Hepatic Encephalopathy

Juan Córdoba; Beatriz Mínguez

doi:10.1055/s-2008-1040322

Seminars in Liver Disease, Table of Contents

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

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

Abstract

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.

KEYWORDS

Hepatic encephalopathy - ammonia - pathogenesis - diagnostic methods - therapy

Full Text

References

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