Semin Liver Dis 2008; 28(1): 070-080
DOI: 10.1055/s-2008-1040322
© Thieme Medical Publishers

Hepatic Encephalopathy

Juan Córdoba1 , Beatriz Mínguez1
  • 1Servei de Medicina Interna-Hepatologia, Hospital Vall d'Hebron, Departament de Medicina, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
Further Information

Publication History

Publication Date:
22 February 2008 (online)

ABSTRACT

Hepatic encephalopathy is a severe complication of cirrhosis that is related to the effects of ammonia. Analysis of interorgan ammonia trafficking has identified an important role of skeletal muscle in ammonia removal and has highlighted the importance of the nutritional status. Ammonia causes neurotransmitter abnormalities and induces injury to astrocytes that is partially mediated by oxidative stress. These disturbances lead to astrocyte swelling and brain edema, which appear to be involved in the pathogenesis of neurological manifestations. Inflammatory mediators worsen brain disturbances. New methods for assessing hepatic encephalopathy include clinical scales, neuropsychological tests, imaging of portal-systemic circulation, and magnetic resonance of the brain. Reappraisal of current therapy indicates the need for performing placebo-controlled trials and the lack of evidence for administering diets with restricted protein content. Liver transplant should be considered in selected patients with hepatic encephalopathy. Future prospects include new drugs that decrease plasma ammonia, measures to reduce brain edema, and liver-support devices.

REFERENCES

  • 1 Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei A T. Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.  Hepatology. 2002;  35 716-721
  • 2 Conn H O. Portal-systemic shunting and portal-systemic encephalopathy: a predictable relationship.  Hepatology. 1995;  22 365-367
  • 3 Shawcross D L, Damink S W, Butterworth R F, Jalan R. Ammonia and hepatic encephalopathy: the more things change, the more they remain the same.  Metab Brain Dis. 2005;  20 169-179
  • 4 Huizenga J R, Gips C H, Tangerman A. The contribution of various organs to ammonia formation: a review of factors determining the arterial ammonia concentration.  Ann Clin Biochem. 1996;  33 23-30
  • 5 Romero-Gomez M. Role of phosphate-activated glutaminase in the pathogenesis of hepatic encephalopathy.  Metab Brain Dis. 2005;  20 319-325
  • 6 Romero-Gomez M, Ramos-Guerrero R, Grande L et al.. Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy.  J Hepatol. 2004;  41 49-54
  • 7 Hawkins R A, Jessy J, Mans A M, Chedid A, DeJoseph M R. Neomycin reduces the intestinal production of ammonia from glutamine.  Adv Exp Med Biol. 1994;  368 125-134
  • 8 Albrecht J, Norenberg M D. Glutamine: a Trojan horse in ammonia neurotoxicity.  Hepatology. 2006;  44 788-794
  • 9 Olde Damink S W, Jalan R, Redhead D N, Hayes P C, Deutz N E, Soeters P B. Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS.  Hepatology. 2002;  36 1163-1171
  • 10 Kondrup J, Nielsen K, Juul A. Effect of long-term refeeding on protein metabolism in patients with cirrhosis of the liver.  Br J Nutr. 1997;  77 197-212
  • 11 Olde Damink S W, Jalan R, Deutz N E et al.. Isoleucine infusion during “simulated” upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.  Hepatology. 2007;  45 560-568
  • 12 Mendenhall C L, Moritz T E, Roselle G A et al.. Protein energy malnutrition in severe alcoholic hepatitis: diagnosis and response to treatment. The VA Cooperative Study Group #275.  JPEN J Parenter Enteral Nutr. 1995;  19 258-265
  • 13 Córdoba J, López-Hellin J, Planas M et al.. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study.  J Hepatol. 2004;  41 38-43
  • 14 Plauth M, Merli M, Weimann A, Ferenci P, Mueller M J. ESPEN guidelines for nutrition in liver disease and transplantation.  Clin Nutr. 1997;  16 43-55
  • 15 Moriwaki H, Miwa Y, Tajika M, Kato M, Fukushima H, Shiraki M. Branched-chain amino acids as a protein- and energy-source in liver cirrhosis.  Biochem Biophys Res Commun. 2004;  313 405-409
  • 16 Marchesini G, Bianchi G, Merli M et al.. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind randomized trial.  Gastroenterology. 2003;  124 1792-1801
  • 17 Marchesini G, Dioguardi F S, Bianchi G P et al.. Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy: a randomized double-blind casein-controlled trial.  J Hepatol. 1990;  11 92-101
  • 18 Olde Damink S WM, Jalan R, Deutz N E et al.. The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.  Hepatology. 2003;  37 1277-1285
  • 19 Jalan R, Kapoor D. Enhanced renal ammonia excretion following volume expansion in patients with well compensated cirrhosis of the liver.  Gut. 2003;  52 1041-1045
  • 20 Lockwood A H. Blood ammonia levels and hepatic encephalopathy.  Metab Brain Dis. 2004;  19(3-4) 345-349
  • 21 Kramer L, Tribl B, Gendo A et al.. Partial pressure of ammonia versus ammonia in hepatic encephalopathy.  Hepatology. 2000;  31 30-34
  • 22 Nicolao F, Efrati C, Masini A, Merli M, Attili A F, Riggio O. Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy.  J Hepatol. 2003;  38 441-446
  • 23 Ott P, Larsen F S. Blood-brain barrier permeability to ammonia in liver failure: a critical reappraisal.  Neurochem Int. 2004;  44 185-198
  • 24 Lockwood A H, Yap E W, Wong W H. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy.  J Cereb Blood Flow Metab. 1991;  11 337-341
  • 25 Watanabe A. Portal-systemic encephalopathy in non-cirrhotic patients: classification of clinical types, diagnosis and treatment.  J Gastroenterol Hepatol. 2000;  15 969-979
  • 26 Ortiz M, Córdoba J, Alonso J et al.. Oral glutamine challenge and magnetic resonance spectroscopy in three patients with congenital portosystemic shunts.  J Hepatol. 2004;  40 552-557
  • 27 Blei A T. Infection, inflammation and hepatic encephalopathy, synergism redefined.  J Hepatol. 2004;  40 327-330
  • 28 Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure.  Hepatology. 2000;  32 734-739
  • 29 Vaquero J, Polson J, Chung C et al.. Infection and the progression of hepatic encephalopathy in acute liver failure.  Gastroenterology. 2003;  125 755-764
  • 30 Häussinger D, Schliess F. Astrocyte swelling and protein tyrosine nitration in hepatic encephalopathy.  Neurochem Int. 2005;  47;  (1-2) 64-70
  • 31 Pedersen H R, Ring-Larsen H, Olsen N V, Larsen F S. Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital.  J Hepatol. 2007;  47 245-252
  • 32 Jalan R, Bernuau J. Induction of cerebral hyperemia by ammonia plus endotoxin: does hyperammonemia unlock the blood-brain barrier?.  J Hepatol. 2007;  47 168-171
  • 33 Such J, Frances R, Munoz C et al.. Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites.  Hepatology. 2002;  36 135-141
  • 34 Butterworth R F. Pathophysiology of hepatic encephalopathy: a new look at ammonia.  Metab Brain Dis. 2002;  17 221-227
  • 35 Norenberg M D. Astrocytic-ammonia interactions in hepatic encephalopathy.  Semin Liver Dis. 1996;  16 245-253
  • 36 Butterworth R F. Hepatic encephalopathy and brain edema in acute hepatic failure: does glutamate play a role?.  Hepatology. 1997;  25 1032-1033
  • 37 Vogels B A, Maas M A, Daalhuisein J, Quack G, Chamuleau R A. Memantine, a non-competitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats.  Hepatology. 1997;  25 820-827
  • 38 Ahboucha S, Layrargues G P, Mamer O, Butterworth R F. Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy.  Ann Neurol. 2005;  58 169-170
  • 39 Norenberg M D. Oxidative and nitrosative stress in ammonia neurotoxicity.  Hepatology. 2003;  37 245-248
  • 40 Chatauret N, Zwingmann C, Rose C, Leibfritz D, Butterworth R F. Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study.  Gastroenterology. 2003;  125 815-824
  • 41 Wendon J A, Harrison P M, Keays R, Williams R. Cerebral blood flow and metabolism in fulminant liver failure.  Hepatology. 1994;  19 1407-1413
  • 42 Schliess F, Gorg B, Häussinger D. Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm.  Biol Chem. 2006;  387(10-11) 1363-1370
  • 43 Norenberg M D, Baker L, Norenberg L O. Ammonia-induced astrocyte swelling in primary cultures.  Neurochem Res. 1991;  16 833-836
  • 44 Gorg B, Foster N, Reinehr R et al.. Benzodiazepine-induced protein tyrosine nitration in rat astrocytes.  Hepatology. 2003;  37 334-342
  • 45 Häussinger D, Kircheis G, Fischer R, Schliess F, vom Dahl S. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?.  J Hepatol. 2000;  32 1035-1038
  • 46 Amodio P, Gatta A. Neurophysiological investigation of hepatic encephalopathy.  Metab Brain Dis. 2005;  20 369-379
  • 47 Inouye S K, van Dyck C H, Alessi C A, Balkin S, Siegal A P, Horwitz R I. Clarifying confusion-the confusion assessment method: a new method for detection of delirium.  Ann Intern Med. 1990;  113 941-948
  • 48 Hassanein T I, Hilsabeck R C, Perry W. Introduction to the Hepatic Encephalopathy Scoring Algorithm (HESA).  Dig Dis Sci. 2008;  53 529-538
  • 49 Ortiz M, Córdoba J, Doval E et al.. Development of a clinical hepatic encephalopathy staging scale.  Aliment Pharmacol Ther. 2007;  26 859-867
  • 50 Ortiz M, Jacas C, Córdoba J. Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations.  J Hepatol. 2005;  42(suppl 1) S45-S53
  • 51 Weissenborn K, Ennen J C, Rückert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy.  J Hepatol. 2001;  34 768-773
  • 52 Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Häussinger D. Critical flicker frequency for quantification of low-grade hepatic encephalopathy.  Hepatology. 2002;  35 357-366
  • 53 Romero-Gomez M, Córdoba J, Jover R et al.. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy.  Hepatology. 2007;  45 879-885
  • 54 Hassoun Z, Deschenes M, Lafortune M et al.. Relationship between pre-TIPS liver perfusion by the portal vein and the incidence of post-TIPS chronic hepatic encephalopathy.  Am J Gastroenterol. 2001;  96 1205-1209
  • 55 Blei A T. Hepatic encephalopathy in the age of TIPS.  Hepatology. 1994;  20(1 Pt 1) 249-252
  • 56 Riggio O, Efrati C, Catalano C et al.. High prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy: a case-control study.  Hepatology. 2005;  42 1158-1165
  • 57 Córdoba J, Hinojosa C, Sampedro F et al.. Usefulness of magnetic resonance spectroscopy for diagnosis of hepatic encephalopathy in a patient with relapsing confusional syndrome.  Dig Dis Sci. 2001;  46 2451-2455
  • 58 Ohnishi K, Saito M, Sato S et al.. Direction of splenic venous flow assessed by pulsed Doppler flowmetry in patients with a large splenorenal shunt: relation to spontaneous hepatic encephalopathy.  Gastroenterology. 1985;  89 180-185
  • 59 Uflacker R, Silva A, d'Albuquerque L A, Piske R L, Mourao G S. Chronic portosystemic encephalopathy: embolization of portosystemic shunts.  Radiology. 1987;  165 721-725
  • 60 Mínguez B, Garcia-Pagan J C, Bosch J et al.. Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy.  Hepatology. 2006;  43 707-714
  • 61 Francoz C, Belghiti J, Vilgrain V et al.. Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation.  Gut. 2005;  54 691-697
  • 62 Kulisevsky J, Pujol J, Balanzo J et al.. Pallidal hyperintensity on magnetic resonance imaging in cirrhotic patients: clinical correlations.  Hepatology. 1992;  16 1382-1388
  • 63 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. 1999;  117 640-644
  • 64 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. 1996;  24 1116-1120
  • 65 Kreis R, Ross B D, Farrow N A, Ackerman Z. Metabolic disorders of the brain in chronic hepatic encephalopathy detected with H-1 MR spectroscopy.  Radiology. 1992;  182 19-27
  • 66 Lee J H, Seo D W, Lee Y-S et al.. Proton magnetic resonance spectroscopy (1H-MRS) findings for the brain in patients with liver cirrhosis reflect the hepatic functional reserve.  Am J Gastroenterol. 1999;  94 2206-2213
  • 67 Córdoba J, Alonso J, Rovira A, Jacas C, Sanpedro F, Castells L L et al.. The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation.  J Hepatol. 2001;  35 598-604
  • 68 Lodi R, Tonon C, Stracciari A et al.. Diffusion MRI shows increased water apparent diffusion coefficient in the brains of cirrhotics.  Neurology. 2004;  62 762-766
  • 69 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. 2006;  43 698-706
  • 70 Córdoba J, Blei A T. Brain edema and hepatic encephalopathy.  Semin Liver Dis. 1996;  16 271-280
  • 71 Rovira A, Mínguez B, Aymerich F X et al.. Decreased white matter lesion volume and improved cognitive function after liver transplantation.  Hepatology. 2007;  46 1485-1490
  • 72 Córdoba J, Blei A T. Treatment of hepatic encephalopathy.  Am J Gastroenterol. 1997;  92 1429-1439
  • 73 Shawcross D, Jalan R. Dispelling myths in the treatment of hepatic encephalopathy.  Lancet. 2005;  365 431-433
  • 74 Als-Nielsen B, Gluud L L, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials.  BMJ. 2004;  328 1046
  • 75 Blei A T. Treatment of hepatic encephalopathy.  Lancet. 2005;  365 1383-1384
  • 76 Curioso W H, Monkemuller K E. Neomycin should not be used to treat hepatic encephalopathy.  BMJ. 2001;  323 233
  • 77 Riordan S M, Williams R. Treatment of hepatic encephalopathy.  N Engl J Med. 1997;  337 473-479
  • 78 Soulsby C T, Morgan M Y. Dietary management of hepatic encephalopathy in cirrhotic patients: survey of current practice in United Kingdom.  BMJ. 1999;  318 1391
  • 79 Plauth M, Cabre E, Riggio O et al.. ESPEN guidelines on enteral nutrition: liver disease.  Clin Nutr. 2006;  25 285-294
  • 80 Mullen K D, Weber Jr F L. Role of nutrition in hepatic encephalopathy.  Semin Liver Dis. 1991;  11 292-304
  • 81 Kondrup J, Muller M J. Energy and protein requirements of patients with chronic liver disease.  J Hepatol. 1997;  27 239-247
  • 82 Felipo V, Miñana D, Grisolia S. Control of urea synthesis and ammonia utilization in protein deprivation and refeeding.  Arch Biochem Biophys. 1991;  285 351-356
  • 83 Bustamante J, Rimola A, Ventura P et al.. Prognostic significance of hepatic encephalopathy in patients with cirrhosis.  J Hepatol. 1999;  30 890-895
  • 84 Murray K F, Carithers Jr R L. AASLD practice guidelines: evaluation of the patient for liver transplantation.  Hepatology. 2005;  41 1407-1432
  • 85 Stewart C A, Malinchoc M, Kim W R, Kamath P S. Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease.  Liver Transpl. 2007;  13 1366-1371
  • 86 Weissenborn K, Tietge U J, Bokemeyer M et al.. Liver transplantation improves hepatic myelopathy: evidence by three cases.  Gastroenterology. 2003;  124 346-351
  • 87 Larsen F S, Ranek L, Hansen B A, Kirkegaard P. Chronic portosystemic hepatic encephalopathy refractory to medical treatment successfully reversed by liver transplantation.  Transpl Int. 1995;  8 246-247
  • 88 Zeneroli M L, Cioni G, Crisi G, Vezzelli C, Ventura E. Globus pallidus alterations and brain atrophy in liver cirrhosis patients with encephalopathy: an MR imaging study.  Magn Reson Imaging. 1991;  9 295-302
  • 89 Mechtcheriakov S, Graziadei I W, Mattedi M et al.. Incomplete improvement of visuo-motor deficits in patients with minimal hepatic encephalopathy after liver transplantation.  Liver Transpl. 2004;  10 77-83
  • 90 Rose C, Jalan R. Is minimal hepatic encephalopathy completely reversible following liver transplantation?.  Liver Transpl. 2004;  10 84-87
  • 91 Amodio P, Biancardi A, Montagnese S et al.. Neurological complications after orthotopic liver transplantation.  Dig Liver Dis. 2007;  39 740-747
  • 92 Pujol A, Graus F, Rimola A et al.. Predictive factors of in-hospital CNS complications following liver transplantation.  Neurology. 1994;  44 1226-1230
  • 93 Kanwal F, Chen D, Ting L et al.. A model to predict the development of mental status changes of unclear cause after liver transplantation.  Liver Transpl. 2003;  9 1312-1319
  • 94 Plauth M, Raible A, Vieillard-Baron D, Bauder-Gross D, Hartmann F. Is glutamine essential for the maintenance of intestinal function? A study in the isolated perfused rat small intestine.  Int J Colorectal Dis. 1999;  14 86-94
  • 95 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. 1997;  25 1351-1360
  • 96 Jalan R, Wright G, Davies N A, Hodges S J. L-ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy.  Med Hypotheses. 2007;  69 1064-1069
  • 97 Córdoba J, Gottstein J, Blei A T. Chronic hyponatremia exacerbates ammonia-induced brain edema in rats after portacaval anastomosis.  J Hepatol. 1998;  29 589-594
  • 98 Restuccia T, Gomez-Anson B, Guevara M et al.. Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis.  Hepatology. 2004;  39 1613-1622
  • 99 Murphy N, Auzinger G, Bernel W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure.  Hepatology. 2004;  39 464-470
  • 100 Ginès P, Jimenez W. Aquaretic agents: a new potential treatment of dilutional hyponatremia in cirrhosis.  J Hepatol. 1996;  24 506-512
  • 101 Liu Q, Duan Z P, Ha D K, Bengmark S, Kurtovic J, Riordan S M. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis.  Hepatology. 2004;  39 1441-1449
  • 102 Chiva M, Soriano G, Rochat I et al.. Effect of lactobacillus johnsonii La1 and antioxidants on intestinal flora and bacterial translocation in rats with experimental cirrhosis.  J Hepatol. 2002;  37 456-462
  • 103 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. 2007;  46 1853-1862

Juan CórdobaM.D. 

Servei de Medicina Interna-Hepatologia, Hospital Vall d'Hebron

Paseo Vall d'Hebron 119, Barcelona 08035, Spain

Email: jcordoba@vhebron.net