Overview on Current Management of Hepatic Encephalopathy

Zhixian Wang, MD, zujiang Yu, MD, Ke-Qin Hu, MD

Abstract


Hepatic encephalopathy (HE) is one of the most serious complications of chronic or fulminant liver failure. It’s main clinical manifestations involving disturbance of consciousness, behavioral disorders and coma. According to the degree of impaired consciousness, neurological signs and EEG changes, the clinical course of HE may be divided into four phases, ranging from cognitive alteration to coma and even death, staging contribute to early diagnosis, prognosis and therapeutic evaluation. Management of HE primarily involves avoidance of precipitating factors, protect live function from further damage, treatment of ammonia poisoning and regulation of neurotransmitter. This review mainly discusses the current available options for therapy in Hepatic encephalopathy and some new studied agents.

[N A J Med Sci. 2016;9(2):59-65.   DOI:  10.7156/najms.2016.0902059]


Keywords


hepatic encephalopathy, treatment, nonabsorbable disaccharides, antibiotics

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References


Poordad FF. Review article: the burden of hepatic encephalopathy. Aliment Pharmacol Ther. 2007;25(Suppl 1):3-9.

D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217-231.

Eroglu Y, Byrne WJ. Hepatic encephalopathy. Emerg Med Clin North Am. 2009;27:401-414.

Ferenci P. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology (Baltimore, Md.) 35, 716-721 (2002).

Vilstrup H. 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;60:715-735.

Yen CL, Liaw YF. Somatosensory evoked potentials and number connection test in the detection of subclinical hepatic encephalopathy. Hepatogastroenterology. 1990;37:332-334.

Schomerus H. Latent portasystemic encephalopathy. I. Nature of cerebral functional defects and their effect on fitness to drive. Dig Dis Sci. 1981;26:622-630.

Patidar KR. Covert hepatic encephalopathy is independently associated with poor survival and increased risk of hospitalization. Am J Gastroenterol. 2014;109:1757-1763.

Hartmann IJ. The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol. 2000;95:2029-2034.

Butterworth RF, Giguere JF, Michaud J, Lavoie J, Layrargues GP. Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol. 1987;6:1-12.

Windmueller HG, Spaeth AE. Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem. 1974;249:5070-5079.

Castell DO, Moore EW. Ammonia absorption from the human colon. The role of nonionic diffusion. Gastroenterology. 1971;60:33-42.

Luo M, Guo JY, Cao WK. Inflammation: A novel target of current therapies for hepatic encephalopathy in liver cirrhosis. World J Gastroenterol. 2015;21:11815-11824.

Milewski K, Oria M. What we know: the inflammatory basis of hepatic encephalopathy. Metab Brain Dis. 2015. [Epub ahead of print]

Bemeur C, Desjardins P, Butterworth RF. Evidence for oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy. Metab Brain Dis. 2010;25:3-9.

Butterworth RF. Neurosteroids in hepatic encephalopathy: Novel insights and new therapeutic opportunities. J Steroid Biochem Mol Biol. 2015. [Epub ahead of print]

Petersen KU. Options in the treatment of hepatic encephalopathy. Medizinische Monatsschrift fur Pharmazeuten. 38, 160-164 (2015).

Hepatic encephalopathy. Early therapy is most important!. MMW Fortschritte der Medizin. 2014;156:28.

Toris GT, Bikis CN, Tsourouflis GS, Theocharis SE. Hepatic encephalopathy: an updated approach from pathogenesis to treatment. Med Sci Monit. 2011;17:Ra53-63.

Bresci G, Parisi G, Banti S. Management of hepatic encephalopathy with oral zinc supplementation: a long-term treatment. Eur J Med. 1993;2:414-416.

Amodio P, Canesso F, Montagnese S. Dietary management of hepatic encephalopathy revisited. Curr Opin Clin Nutr Metab Care. 2014;17:448-452.

Yang HC, Lin SY. Evidence-based clinical decision making: dietary protein intake recommendations for hepatic encephalopathy patients. The Journal of Nursing. 2013;60:90-96.

Jurado Garcia J, Costan Rodero G, Calanas-Continente A. Importance of nutritional support in patients with hepatic encephalopathy. Nutr Hosp. 2012;27:372-381.

Cordoba J. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. 2004;41:38-43.

Antar R, Wong P, Ghali P. A meta-analysis of nutritional supplementation for management of hospitalized alcoholic hepatitis. Can J Gastroenterol. 2012;26:463-467.

Bianchi GP. Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison. J Int Med. 1993;233:385-392.

Amodio P. The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus. Hepatology. 2013;58:325-336.

Blei AT, Cordoba J. Hepatic Encephalopathy. Am J Gastroenterol. 2001;96:1968-1976.

Riordan, S.M. & Williams, R. Treatment of hepatic encephalopathy. The New England journal of medicine 337, 473-479 (1997).

Sharma, P. & Sharma, B.C. Disaccharides in the treatment of hepatic encephalopathy. Metabolic brain disease 28, 313-320 (2013).

Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs polyethylene glycol 3350--electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA. 2014;174:1727-1733.

Guslandi M, Cella A. Rifaximin and nonabsorbable disaccharides for hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2010;22:376.

Als-Nielsen BE, Gluud LL, Gluud CN. Nonabsorbable disaccharides for the treatment of hepatic encephalopathy--a systemic review of randomized clinical trials--a secondary publication. Ugeskr Laeger. 2005;167:179-182.

Morgan MY, Hawley KE. Lactitol vs. lactulose in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double-blind, randomized trial. Hepatology. 1987;7:1278-1284.

Als-Nielsen B, Gluud LL, Gluud C. Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database Syst Rev. 2004; (2):CD003044.

Sharma P, Sharma BC, Sarin SK. Predictors of nonresponse to lactulose in patients with cirrhosis and hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2010;22:526-531.

Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. 2004;328:1046.

DuPont HL. Rifaximin: An Antibiotic with Important Biologic Effects. Mini Rev Med Chem. 2015;16:200-205.

Hirota SA. Understanding the molecular mechanisms of rifaximin in the treatment of gastrointestinal disorders - a focus on the modulation of host tissue function. Mini Rev Med Chem. 2015;16:206-217.

Conn HO. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology. 1977;72:573-583.

Leise MD, Poterucha JJ, Kamath PS, Kim WR. Management of hepatic encephalopathy in the hospital. Mayo Clin Proc. 2014;89:241-253.

Sharma P, Sharma BC. Management of overt hepatic encephalopathy. J Clin Exp Hepatol. 2015;5:S82-87.

Pedretti G, Calzetti C, Missale G, Fiaccadori F. Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial. Ital J Gastroenterol. 1991;23:175-178.

Di Piazza, S. et al. Rifaximine versus neomycin in the treatment of portosystemic encephalopathy. Ital J Gastroenterol. 1991;23:403-407.

Sanchez-Delgado J, Miquel M. Role of rifaximin in the treatment of hepatic encephalopathy. Gastroenterol Hepatol. 2016;39:282-292.

Wahib AA. Evaluation of rifaximin in management of hepatic encephalopathy. J Egypt Soc Parasitol. 2014;44:677-685.

Sharma BC. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. The American journal of gastroenterology 108, 1458-1463 (2013).

Loguercio C, Federico A, De Girolamo V, Ferrieri A, Del Vecchio Blanco C. Cyclic treatment of chronic hepatic encephalopathy with rifaximin. Results of a double-blind clinical study. Minerva gastroenterologica e dietologica 49, 53-62 (2003).

Mohammad RA, Regal RE, Alaniz C. Combination therapy for the treatment and prevention of hepatic encephalopathy. The Annals of pharmacotherapy 46, 1559-1563 (2012).

Saab S. Probiotics are Helpful in Hepatic Encephalopathy: A Meta-Analysis of Randomized Trials. Liver international : official journal of the International Association for the Study of the Liver (2015).

Solga, S.F. Probiotics can treat hepatic encephalopathy. Medical hypotheses 61, 307-313 (2003).

Liu Q. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology (Baltimore, Md.) 39, 1441-1449 (2004).

Xu J. Effects of probiotic therapy on hepatic encephalopathy in patients with liver cirrhosis: an updated meta-analysis of six randomized controlled trials. Hepatobiliary & pancreatic diseases international: HBPD INT. 13, 354-360 (2014).

McGee RG, Bakens A, Wiley K, Riordan SM, Webster AC. Probiotics for patients with hepatic encephalopathy. The Cochrane database of systematic reviews, Cd008716 (2011).

Blanco Vela, Poo Ramirez JL. Efficacy of oral L-ornithine L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Annals of hepatology 10 Suppl 2, S55-59 (2011).

Zhou ZW. Ornithine aspartate and naloxone combined therapy for hepatic encephalopathy affects cognitive function, prognosis, and neuropeptide levels. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 21, 385-388 (2013).

Rose C. L-ornithine-L-aspartate in experimental portal-systemic encephalopathy: therapeutic efficacy and mechanism of action. Metabolic brain disease 13, 147-157 (1998).

Kircheis Gl. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology (Baltimore, Md.) 25, 1351-1360 (1997).

Stauch S. Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study. J Hepatol. 1998;28:856-864.

Soarez PC, Oliveira AC, Padovan J, Parise ER, Ferraz MB. A critical analysis of studies assessing L-ornithine-L-aspartate (LOLA) in hepatic encephalopathy treatment. Arquivos de Gastroenterologia 46, 241-247 (2009).

Bai M. Randomised clinical trial: L-ornithine-L-aspartate reduces significantly the increase of venous ammonia concentration after TIPSS. Aliment Pharmacol Ther. 2014;40:63-71.

Gluud LL. Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials. J Nutri. 2013;143:1263-1268.

Holecek M. Three targets of branched-chain amino acid supplementation in the treatment of liver disease. Nutrition. 2010;26:482-490.

Gluud, L.L. et al. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2015;9:CD001939.

Kawaguchi T, Taniguchi E, Sata M. Effects of oral branched-chain amino acids on hepatic encephalopathy and outcome in patients with liver cirrhosis. Nutr Clin Pract. 2013;28:580-588.

Ndraha S, Hasan I, Simadibrata M. The effect of L-ornithine L-aspartate and branch chain amino acids on encephalopathy and nutritional status in liver cirrhosis with malnutrition. Acta Med Indones. 2011;43:18-22.

Kawaguchi T, Izumi N, Charlton MR, Sata M. Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 2011;54:1063-1070.

Plauth M. Long-term treatment of latent portosystemic encephalopathy with branched-chain amino acids. A double-blind placebo-controlled crossover study. J Hepatol. 1993;17:308-314.

Als-Nielsen B, Koretz RL, Kjaergard LL, Gluud C. Branched-chain amino acids for hepatic encephalopathy. Cochrane Database Syst Rev; 2003:CD001939.

Banares R, Catalina MV, Vaquero J. Molecular adsorbent recirculating system and bioartificial devices for liver failure. Clin Liver Dis. 2014;18:945-956.

Kobashi-Margain RA. Albumin dialysis with molecular adsorbent recirculating system (MARS) for the treatment of hepatic encephalopathy in liver failure. Ann Hepatol. 2011;10(Suppl 2):S70-76.

Steiner C, Mitzner S. Experiences with MARS liver support therapy in liver failure: analysis of 176 patients of the International MARS Registry. Liver. 2002;22(Suppl 2):20-25.

Hassanein TI. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology. 2007;46:1853-1862.

Leise MD. Treatment of persistent/medically refractory covert hepatic encephalopathy with the molecular adsorbent recirculating system. Liver Transpl. 2014;20:867-868.

Cisneros-Garza LE. The molecular adsorbent recirculating system as a liver support system: summary of Mexican experience. Ann Hepatol. 2014;13:240-247.

Schliess F, Gorg B, Haussinger D. RNA oxidation and zinc in hepatic encephalopathy and hyperammonemia. Metab Brain Dis. 2009;24:119-134.

Poo JL. Serum zinc concentrations in two cohorts of 153 healthy subjects and 100 cirrhotic patients from Mexico City. Digestive diseases. 2015;3:136-142.

Reding P, Duchateau J, Bataille C. Oral zinc supplementation improves hepatic encephalopathy. Results of a randomised controlled trial. Lancet. 1984;2:493-495.

Hayashi M, Ikezawa K, Ono A, et al. Evaluation of the effects of combination therapy with branched-chain amino acid and zinc supplements on nitrogen metabolism in liver cirrhosis. Hepatol Res. 2007;37:615-619.

Tuerk MJ Fazel N. Zinc deficiency. Curr Opin Gastroenterol. 2009;25:136-143.

Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M. Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology. 1996;23:1084-1092.

Takeda A. Zinc homeostasis and functions of zinc in the brain. Biometals. 2001;14:343-351.

Chavez-Tapia NC. A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy. Nutr J. 2013;12:74.

Misel ML, Gish RG, Patton H, Mendler, M. Sodium benzoate for treatment of hepatic encephalopathy. Gastroenterol Hepatol. 2013;9:219-227.

Sushma S. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology. 1992;16:138-144.

Matoori S, Leroux JC. Recent advances in the treatment of hyperammonemia. Adv Drug Deliv Rev. 2015;90:55-68.

Paik YH. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Yonsei Med J. 2005;46:399-407.

Jiang Q. Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol. 2008;20:1064-1070.

Bass NM. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362:1071-1081.

Sanyal A. Randomised clinical trial: rifaximin improves health-related quality of life in cirrhotic patients with hepatic encephalopathy - a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2011;34:853-861.

Eltawil, K.M., Laryea, M., Peltekian, K. & Molinari, M. Rifaximin vs. conventional oral therapy for hepatic encephalopathy: a meta-analysis. World J Gastroenterol. 2012;18:767-777.

Mullen, K.D. et al. Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy. Clin Gastroenterol Hepatol. 2014;12:1390-1397.

Bajaj JS, Barrett AC, Bortey E, Paterson C, Forbes WP. Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis. Aliment Pharmacol Ther. 2015;41:39-45.


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