      There is compelling evidence for a multifactorial causation in HE with factors like infections,
      • Butterworth R.F.
      The concept of “the inflamed brain” in acute liver failure: mechanisms and new therapeutic opportunities.
      reactive oxygen species,
      • Häussinger D.
      • Schliess F.
      Pathogenetic mechanisms of hepatic encephalopathy.
      inflammatory cytokines,
      • Jain L.
      • Sharma B.C.
      • Srivastava S.
      • Puri S.K.
      • Sharma P.
      • Sarin S.
      Serum endotoxin, inflammatory mediators, and magnetic resonance spectroscopy before and after treatment in patients with minimal hepatic encephalopathy.
      altered cerebral blood flow,
      • Iversen P.
      • Sorensen M.
      • Bak L.K.
      • et al.
      Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy.
      hyperthermia,
      • Jalan R.
      • Olde Daminck S.W.
      • Deutz N.E.
      • et al.
      Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure.
      hyponatremia,
      • Guevara M.
      • Baccaro M.E.
      • Torre A.
      • et al.
      Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: a prospective study with time-dependent analysis.
      lactic acid,
      • Witt A.M.
      • Larsen F.S.
      • Bjerring P.N.
      Accumulation of lactate in the rat brain during hyperammonaemia is not associated with impaired mitochondrial respiratory capacity.
      neurosteroids,
      • Butterworth R.F.
      Neurosteroids in hepatic encephalopathy: novel insights and new therapeutic opportunities.
      and more recently, the accumulation of cholesterol
      • McMillin M.
      • Grant S.
      • Frampton G.
      • et al.
      FXR-mediated cortical cholesterol accumulation contributes to the pathogenesis of type A hepatic encephalopathy.
      contributing to the pathogenesis. Azhari and Swain
      • Azhari H.
      • Swain M.
      Role of Peripheral Inflammation in Hepatic Encephalopathy.
      elaborate on the role of peripheral inflammation in the pathogenesis of HE. This article explores the new concept of periphery-to-brain communication pathways such as the gut–liver–brain axis as opposed to conventional pathways that involve neural networks
      • Jao T.
      • Schröter M.
      • Chen C.L.
      • et al.
      Functional brain network changes associated with clinical and biochemical measures of the severity of hepatic encephalopathy.
      and humoral (blood-borne) pathways, with increased circulating levels of endotoxin and cytokines, which activate cerebral endothelial cells and immune cells.
      • D’Mello C.
      • Le T.
      • Swain M.G.
      Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor alpha signaling during peripheral organ inflammation.
      Bjerring et al.
      • Bjerring P.
      • Gluud L.
      • Larsen F.S.
      Cerebral blood flow and metabolism in hepatic encephalopathy – a meta-analysis.
      present a meta-analysis on the published data on cerebral blood flow (CBF) and metabolic rates from clinical studies of patients with HE. They provide interesting conclusions from the analysis. Firstly, HE due to portacaval shunting (type B) was associated to an increased CBF, in contrast to studies of patients with HE of type A and C and secondly they found a cerebral accumulation of lactate due to hypoxic metabolism. Görg et al.
      • McPhail M.J.
      • Leech R.
      • Grover V.P.
      • et al.
      Modulation of neural activation following treatment of hepatic encephalopathy.
      comment on ammonia-induced senescence in astrocytes that involves glutamine synthesis-dependent formation of reactive oxygen species.
      • Görg B.
      • Karababa A.
      • Häussinger D.
      Hepatic encephalopathy and astrocyte senescence.
      They review the available data on premature senescence in astrocytes as a functional consequence of osmotic and oxidative stress in the pathogenesis of HE.
      • Schliess F.
      • Görg B.
      • Häussinger D.
      Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm.
      Finally, Butterworth et al.
      • Butterworth R.F.
      • Kircheis G.
      • Hilger N.
      • McPhail M.J.
      Efficacy of l-ornithine l-aspartate for the treatment of hepatic encephalopathy and hyperammonemia in cirrhosis: systematic review and meta-analysis of randomized controlled trials.
      present a systematic review and meta-analysis on the efficacy of l-ornithine l-aspartate (LOLA). They have concluded that LOLA was effective for improvement of mental state in all types of HE,
      • Kircheis G.
      • Nilius R.
      • Held C.
      • et al.
      Therapeutic efficacy of l-ornithine- l-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo controlled, double-blind study.
      lowering of blood ammonia
      • Bai M.
      • He C.
      • Yin Z.
      • et al.
      Randomised clinical trial: l-ornithine-l-aspartate reduces significantly the increase of venous ammonia concentration after TIPSS.
      and even the oral formulation was useful in minimal HE.
      • Bai M.
      • Yang Z.
      • Qi X.
      • Fan D.
      • Han G.
      l-Ornithine l-aspartate for hepatic encephalopathy in patients with cirrhosis: a meta-analysis of randomized controlled trials.
      An enhanced understanding of the pathways that link the gut, liver and the brain in HE will allow for the development of targeted therapies to better manage the neurological, cognitive and behavioural complications of the liver disease. The Editors believe that the resulting compilation of reviews is informative and hope this appreciation will be shared by the reader.

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