Hepatic Encephalopathy: Pathophysiology and Emerging Therapies

Medical Clinics of North America

Volumn 93, Issue 4, 2009, Pages 819-836

  Sundaram, Vinay ^a   Shaikh, Obaid S ^a  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

Ammonia; Cirrhosis; Coma; Liver failure; Neuropsychiatric dysfunction

Indexed keywords

4 AMINOBUTYRIC ACID; ACARBOSE; AMMONIA; ANALGESIC AGENT; ANTIBIOTIC AGENT; ANTIDEPRESSANT AGENT; BENZODIAZEPINE DERIVATIVE; BENZOIC ACID; CARNITINE; DOPAMINE RECEPTOR STIMULATING AGENT; FLUMAZENIL; INFUSION FLUID; LACTITOL; LACTULOSE; MANGANESE; METRONIDAZOLE; NARCOTIC AGENT; NEOMYCIN; ORNITHINE ASPARTATE; PLACEBO; POTASSIUM; PROBIOTIC AGENT; RIFAXIMIN; SEDATIVE AGENT; VASOPRESSIN RECEPTOR ANTAGONIST; ZINC ACETATE; ZINC SULFATE;

ABDOMINAL DISCOMFORT; ABDOMINAL PAIN; ABSENCE OF SIDE EFFECTS; CHRONIC LIVER DISEASE; CLINICAL FEATURE; CLINICAL TRIAL; COGNITIVE DEFECT; CREATININE BLOOD LEVEL; DEHYDRATION; DIARRHEA; DIET THERAPY; DIETARY INTAKE; DISEASE SEVERITY; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; FLATULENCE; HEPATIC ENCEPHALOPATHY; HUMAN; HYPOKALEMIA; HYPONATREMIA; INFECTION; LIVER CIRRHOSIS; LIVER SUPPORT; MALABSORPTION; MENTAL HEALTH; METALLIC TASTE; NAUSEA; NEPHROTOXICITY; NEUROPSYCHOLOGICAL TEST; NUCLEAR MAGNETIC RESONANCE IMAGING; OTOTOXICITY; PATHOPHYSIOLOGY; PERIPHERAL NEUROPATHY; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; SYSTEMIC INFLAMMATORY RESPONSE SYNDROME; TASTE AVERSION; TASTE DISORDER; TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT; UNSPECIFIED SIDE EFFECT; VOMITING;

AMMONIA; ANTI-INFECTIVE AGENTS; DRUG THERAPY, COMBINATION; DYSKINESIAS; GASTROINTESTINAL AGENTS; HEPATIC ENCEPHALOPATHY; HUMANS; LACTULOSE; LIVER; LIVER CIRRHOSIS; LIVER, ARTIFICIAL; MANGANESE; METRONIDAZOLE; NEOMYCIN; NEUROPSYCHOLOGICAL TESTS; PORTASYSTEMIC SHUNT, TRANSJUGULAR INTRAHEPATIC; PROTEIN-ENERGY MALNUTRITION; RECURRENCE; RIFAMYCINS; TRACE ELEMENTS; ZINC;

EID: 67649388055     PISSN: 00257125     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.mcna.2009.03.009     Document Type: Review

References (138)

1. Ferenci P., Lockwood A., Mullen K., et al. Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35 (2002) 716-721
2. Munoz S.J. Hepatic encephalopathy. Med Clin North Am 92 (2008) 795-812 viii
3. Haussinger D., and Schliess F. Pathogenetic mechanisms of hepatic encephalopathy. Gut 57 (2008) 1156-1165
4. Gerber T., and Schomerus H. Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management. Drugs 60 (2000) 1353-1370
5. Butterworth R.F. Complications of cirrhosis III. Hepatic encephalopathy. J Hepatol 32 (2000) 171-180
6. 4-induced liver disease. Acta Neurol Scand 55 (1977) 1-15
7. Pilbeam C.M., Anderson R.M., and Bhathal P.S. The brain in experimental portal-systemic encephalopathy. I. Morphological changes in three animal models. J Pathol 140 (1983) 331-345
8. Albrecht J., and Norenberg M.D. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 44 (2006) 788-794
9. Corbalan R., Hernandez-Viadel M., Llansola M., et al. Chronic hyperammonemia alters protein phosphorylation and glutamate receptor-associated signal transduction in brain. Neurochem Int 41 (2002) 103-108
10. Schliess F., Gorg B., Fischer R., et al. Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. FASEB J 16 (2002) 739-741
11. Schliess F., Foster N., Gorg B., et al. Hypoosmotic swelling increases protein tyrosine nitration in cultured rat astrocytes. Glia 47 (2004) 21-29
12. Murthy C.R., Rama Rao K.V., Bai G., et al. Ammonia-induced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res 66 (2001) 282-288
13. Jayakumar A.R., Rama Rao K.V., Schousboe A., et al. Glutamine-induced free radical production in cultured astrocytes. Glia 46 (2004) 296-301
14. Rama Rao K.V., Chen M., Simard J.M., et al. Suppression of ammonia-induced astrocyte swelling by cyclosporin A. J Neurosci Res 74 (2003) 891-897
15. Rama Rao K.V., and Norenberg M.D. Aquaporin-4 in hepatic encephalopathy. Metab Brain Dis 22 (2007) 265-275
16. Chepkova A.N., Sergeeva O.A., and Haas H.L. Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment. Neurobiol Dis 23 (2006) 512-521
17. Jalan R., Olde Damink S.W., Lui H.F., et al. Oral amino acid load mimicking hemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver. Metab Brain Dis 18 (2003) 37-49
18. Lockwood A.H., Yap E.W., and Wong W.H. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metab 11 (1991) 337-341
19. Weissenborn K., Bokemeyer M., Ahl B., et al. Functional imaging of the brain in patients with liver cirrhosis. Metab Brain Dis 19 (2004) 269-280
20. Bansky G., Meier P.S., Ziegler W.H., et al. Reversal of hepatic coma by benzodiazepine antagonists (Ro 15-1788). [letter]. Lancet 1 (1985) 1324-1325
21. Scollo-Lavizzari G., and Steinmann E. Reversal of hepatic coma by benzodiazepine antagonist (Ro 15-1788). [letter]. Lancet 1 (1985) 1324
22. Lighthouse J., Naito Y., Helmy A., et al. Endotoxinemia and benzodiazepine-like substances in compensated cirrhotic patients: a randomized study comparing the effect of rifaximine alone and in association with a symbiotic preparation. Hepatol Res 28 (2004) 155-160
23. Zeneroli M.L., Venturini I., Corsi L., et al. Benzodiazepine-like compounds in the plasma of patients with fulminant hepatic failure. Scand J Gastroenterol 33 (1998) 310-313
24. Zeneroli M.L., Venturini I., Stefanelli S., et al. Antibacterial activity of rifaximin reduces the levels of benzodiazepine-like compounds in patients with liver cirrhosis. Pharmacol Res 35 (1997) 557-560
25. Basile A.S., and Jones E.A. The involvement of benzodiazepine receptor ligands in hepatic encephalopathy. Hepatology 20 (1994) 541-543
26. Stewart C.A., Reivich M., Lucey M.R., et al. Neuroimaging in hepatic encephalopathy. Clin Gastroenterol Hepatol 3 (2005) 197-207
27. Cagnin A., Taylor-Robinson S.D., Forton D.M., et al. In vivo imaging of cerebral "peripheral benzodiazepine binding sites" in patients with hepatic encephalopathy. Gut 55 (2006) 547-553
28. Ahboucha S., Layrargues G.P., Mamer O., et al. Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy. Ann Neurol 58 (2005) 169-170
29. Baraldi M., Zeneroli M.L., Ventura E., et al. Supersensitivity of benzodiazepine receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat: reversal by a benzodiazepine antagonist. Clin Sci (Lond) 67 (1984) 167-175
30. Schafer D.F., Fowler J.M., Munson P.J., et al. Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure. J Lab Clin Med 102 (1983) 870-880
31. 3H]muscimol (GABA-A) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Hepatology 8 (1988) 1084-1088
32. Ahboucha S., Desjardins P., Chatauret N., et al. Normal coupling of brain benzodiazepine and neurosteroid modulatory sites on the GABA-A receptor complex in human hepatic encephalopathy. Neurochem Int 43 (2003) 551-556
33. Dodd P.R., Thomas G.J., Harper C.G., et al. Amino acid neurotransmitter receptor changes in cerebral cortex in alcoholism: effect of cirrhosis of the liver. J Neurochem 59 (1992) 1506-1515
34. Blei A.T. Infection, inflammation and hepatic encephalopathy, synergism redefined. J Hepatol 40 (2004) 327-330
35. Rolando N., Wade J., Davalos M., et al. The systemic inflammatory response syndrome in acute liver failure. Hepatology 32 (2000) 734-739
36. Vaquero J., Polson J., Chung C., et al. Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology 125 (2003) 755-764
37. Haussinger D., and Schliess F. Astrocyte swelling and protein tyrosine nitration in hepatic encephalopathy. Neurochem Int 47 (2005) 64-70
38. Pedersen H.R., Ring-Larsen H., Olsen N.V., et al. Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital. J Hepatol 47 (2007) 245-252
39. Shawcross D.L., Davies N.A., Williams R., et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 40 (2004) 247-254
40. Hazell A.S. Astrocytes and manganese neurotoxicity. Neurochem Int 41 (2002) 271-277
41. Hazell A.S., Desjardins P., and Butterworth R.F. Increased expression of glyceraldehyde-3-phosphate dehydrogenase in cultured astrocytes following exposure to manganese. Neurochem Int 35 (1999) 11-17
42. 3H-PK 11195. Neurosci Lett 271 (1999) 5-8
43. Krieger D., Krieger S., Jansen O., et al. Manganese and chronic hepatic encephalopathy. Lancet 346 (1995) 270-274
44. Spahr L., Butterworth R.F., Fontaine S., et al. Increased blood manganese in cirrhotic patients: relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms. Hepatology 24 (1996) 1116-1120
45. Weissenborn K., Ehrenheim C., Hori A., et al. Pallidal lesions in patients with liver cirrhosis: clinical and MRI evaluation. Metab Brain Dis 10 (1995) 219-231
46. Rose C., Butterworth R.F., Zayed J., et al. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology 117 (1999) 640-644
47. Adams R.D., and Foley J.M. The neurological disorder associated with liver disease. Res Publ Assoc Res Nerv Ment Dis 32 (1953) 198-237
48. Timmermann L., Gross J., Butz M., et al. Mini-asterixis in hepatic encephalopathy induced by pathologic thalamo-motor-cortical coupling. Neurology 61 (2003) 689-692
49. Joebges E.M., Heidemann M., Schimke N., et al. Bradykinesia in minimal hepatic encephalopathy is due to disturbances in movement initiation. J Hepatol 38 (2003) 273-280
50. Mendoza G., Marti-Fabregas J., Kulisevsky J., et al. Hepatic myelopathy: a rare complication of portacaval shunt. Eur Neurol 34 (1994) 209-212
51. Schomerus H., and Hamster W. Quality of life in cirrhotics with minimal hepatic encephalopathy. Metab Brain Dis 16 (2001) 37-41
52. Weissenborn K., Ennen J.C., Schomerus H., et al. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 34 (2001) 768-773
53. Howieson D.B., and Lezak M.D. The neuropsychological evaluation. In: Yudofsky S.C., and Hales R.E. (Eds). Textbook of neuropsychiatry and clinical neurosciences (2002), American Psychiatric Publishing, Washington, DC
54. McCrea M., Cordoba J., Vessey G., et al. Neuropsychological characterization and detection of subclinical hepatic encephalopathy. Arch Neurol 53 (1996) 758-763
55. Weissenborn K., Bokemeyer M., Krause J., et al. Neurological and neuropsychiatric syndromes associated with liver disease. AIDS 3 Suppl 19 (2005) S93-S98
56. Romero-Gomez M., Cordoba J., Jover R., et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology 45 (2007) 879-885
57. Sharma P., Sharma B.C., Puri V., et al. Critical flicker frequency: diagnostic tool for minimal hepatic encephalopathy. J Hepatol 47 (2007) 67-73
58. O'Carroll R.E., Hayes P.C., Ebmeier K.P., et al. Regional cerebral blood flow and cognitive function in patients with chronic liver disease. Lancet 337 (1991) 1250-1253
59. Trzepacz P.T. The neuropathogenesis of delirium. A need to focus our research. Psychosomatics 35 (1994) 374-391
60. Catafau A.M., Kulisevsky J., Berna L., et al. Relationship between cerebral perfusion in frontal-limbic-basal ganglia circuits and neuropsychologic impairment in patients with subclinical hepatic encephalopathy. J Nucl Med 41 (2000) 405-410
61. Morgan M.Y. Cerebral magnetic resonance imaging in patients with chronic liver disease. Metab Brain Dis 13 (1998) 273-290
62. Malecki E.A., Devenyi A.G., Barron T.F., et al. Iron and manganese homeostasis in chronic liver disease: relationship to pallidal T1-weighted magnetic resonance signal hyperintensity. Neurotoxicology 20 (1999) 647-652
63. Weissenborn K., Ahl B., Fischer-Wasels D., et al. Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy. Gut 56 (2007) 1736-1742
64. Kale R.A., Gupta R.K., Saraswat V.A., et al. Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy. Hepatology 43 (2006) 698-706
65. Watanabe A., Tuchida T., Yata Y., et al. Evaluation of neuropsychological function in patients with liver cirrhosis with special reference to their driving ability. Metab Brain Dis 10 (1995) 239-248
66. Wein C., Koch H., Popp B., et al. Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 39 (2004) 739-745
67. Jalan R., Elton R.A., Redhead D.N., et al. Analysis of prognostic variables in the prediction of mortality, shunt failure, variceal rebleeding and encephalopathy following the transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage. J Hepatol 23 (1995) 123-128
68. Sanyal A.J., Freedman A.M., Shiffman M.L., et al. Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. Hepatology 20 (1994) 46-55
69. Somberg K.A., Riegler J.L., LaBerge J.M., et al. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunts: incidence and risk factors. Am J Gastroenterol 90 (1995) 549-555
70. Casado M., Bosch J., Garcia-Pagan J.C., et al. Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings. Gastroenterology 114 (1998) 1296-1303
71. Nolte W., Wiltfang J., Schindler C., et al. Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: clinical, laboratory, psychometric, and electroencephalographic investigations. Hepatology 28 (1998) 1215-1225
72. Kochar N., Tripathi D., Ireland H., et al. Transjugular intrahepatic portosystemic stent shunt (TIPSS) modification in the management of post-TIPSS refractory hepatic encephalopathy. Gut 55 (2006) 1617-1623
73. Phillips G.B., Schwartz R., Gabuzda Jr. G.J., et al. The syndrome of impending hepatic coma in patients with cirrhosis of the liver given certain nitrogenous substances. N Engl J Med 247 (1952) 239-246
74. Schwartz R., Phillips G.B., Seegmiller J.E., et al. Dietary protein in the genesis of hepatic coma. N Engl J Med 251 (1954) 685-689
75. Schrier R.W., Gross P., Gheorghiade M., et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355 (2006) 2099-2112
76. van Leeuwen P.A., van Berlo C.L., and Soeters P.B. New mode of action for lactulose. Lancet 1 (1988) 55-56
77. Cordoba J., Minguez B., and Vergara M. Treatment of hepatic encephalopathy. Lancet 365 (2005) 1384-1385 [author reply 1385-6]
78. 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 7 (1987) 639-643
79. Morgan M.Y., and Hawley K.E. Lactitol vs. lactulose in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double-blind, randomized trial. Hepatology 7 (1987) 1278-1284
80. Morgan M.Y., Alonso M., and Stanger L.C. Lactitol and lactulose for the treatment of subclinical hepatic encephalopathy in cirrhotic patients. A randomised, cross-over study. J Hepatol 8 (1989) 208-217
81. Prasad S., Dhiman R.K., Duseja A., et al. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 45 (2007) 549-559
82. Als-Nielsen B., Gluud L.L., and Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ 328 (2004) 1046
83. Strauss E., Tramote R., Silva E.P., et al. Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 39 (1992) 542-545
84. Atterbury C.E., Maddrey W.C., and Conn H.O. Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy. A controlled, double-blind clinical trial. Am J Dig Dis 23 (1978) 398-406
85. Conn H.O., Leevy C.M., Vlahcevic Z.R., et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 72 (1977) 573-583
86. Blanc P., Daures J.P., Liautard J., et al. [Lactulose-neomycin combination versus placebo in the treatment of acute hepatic encephalopathy. Results of a randomized controlled trial]. Gastroenterol Clin Biol 18 (1994) 1063-1068 [in French]
87. Morgan M.H., Read A.E., and Speller D.C. Treatment of hepatic encephalopathy with metronidazole. Gut 23 (1982) 1-7
88. Hawkins R.A., Jessy J., Mans A.M., et al. Neomycin reduces the intestinal production of ammonia from glutamine. Adv Exp Med Biol 368 (1994) 125-134
89. Green P.H., and Tall A.R. Drugs, alcohol and malabsorption. Am J Med 67 (1979) 1066-1076
90. Bustamante J., Rimola A., Ventura P.J., et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 30 (1999) 890-895
91. Bass N.M., Ahmed A., Johnson L., et al. Rifaximin treatment is beneficial for mild hepatic encephalopathy. Hepatology 40 (2004) 646A [abstract]
92. Pedretti G., Calzetti C., Missale G., et al. Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial. Ital J Gastroenterol 23 (1991) 175-178
93. Mas A., Rodes J., Sunyer L., et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol 38 (2003) 51-58
94. Williams R., James O.F., Warnes T.W., et al. Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study. Eur J Gastroenterol Hepatol 12 (2000) 203-208
95. Bucci L., and Palmieri G.C. Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res Opin 13 (1993) 109-118
96. Giacomo F., Francesco A., Michele N., et al. Rifaximin in the treatment of hepatic encephalopathy. Eur J Clin Res 4 (1993) 57-66
97. Massa P., Vallerino E., and Dodero M. Treatment of hepatic encephalopathy with rifaximin: double blind, double dummy study versus lactulose. Eur J Clin Res 4 (1993) 7-18
98. Rabbani P., and Prasad A.S. Plasma ammonia and liver ornithine transcarbamoylase activity in zinc-deficient rats. Am J Physiol 235 (1978) E203-E206
99. Riggio O., Merli M., Capocaccia L., et al. Zinc supplementation reduces blood ammonia and increases liver ornithine transcarbamylase activity in experimental cirrhosis. Hepatology 16 (1992) 785-789
100. Prasad A.S., Rabbani P., Abbasii A., et al. Experimental zinc deficiency in humans. Ann Intern Med 89 (1978) 483-490
101. Reding P., Duchateau J., and Bataille C. Oral zinc supplementation improves hepatic encephalopathy. Results of a randomised controlled trial. Lancet 2 (1984) 493-495
102. Grungreiff K., Presser H.J., Franke D., et al. Correlations between zinc, amino acids and ammonia in liver cirrhosis. Z Gastroenterol 27 (1989) 731-735
103. Marchesini G., Fabbri A., Bianchi G., et al. Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology 23 (1996) 1084-1092
104. Riggio O., Ariosto F., Merli M., et al. Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy. Results of a double-blind crossover trial. Dig Dis Sci 36 (1991) 1204-1208
105. Abou-Assi S., and Vlahcevic Z.R. Hepatic encephalopathy. Metabolic consequence of cirrhosis often is reversible. Postgrad Med 109 (2001) 52-54 57-60, 63-5 passim
106. Sushma S., Dasarathy S., Tandon R.K., et al. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology 16 (1992) 138-144
107. Blei A.T., and Cordoba J. Hepatic encephalopathy. Am J Gastroenterol 96 (2001) 1968-1976
108. Uribe M., Farca A., Marquez M.A., et al. Treatment of chronic portal systemic encephalopathy with bromocriptine: a double-blind controlled trial. Gastroenterology 76 (1979) 1347-1351
109. Pomier-Layrargues G., Giguere J.F., Lavoie J., et al. Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial. Hepatology 19 (1994) 32-37
110. Barbaro G., Di Lorenzo G., Soldini M., et al. Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: an Italian multicenter double-blind, placebo-controlled, cross-over study. Hepatology 28 (1998) 374-378
111. Dursun M., Caliskan M., Canoruc F., et al. The efficacy of flumazenil in subclinical to mild hepatic encephalopathic ambulatory patients. A prospective, randomised, double-blind, placebo-controlled study. Swiss Med Wkly 133 (2003) 118-123
112. Kircheis G., Nilius R., Held C., et al. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology 25 (1997) 1351-1360
113. Stauch S., Kircheis G., Adler G., et al. Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study. J Hepatol 28 (1998) 856-864
114. Malaguarnera M., Pistone G., Elvira R., et al. Effects of L-carnitine in patients with hepatic encephalopathy. World J Gastroenterol 11 (2005) 7197-7202
115. del Olmo J.A., Castillo M., Rodrigo J.M., et al. Effect of L-carnitine upon ammonia tolerance test in cirrhotic patients. Adv Exp Med Biol 272 (1990) 197-208
116. Gentile S., Guarino G., Romano M., et al. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 3 (2005) 184-191
117. Solga S.F. Probiotics can treat hepatic encephalopathy. Med Hypotheses 61 (2003) 307-313
118. Bongaerts G., Severijnen R., and Timmerman H. Effect of antibiotics, prebiotics and probiotics in treatment for hepatic encephalopathy. Med Hypotheses 64 (2005) 64-68
119. Liu Q., Duan Z.P., Ha D.K., et al. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 39 (2004) 1441-1449
120. Loguercio C., Abbiati R., Rinaldi M., et al. Long-term effects of Enterococcus faecium SF68 versus lactulose in the treatment of patients with cirrhosis and grade 1-2 hepatic encephalopathy. J Hepatol 23 (1995) 39-46
121. Malaguarnera M., Greco F., Barone G., et al. Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Dig Dis Sci 52 (2007) 3259-3265
122. Bajaj J.S., Saeian K., Christensen K.M., et al. Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol 103 (2008) 1707-1715
123. Charlton M. Branched-chain amino acid enriched supplements as therapy for liver disease. J Nutr 136 (2006) 295S-298S
124. Plauth M., Cabre E., Riggio O., et al. ESPEN guidelines on enteral nutrition: liver disease. Clin Nutr 25 (2006) 285-294
125. Cordoba J., Lopez-Hellin J., Planas M., et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol 41 (2004) 38-43
126. Nielsen K., Kondrup J., Martinsen L., et al. Long-term oral refeeding of patients with cirrhosis of the liver. Br J Nutr 74 (1995) 557-567
127. Iwasa M., Matsumura K., Watanabe Y., et al. Improvement of regional cerebral blood flow after treatment with branched-chain amino acid solutions in patients with cirrhosis. Eur J Gastroenterol Hepatol 15 (2003) 733-737
128. Muto Y., Sato S., Watanabe A., et al. Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 3 (2005) 705-713
129. Als-Nielsen B., Koretz R.L., Kjaergard L.L., et al. Branched-chain amino acids for hepatic encephalopathy. Cochrane Database Syst Rev 2 (2003) CD001939
130. Sen S., Davies N.A., Mookerjee R.P., et al. Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study. Liver Transpl 10 (2004) 1109-1119
131. Heemann U., Treichel U., Loock J., et al. Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study. Hepatology 36 (2002) 949-958
132. Hassanein T.I., Tofteng F., Brown Jr. R.S., et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology 46 (2007) 1853-1862
133. Krisper P., Haditsch B., Stauber R., et al. In vivo quantification of liver dialysis: comparison of albumin dialysis and fractionated plasma separation. J Hepatol 43 (2005) 451-457
134. Sorkine P., Ben Abraham R., Szold O., et al. Role of the molecular adsorbent recycling system (MARS) in the treatment of patients with acute exacerbation of chronic liver failure. Crit Care Med 29 (2001) 1332-1336
135. Stange J., Mitzner S.R., Risler T., et al. Molecular adsorbent recycling system (MARS): clinical results of a new membrane-based blood purification system for bioartificial liver support. Artif Organs 23 (1999) 319-330
136. Sen S., Rose C., Ytrebo L.M., et al. Effect of albumin dialysis on intracranial pressure increase in pigs with acute liver failure: a randomized study. Crit Care Med 34 (2006) 158-164
137. Stange J., and Mitzner S. A carrier-mediated transport of toxins in a hybrid membrane. Safety barrier between a patients blood and a bioartificial liver. Int J Artif Organs 19 (1996) 677-691
138. Mitzner S., Loock J., Peszynski P., et al. Improvement in central nervous system functions during treatment of liver failure with albumin dialysis MARS - a review of clinical, biochemical, and electrophysiological data. Metab Brain Dis 17 (2002) 463-475