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hepatic encephalopathy

Etiology: 1) underlying disease processes - acute & chronic liver disease (cirrhosis) 2) precipitating factors a) GI bleeding b) azotemia (renal failure) c) constipation d) high protein meal e) hypokalemic metabolic alkalosis f) CNS depressants 1] benzodiazepines 2] barbiturates 3] opiates g) hypoxia h) hypercarbia i) infection (sepsis) j) volume depletion Pathology: 1) failure of liver to detoxify agents noxious to CNS due to decreased hepatic function & portocaval shunting 2) retention of neurotoxins of intestinal origin a) NH3 (intracellular) - hypokalemic metabolic alkalosis - pardoxical intracellular acidosis shifts NH3 intracellularly b) mercaptans c) short-chain fatty acids d) phenolic compound 3) diffuse brain edema [11] 4) structural brain-stem injury [11] 5) increased GABA activity 6) presence of benzodiazepine-like substances in the brain 7) Streptococcus salivarius may play a role [8] Clinical manifestations: 1) grade 1 a) attention deficit b) personality change c) irritability d) mild confusion e) tremor f) abnormal psychometric testing g) disordered handwriting 2) grade 2 a) day/night reversal of sleep cycle b) inappropriate behavior c) drowsiness, fatigue d) cognitive impairment e) asterixis (flapping tremor) f) ataxia g) slow speach 3) grade 3 a) stupor b) somnolence c) marked confusion d) disorientation e) amnesia f) inarticulate speech g) muscle rididity h) nystagmus i) clonus j) Babinski sign k) hyporeflexia 4) grade 4 a) coma b) extrapyramidal signs (occasional) c) muscle twitching d) hyperventilation 5) Fetor hepaticus (breath & urine odor of mercaptans) Laboratory: - elevated serum ammonia - monitoring serial ammonia levels of no benefit [2] - ammonia levels do not correlate with severity in patients with cirrhosis [15] & do not change management [14] Special laboratory: - electroencephalography (EEG) reserved for patients without evidence of common precipitants [2] Radiology: - CT of head (neuroimaging) generally unnecessary - indicated only with head trauma, unwitnessed fall(s) with suspected head trauma or diagnostic uncertainty [2] Management: 1) correct precipitating cause 2) liver transplantation for hepatic encephalopathy due to fulminant hepatic failure - transplantation centers monitor intracranial pressure for cerebral edema due to hepatic encephalopathy [2] 3) pharmacologic agents a) lactulose* 30-45 mL PO TID/QID, or as enema [4] - polyethylene glycol (PEG) more effective than lactulose [10] - 24 hour response rates 84% with PEG, 40% with lactulose [10] - titrate to 3 stools/day for prevention [2] - intravenous albumin + lactulose superior to lactulose alone [12] b) rifaximin may improve outcomes, but cost is high [5] - indicated if lactulose ineffective [2] - combination of lactulose plus rifaximin improves outcomes relative to lactulose alone [9] - combination reduces hospitalizations & recurrence [2] - rifaximin alone reduces recurrence & mortality vs lactulose [16] c) neomycin 4-12 g/day PO, divided every 4 hours - avoid: adverse effects substantial [2] d) metronidazole 250 mg PO TID 1] associated with neurotoxicity 2] not recommended for patients with cirrhosis [2] e) vancomycin 1 g PO BID f) sorbitol 2 mL/kg up to 50 mL of a 70% solution PO g) flumazenil h) unproven therapies: branched chain amino acids, levodopa, bromocryptine 4) Harris flush (high colonic enema) to evacuate colonic gases 5) low protein diet not useful for prevention [2] 6) amino acid formulations high in branched-chain amino acids & low in aromatic amino acids for encephalopathy refractory to lactulose [2] 7) probiotics may work as well as lactulose [6] * may reduce morbidity, but not mortality [3]

Related

cirrhosis liver transplantation portal systemic encephalopathy (PSE)

Specific

hepatic coma

General

hyperammonemia liver (hepatic) failure/insufficiency metabolic encephalopathy; toxic encephalopathy

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 538-40
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Journal Watch 24(14):113, 2004 Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. 2004 May 1;328(7447):1046. Epub 2004 Mar 30. Review. PMID: 15054035 - Als-Nielsen B et al, BMJ. 2004 May 1;328(7447):1046 http://bmj.bmjjournals.com/cgi/content/full/328/7447/1046
  4. Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology. 2007 Mar;45(3):549-59. PMID: 17326150
  5. FDA NEWS RELEASE, March 24, 2010 FDA Approves New Use of Xifaxan for Patients with Liver Disease http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm206104.htm - Bass NM, Mullen KD, Sanyal A et al Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81 PMID: 20335583 - Prescriber's Letter 17(6): 2010 Rifaximin (Xifaxan) for Hepatic Encephalopathy Detail-Document#: 260608 (subscription needed) http://www.prescribersletter.com - Sidhu SS 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 Feb; 106:307. PMID: 21157444 - Bajaj JS et al. Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology 2011 Feb; 140:478. PMID: 20849805
  6. Agrawal A et al Secondary prophylaxis of hepatic encephalopathy in cirrhosis: An open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol 2012 Jul; 107:1043. PMID: 22710579
  7. Cordoba J, Minguez B. Hepatic encephalopathy. Semin Liver Dis. 2008 Feb;28(1):70-80 PMID: 18293278
  8. Zhang Z et al. Large-scale survey of gut microbiota associated with MHE via 16S rRNA-based pyrosequencing. Am J Gastroenterol 2013 Oct; 108:1601 PMID: 23877352 http://www.nature.com/ajg/journal/v108/n10/full/ajg2013221a.html
  9. 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 Gastroenterol. 2013 Sep;108(9):1458-63. PMID: 23877348
  10. Rahimi RS et al. Lactulose vs. polyethylene glycol 3350-eletrolyte solution for treatment of overt hepatic encephalopathy: The HELP randomized clinical trial. JAMA Intern Med 2014 Sep 22 PMID: 25243839
  11. Wijdicks EF Hepatic Encephalopathy. N Engl J Med 2016; 375:1660-1670. October 27, 2016 PMID: 27783916 http://www.nejm.org/doi/full/10.1056/NEJMra1600561
  12. Sharma BC, Singh J, Srivastava S et al. A randomized controlled trial comparing lactulose plus albumin versus lactulose alone for treatment of hepatic encephalopathy. J Gastroenterol Hepatol 2016 Nov 25 PMID: 27885712 http://onlinelibrary.wiley.com/doi/10.1111/jgh.13666/abstract
  13. 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 Aug;60(2):715-35. PMID: 25042402
  14. Haj M, Rockey DC. Ammonia levels do not guide clinical management of patients with hepatic encephalopathy caused by cirrhosis. Am J Gastroenterol 2020 May; 115:723 PMID: 31658104 https://journals.lww.com/ajg/FullText/2020/05000/Ammonia_Levels_Do_Not_Guide_Clinical_Management_of.20.aspx
  15. Bajaj JS, Pyrsopoulos NT, Rahimi RS, Heimanson Z, Allen C, Rockey DC. Serum ammonia levels do not correlate with overt hepatic encephalopathy severity in hospitalized patients with cirrhosis. Clin Gastroenterol Hepatol 2024 Sep; 22:1950. PMID: 38423347 Free article. https://www.cghjournal.org/article/S1542-3565(24)00219-2/fulltext
  16. Haelle T Rifaximin Reduced Overt Hepatic Encephalopathy Recurrence Over Lactulose. Rifaximin also reduced mortality, but its high cost may be a barrier. MedPage Today November 1, 2024 https://www.medpagetoday.com/meetingcoverage/acg/112698

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