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Review

Hepatic encephalopathy – recent advances in treatment and diagnosis

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Pages 225-235 | Received 15 Oct 2022, Accepted 18 Feb 2023, Published online: 26 Feb 2023

References

  • European Association for the Study of the Liver. 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.
  • 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):715–735.
  • Romero-Gomez M, Boza F, Garcia-Valdecasas MS, et al. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol. 2001;96:2718–2723.
  • Riggio O, Nardelli S, Moscucci F, et al. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Clin Liver Dis. 2012;16(1):133–146.
  • Ridola L, Cardinale V, Riggio O. The burden of minimal hepatic encephalopathy: from diagnosis to therapeutic strategies. Ann Gastroenterol. 2018;31:151–164.
  • Di Pascoli M, Ceranto E, Nardi PD, et al. Hospitalizations due to cirrhosis: clinical aspects in a large cohort of Italian patients and cost analysis report. Dig Dis. 2017;35:433–438.
  • Bajaj JS, Riggio O, Allampati S, et al. Cognitive dysfunction is associated with poor socioeconomic status in patients with cirrhosis: an international multicenter study. Clin Gastroenterol Hepatol. 2013;11(11):1511–1516.
  • Bajaj JS, Schubert CM, Heuman DM, et al. Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Gastroenterology. 2010;138(7):2332–2340.
  • Nardelli S, Allampati S, Riggio O, et al. Hepatic encephalopathy is associated with persistent learning impairments despite adequate medical treatment: a multicenter, international study. Dig Dis Sci. 2017;62(3):794–800.
  • Labenz C, Baron JS, Toenges G, et al. Prospective evaluation of the impact of covert hepatic encephalopathy on quality of life and sleep in cirrhotic patients. Aliment Pharmacol Ther. 2018;48:313–321.
  • Younossi ZM, Boparai N, Price LL, et al. Health-related quality of life in chronic liver disease: the impact of type and severity of disease. Am J Gastroenterol. 2001;96:2199–2205.
  • Nardelli S, Gioia S, Ridola L, et al. Risk of falls in patients with cirrhosis evaluated by timed up and go test: does muscle or brain matter more? Dig Liver Dis. 2022;54(3):371–377.
  • Bajaj JS, Hafeezullah M, Hoffmann RG, et al. Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations. Am J Gastroenterol. 2007;102:1903–1909.
  • Levitt DG, Levitt MD. A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in 436 the multiple organs involved in the production, catabolism, and excretion of ammonia in humans. Clin Exp Gastroenterol. 2018;437(11):193–215.
  • Elwir S, Rahimi RS. Hepatic encephalopathy: an update on the pathophysiology and therapeutic options. J Clin Transl Hepatol. 2017;5:1–10.
  • Wright G, Noiret L, Olde Damink SW, et al. Interorgan ammonia metabolism in liver failure: the basis of current and future therapies. Liver Int. 2011;31:163–175.
  • Shawcross DL, Sharifi Y, Canavan JB, et al. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol. 2011;54:640–649.
  • Dhiman RK. Gut microbiota, inflammation and hepatic encephalopathy: a puzzle with a solution in sight. J Clin Exp Hepatol. 2012;2:207–210.
  • Gupta A, Dhiman RK, Kumari S, et al. Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy. J Hepatol. 2010;53:849–855.
  • Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J PhysiolGastrointest Liver Physiol. 2012;302(1):G168–75.
  • Bajaj JS, Hylemon PB, Ridlon JM, et al. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to 454 cognition and inflammation. Am J Physiol Gastrointest Liver Physiol. 2012;303((6)):G675–85.
  • Montano-Loza AJ, Angulo P, Meza-Junco J, et al. Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis. J Cachexia Sarcopenia Muscle. 2016;7:126–135.
  • Eslamparast T, Montano-Loza AJ, Raman M, et al. Sarcopenic obesity in cirrhosis—the confluence of 2 prognostic titans. Liver Int. 2018;38:1706–1717.
  • Bhanji RA, Moctezuma-Velazquez C, Duarte-Rojo A, et al. Myosteatosis and sarcopenia are associated with hepatic encephalopathy in patients with cirrhosis. Hepatol Int. 2018;12:377–386.
  • Gallagher D, Kuznia P, Heshka S, et al. Adipose tissue in muscle: a novel depot similar in size to visceral adipose tissue. Am J Clin Nutr. 2005;81:903–910.
  • Dasarathy S, Mookerjee RP, Rackayova V, et al. Ammonia toxicity: from head to toe? Metab Brain Dis. 2017;32:529–538.
  • Dasarathy SJ. Myostatin and beyond in cirrhosis: all roads lead to sarcopenia. J Cachexia Sarcopenia Muscle. 2017;8:864–869.
  • Gioia S, Ridola L, Cristofaro L, et al. The improvement in body composition including subcutaneous and visceral fat reduces ammonia and hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Liver Int. 2021;41(12):2965–2973.
  • Romero-Gómez M, Montagnese S, Jalan R. Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure. J Hepatol. 2015;62(2):437–447.
  • Riggio O, Efrati C, Catalano C, et al. High prevalence of spontaneous portosystemic shunts in persistent hepatic encephalopathy: a case-control study. Hepatology. 2005;42:1158–1165.
  • Simon-Talero M, Roccarina D, Martinez J, et al. Association between portosystemic shunts and increased complications and mortality in patients with cirrhosis. Gastroenterology. 2018;154:1694–1705.
  • Montagnese S, Russo FP, Amodio P, et al. Hepatic encephalopathy 2018: a clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis. 2019;51:190–205.
  • Amodio P. Hepatic encephalopathy: diagnosis and management. Liver Int. 2018;38(6):966–975.
  • Nardelli S, Ridola L, Gioia S, et al. Management of hepatic encephalopathy not responsive to first-line treatments. Curr Treat Options Gastroenterol. 2018;16:253–259.
  • Weissenborn K. Hepatic encephalopathy: definition, clinical grading and diagnostic principles. Drugs. 2019;79(Suppl 1):5–9.
  • Nardone R, Taylor AC, Höller Y, et al. Minimal hepatic encephalopathy: a review. Neurosci Res. 2016;111:1–12.
  • Kircheis G, Wettstein M, Timmermann L, et al. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology. 2002;35:357–366.
  • Bajaj JS, Thacker LR, Heuman DM, et al. The Stroop smartphone application is a short and valid method to screen for minimal hepatic encephalopathy. Hepatology. 2013;58(3):1122–1132.
  • Amodio P, Ridola L, Schiff S, et al. Improving the inhibitory control task to detect minimal hepatic encephalopathy. Gastroenterology. 2010;139:510–518.
  • Luo M, Ma P, Li L, et al. Advances in psychometric tests for screening minimal hepatic encephalopathy: from paper-and-pencil to computer-aided assessment. Turk J Gastroenterol. 2019;30:398–407.
  • Campagna F, Montagnese S, Ridola L, et al. The animal naming test: an easy tool for the assessment of hepatic encephalopathy. Hepatology. 2017;66:198–208.
  • Pantham G, Mullen KD. Practical issues in the management of overt hepatic encephalopathy. Gastroenterol Hepatol. 2017;13(11):659–665.
  • Merli M, Lucidi C, Pentassuglio I, et al. Increased risk of cognitive impairment in cirrhotic patients with bacterial infections. J Hepatol. 2013;59:243–250.
  • Montano-Loza AJ, Meza-Junco J, Prado CM, et al. Muscle wasting is associated with mortality in patients with cirrhosis. Clin Gastroenterol Hepatol. 2012;10(2):166–173.
  • Kim G, Kang SH, Kim MY, et al. Prognostic value of sarcopenia in patients with liver cirrhosis: a systematic review and meta-analysis. PLoS One. 2017;12:e0186990.
  • European Association for the Study of the Liver. EASL Clinical Practice Guidelines on nutrition in chronic liver disease. J Hepatol. 2019;70:172–193.
  • Hanai T, Shiraki M, Nishimura K, et al. Sarcopenia impairs prognosis of patients with liver cirrhosis. Nutrition. 2015;31:193–199.
  • Nardelli S, Lattanzi B, Merli M, et al. Muscle alterations are associated with minimal and overt hepatic encephalopathy in patients with liver cirrhosis. Hepatology. 2019;70(5):1704–1713.
  • Merli M, Giusto M, Lucidi C, et al. Muscle depletion increases the risk of overt and minimal hepatic encephalopathy: results of a prospective study. Metab Brain Dis. 2013;28:281–284.
  • Nardelli S, Lattanzi B, Torrisi S, et al. Sarcopenia is risk factor for development of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt placement. Clin Gastroenterol Hepatol. 2017;15:934–936.
  • Lattanzi B, D’Ambrosio D, Manuela Merli. Sarcopenia: two faces of the same metabolic alteration. J Clin Exp Hepatol. 2019;9:125–130.
  • Kalaitzakis E, Olsson R, Henfridsson P, et al. Malnutrition and diabetes mellitus are related to hepatic encephalopathy in patients with liver cirrhosis. Liver Int. 2007;27(9):1194–1201.
  • Meza-Junco J, Montano-Loza AJ, Baracos VE, et al. Sarcopenia as a Prognostic Index of Nutritional Status in Concurrent Cirrhosis and Hepatocellular carcinoma. J Clin Gastroenterol. 2013;47(10):861–870.
  • Praktiknjo M, Simón-Talero M, Römer J, et al. Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis. J Hepatol. 2020;72(6):1140–1150.
  • Nardelli S, Riggio O, Turco L, et al. Relevance of spontaneous portosystemic shunts detected with CT in patients with cirrhosis. Radiology. 2021;299(1):133–140.
  • Sharma P, Agrawal A, Sharma BC, et al. Prophylaxis of hepatic encephalopathy in acute variceal bleed: a randomized controlled trial of lactulose versus no lactulose. J Gastroenterol Hepatol. 2011;26(6):996–1003.
  • Tromm A, Griga T, Greving I, et al. Orthograde whole gut irrigation with mannite versus paromomycine + lactulose as pro-phylaxis of hepatic encephalopathy in patients with cirrhosis and upper gastrointestinal bleeding: results of a controlled randomized trial. Hepato-gastroenterology. 2000;47(32):473–477.
  • Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071–1081.
  • 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):674–679.
  • Bureau C, Thabut D, Jezequel C, et al. The use of rifaximin in the prevention of overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled trial. Ann Intern Med. 2021;174(5):633–640.
  • Miraglia R, Maruzzelli L, Di Piazza A, et al. Transjugular intrahepatic portosystemic shunt using the new gore viatorr controlled expansion endoprosthesis: prospective, single-center, preliminary experience. Cardiovasc Intervent Radiol. 2019;42(1):78–86.
  • Riggio O, Ridola L, Angeloni S, et al. Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: results of a randomized controlled trial. J Hepatol. 2010;53(2):267–272.
  • 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;66:1727–1738.
  • Nardelli S, Gioia S, Ridola L, et al. Radiological intervention for shunt related encephalopathy. J Clin Exp Hepatol. 2018;8(4):452–459.
  • 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):2448–2457.
  • Lv Y, Chen H, Luo B, et al. Concurrent large spontaneous portosystemic shunt embolization for the prevention of overt hepatic encephalopathy after TIPS: a randomized controlled trial. Hepatology. 2022;76(3):676–688.
  • Sharma BC, Singh J, Srivastava S, et al. Randomized controlled trial comparing lactulose plus albumin versus lactulose alone for treatment of hepatic encephalopathy. J Gastroenterol Hepatol. 2017;32:1234–1239.
  • 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;108:1458–1463.
  • Rahimi RS, Singal AG, Cuthbert JA, et al. Lactulose vs polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med. 2014;174:1727–1733.
  • Sidhu SS, Sharma BC, Goyal O, et al. L-ornithine L-aspartate in bouts of overt hepatic encephalopathy. Hepatology. 2018;67(2):700–710.
  • Shehata HH, Elfert AA, Abdin AA, et al. Randomized controlled trial of polyethylene glycol versus lactulose for the treatment of overt hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2018;30(12):1476–1481.
  • Sharma BC, Sharma P, Agrawal A, et al. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology. 2009;137:885–891.
  • Les I, Doval E, García-Martínez R, et al. Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study. Am J Gastroenterol. 2011;106:1081–1088.
  • Agrawal A, Sharma BC, Sharma P, 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;107:1043–1050.
  • Dhiman RK, Rana B, Agrawal S, et al. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology. 2014;147:1327–1337.
  • Rockey DC, Vierling JM, Mantry P, et al. Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy. Hepatology. 2014;59:1073–1083.
  • Varakanahalli S, Sharma BC, Srivastava S, et al. 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(8):951–958.
  • Larsen FS, Schmidt LE, Bernsmeier C, et al. High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial. J Hepatol. 2016;64:69–78.
  • Hassanein TI, Tofteng F, Brown JRS, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology. 2007;46:1853–1862.
  • Bañares 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;57:1153–1162.
  • Ridola L, Nardelli S, Gioia S, et al. How to Design a multicenter clinical trial in hepatic encephalopathy. J Clin Exp Hepatol. 2019;9(1):137–145.
  • Dalal R, McGee RG, Riordan SM, et al. Probiotics for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017;2:CD008716
  • Riggio O, Mannaioni G, Ridola L, et al. Peripheral and splanchnic indole and oxindole levels in cirrhotic patients: a study on the pathophysiology of hepatic encephalopathy. Am J Gastroenterol. 2010;105:1374–1381.
  • Bajaj JS, Salzman NH, Acharya C, et al. Faecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial. Hepatology. 2019;70:1690–1703.
  • Mehta R, Kabrawala M, Nandwani S, et al. Preliminary experience with single fecal microbiota transplant for treatment of recurrent overt hepatic encephalopathy-A case series. Indian J Gastroenterol. 2018;37:559–562.
  • Bajaj JS, Fagan A, Gavis EA, et al. Longterm outcomes of fecal microbiota transplantation in patients with cirrhosis. Gastroenterology. 2019;156:1921–1923.
  • de Cena JA, Zhang J, Deng D, et al. Low-abundant microorganisms: the human microbiome’s dark matter, a scoping review. Front Cell Infect Microbiol. 2021;11:689197.
  • Fagan A, Gavis EA, Gallagher ML, et al. A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study. J Hepatol. 2022 Sep 22;78(2):312–321.
  • Nardelli S, Gioia S, Faccioli J, et al. Albumin for cognitive impairment after TIPS: a road to be explored. J Hepatol. 2023 Mar;78(3):e96–e97.

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