Liver Diseases pp 695-706 | Cite as

Hepatic Encephalopathy

  • Stephen M. RiordanEmail author


Hepatic encephalopathy (HE) encompasses a spectrum of neuropsychiatric manifestations, ranging from covert disturbances such as deficits in memory and learning evident only by psychometric testing (referred to as minimal HE) through to clinically overt disturbances reflected by changes in personality, inversion of the sleep cycle, confusion and, in its most extreme form, coma. HE, in either of its covert or overt forms, occurs either as a consequence of severe acute, chronic or acute-on-chronic liver disease or in the setting of porto-systemic venous shunting. The exception is the rare patient with HE due to a congenital urea cycle enzyme defect.


  1. 1.
    Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology. 1977;72:573–83.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Groeneweg M, Quero J, De Bruijn I, et al. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology. 1998;28:45–9.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Gadiparthi C, Cholankeril G, Yoo ER, Hu M, Wong RJ, Ahmen A. Waitlist outcomes in liver transplant candidates with high MELD and severe hepatic encephalopathy. Dig Dis Sci. 2018;63:1647–53.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    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;144:1426–77.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997;337:473–9.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Prakash R, Mullen KD. Mechanisms, diagnosis and management of hepatic encephalopathy. Nat Rev Gastroenterol Hepatol. 2010;7:515–25.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Ott P, Clemmensen O, Larsen FS. Cerebral metabolic disturbance in the brain during acute liver failure: from hyperammonaemia to energy failure and proteolysis. Neurochem Int. 2005;47:13–8.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Rose C. Effect of ammonia on astrocytic glutamate release/uptake mechanisms. J Neurochem. 2006;97(Suppl 1):11–5.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Ellis AJ, Wendon JA, Williams R. Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure; a controlled clinical trial. Hepatology. 2000;32:666–9.CrossRefGoogle Scholar
  10. 10.
    Bernal W, Hall C, Karvellas C, et al. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology. 2007;46:1844–52.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Wright G, Soper R, Brooks HF, et al. Role of aquaporin-4 in the development of brain oedema in liver failure. J Hepatol. 2010;53:91–7.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Joshi D, O’Grady J, Patel A, et al. Cerebral oedema is rare in acute-on-chronic liver failure patients with high grade hepatic encephalopathy. Liver Int. 2014;34:362–6.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Kale RA, Gupta RK, Saraswat VA, et al. Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy. Hepatology. 2006;43:698–706.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Chavarria L, Oria M, Romero-Gimenez J, et al. Brain magnetic resonance in experimental acute-on-chronic liver failure. Liver Int. 2013;33:294–300.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Cauli O, Llansola M, Agusti A, et al. Cerebral oedema is not responsible for motor or cognitive deficits in rats with hepatic encephalopathy. Liver Int. 2014;34:379–87.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Butterworth RF. Pathophysiology of hepatic encephalopathy: the concept of synergism. Hepatol Res. 2008;38:S116–21.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Palomero-Gallagher N, Zilles K. Neurotransmitter receptor alterations in hepatic encephalopathy: a review. Arch Biochem Biophys. 2013;536:109–21.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Ahboucha S, Butterworth RF. The neurosteroid system: an emerging therapeutic target for hepatic encephalopathy. Metab Brain Dis. 2007;22:291–308.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Keiding S, Pavese N. Brain metabolism in patients with hepatic encephalopathy studied by PET and MR. Arch Biochem Biophys. 2013;536:131–42.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Iversen P, Sorenson M, Bak L, et al. Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy. Gastroenterology. 2009;136:863–71.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Odeh M. Pathogenesis of hepatic encephalopathy: the tumour necrosis factor-alpha theory. Eur J Clin Invest. 2007;37:291–304.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Bernal W, Donaldson P, Underhill J, Wendon J, Williams R. Tumour necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure. J Hepatol. 1998;29:53–9.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–74.CrossRefGoogle Scholar
  24. 24.
    Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol. 2004;40:247–54.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2012;302:G168–75.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Bajaj JS, Hylemon PB, Ridlon JM, et al. 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. 2012;303:G675–85.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Ahluwalia V, Betrapally NS, Hylemon PB, et al. Impaired gut-liver –brain axis in patients with cirrhosis. Sci Rep. 2016;6:26800.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Moldawer LL, Marano MA, Wei H, et al. Cachectin/tumor necrosis factor-α alters red blood cell kinetics and induces anemia in vivo. FASEB J. 1989;3:1637–43.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Blei AT. Brain edema and portal-systemic encephalopathy. Liver Transpl. 2000;6(Suppl 1):S14–20.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Anderson AK, Ronnback L, Hansson E. Lactate induces tumour necrosis factor-alpha, interleukin-6 and interleukin-1 beta release in microglial- and astroglial-enriched primary cultures. J Neurochem. 2005;93:1327–33.CrossRefGoogle Scholar
  31. 31.
    Bemeur C, Butterworth RF. Liver-brain proinflammatory signalling in acute liver failure: role in the pathogenesis of hepatic encephalopathy and brain edema. Metab Brain Dis. 2013;28:145–50.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Coltart I, Tranah TH, Shawcross DL. Inflammation and hepatic encephalopathy. Arch Biochem Biophys. 2013;536:189–96.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Strauss G, Adel-Hansen B, Kirkegaard P, et al. Liver function, cerebral blood flow autoregulation, and hepatic encephalopathy in fulminant hepatic failure. Hepatology. 1997;25:837–9.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Didier N, Romero IA, Creminon C, et al. Secretion of interleukin-1β by astrocytes mediates endothelin-1 and tumour necrosis factor-α effects on human brain microvascular endothelial cell permeability. J Neurochem. 2003;86:246–54.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Duchini A. Effects of tumour necrosis factor-α and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Invest Med. 1996;44:474–82.Google Scholar
  37. 37.
    Garcia-Martinez R, Cordoba J. Acute-on-chronic-liver failure: the brain. Curr Opin Crit Care. 2011;17:177–83.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    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;21:713–22.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    O’Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97:439–45.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Rajajee V, Fontana RJ, Courey AJ, Patil PG. Protocol based invasive intracranial pressure monitoring in acute liver failure: feasibility, safety and impact on management. Crit Care. 2017;21:178.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Wendon JA, Harrison PM, Keays R, et al. Cerebral blood flow and metabolism in fulminant hepatic failure. Hepatology. 1994;19:1407–13.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Davenport A, Will EJ, Davidson AM. Improved cardiovascular stability during continuous modes of renal replacement therapy in critically ill patients with acute hepatic and renal failure. Crit Care Med. 1993;21:328–38.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Jalan R, Olde Damink SW, Deutz NE, et al. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology. 2004;127:1338–46.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Stenbog P, Busk T, Larsen FS. Efficacy of liver assisting in patients with hepatic encephalopathy with special focus on plasma exchange. Metab Brain Dis. 2013;28:333–5.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Pugliese F, Ruberto F, Perrella SM, et al. Modifications of intracranial pressure after molecular adsorbent recirculating system treatment in patients with acute liver failure: case reports. Transplant Proc. 2007;39:2042–4.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Bernal W, Hyyrylainen A, Gera A, et al. Lessons from look-back in acute liver failure? A single centre experience of 3300 patients. J Hepatol. 2013;59:74–80.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Bajaj JS, Schubert CM, Heuman DM, et al. Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Gastroenterology. 2010;138:2332–40.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Bianchi GP, Marchesini G, Fabbri A, et al. Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy: a randomized cross-over comparison. J Intern Med. 1993;233:385–92.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Camma FF, Tine F, et al. Lactitol in treatment of chronic hepatic encephalopathy. A meta-analysis. Dig Dis Sci. 1993;38:916–22.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Uribe M, Campollo O, Vargas F, et al. Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial. Hepatology. 1987;7:639–43.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. 2004;328:1046.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Sharma P, Sharma BC, Sarin SK. Predictors of non-response to lactulose in patients with cirrhosis and hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2010;22:526–31.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Dhiman RK, Saraswat VA, Sharma BK, et al. Minimal hepatic encephalopathy: consensus statement of a working party of the Indian National Association for Study of the Liver. J Gastroenterol Hepatol. 2010;25:1029–41.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Luo M, Li L, Lu CZ, et al. Clinical efficacy and safety of lactulose for minimal hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol. 2011;23:1250–7.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Sharma P, Sharma BC, Sarin SK. Predictors of nonresponse to lactulose for minimal hepatic encephalopathy in patients with cirrhosis. Liver Int. 2009;29:1365–71.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Jiang Q, Jiang XH, Zheng MH, et al. Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol. 2008;20:1064–70.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Eltawil KM, Laryea M, Peltekian K, Molinari M. Rifaximin vs conventional oral therapy for hepatic encephalopathy: a meta-analysis. World J Gastroenterol. 2012;18:767–77.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Sharma BC, Sharma P, Lunia MK, et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastoenterol. 2013;108:1458–63.CrossRefGoogle Scholar
  59. 59.
    Bajaj JS, Heuman DM, Wade JB, et al. Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology. 2011;140:478–87.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Sidhu SS, Goyal O, Mishra BP, et al. Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME trial). Am J Gastroenterol. 2011;106:307–16.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Kaji K, Takaya H, Saikawa S, et al. Rifaximin ameliorates hepatic encephalopathy and endotoxaemia without affecting the gut microbiome diversity. World J Gastroenterol. 2017;23:8355–66.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Shukla S, Shukla A, Mehboob S, Guha S. Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy. Alim Pharmacol Ther. 2011;33:662–71.CrossRefGoogle Scholar
  63. 63.
    Viramontes Horner D, Avery A, Stow R. The effects of probiotics and symbiotics on risk factors for hepatic encephalopathy: a systematic review. J Clin Gastroenterol. 2017;51:312–23.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Cao Q, Yu CB, Yang SG, et al. Effect of probiotic treatment on cirrhotic patients with minimal hepatic encephalopathy: a meta-analysis. Hepatobiliary Pancreat Dis Int. 2018;17:9–16.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with liver cirrhosis. Hepatology. 2004;39:1441–9.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Bajaj JS, Kassam Z, Fagan A, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology. 2017;66:1727–38.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Mai M, Yang Z, Qi X, Fan D, Han G. l-ornithine-l-aspartate for hepatic encephalopathy in patients with cirrhosis: a meta-analysis of randomised controlled trials. J Gastroenterol Hepatol. 2013;28:783–92.CrossRefGoogle Scholar
  68. 68.
    Varakanahalli S, Sharma BC, Srivastava S, Sachdeva S, Dahale AS. Secondary prophylaxis of hepatic encephalopathy in cirrhosis of liver: a double-blind randomized controlled trial of L-ornithine L-aspartate versus placebo. Eur J Gastroenterol Hepatol. 2018;30:951–8.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Sushma S, Dasarathy S, Tandon RK, et al. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology. 1992;16:138–44.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Takuma Y, Nouso K, Makino Y, Hayashi M, Takahashi H. Clinical trial: oral zinc in hepatic encephalopathy. Alim Pharmacol Ther. 2010;32:1080–90.CrossRefGoogle Scholar
  71. 71.
    Rockey DC, Vierling JM, Mantry P, et al. Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy. Hepatology. 2014;59:1073–83.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Weiss N, Tripon S, Lodey M, et al. Treating hepatic encephalopathy in cirrhotic patients admitted to ICU with sodium phenylbutyrate: a preliminary study. Fundam Clin Pharmacol. 2018;32:209–15.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Jain L, Sharma BC, Srivastava S, Puri SK, Sharma P, Sarin S. Serum endotoxin, inflammatory mediators, and magnetic resonance spectroscopy before and after treatment in patients with minimal hepatic encephalopathy. J Gastroenterol Hepatol. 2013;28:1187–93.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Dhiman RK, Rana B, Garg A, et al. Efficacy and safety of a probiotic preparation in the secondary prophylaxis of hepatic encephalopathy in cirrhotic patients: interim results of a double blind, randomized, placebo controlled study. Hepatology. 2012;56:255A.Google Scholar
  75. 75.
    Laleman W, Simon-Talero M, Maleux G, et al. Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicentre survey on safety and efficacy. Hepatology. 2013;57:2448–57.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Park HY, Tsauo J, Shin JH, Kim PH. Percutaneous transparaumbilical embolization of spontaneous portosystemic shunts for the treatment of hepatic encephalopathy. J Vasc Interv Radiol. 2017;28:1563–8.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Hauenstein KH, Haag K, Ochs A, Langer M, Rossle M. The reducing stent: treatment for transjugular intrahepatic portosystemic shunt-induced refractory hepatic encephalopathy and liver failure. Radiology. 1995;194:175–9.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Hassanein TI, Tofteng F, Brown RS, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology. 2007;46:1853–62.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    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;57:1153–62.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Gastrointestinal and Liver Unit, Prince of Wales Hospital, Prince of Wales Clinical SchoolUniversity of New South WalesSydneyAustralia

Personalised recommendations