Hepatic encephalopathy: a critical current review

Anna Hadjihambi1, Natalia Arias1, Mohammed Sheikh1, Rajiv Jalan1
1Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK

Tóm tắt

Từ khóa


Tài liệu tham khảo

American Association for the Study of Liver D, European Association for the Study of the L. Hepatic encephalopathy in chronic liver disease. Practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol. 2014;2014(61):642–59.

Amodio P. Hepatic encephalopathy: historical remarks. J Clin Exp Hepatol. 2015;5:S4–6.

Parsons-Smith BG, Summerskill WH, Dawson AM, Sherlock S. The electroencephalograph in liver disease. Lancet. 1957;273:867–71.

Rikkers L, Jenko P, Rudman D, Freides D. Subclinical hepatic encephalopathy: detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology. 1978;75:462–9.

Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy–definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002;35:716–21.

Cordoba J. New assessment of hepatic encephalopathy. J Hepatol. 2011;54:1030–40.

Bajaj JS, Cordoba J, Mullen KD, Amodio P, Shawcross DL, Butterworth RF, Morgan MY, et al. Review article: the design of clinical trials in hepatic encephalopathy—an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther. 2011;33:739–47.

Hassanein TI, Hilsabeck RC, Perry W. Introduction to the hepatic encephalopathy scoring algorithm (HESA). Dig Dis Sci. 2008;53:529–38.

Hassanein T, Blei AT, Perry W, Hilsabeck R, Stange J, Larsen FS, Brown RS Jr, et al. Performance of the hepatic encephalopathy scoring algorithm in a clinical trial of patients with cirrhosis and severe hepatic encephalopathy. Am J Gastroenterol. 2009;104:1392–400.

Ortiz M, Cordoba J, Doval E, Jacas C, Pujadas F, Esteban R, Guardia J. Development of a clinical hepatic encephalopathy staging scale. Aliment Pharmacol Ther. 2007;26:859–67.

Bajaj JS, Wade JB, Sanyal AJ. Spectrum of neurocognitive impairment in cirrhosis: implications for the assessment of hepatic encephalopathy. Hepatology. 2009;50:2014–21.

Montagnese S, Balistreri E, Schiff S, De Rui M, Angeli P, Zanus G, Cillo U, et al. Covert hepatic encephalopathy: agreement and predictive validity of different indices. World J Gastroenterol. 2014;20:15756–62.

Thomsen KL, Macnaughtan J, Tritto G, Mookerjee RP, Jalan R. Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy. PLoS ONE. 2016;11:e0146076.

Montagnese S, De Rui M, Angeli P et al. Neuropsychiatric performance in patients with cirrhosis: who is "normal"? J Hepatol 2017;66:825–835.

Prakash RK, Mullen KD. Is poor quality of life always present with minimal hepatic encephalopathy? Liver Int. 2011;31:908–10.

Agrawal S, Umapathy S, Dhiman RK. Minimal hepatic encephalopathy impairs quality of life. J Clin Exp Hepatol. 2015;5:S42–8.

Roman E, Cordoba J, Torrens M, Torras X, Villanueva C, Vargas V, Guarner C, et al. Minimal hepatic encephalopathy is associated with falls. Am J Gastroenterol. 2011;106:476–82.

Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs fitness to drive. Hepatology. 2004;39:739–45.

Schomerus H, Hamster W. Quality of life in cirrhotics with minimal hepatic encephalopathy. Metab Brain Dis. 2001;16:37–41.

Romero-Gomez M, Boza F, Garcia-Valdecasas MS, Garcia E, Aguilar-Reina J. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol. 2001;96:2718–23.

Ampuero J, Simon M, Montoliu C, Jover R, Serra MA, Cordoba J, Romero-Gomez M. Minimal hepatic encephalopathy and critical flicker frequency are associated with survival of patients with cirrhosis. Gastroenterology. 2015;149:1483–9.

Dhiman RK, Kurmi R, Thumburu KK, Venkataramarao SH, Agarwal R, Duseja A, Chawla Y. Diagnosis and prognostic significance of minimal hepatic encephalopathy in patients with cirrhosis of liver. Dig Dis Sci. 2010;55:2381–90.

Weissenborn K. Challenges in diagnosing hepatic encephalopathy. Neurochem Res. 2015;40:265–73.

Bajaj JS. Diagnosing minimal hepatic encephalopathy: from the ivory tower to the real world. Gastroenterology. 2015;149:1330–3.

Bernardin F, Maheut-Bosser A, Paille F. Cognitive impairments in alcohol-dependent subjects. Front Psychiatry. 2014;5:78.

Bocarsly ME, Fasolino M, Kane GA, LaMarca EA, Kirschen GW, Karatsoreos IN, McEwen BS, et al. Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function. Proc Natl Acad Sci USA. 2015;112:15731–6.

McAndrews MP, Farcnik K, Carlen P, Damyanovich A, Mrkonjic M, Jones S, Heathcote EJ. Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology. 2005;41:801–8.

Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, Durand F, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144:1426–37.

Cordoba J, Ventura-Cots M, Simon-Talero M, Amoros A, Pavesi M, Vilstrup H, Angeli P, et al. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF). J Hepatol. 2014;60:275–81.

Merli M, Lucidi C, Pentassuglio I, Giannelli V, Giusto M, Di Gregorio V, Pasquale C, et al. Increased risk of cognitive impairment in cirrhotic patients with bacterial infections. J Hepatol. 2013;59:243–50.

Romero-Gomez M, Montagnese S, Jalan R. Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure. J Hepatol. 2015;62:437–47.

Jalan R, Olde Damink SW, Hayes PC, Deutz NE, Lee A. Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. J Hepatol. 2004;41:613–20.

Bosoi CR, Rose CF. Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy. Metab Brain Dis. 2013;28:175–8.

Rama Rao KV, Norenberg MD. Brain energy metabolism and mitochondrial dysfunction in acute and chronic hepatic encephalopathy. Neurochem Int. 2012;60:697–706.

Zwingmann C. The anaplerotic flux and ammonia detoxification in hepatic encephalopathy. Metab Brain Dis. 2007;22:235–49.

Zwingmann C, Butterworth R. An update on the role of brain glutamine synthesis and its relation to cell-specific energy metabolism in the hyperammonemic brain: further studies using NMR spectroscopy. Neurochem Int. 2005;47:19–30.

Felipo V, Butterworth RF. Neurobiology of ammonia. Prog Neurobiol. 2002;67:259–79.

Joshi D, O’Grady J, Patel A, Shawcross D, Connor S, Deasy N, Willars C, et al. Cerebral edema is rare in acute-on-chronic liver failure patients presenting with high-grade hepatic encephalopathy. Liver Int. 2014;34:362–6.

Bosoi CR, Zwingmann C, Marin H, Parent-Robitaille C, Huynh J, Tremblay M, Rose CF. Increased brain lactate is central to the development of brain edema in rats with chronic liver disease. J Hepatol. 2014;60:554–60.

Hadjihambi A, De Chiara F, Hosford PS, Habtetion A, Karagiannis A, Davies N, Gourine AV, et al. Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease. Hepatology. 2017;65:1306–18.

Rackayova V, Braissant O, McLin VA, Berset C, Lanz B, Cudalbu C. 1H and 31P magnetic resonance spectroscopy in a rat model of chronic hepatic encephalopathy: in vivo longitudinal measurements of brain energy metabolism. Metab Brain Dis. 2016;31:1303–14.

Weiss N, Barbier Saint Hilaire P, Colsch B, Isnard F, Attala S, Schaefer A, Amador MD, et al. Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy. J Hepatol. 2016;65:1120–30.

Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology. 2010;51:1062–9.

Benyoub K, Muller M, Bonnet A, Simon R, Gazon M, Duperret S, Aubrun F, et al. Amounts of bile acids and bilirubin removed during single-pass albumin dialysis in patients with liver failure. Ther Apher Dial. 2011;15:504–6.

Tanaka N, Matsubara T, Krausz KW, Patterson AD, Gonzalez FJ. Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis. Hepatology. 2012;56:118–29.

Cordoba J, Alonso J, Rovira A, Jacas C, Sanpedro F, Castells L, Vargas V, et al. The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation. J Hepatol. 2001;35:598–604.

Josephs KA, Ahlskog JE, Klos KJ, Kumar N, Fealey RD, Trenerry MR, Cowl CT. Neurologic manifestations in welders with pallidal MRI T1 hyperintensity. Neurology. 2005;64:2033–9.

Bezzi P, Domercq M, Vesce S, Volterra A. Neuron-astrocyte cross-talk during synaptic transmission: physiological and neuropathological implications. Prog Brain Res. 2001;132:255–65.

Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918–34.

McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation. 2008;5:45.

Butterworth RF. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat Rev Gastroenterol Hepatol. 2013;10:522–8.

Shawcross DL, Wright G, Olde Damink SW, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis. 2007;22:125–38.

Coltart I, Tranah TH, Shawcross DL. Inflammation and hepatic encephalopathy. Arch Biochem Biophys. 2013;536:189–96.

Prakash R, Mullen KD. Mechanisms, diagnosis and management of hepatic encephalopathy. Nat Rev Gastroenterol Hepatol. 2010;7:515–25.

Hung TH, Lay CJ, Chang CM, Tsai JJ, Tsai CC, Tsai CC. The effect of infections on the mortality of cirrhotic patients with hepatic encephalopathy. Epidemiol Infect. 2013;141:2671–8.

Gluud LL, Dam G, Borre M, Les I, Cordoba J, Marchesini G, Aagaard NK, et al. Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: What is the evidence? Metab Brain Dis. 2013;28:221–5.

Gluud LL, Vilstrup H, Morgan MY. Nonabsorbable disaccharides for hepatic encephalopathy: a systematic review and meta-analysis. Hepatology. 2016;64:908–22.

Als-Nielsen BGL, Gluud C. Treatment of hepatic encephalopathy: authors’ reply. BMJ. 2004;329:112.

Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31:1012–7.

Sharma P, Sharma BC, Agrawal A, Sarin SK. Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose. J Gastroenterol Hepatol. 2012;27:1329–35.

Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs polyethylene glycol 3350–electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med. 2014;174:1727–33.

Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology. 1977;72:573–83.

Strauss E, Tramote R, Silva EP, Caly WR, Honain NZ, Maffei RA, de Sa MF. Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology. 1992;39:542–5.

Patidar KR, Bajaj JS. Antibiotics for the treatment of hepatic encephalopathy. Metab Brain Dis. 2013;28:307–12.

Wu D, Wu SM, Lu J, Zhou YQ, Xu L, Guo CY. Rifaximin versus nonabsorbable disaccharides for the treatment of hepatic encephalopathy: a meta-analysis. Gastroenterol Res Pract. 2013;2013:236963.

Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013;108:1458–63.

Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362:1071–81.

Poh Z, Chang PE. A current review of the diagnostic and treatment strategies of hepatic encephalopathy. Int J Hepatol. 2012;2012:480309.

Zullo A, Ridola L, Hassan C. Rifaximin therapy and Clostridium difficile infection: a note of caution. J Clin Gastroenterol. 2013;47:737.

Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of l-ornithine l-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology. 2009;136:2159–68.

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. J Gastroenterol Hepatol. 2013;28:783–92.

Hadjihambi A, Khetan V, Jalan R. Pharmacotherapy for hyperammonemia. Expert Opin Pharmacother. 2014;15:1685–95.

Ventura-Cots M, Arranz JA, Simon-Talero M, Torrens M, Blanco A, Riudor E, Fuentes I, et al. Safety of ornithine phenylacetate in cirrhotic decompensated patients: an open-label, dose-escalating, single-cohort study. J Clin Gastroenterol. 2013;47:881–7.

Jover-Cobos M, Noiret L, Lee K, Sharma V, Habtesion A, Romero-Gomez M, Davies N, et al. Ornithine phenylacetate targets alterations in the expression and activity of glutamine synthase and glutaminase to reduce ammonia levels in bile duct ligated rats. J Hepatol. 2014;60:545–53.

Ytrebo LM, Kristiansen RG, Maehre H, Fuskevag OM, Kalstad T, Revhaug A, Cobos MJ, et al. l-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure. Hepatology. 2009;50:165–74.

Ventura-Cots M, Concepcion M, Arranz JA, Simon-Talero M, Torrens M, Blanco-Grau A, Fuentes I, et al. Impact of ornithine phenylacetate (OCR-002) in lowering plasma ammonia after upper gastrointestinal bleeding in cirrhotic patients. Therap Adv Gastroenterol. 2016;9:823–35.

Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Alexeeva O, Zupanets IA, et al. Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy. Hepatology. 2014;59:1073–83.

Hassanein TI, Tofteng F, Brown RS Jr, McGuire B, Lynch P, Mehta R, Larsen FS, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology. 2007;46:1853–62.

Laleman W, Wilmer A, Evenepoel P, Elst IV, Zeegers M, Zaman Z, Verslype C, et al. Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure. Crit Care. 2006;10:R108.

Banares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M, Saliba F, et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology. 2013;57:1153–62.

An J, Kim KW, Han S, Lee J, Lim YS. Improvement in survival associated with embolisation of spontaneous portosystemic shunt in patients with recurrent hepatic encephalopathy. Aliment Pharmacol Ther. 2014;39:1418–26.

Laleman W, Simon-Talero M, Maleux G, Perez M, Ameloot K, Soriano G, Villalba J, et al. Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy. Hepatology. 2013;57:2448–57.

Saad WE. Portosystemic shunt syndrome and endovascular management of hepatic encephalopathy. Semin Intervent Radiol. 2014;31:262–5.

Bosoi CR, Parent-Robitaille C, Anderson K, Tremblay M, Rose CF. AST-120 (spherical carbon adsorbent) lowers ammonia levels and attenuates brain edema in bile duct-ligated rats. Hepatology. 2011;53:1995–2002.

Bajaj JS, Sheikh MY, Chojkier M, Balart L, Sherker AH, Vemuru R, Sussman NL, Vierling J, Morelli G, Anderson KE, Harris MS, Mullen KD. 190 AST-120 (spherical carbon adsorbent) in covert hepatic encephalopathy: results of the ASTUTE trial. J Hepatol. 2013;58:S84.

McGee RG, Bakens A, Wiley K, Riordan SM, Webster AC. Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev 2011:CD008716

Zhao LN, Yu T, Lan SY, Hou JT, Zhang ZZ, Wang SS, Liu FB. Probiotics can improve the clinical outcomes of hepatic encephalopathy: an update meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39:674–82.

Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol. 2012;107:1043–50.

Stein TP. Nutrition and protein turnover: a review. J Parenter Enteral Nutr. 1982;6:444–54.

Cunningham-Rundles S. Effect of nutritional status on immunological function. Am J Clin Nutr. 1982;35:1202–10.

Merli M, Riggio O, Dally L. Does malnutrition affect survival in cirrhosis? PINC (Policentrica Italiana Nutrizione Cirrosi). Hepatology. 1996;23:1041–6.

Cordoba J, Lopez-Hellin J, Planas M, Sabin P, Sanpedro F, Castro F, Esteban R, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. 2004;41:38–43.

Dam G, Keiding S, Munk OL, Ott P, Buhl M, Vilstrup H, Bak LK, et al. Branched-chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects. Am J Physiol Gastrointest Liver Physiol. 2011;301:G269–77.

Gluud LL, Dam G, Borre M, Les I, Cordoba J, Marchesini G, Aagaard NK, et al. Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials. J Nutr. 2013;143:1263–8.

Goulenok C, Bernard B, Cadranel JF, Thabut D, Di Martino V, Opolon P, Poynard T. Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis. Aliment Pharmacol Ther. 2002;16:361–72.

Als-Nielsen B, Gluud LL, Gluud C. Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2004

Therrien G, Rose C, Butterworth J, Butterworth RF. Protective effect of l-carnitine in ammonia-precipitated encephalopathy in the portacaval shunted rat. Hepatology. 1997;25:551–6.

Jiang Q, Jiang G, Shi KQ, Cai H, Wang YX, Zheng MH. Oral acetyl-l-carnitine treatment in hepatic encephalopathy: view of evidence-based medicine. Ann Hepatol. 2013;12:803–9.

Larsen FS, Hansen BA, Ejlersen E, Secher NH, Clemmesen JO, Tygstrup N, Knudsen GM. Cerebral blood flow, oxygen metabolism and transcranial Doppler sonography during high-volume plasmapheresis in fulminant hepatic failure. Eur J Gastroenterol Hepatol. 1996;8:261–5.

Larsen FS, Schmidt LE, Bernsmeier C, Rasmussen A, Isoniemi H, Patel VC, Triantafyllou E, et al. High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial. J Hepatol. 2016;64:69–78.

Ahboucha S, Layrargues GP, Mamer O, Butterworth RF. Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy. Ann Neurol. 2005;58:169–70.

Bosman DK, van den Buijs CA, de Haan JG, Maas MA, Chamuleau RA. The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat. Gastroenterology. 1991;101:772–81.

Ahboucha S, Coyne L, Hirakawa R, Butterworth RF, Halliwell RF. An interaction between benzodiazepines and neuroactive steroids at GABA A receptors in cultured hippocampal neurons. Neurochem Int. 2006;48:703–7.

Kao D, Roach B, Park H, Hotte N, Madsen K, Bain V, Tandon P. Fecal microbiota transplantation in the management of hepatic encephalopathy. Hepatology. 2016;63:339–40.

Cauli O, Rodrigo R, Piedrafita B, Boix J, Felipo V. Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts. Hepatology. 2007;46:514–9.

Jiang W, Desjardins P, Butterworth RF. Minocycline attenuates oxidative/nitrosative stress and cerebral complications of acute liver failure in rats. Neurochem Int. 2009;55:601–5.

Hernandez-Rabaza V, Agusti A, Cabrera-Pastor A, Fustero S, Delgado O, Taoro-Gonzalez L, Montoliu C, et al. Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms. J Neuroinflammation. 2015;12:195.

Hadjihambi A, Rose CF, Jalan R. Novel insights into ammonia-mediated neurotoxicity pointing to potential new therapeutic strategies. Hepatology. 2014;60:1101–3.