Latest Concepts in Inpatient Hepatic Encephalopathy Management

  • Thoetchai (Bee) Peeraphatdit
  • Patrick S. KamathEmail author
  • Michael D. Leise


Hepatic encephalopathy (HE), a common complication in patients with decompensated cirrhosis, significantly impacts quality of life and also survival. Current nomenclature recognizes type A HE (acute liver failure), type B (portosystemic shunts absent liver disease), and type C (liver disease). Recently, it has been observed that HE is an additional risk factor for death in patients with acute-on-chronic liver failure (ACLF). Thus, it has been proposed that HE in the setting of ACLF be considered a separate entity and that there may be important subtypes, namely isolated HE (without extrahepatic organ failure) and HE-associated ACLF (with extrahepatic organ failure), that carry different prognoses. The mechanism of the latter is not well known but thought to be from the combination of hyperammonemia and systemic inflammation. The confirmation of HE diagnosis requires exclusion of other possible causes. Precipitating factors of HE must be treated if they are identified. Early detection of extrahepatic organ failure is vital for risk stratification purposes and to determine the need for organ support. Specific HE treatment should be initiated with a nonabsorbable disaccharide (i.e., lactulose) in most cases. Rifaximin can be added in patients not responding to lactulose. Other treatments including zinc, l-ornithine l-aspartate, branched-chain amino acids, and molecular adsorbent recirculating system (MARS) can be considered in refractory HE. If technically feasible, large portosystemic shunts may be embolized. Ultimately, liver transplant is the most definitive treatment option for HE, especially in the setting of ACLF. However, current organ allocation system does not take HE into account and active infection in ACLF can be a contraindication for liver transplant.


Hepatic encephalopathy Acute-on-chronic liver failure Cirrhosis Inpatient Hospitalized 



Acute-on-chronic liver failure


Branched-chain amino acids


Chronic Liver Failure Consortium ACLF Score


Damage-associated molecular patterns


European Society for Parenteral and Enteral Nutrition


Food and Drug Administration


Hepatic encephalopathy




l-ornithine l-aspartate


Liver transplant


Molecular adsorbent recirculating system


Model for end-stage liver disease


Pathogen-associated molecular patterns


Randomized controlled trial


Transjugular intrahepatic portosystemic shunt


  1. 1.
    Amodio P, Del Piccolo F, Petteno E, et al. Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients. J Hepatol. 2001;35(1):37–45.CrossRefPubMedGoogle Scholar
  2. 2.
    Romero-Gómez M, Boza F, Garcı́a-Valdecasas MS, Garcı́a E, Aguilar-Reina J. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol. 2001;96(9):2718–23.CrossRefPubMedGoogle Scholar
  3. 3.
    Boyer TD, Haskal ZJ, American Association for the Study of Liver Diseases. The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension. Hepatology. 2005;41(2):386–400.CrossRefPubMedGoogle Scholar
  4. 4.
    Stepanova M, Mishra A, Venkatesan C, Younossi ZM. In-hospital mortality and economic burden associated with hepatic encephalopathy in the United States from 2005 to 2009. Clin Gastroenterol Hepatol. 2012;10(9):1034–1041.e1031.CrossRefPubMedGoogle Scholar
  5. 5.
    Stewart CA, Malinchoc M, Kim WR, Kamath PS. Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease. Liver Transplant. 2007;13(10):1366–71.CrossRefGoogle Scholar
  6. 6.
    Bajaj JS, O’Leary JG, Tandon P, et al. Hepatic encephalopathy is associated with mortality in patients with cirrhosis independent of other extrahepatic organ failures. Clin Gastroenterol Hepatol. 2017;15(4):565–574.e564.CrossRefPubMedGoogle Scholar
  7. 7.
    Asrani SK, Simonetto DA, Kamath PS. Acute-on-chronic liver failure. Clin Gastroenterol Hepatol. 2015;13(12):2128–39.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426–37. 1437.e1421–9CrossRefGoogle Scholar
  9. 9.
    Bajaj JS, O’Leary JG, Reddy KR, et al. Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures. Hepatology. 2014;60(1):250–6.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sarin SK, Kumar A, Almeida JA, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL). Hepatol Int. 2008;3(1):269.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Jalan R, Yurdaydin C, Bajaj JS, et al. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology. 2014;147(1):4–10.CrossRefPubMedGoogle Scholar
  12. 12.
    Allen AM, Kim WR, Moriarty JP, Shah ND, Larson JJ, Kamath PS. Time trends in the health care burden and mortality of acute on chronic liver failure in the United States. Hepatology. 2016;64(6):2165–72.CrossRefPubMedGoogle Scholar
  13. 13.
    Fichet J, Mercier E, Genee O, et al. Prognosis and 1-year mortality of intensive care unit patients with severe hepatic encephalopathy. J Crit Care. 2009;24(3):364–70.CrossRefPubMedGoogle Scholar
  14. 14.
    Cordoba J, Ventura-Cots M, Simon-Talero M, 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(2):275–81.CrossRefPubMedGoogle Scholar
  15. 15.
    Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol. 2004;40(2):247–54.CrossRefPubMedGoogle Scholar
  16. 16.
    Jalan R, Gines P, Olson JC, et al. Acute-on chronic liver failure. J Hepatol. 2012;57(6):1336–48.CrossRefPubMedGoogle Scholar
  17. 17.
    Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol. 2011;26(Suppl 1):173–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143(5):1158–72.CrossRefGoogle Scholar
  19. 19.
    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(6):1995–2002.CrossRefPubMedGoogle Scholar
  20. 20.
    Wright G, Vairappan B, Stadlbauer V, Mookerjee RP, Davies NA, Jalan R. Reduction in hyperammonaemia by ornithine phenylacetate prevents lipopolysaccharide-induced brain edema and coma in cirrhotic rats. Liver Int. 2012;32(3):410–9.PubMedGoogle Scholar
  21. 21.
    Joshi D, O’Grady J, Patel A, et al. Cerebral oedema is rare in acute-on-chronic liver failure patients presenting with high-grade hepatic encephalopathy. Liver Int. 2014;34(3):362–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Nath K, Saraswat VA, Krishna YR, et al. Quantification of cerebral edema on diffusion tensor imaging in acute-on-chronic liver failure. NMR Biomed. 2008;21(7):713–22.CrossRefPubMedGoogle Scholar
  23. 23.
    Wright G, Davies NA, Shawcross DL, et al. Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatology. 2007;45(6):1517–26.CrossRefPubMedGoogle Scholar
  24. 24.
    Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. 2004;328(7447):1046.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Leise MD, Kim WR. Rifaximin in hepatic encephalopathy: is an ounce of prevention worth a pretty penny? Gastroenterology. 2010;139(4):1416–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715–35.CrossRefPubMedGoogle Scholar
  27. 27.
    Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071–81.CrossRefGoogle Scholar
  28. 28.
    Riggio O, Masini A, Efrati C, et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study. J Hepatol. 2005;42(5):674–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Mas A, Rodes J, Sunyer L, et al. 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. 2003;38(1):51–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Paik YH, Lee KS, Han KH, et al. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Yonsei Med J. 2005;46(3):399–407.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Jiang Q, Jiang XH, Zheng MH, Jiang LM, Chen YP, Wang L. Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol. 2008;20(11):1064–70.CrossRefPubMedGoogle Scholar
  32. 32.
    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(9):1458–63.CrossRefPubMedGoogle Scholar
  33. 33.
    Congly SE, Leise MD. Rifaximin for episodic, overt hepatic encephalopathy: the data are catching up to clinical practice, but questions remain. Am J Gastroenterol. 2014;109(4):598.CrossRefPubMedGoogle Scholar
  34. 34.
    Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy. A controlled, double-blind clinical trial. Am J Dig Dis. 1978;23(5):398–406.CrossRefPubMedGoogle Scholar
  35. 35.
    Strauss E, Tramote R, Silva EP, et al. Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepato-Gastroenterology. 1992;39(6):542–5.PubMedGoogle Scholar
  36. 36.
    Tarao K, Ikeda T, Hayashi K, et al. Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy. Gut. 1990;31(6):702–6.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Morgan MH, Read AE, Speller DC. Treatment of hepatic encephalopathy with metronidazole. Gut. 1982;23(1):1–7.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M. Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology. 1996;23(5):1084–92.CrossRefPubMedGoogle Scholar
  39. 39.
    Bresci G, Parisi G, Banti S. Management of hepatic encephalopathy with oral zinc supplementation: a long-term treatment. Eur J Med. 1993;2(7):414–6.PubMedGoogle Scholar
  40. 40.
    Reding P, Duchateau J, Bataille C. Oral zinc supplementation improves hepatic encephalopathy. Results of a randomised controlled trial. Lancet. 1984;2(8401):493–5.CrossRefPubMedGoogle Scholar
  41. 41.
    Riggio O, Ariosto F, Merli M, et al. Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy. Dig Dis Sci. 1991;36(9):1204–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Takuma Y, Nouso K, Makino Y, Hayashi M, Takahashi H. Clinical trial: oral zinc in hepatic encephalopathy. Aliment Pharmacol Ther. 2010;32(9):1080–90.CrossRefPubMedGoogle Scholar
  43. 43.
    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. Hepatology. 1997;25(6):1351–60.CrossRefPubMedGoogle Scholar
  44. 44.
    Stauch S, Kircheis G, Adler G, et al. Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study. J Hepatol. 1998;28(5):856–64.CrossRefPubMedGoogle Scholar
  45. 45.
    Abid S, Jafri W, Mumtaz K, et al. Efficacy of L-ornithine-L-aspartate as an adjuvant therapy in cirrhotic patients with hepatic encephalopathy. J Coll Physicians Surg Pak. 2011;21(11):666–71.PubMedGoogle Scholar
  46. 46.
    Kawaguchi T, Izumi N, Charlton MR, Sata M. Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 2011;54(3):1063–70.CrossRefPubMedGoogle Scholar
  47. 47.
    Marchesini G, Bianchi G, Merli M, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology. 2003;124(7):1792–801.CrossRefPubMedGoogle Scholar
  48. 48.
    Muto Y, Sato S, Watanabe A, et al. Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol. 2005;3(7):705–13.CrossRefPubMedGoogle Scholar
  49. 49.
    Gluud LL, Dam G, Les I, et al. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017;5:Cd001939.Google Scholar
  50. 50.
    Plauth M, Cabre E, Riggio O, et al. ESPEN guidelines on enteral nutrition: liver disease. Clin Nutr. 2006;25(2):285–94.CrossRefPubMedGoogle Scholar
  51. 51.
    Plauth M, Cabre E, Campillo B, et al. ESPEN guidelines on parenteral nutrition: hepatology. Clin Nutr. 2009;28(4):436–44.CrossRefPubMedGoogle Scholar
  52. 52.
    Laleman W, Simon-Talero M, Maleux G, et al. Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy. Hepatology. 2013;57(6):2448–57.CrossRefPubMedGoogle Scholar
  53. 53.
    Singh S, Kamath PS, Andrews JC, Leise MD. Embolization of spontaneous portosystemic shunts for management of severe persistent hepatic encephalopathy. Hepatology. 2014;59(2):735–6.CrossRefPubMedGoogle Scholar
  54. 54.
    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(12):1418–26.CrossRefPubMedGoogle Scholar
  55. 55.
    Lynn AM, Singh S, Congly SE, et al. Embolization of portosystemic shunts for treatment of medically refractory hepatic encephalopathy. Liver Transplant. 2016;22(6):723–31.CrossRefGoogle Scholar
  56. 56.
    Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications. Hepatology. 2013;58(5):1836–46.CrossRefPubMedGoogle Scholar
  57. 57.
    Leise MD, Poterucha JJ, Kamath PS, Kim WR. Management of hepatic encephalopathy in the hospital. Mayo Clin Proc. 2014;89(2):241–53.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Hassanein TI, Tofteng F, Brown RS Jr, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology. 2007;46(6):1853–62.CrossRefPubMedGoogle Scholar
  59. 59.
    Banares R, Nevens F, Larsen FS, et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology. 2013;57(3):1153–62.CrossRefPubMedGoogle Scholar
  60. 60.
    Pares A, Deulofeu R, Cisneros L, et al. Albumin dialysis improves hepatic encephalopathy and decreases circulating phenolic aromatic amino acids in patients with alcoholic hepatitis and severe liver failure. Crit Care. 2009;13(1):R8.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Garcia-Martinez R, Rovira A, Alonso J, et al. Hepatic encephalopathy is associated with posttransplant cognitive function and brain volume. Liver Transplant. 2011;17(1):38–46.CrossRefGoogle Scholar
  62. 62.
    Jalan R, Saliba F, Pavesi M, et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol. 2014;61(5):1038–47.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Thoetchai (Bee) Peeraphatdit
    • 1
  • Patrick S. Kamath
    • 1
    Email author
  • Michael D. Leise
    • 1
  1. 1.Division of Gastroenterology and HepatologyMayo Clinic College of MedicineRochesterUSA

Personalised recommendations