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Special Section: Update in Hepatic Encephalopathy- Part III

      The current issue of the Journal of Clinical and Experimental Hepatology presents the third and last series of peer reviewed review articles based on their research and clinical experience as a Special Section: “Update in Hepatic Encephalopathy- Part III”. The International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) organized 17th ISHEN Symposium that took place in Gurugram, India from 9th to 11th March 2017 where experts discussed various aspects of HE, from nomenclature to etiology, pathogenesis, classification, diagnosis, treatment and to outcome and the current section represents a consolidated effort at presenting the consensus on pathogenesis, monitoring and management of hepatic encephalopathy (HE).
      Singh and Anand
      • Anand A.C.
      • Singh P.
      Neurological recovery after recovery from acute liver failure: Is it complete?.
      discuss new insights on the residual cognitive defects after neurological recovery in acute liver failure (ALF). Structural damage and persistent neurological abnormalities seen after ALF are more likely to be related to cerebral edema, raised intracranial tension and cerebral hypoxemia, while neurocognitive dysfunctions are likely related to the critical illness. Evaluation of cerebral injury in ALF using Magnetic Resonance imaging with or without spectroscopy, PET (positron emission tomography) scan and EEG (electroencephalography) reveals structural abnormalities as well as cognitive impairment, which may take months to resolve.
      • Naegele T.
      • Grodd W.
      • Viebahn R.
      • Seeger U.
      • Klose U.
      • Seitz D.
      • et al.
      MR imaging and 1H spectroscopy of brain metabolites in hepatic encephalopathy: time-course of renormalization after liver transplantation.
      • Burra P.
      • Dam M.
      • Chierichetti F.
      • Tedeschi U.
      • Senzolo M.
      • Sale E.
      • et al.
      18F-fluorodeoxyglucose positron emission tomography study of brain metabolism in cirrhosis: effect of liver transplantation.
      Weissenborn
      • Weissenborn K.
      Minimal /Covert Hepatic Encephalopathy Impact of co-morbid conditions.
      reviews the importance of minimal or covert encephalopathy which affects motor speed, attention and reasoning and are affected by a multitude of factors in cirrhosis, neuroinflammation, hyperammonemia,
      • Shawcross D.L.
      • Davies N.A.
      • Williams R.
      • Jalan R.
      Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
      hyponatremia,
      • Guevara M.
      • Baccaro M.E.
      • Ríos J.
      • Martín-Llahí M.
      • Uriz J.
      • Ruiz del Arbol L.
      • et al.
      Risk factors for hepatic encephalopathy in patients with cirrhosis and refractory ascites: relevance of serum sodium concentration.
      sepsis
      • Ampuero J.
      • Ranchal I.
      • del Mar Díaz-Herrero M.
      • del Campo J.A.
      • Bautista J.D.
      • Romero-Gómez M.
      Role of diabetes mellitus on hepatic encephalopathy.
      and co morbidities like diabetes
      • Merli M.
      • Lucidi C.
      • Pentassuglio I.
      • Giannelli V.
      • Giusto M.
      • Di Gregorio V.
      • et al.
      Increased risk of cognitive impairment in cirrhotic patients with bacterialinfections.
      and alcohol intake. Fluid and Duarte-Rojo
      • Fluid C.R.
      • Duarte-Rojo A.
      Prognostic implications of minimal/covert hepatic encephalopathy:large-scale validation cohort studies.
      describe the prognostic usefulness of minimal or covert HE by analyzing >100 large-scale validation cohort studies which confirm MHE or covert HE as predictors of overt hepatic encephalopathy, decreased quality of life (QOL), and mortality.
      • Riggio O.
      • Amodio P.
      • Farcomeni A.
      • Merli M.
      • Nardelli S.
      • Pasquale C.
      • et al.
      A Model for Predicting Development of Overt Hepatic Encephalopathy in Patients With Cirrhosis.
      • Thomsen K.L.
      • Macnaughtan J.
      • Tritto G.
      • Mookerjee R.P.
      • Jalan R.
      Clinical andpathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.
      DeMorrow
      • DeMorrow S.
      Bile acids in hepatic encephalopathy.
      reviews the role of bile acid signaling in key pathogenic features of HE development and includes discussion of some possible explanations of potential downstream consequences of aberrant bile acid signaling. The role of Farnesoid X receptor (FXR) immunoreactivity,
      • Degirolamo C.
      • Rainaldi S.
      • Bovenga F.
      • Murzilli S.
      • Moschetta A.
      Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice.
      intestinal microbiota
      • Ramirez-Perez O.
      • Cruz-Ramon V.
      • Chinchilla-Lopez P.
      • Mendez-Sanchez N.
      The Role of the Gut Microbiota in Bile Acid Metabolism.
      and Takeda G-protein coupled receptor (TGR5) expression
      • McMillin M.A.
      • Frampton G.A.
      • Seiwell A.P.
      • Patel N.S.
      • Jacobs A.N.
      • DeMorrow S.
      TGFbeta1 exacerbates blood-brain barrier permeability in a mouse model of hepatic encephalopathy via upregulation of MMP9 and downregulation of claudin-5.
      is also explained lucidly.
      Lattanzi et al.
      • Lattanzi B.
      • D’Ambrosio D.
      • Merli M.
      Hepatic encephalopathy and sarcopenia: Two faces of the same metabolic alteration.
      present the available data on the synergistic effect of HE and sarcopenia, which affects patients with advanced cirrhosis and worsens their outcome. The brain-muscle-liver axis is de-ranged and muscle tissue becomes the main alternative organ for ammonia metabolism via glutaminase by incorporating it into glutamine.
      • Dasarathy S.
      Myostatin and beyond in cirrhosis: all roads lead to sarcopenia.
      Ammonia itself impairs muscle protein synthesis in part through the up-regulation of myostatin production.
      • Qiu J.
      • Tsien C.
      • Thapalaya S.
      • et al.
      Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis.
      Myostatin, a member of the TGFβ superfamily, is a powerful catabolic signal that inhibits protein synthesis and satellite cells proliferation and differentiation through SMAD 2/3 signaling.
      Aamann, et al.
      • Aamann L.
      • Tandon P.
      • Bémeur C.
      Role of exercise in the management of hepatic encephalopathy: Experience from animal and human studies.
      define the concepts of frailty, sarcopenia and malnutrition in cirrhosis review the role of optimizing muscle mass in patients with HE using exercise as a potential strategy to decrease ammonia levels. Further studies measuring the impact of exercise training on HE, using animal as well as human studies, are warranted.
      • Rombouts K.
      • Bémeur C.
      • Rose C.F.
      Targeting the muscle for the treatment and prevention of hepatic encephalopathy.
      Finally Ridola et al.
      • Ridola L.
      • Nardelli S.
      • Gioia S.
      • Riggio O.
      How to design a multicenter clinical trial in Hepatic Encephalopathy.
      describe the methodology for designing randomized controlled trials in three different settings in HE: 1) management of hospitalized patients with episodic HE; 2) secondary prophylaxis in patients following an episode of HE; and 3) management of minimal/covert HE.
      This is the final and Part III compilation of “Update in Hepatic Encephalopathy”. The Editors believe that the resulting compilation of reviews is extremely informative and hope the readers will share this appreciation.

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