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Pathophysiology, diagnosis, and management of hepatic encephalopathy

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Abstract

Hepatic encephalopathy (HE) is a common complication of cirrhosis of the liver. It is also extremely debilitating, with an untreated 3-year survival of only 23 %. While the exact pathophysiology of HE has yet to be elucidated, a number of contributing factors have been described. Abnormal levels and altered metabolism of ammonia play a central role. Recently, inflammation has also been identified as a contributor to HE. Improved understanding of the pathophysiology of HE is crucial, as current therapy centers on reduction of the body’s ammonia load. Lactulose is the first-line therapy for HE, with some antibiotics recently showing promise for improved outcomes in patients with HE. The role of anti-inflammatory therapies has yet to be evaluated.

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References

  • Agrawal A, Sharma BC, Sharma P, Sarin SK (2012) Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol 107:1043–1050

    Article  CAS  PubMed  Google Scholar 

  • Als-Nielsen B, Gluud LL, Gluud C (2004) Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database Syst Rev CD003044

  • American College of Chest Physicians/Society of Critical Care Medicine (1992) Consensus conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864–874

    Article  Google Scholar 

  • Amodio P, Bemeur C, Butterworth R, Cordoba J, Kato A, Montagnese S, Uribe M, Vilstrup H, Morgan MY (2013) The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus. Hepatology 58:325–336

    Article  CAS  PubMed  Google Scholar 

  • Bachmann C (2002) Mechanisms of hyperammonemia. Clin Chem Lab Med 40(7):653–662

    Article  CAS  PubMed  Google Scholar 

  • Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, Monteith P, Noble NA, Sikaroodi M, Gillevet PM (2012) Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol 303:G675–G685

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bass NM, Mullen KD, Sanyal A et al (2010) Rifaximin treatment in hepatic encephalopathy. N Engl J Med 362:1071–1081

    Article  CAS  PubMed  Google Scholar 

  • Berk DP, Chalmers T (1970) Deafness complicating antibiotic therapy of hepatic encephalopathy. Ann Intern Med 73:393–396

    Article  CAS  PubMed  Google Scholar 

  • Bianchi GP, Marchesini G, Fabbri A, Rondelli A, Bugianesi E, Zoli M, Pisi E (1993) Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison. J Intern Med 233:385–392

    Article  CAS  PubMed  Google Scholar 

  • Blei AT, Cordoba J (2001) Hepatic encephalopathy. Am J Gastroenterol 96:1968–1976

    Article  CAS  PubMed  Google Scholar 

  • Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, Rodes J (1999) Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 30:890–895

    Article  CAS  PubMed  Google Scholar 

  • Butterworth RF, Giguère JF, Michaud J, Lavoie J, Layrargues GP (1987) Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol 6:1–12

    Article  CAS  PubMed  Google Scholar 

  • Clay AS, Hainline BE (2007) Hyperammonemia in the ICU. Chest 132:1368–1378

    Article  CAS  PubMed  Google Scholar 

  • Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL (1977) Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 72:573–583

    CAS  PubMed  Google Scholar 

  • Cordoba J, Lopez-Hellín J, Planas M, Sabin P, Sanpedro F, Castro F, Esteban R, Guardia J (2004) Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol 41:38–43

    Article  CAS  PubMed  Google Scholar 

  • Dam G, Keiding S, Munk OL, Ott P, Vilstrup H, Bak LK, Waagepetersen HS, Arne Schousboe, Sørenson M (2013) Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake. Hepatology 57:258–265

    Article  CAS  PubMed  Google Scholar 

  • Dawson AM, McLaren J, Sherlock S (1957) Neomycin in the treatment of hepatic coma. Lancet 2:1263–1268

    Article  Google Scholar 

  • Didier N, Romero IA, Creminon C, Wijkhuisen A, Grassi J, Mabondzo A (2003) Secretion of interleukin-1b by astrocytes mediates endothelin-1 and tumour necrosis factor-a effects on human brain microvascular endothelial cell permeability. J Neurochem 86:246–254

    Article  CAS  PubMed  Google Scholar 

  • Felipo V, Urios A, Montesinos E, Molina I, Garcia-Torres ML, Civera M, Del Olmo JA, Ortega J, Martinez-Valls J, Serra MA, Cassinello N, Wassel A, Jorda E, Montoliu C (2012) Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metab Brain Dis 27:51–58

    Article  CAS  PubMed  Google Scholar 

  • Ferenci P, Herneth A, Steindl P (1996) Newer approaches to therapy of hepatic encephalopathy. Semin Liver Dis 16:329–338

    Article  CAS  PubMed  Google Scholar 

  • Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT (2002) Hepatic encephalopathy—Definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35:716–721

    Article  PubMed  Google Scholar 

  • Hassanein TI, Tofteng F, Brown RS Jr et al (2007) Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology 46:1853–1862

    Article  CAS  PubMed  Google Scholar 

  • Heemann U, Treichel U, Loock J et al (2002) Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study. Hepatology 36:949–958

    Article  CAS  PubMed  Google Scholar 

  • Horst D, Grace ND, Conn HO, Schiff E, Schenker S, Viteri A, Law D, Atterbury CE (1984) Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial. Hepatology 4:279–287

    Article  CAS  PubMed  Google Scholar 

  • Jiang ZD, DuPont HL (2005) Rifaximin: in vitro and in vivo antibacterial activity—a review. Chemotherapy 51:67–72

    Article  CAS  PubMed  Google Scholar 

  • Jiang Q, Jiang XH, Zheng MH, Jiang LM, Chen YP, Wang L (2008) Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol 20:1064

    Article  CAS  PubMed  Google Scholar 

  • Jiang Q, Jiang XH, Zheng MH, Chen YP (2009) L-ornithine-l-aspartate in the management of hepatic encephalopathy: a meta-analysis. J Gastroenterol Hepatol 24:9–14

    Article  CAS  PubMed  Google Scholar 

  • Khungar V, Poordad F (2012) Hepatic encephalopathy. Clin Liver Dis 16:301–320

    Article  PubMed  Google Scholar 

  • Kramer L, Tribl B, Gendo A, Zauner C, Schneider B, Ferenci P, Madl C (2000) Parial pressure of ammonia versus ammonia in hepatic encephalopathy. Hepatology 31:30–34

    Article  CAS  PubMed  Google Scholar 

  • Kundra A, Jain A, Banga A, Bajaj G, Kar P (2005) Evaluation of plasma ammonia levels in patients with acute liver failure and chronic liver disease and its correlation with the severity of hepatic encephalopathy and clinical features of raise intracranial tension. Clin Biochem 38:696–699

    Article  CAS  PubMed  Google Scholar 

  • Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM (2004) Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 39:1441–1449

    Article  PubMed  Google Scholar 

  • Lockwood AH (1987) Metabolic encephalopathies: opportunities and challenges. J Cerebr Blood F Met 7:523–526

    Article  CAS  Google Scholar 

  • Lockwood AH, McDonald JM, Reiman RE, Gelbard AS, Laughlin JS, Duffy TE, Plum F (1979) The dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia. J Clin Invest 63:449–460

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lockwood AH, Yap EW, Wong WH (1991) Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood F Metab 11(2):337–341

    Article  CAS  Google Scholar 

  • Luo M, Li L, Yang E, Dai C, Liang S, Cao W (2013) Correlation between interleukin-6 and ammonia in patients with overt hepatic encephalopathy due to cirrhosis. Clin Res Hepatol Gastroenterol 37:384–390

    Article  CAS  PubMed  Google Scholar 

  • Marchesini G, Dioguardi FS, Bianchi GP, Zoli M, Bellati G, Roffi L, Martines D, Abbiati R (1990) Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. The Italian Multicenter Study Group. J Hepatol 11:92–101

    Article  CAS  PubMed  Google Scholar 

  • Mas A, Rodes J, Sunyer L et al (2003) Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol 38:51–58

    Article  CAS  PubMed  Google Scholar 

  • Miglio F, Valpiani D, Rossellini SR, Ferrieri A (1997) Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy. A double-blind, randomised trial. Curr Med Res Opin 13:593–601

    Article  CAS  PubMed  Google Scholar 

  • Morgan MH, Read AE, Speller DC (1982) Treatment of hepatic encephalopathy with metronidazole. Gut 23:1–7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Morgan TR, Moritz TE, Mendenhall CL, Haas R (1995) Protein consumption and hepatic encephalopathy in alcoholic hepatitis. VA Cooperative Study Group #275. J Am Coll Nutr 14:152–158

    Article  CAS  PubMed  Google Scholar 

  • Mortensen PB (1992) The effect of oral-administered lactulose on colonic nitrogen metabolism and excretion. Hepatology 16:1350–1356

    Article  CAS  PubMed  Google Scholar 

  • Nicolao F, Efrati C, Masini A, Merli M, Attili AF, Riggio O (2003) Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy. J Hepatol 38:441–446

    Article  CAS  PubMed  Google Scholar 

  • Odeh M, Sabo E, Srugo I, Oliven A (2005) Relationship between tumour necrosis factor-alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure. Ann Med 37:603–612

    Article  CAS  PubMed  Google Scholar 

  • Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van Lente F, Arroliga AC, Mullen KD (2003) Ammonia and hepatic encephalopathy. Am J Med 114:188–193

    Article  CAS  PubMed  Google Scholar 

  • Orlandi F, Feddara U, Candelaresi MT, Morettini A, Corazza GR, Di Simone A, Dobrilla G, Cavallini G (1981) Comparison between neomycin and lactulose in 173 patients with hepatic encephalopathy. A randomized clinical trial. Dig Dis Sci 26:498–506

    Article  CAS  PubMed  Google Scholar 

  • Poordad FF (2006) Review article: the burden of hepatic encephalopathy. Aliment pharmacol ther 25(Suppl. 1):3–9

    Google Scholar 

  • Prakash R, Mullen KD (2010) Mechanisms, diagnosis and management of hepatic encephalopathy. Nat Rev Gastroenterol Hepatol 7:515–525

    Article  PubMed  Google Scholar 

  • Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R (2007) Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 45:549–559

    Article  PubMed  Google Scholar 

  • Qureshi MO, Khokhar N, Shafqat F (2014) Ammonia levels and the severity of hepatic encephalopathy. J Coll Physicians Surg Pak 24:160–163

    PubMed  Google Scholar 

  • Riggio O, Varriale M, Testore GP, Di Rosa R, Di Rosa E, Merli M, Romiti A, Candiani C, Capocaccia L (1990) Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients. J Clin Gastroenterol 12:433–436

    Article  CAS  PubMed  Google Scholar 

  • Riggio O, Ridola L, Pasquale C (2010) Hepatic encephalopathy therapy: an overview. World J Pharmacol Ther 1:54–63

    Google Scholar 

  • Riordan SM, Williams R (1997) Treatment of Hepatic Encephalopathy. New Engl J Med 337:473–479

    Article  CAS  PubMed  Google Scholar 

  • Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R (2000) The systemic inflammatory response syndrome in acute liver failure. Hepatology 32:734–739

    Article  CAS  PubMed  Google Scholar 

  • Runyon BA (2009) Management of adult patients with ascites due to cirrhosis: an update. Hepatology 49:2087–2107

    Article  PubMed  Google Scholar 

  • Sen S, Davies NA, Mookerjee RP, Cheshire LM, Hodges SJ, Williams R, Jalan R (2004) Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study. Liver Transpl 10:1109–1119

    Article  PubMed  Google Scholar 

  • Sharma BC, Sharma P, Agrawal A, Sarin SK (2009) Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 137:885–891

    Article  CAS  PubMed  Google Scholar 

  • Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK (2013) A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol 108:1458–1463

    Article  CAS  PubMed  Google Scholar 

  • Shawcross DL, Davies NA, Williams R, Jalan R (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 40:247–254

    Article  CAS  PubMed  Google Scholar 

  • Shawcross DL, Wright G, Olde Damink SW, Jalan R (2007) Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis 22:125–138

    Article  CAS  PubMed  Google Scholar 

  • Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, Auzinger G, Bernal W, Wendon JA (2011) Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol 54:640–649

    Article  CAS  PubMed  Google Scholar 

  • Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK (2011) Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol 106:307–316

    Article  CAS  PubMed  Google Scholar 

  • Sonnewald U, Westergaard N, Schousboe A (1997) Glutamate transport and metabolism in astrocytes. Glia 21:56–63

    Article  CAS  PubMed  Google Scholar 

  • Stahl J (1963) Studies of the blood ammonia in liver disease: its diagnostic, prognostic, and therapeutic significance. Ann Intern Med 58:1–24

    Article  CAS  PubMed  Google Scholar 

  • Sushma S, Dasarathy S, Tandon RK, Jain S, Gupta S, Bhist MS (1992) Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology 16:138–144

    Article  CAS  PubMed  Google Scholar 

  • Tarao K, Ikeda T, Hayashi K, Sakurai A, Okada T, Ito T, Karube H, Nomoto T, Mizuno T, Shindo K (1990) Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy. Gut 31:702–706

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tisdale WA, Fenster LF, Klatskin G (1960) Acute staphylococcal enterocolitis complicating oral neomycin therapy in cirrhosis. N Engl J Med 263:1014–1016

    Article  CAS  PubMed  Google Scholar 

  • Vaquero J, Chung C, Cahill ME, Blei AT (2003a) Pathogenesis of hepatic encephalopathy in acute liver failure. Semin Liver Dis 23:259–269

    Article  CAS  PubMed  Google Scholar 

  • Vaquero J, Polson J, Chung C, Helenowski I, Schiodt FV, Reisch J, Lee WM, Blei AT (2003b) Infection and the progression of hepatic encephalopathy in acute liver failure. Gasteroenterol 125:755–764

    Article  Google Scholar 

  • Vince A, Dawson AM, Park N, O’grady F (1973) Ammonia production by intestinal bacteria. Gut 14:171–177

    CAS  Google Scholar 

  • Watanabe A, Sakai T, Sato S et al (1997) Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 26:1410–1414

    Article  CAS  PubMed  Google Scholar 

  • Wright G, Noiret L, Olde Damink SW, Jalan R (2010) Inter-organ ammonia metabolism in liver failure: the basis of current and future therapies. Liver Int. doi:10.1111/j.1478-3231.2010.02302.x

    PubMed  Google Scholar 

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The authors thank Dr Hector Baillie for reviewing the manuscript.

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Correspondence to Ameen Patel.

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Sheasgreen, C., Lu, L. & Patel, A. Pathophysiology, diagnosis, and management of hepatic encephalopathy. Inflammopharmacol 22, 319–326 (2014). https://doi.org/10.1007/s10787-014-0217-9

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