Top

Current Hepatology Reports

Published in:

08-01-2024 | Hepatic Encephalopathy

Current Management of Hepatic Encephalopathy

Authors: Margaret C. Liu, Julton Tomanguillo Chumbe, David M. H. Chascsa, Blanca Lizaola-Mayo

Published in: Current Hepatology Reports | Issue 1/2024

Abstract

Purpose of Review

Hepatic encephalopathy (HE) is a complication of liver dysfunction and portosystemic shunting. The purpose of this review is to discuss the management of HE.

Recent Findings

Traditional therapies include lactulose and rifaximin, but other treatment options have recently emerged. Branched chain amino acids are involved in the Krebs cycle and have an inverse relationship with ammonia. Flumazenil, a benzodiazepine antagonist, has a negative effect on the gamma-aminobutyric acid receptor, which plays a role in cognitive deficits. Because of microbiome changes, fecal microbiota transplantation and probiotics are emerging therapeutic considerations.

Summary

Despite multiple therapies for HE, the emerging options have shown varying degrees of evidence. Future studies are needed to examine the impact of each therapy on the different grades of HE, as most studies showed benefit for primarily lower grades. Future studies should also investigate whether certain therapeutic combinations are favored.

Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, 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. https://doi.org/10.1002/hep.27210.CrossRefPubMed

Rose CF, Amodio P, Bajaj JS, Dhiman RK, Montagnese S, Taylor-Robinson SD, et al. Hepatic encephalopathy: novel insights into classification, pathophysiology and therapy. J Hepatol. 2020;73(6):1526–47. https://doi.org/10.1016/j.jhep.2020.07.013.CrossRefPubMed

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatic encephalopathy. J Hepatol. 2022;77(3):807–824. https://doi.org/10.1016/j.jhep.2022.06.001. Erratum in: J Hepatol. 2023;79(5):1340.

Weissenborn K. Hepatic encephalopathy: definition, clinical grading and diagnostic principles. Drugs. 2019;79(Suppl 1):5–9. https://doi.org/10.1007/s40265-018-1018-z.CrossRefPubMedPubMedCentral

Romero-Gómez M, et al. Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure. J Hepatol. 2015;62(2):437–47. https://doi.org/10.1016/j.jhep.2014.09.005.CrossRefPubMed

Aldridge DR, et al. Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation. J Clin Exp Hepatol. 2015;1:S7–20. https://doi.org/10.1016/j.jceh.2014.06.004.CrossRef

Romero-Gómez M. Role of phosphate-activated glutaminase in the pathogenesis of hepatic encephalopathy. Metab Brain Dis. 2005;20(4):319–25. https://doi.org/10.1007/s11011-005-7913-5.CrossRefPubMed

Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol. 2014;60(6):1310–24. https://doi.org/10.1016/j.jhep.2014.01.024.CrossRefPubMed

Rose C, Butterworth RF, Zayed J, Normandin L, Todd K, Michalak A, et al. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology. 1999;117(3):640–4. https://doi.org/10.1016/s0016-5085(99)70457-9.CrossRefPubMed

10.

Rovira A, et al. MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol. 2008;9:1612–21. https://doi.org/10.3174/ajnr.A1139.CrossRef

11.

Poo JL, Rosas-Romero R, Rodríguez F, Silencio JL, Muñoz R, Bourges H, et al. Serum zinc concentrations in two cohorts of 153 healthy subjects and 100 cirrhotic patients from Mexico City. Dig Dis. 1995;2:136–42. https://doi.org/10.1159/000171495.CrossRef

12.

Takuma Y, et al. Clinical trial: oral zinc in hepatic encephalopathy. Aliment Pharmacol Ther. 2010;32(9):1080–90. https://doi.org/10.1111/j.1365-2036.2010.04448.x.CrossRefPubMed

13.

Aceto P, et al. Postoperative cognitive dysfunction after liver transplantation. Gen Hosp Psychiatry. 2015;37(2):109–15. https://doi.org/10.1016/j.genhosppsych.2014.12.001.CrossRefPubMed

14.

Amodio P, Biancardi A, Montagnese S, Angeli P, Iannizzi P, Cillo U, et al. Neurological complications after orthotopic liver transplantation. Dig Liver Dis. 2007;39(8):740–7. https://doi.org/10.1016/j.dld.2007.05.004.CrossRefPubMed

15.

Schiano TD. Treatment options for hepatic encephalopathy. Pharmacotherapy. 2010;30(5 Pt 2):16S-21S. https://doi.org/10.1592/phco.30.pt2.16S.CrossRefPubMed

16.

FiatiKenston SS, et al. Mechanistic insight, diagnosis, and treatment of ammonia-induced hepatic encephalopathy. J Gastroenterol Hepatol. 2019;34(1):31–9. https://doi.org/10.1111/jgh.14408.CrossRef

17.

Ferenci P. Hepatic encephalopathy in adults: treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 2, 2021.

18.

Mohammad RA, et al. Combination therapy for the treatment and prevention of hepatic encephalopathy. Ann Pharmacother. 2012;46(11):1559–63. https://doi.org/10.1345/aph.1R146.CrossRefPubMed

19.

Ullah MI, Alameen AAM, Al-Oanzi ZH, Eltayeb LB, Atif M, Munir MU, et al. Biological role of zinc in liver cirrhosis: an updated review. Biomedicines. 2023;11(4):1094. https://doi.org/10.3390/biomedicines11041094.CrossRefPubMedPubMedCentral

20.

Grüngreiff K, et al. The role of zinc in liver cirrhosis. Ann Hepatol. 2016;15(1):7–16. https://doi.org/10.5604/16652681.1184191.CrossRefPubMed

21.

Yoshida Y, Higashi T, Nouso K, Nakatsukasa H, Nakamura SI, Watanabe A, et al. Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Acta Med Okayama. 2001;55(6):349–55. https://doi.org/10.18926/AMO/32003.CrossRefPubMed

22.

Plum LM, et al. The essential toxin: impact of zinc on human health. Int J Environ Res Public Health. 2010;7(4):1342–65. https://doi.org/10.3390/ijerph7041342.MathSciNetCrossRefPubMedPubMedCentral

23.

Sengupta S, Wroblewski K, Aronsohn A, Reau N, Reddy KG, Jensen D, et al. Screening for zinc deficiency in patients with cirrhosis: when should we start? Dig Dis Sci. 2015;60(10):3130–5. https://doi.org/10.1007/s10620-015-3613-0.CrossRefPubMed

24.

Deep V, Sondhi S, Gupta S. Assessment of serum zinc levels in patients with decompensated cirrhosis of the liver and its association with disease severity and hepatic encephalopathy: a prospective observational study from North India. Cureus. 2023;15(6):e41207. https://doi.org/10.7759/cureus.41207.

25.

Janyajirawong R, et al. Efficacy of zinc supplement in minimal hepatic encephalopathy: a prospective, randomized controlled study (Zinc-MHE Trial). Asian Pac J Cancer Prev. 2021;22(9):2879–87. https://doi.org/10.31557/APJCP.2021.22.9.2879.CrossRefPubMedPubMedCentral

26.

Shen YC, et al. Zinc supplementation in patients with cirrhosis and hepatic encephalopathy: a systematic review and meta-analysis. Nutr J. 2019;18(1):34. https://doi.org/10.1186/s12937-019-0461-3.CrossRefPubMedPubMedCentral

27.

Diglio DC, et al. Role of zinc supplementation in the management of chronic liver diseases: a systematic review and meta-analysis. Ann Hepatol. 2020;19(2):190–6. https://doi.org/10.1016/j.aohep.2019.08.011.CrossRefPubMed

28.

Duncan A, et al. The risk of copper deficiency in patients prescribed zinc supplements. J Clin Pathol. 2015;68(9):723–5. https://doi.org/10.1136/jclinpath-2014-202837.CrossRefPubMed

29.

Institute of Medicine (US) Committee on nutrition, trauma, and the brain; Erdman J, Oria M, Pillsbury L, editors. Nutrition and traumatic brain injury: improving acute and subacute health outcomes in military personnel. Washington (DC): National Academies Press (US); 2011. 8, Branched-Chain Amino Acids. Available from: https://www.ncbi.nlm.nih.gov/books/NBK209312/

30.

Holecek M. Branched-chain amino acids and ammonia metabolism in liver disease: therapeutic implications. Nutrition. 2013;29(10):1186–91. https://doi.org/10.1016/j.nut.2013.01.022.CrossRefPubMed

31.

Gluud LL, Dam G, Les I, Marchesini G, Borre M, Aagaard NK, et al. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017;5:CD001939. https://doi.org/10.1002/14651858.CD001939.pub4.CrossRefPubMed

32.

Swansson WD, et al. Management of minimal and overt hepatic encephalopathy with branched-chain amino acids: a review of the evidence. Eur J Gastroenterol Hepatol. 2023;35(8):812–21. https://doi.org/10.1097/MEG.0000000000002595.CrossRefPubMed

33.

Amrein R, et al. Flumazenil in benzodiazepine antagonism. Actions and clinical use in intoxications and anaesthesiology. Med Toxicol Adverse Drug Exp. 1987;2(6):411–29. https://doi.org/10.1007/BF03259876.CrossRefPubMed

34.

Rajpurohit S et al 2022 Novel Drugs for the management of hepatic encephalopathy: still a long journey to travel. J Clin Exp Hepatol. 12(4):1200–1214 https://doi.org/10.1016/j.jceh.2022.01.012

35.

Goh ET, et al. Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. Cochrane Database Syst Rev. 2017;8(8):CD002798. https://doi.org/10.1002/14651858.CD002798.pub4.CrossRefPubMed

36.

Laccetti M, et al. Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized placebo controlled study. Dig Liver Dis. 2000;32(4):335–8. https://doi.org/10.1016/s1590-8658(00)80027-4.CrossRefPubMed

37.

Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology. 2011;54(2):562–72. https://doi.org/10.1002/hep.24423.CrossRefPubMed

38.

Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, White MB, Monteith P, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol. 2014;60(5):940–7. https://doi.org/10.1016/j.jhep.2013.12.019.CrossRefPubMed

39.

Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology. 2017;66(6):1727–38. https://doi.org/10.1002/hep.29306.CrossRefPubMed

40.

Gedgaudas R, Bajaj JS, Skieceviciene J, Valantiene I, Kiudeliene E, Bang C, Franke A, Schreiber S, Kupcinskas J. Sterile fecal filtrate from a healthy donor improves microbial diversity in patients with hepatic encephalopathy. J Gastrointestin Liver Dis. 2023;32(3):332–338. https://doi.org/10.15403/jgld-4906.

41.

Dhiman RK, Rana B, Agrawal S, Garg A, Chopra M, Thumburu KK, et al. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology. 2014;147(6):1327-37.e3. https://doi.org/10.1053/j.gastro.2014.08.031.CrossRefPubMed

42.

Dalal R, et al. Probiotics for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017;2(2):008716. https://doi.org/10.1002/14651858.CD008716.pub3.CrossRef

43.

Rahimi RS, et al. Lactulose vs polyethylene glycol 3350–electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med. 2014;174(11):1727–33. https://doi.org/10.1001/jamainternmed.2014.4746.CrossRefPubMedPubMedCentral

44.

Naderian M, et al. Polyethylene glycol and lactulose versus lactulose alone in the treatment of hepatic encephalopathy in patients with cirrhosis: a non-inferiority randomized controlled trial. Middle East J Dig Dis. 2017;9(1):12–9. https://doi.org/10.15171/mejdd.2016.46.CrossRefPubMedPubMedCentral

45.

Shehata HH, Elfert AA, Abdin AA, Soliman SM, Elkhouly RA, Hawash NI, et al. Randomized controlled trial of polyethylene glycol versus lactulose for the treatment of overt hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2018;30(12):1476–81. https://doi.org/10.1097/MEG.0000000000001267.CrossRefPubMed

46.

Is B, Bombassaro IZ, Tovo CV, de Mattos ÂZ, Ahlert M, Chiesa T, et al. Albumin in the management of hepatic encephalopathy: a systematic review and meta-analysis. Ann Hepatol. 2021;26:100541. https://doi.org/10.1016/j.aohep.2021.100541.CrossRefPubMed

47.

Sharma BC, Singh J, Srivastava S, Sangam A, Mantri AK, Trehanpati N, et al. Randomized controlled trial comparing lactulose plus albumin versus lactulose alone for treatment of hepatic encephalopathy. J Gastroenterol Hepatol. 2017;32(6):1234–9. https://doi.org/10.1111/jgh.13666.CrossRefPubMed

48.

Simón-Talero M, García-Martínez R, Torrens M, Augustin S, Gómez S, Pereira G, et al. Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: a randomized double-blind study. J Hepatol. 2013;59(6):1184–92. https://doi.org/10.1016/j.jhep.2013.07.020.CrossRefPubMed

49.

Philips CA, et al. Portosystemic shunts and refractory hepatic encephalopathy: patient selection and current options. Hepat Med. 2019;25(11):23–34. https://doi.org/10.2147/HMER.S169024.CrossRef

50.

Laleman W, Simon-Talero M, Maleux G, Perez M, Ameloot K, Soriano G, et al. EASL-CLIF-Consortium. Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy. Hepatology. 2013;57(6):2448–57. https://doi.org/10.1002/hep.26314.CrossRefPubMed

51.

Goffaux A, et al. Improving the prognosis before and after liver transplantation: is muscle a game changer? World J Gastroenterol. 2022;28(40):5807–17. https://doi.org/10.3748/wjg.v28.i40.5807.CrossRefPubMedPubMedCentral

52.

Nardelli S, Lattanzi B, Torrisi S, Greco F, Farcomeni A, Gioia S, et al. Sarcopenia is risk factor for development of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt placement. Clin Gastroenterol Hepatol. 2017;15(6):934–6. https://doi.org/10.1016/j.cgh.2016.10.028.CrossRefPubMed

Title: Current Management of Hepatic Encephalopathy
Authors: Margaret C. Liu
Julton Tomanguillo Chumbe
David M. H. Chascsa
Blanca Lizaola-Mayo
Publication date: 08-01-2024
Publisher: Springer US
Keywords: Hepatic Encephalopathy
Hepatic Encephalopathy
Flumazenil
Rifaximin
Probiotics
Published in: Current Hepatology Reports / Issue 1/2024
Electronic ISSN: 2195-9595
DOI: https://doi.org/10.1007/s11901-023-00627-2

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 1/2024

Non-Cirrhotic Portal Hypertension: an Overview

Novel Blood-Based Biomarkers for HCC

Hepatic Sarcoidosis: A Review of the Diagnosis and Management

Update on Hepatopulmonary Syndrome

Prophylaxis and Treatment of Bacterial Infections in Cirrhosis

Secondary Sclerosing Cholangiopathies

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials