Pathogenesis of Hepatic Encephalopathy in Acute Liver Failure

Javier Vaquero; Chuhan Chung; Michael E. Cahill; Andres T. Blei

doi:10.1055/s-2003-42644

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2003; 23(3): 259-270
DOI: 10.1055/s-2003-42644

Pathogenesis of Hepatic Encephalopathy in Acute Liver Failure

Javier Vaquero^1,2 , Chuhan Chung² , Michael E. Cahill² , Andres T. Blei²

¹Post-doctoral Research Fellow Department of Medicine Lakeside Veterans Administration Medical Center Northwestern University Feinberg School of Medicine Chicago, Illinois
²Section of Hepatology, Department of Medicine, Lakeside Veterans Administration Medical Center and Northwestern University Feinberg School of Medicine, Chicago, Illinois

Abstract

ABSTRACT

Hepatic encephalopathy (HE) in acute liver injury signifies a serious prognosis. Brain edema and intracranial hypertension are major causes of death in this syndrome. Comparison of HE in acute liver failure (ALF) with that of cirrhosis allows recognition of important differences and similarities. A key role for ammonia in the pathogenesis of both HE and brain edema is now firmly supported by clinical and experimental data. Additional factors, such as infection, products of the necrotic liver, and synergistic toxins, may contribute to an altered mental state. A low plasma osmolarity, high temperature, and both high and low arterial pressure may affect brain water content. A combined derangement of cellular osmolarity coupled with cerebral hyperemia can explain the development of brain edema in ALF. Increasingly, study of the mechanisms responsible for brain swelling provides critical information for understanding the pathogenesis of HE.

KEYWORDS

Hepatic encephalopathy - brain edema - acute liver failure - ammonia - cerebral blood flow

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REFERENCES

1 Trey C, Davidson C S. The management of fulminant hepatic failure. Prog Liver Dis . 1970; 3 282-298
2 Trey C. The fulminant hepatic failure surveillance study. Brief review of the effects of presumed etiology and age of survival. Can Med Assoc J . 1972; 106(Suppl) 525-527
3 Atterbury C E, Maddrey W C, 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 . 1978; 23 398-406
4 Butterworth R F. Hepatic encephalopathy and brain edema in acute hepatic failure: does glutamate play a role?. Hepatology . 1997; 25 1032-1034
5 Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet . 1974; 2 81-84
6 Vaquero J, Oliver D, Hassanein T. et al .Evaluation of mental state in a clinical trial of MARS for patients with acute hepatic encephalopathy: comparison of two scales. In: Chamuleau R, Jones A, Meijers A, eds. Encephalopathy and Nitrogen Metabolism in Liver Failure Amsterdam: Kluwer Academic Publishers 2003: 55-69
7 Steg R E, Wszolek Z K. Electroencephalographic abnormalities in liver transplant recipients: practical considerations and review. J Clin Neurophysiol . 1996; 13 60-68
8 Rakela J, Lange S M, Ludwig J, Baldus W P. Fulminant hepatitis: Mayo Clinic experience with 34 cases. Mayo Clin Proc . 1985; 60 289-292
9 Michalak A, Butterworth R F. Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy. Metab Brain Dis . 1997; 12 171-182
10 Ellis A J, Wendon J A, Williams R. Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial. Hepatology . 2000; 32 536-541
11 Jalan R, Dabos K, Redhead D N. et al . Elevation of intracranial pressure following transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage. J Hepatol . 1997; 27 928-933
12 Donovan J P, Schafer D F, Shaw Jr W B, Sorrell M F. Cerebral oedema and increased intracranial pressure in chronic liver disease. Lancet . 1998; 351 719-721
13 Cordoba J, Alonso J, Rovira A. 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
14 Haussinger D, Kircheis G, Fischer R. et al . Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?. J Hepatol . 2000; 32 1035-1038
15 Blei A T. Brain edema and portal-systemic encephalopathy. Liver Transpl . 2000; 6 S14-S20
16 Almdal T, Schroeder T, Ranek L. Cerebral blood flow and liver function in patients with encephalopathy due to acute and chronic liver diseases. Scand J Gastroenterol . 1989; 24 299-303
17 Rodriguez G, Testa R, Celle G. et al . Reduction of cerebral blood flow in subclinical hepatic encephalopathy and its correlation with plasma-free tryptophan. J Cereb Blood Flow Metab . 1987; 7 768-772
18 Guevara M, Bru C, Gines P. et al . Increased cerebrovascular resistance in cirrhotic patients with ascites. Hepatology . 1998; 28 39-44
19 Arroyo V, Jimenez W. Complications of cirrhosis. II. Renal and circulatory dysfunction. Lights and shadows in an important clinical problem. J Hepatol . 2000; 32 157-170
20 Groszmann R J. Hyperdynamic circulation of liver disease 40 years later: pathophysiology and clinical consequences. Hepatology . 1994; 20 1359-1363
21 Bihari D J, Gimson A E, Williams R. Cardiovascular, pulmonary and renal complications of fulminant hepatic failure. Semin Liver Dis . 1986; 6 119-128
22 Aggarwal S, Kramer D, Yonas H. et al . Cerebral hemodynamic and metabolic changes in fulminant hepatic failure: a retrospective study. Hepatology . 1994; 19 80-87
23 Geiger A, Magnes J, Taylor R M, Veralli M. Effect of blood constituents on uptake of glucose and on metabolic rate of the brain in perfusion experiments. Am J Physiol . 1954; 177 138-149
24 Alexander B, Aslam M, Benjamin I S. An investigation of the relationship between the liver and brain using an isolated perfused rat brain preparation. J Pharmacol Toxicol Methods . 1999; 42 31-37
25 Crespin J, Nemcek A, Rehkemper G, Blei A T. Intrahepatic portal-hepatic venous anastomosis: a portal-systemic shunt with neurological repercussions. Am J Gastroenterol . 2000; 95 1568-1571
26 Clemmesen J O, Larsen F S, Kondrup J. et al . Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology . 1999; 29 648-653
27 Madl C, Kramer L, Gendo A. et al . Prognostic accuracy of sensory evoked potentials (SEP) and arterial ammonia in predicting development of cerebral edema and death by cerebral herniation in patients with fulminant hepatic failure (FHF). Gastroenterology . 2000; 118 1007A
28 Clemmesen J O, Kondrup J, Ott P. Splanchnic and leg exchange of amino acids and ammonia in acute liver failure. Gastroenterology . 2000; 118 1131-1139
29 Nomura F, Ohnishi K, Terabayashi H. et al . Effect of intrahepatic portal-systemic shunting on hepatic ammonia extraction in patients with cirrhosis. Hepatology . 1994; 20 1478-1481
30 Rose C, Michalak A, Pannunzio P. et al . L-ornithine-L-aspartate in experimental portal-systemic encephalopathy: therapeutic efficacy and mechanism of action. Metab Brain Dis . 1998; 13 147-157
31 Felipo V, Butterworth R F. Neurobiology of ammonia. Prog Neurobiol . 2002; 67 259-279
32 Olde Damink W S, Jalan R, Redhead D N. et al . Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS. Hepatology . 2002; 36 1163-1171
33 Rolando N, Wade J, Davalos M. et al . The systemic inflammatory response syndrome in acute liver failure. Hepatology . 2000; 32 734-739
34 Bernal W. Changing patterns of causation and the use of transplantation in the United Kingdom. Semin Liver Dis . 2003; 23 227-238
35 Vaquero J, Polson J, Chung C. et al . Infection and the progression of encephalopathy in acute liver failure (in press). Gaastroenterology . 2003;
36 Matta B F, Stow P J. Sepsis-induced vasoparalysis does not involve the cerebral vasculature: indirect evidence from autoregulation and carbon dioxide reactivity studies. Br J Anaesth . 1996; 76 790-794
37 Licinio J, Wong M L. Pathways and mechanisms for cytokine signaling of the central nervous system. J Clin Invest . 1997; 100 2941-2947
38 Ringe B, Lubbe N, Kuse E. et al . Total hepatectomy and liver transplantation as two-stage procedure. Ann Surg . 1993; 218 3-9
39 Rozga J, Podesta L, LePage E. et al . Control of cerebral oedema by total hepatectomy and extracorporeal liver support in fulminant hepatic failure. Lancet . 1993; 342 898-899
40 Jalan R, Pollok A, Shah S. et al . Liver derived pro-inflammatory cytokines may be important in producing intracranial hypertension in acute liver failure. J Hepatol . 2002; 37 536
41 Cordoba J, Crespin J, Gottstein J, Blei A T. Mild hypothermia modifies ammonia-induced brain edema in rats after portacaval anastomosis. Gastroenterology . 1999; 116 686-693
42 Jalan R, Damink S W, Deutz N E. et al . Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet . 1999; 354 1164-1168
43 Marion D W, Penrod L E, Kelsey S F. et al . Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med . 1997; 336 540-546
44 Zieve L, Nicoloff D M. Pathogenesis of hepatic coma. Annu Rev Med . 1975; 26 143-157
45 Trauner D A. Pathologic changes in a rabbit model of Reye's syndrome. Pediatr Res . 1982; 16 950-953
46 Basile A S, Hughes R D, Harrison P M. et al . Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N Engl J Med . 1991; 325 473-478
47 Basile A S. Direct and indirect enhancement of GABAergic neurotransmission by ammonia: implications for the pathogenesis of hyperammonemic syndromes. Neurochem Int . 2002; 41 115-122
48 Butterworth R. Molecular neurobiology of acute liver failure. Semin Liver Dis . 2003; 23 251-258
49 Record C O, Buxton B, Chase R A. et al . Plasma and brain amino acids in fulminant hepatic failure and their relationship to hepatic encephalopathy. Eur J Clin Invest . 1976; 6 387-394
50 Basile A S, Saito K, al-Mardini H. et al . The relationship between plasma and brain quinolinic acid levels and the severity of hepatic encephalopathy. Gastroenterology . 1995; 108 818-823
51 Blei A T, Larsen F S. Pathophysiology of cerebral edema in fulminant hepatic failure. J Hepatol . 1999; 31 771-776
52 Traber P G, Dal Canto M, Ganger D R, Blei A T. Electron microscopic evaluation of brain edema in rabbits with galactosamine-induced fulminant hepatic failure: ultrastructure and integrity of the blood-brain barrier. Hepatology . 1987; 7 1272-1277
53 Gove C D, Hughes R D, Ede R J, Williams R. Regional cerebral edema and chloride space in galactosamine-induced liver failure in rats. Hepatology . 1997; 25 295-301
54 Kato M, Hughes R D, Keays R T, Williams R. Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology . 1992; 15 1060-1066
55 Norenberg M D. Astroglial dysfunction in hepatic encephalopathy. Metab Brain Dis . 1998; 13 319-335
56 Swain M S, Blei A T, Butterworth R F, Kraig R P. Intracellular pH rises and astrocytes swell after portacaval anastomosis in rats. Am J Physiol . 1991; 261 R1491-1496
57 Cordoba J, Gottstein J, Blei A T. Glutamine, myo-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: implications for ammonia-induced brain edema. Hepatology . 1996; 24 919-923
58 Laubenberger J, Haussinger D, Bayer S. et al . Proton magnetic resonance spectroscopy of the brain in symptomatic and asymptomatic patients with liver cirrhosis. Gastroenterology . 1997; 112 1610-1616
59 Norenberg M D, Bender A S. Astrocyte swelling in liver failure: role of glutamine and benzodiazepines. Acta Neurochir Suppl (Wien) . 1994; 60 24-27
60 Takahashi H, Koehler R C, Brusilow S W, Traystman R J. Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am J Physiol . 1991; 261 H825-H829
61 Blei A T, Olafsson S, Therrien G, Butterworth R F. Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis. Hepatology . 1994; 19 1437-1444
62 McManus M L, Churchwell K B, Strange K. Regulation of cell volume in health and disease. N Engl J Med . 1995; 333 1260-1266
63 Sugimoto H, Koehler R C, Wilson D A. et al . Methionine sulfoximine, a glutamine synthetase inhibitor, attenuates increased extracellular potassium activity during acute hyperammonemia. J Cereb Blood Flow Metab . 1997; 17 44-49
64 Larsen F S, Moller K, Strauss G. Specific cerebral efflux of potassium in patients with fulminant hepatic failure. Liver Transpl . 2001; 7 C22
65 O'Grady J G, Schalm S W, Williams R. Acute liver failure: redefining the syndromes. Lancet . 1993; 342 273-275
66 Ede R J, Williams R W. Hepatic encephalopathy and cerebral edema. Semin Liver Dis . 1986; 6 107-118
67 Wendon J A, Harrison P M, Keays R, Williams R. Cerebral blood flow and metabolism in fulminant liver failure. Hepatology . 1994; 19 1407-1413
68 Powers W J, Grubb Jr L R, Darriet D, Raichle M E. Cerebral blood flow and cerebral metabolic rate of oxygen requirements for cerebral function and viability in humans. J Cereb Blood Flow Metab . 1985; 5 600-608
69 Larsen F S. Cerebral circulation in liver failure: Ohm's law in force. Semin Liver Dis . 1996; 16 281-292
70 Larsen F S, Ejlersen E, Clemmesen J O. et al . Preservation of cerebral oxidative metabolism in fulminant hepatic failure: an autoregulation study. Liver Transpl Surg . 1996; 2 348-353
71 Larsen F S, Ejlersen E, Hansen B A. et al . Functional loss of cerebral blood flow autoregulation in patients with fulminant hepatic failure. J Hepatol . 1995; 23 212-217
72 Jalan R, Olde Damink W S, Deutz N E. et al . Restoration of cerebral blood flow autoregulation and reactivity to carbon dioxide in acute liver failure by moderate hypothermia. Hepatology . 2001; 34 50-54
73 Vavilala M S, Lee L A, Lam A M. Cerebral blood flow and vascular physiology. Anesthesiology Clinics of North America . 2002; 20 247-264
74 Larsen F S, Adel Hansen B, Pott F. et al . Dissociated cerebral vasoparalysis in acute liver failure. A hypothesis of gradual cerebral hyperaemia. J Hepatol . 1996; 25 145-151
75 Strauss G, Hansen B A, Knudsen G M, Larsen F S. Hyperventilation restores cerebral blood flow autoregulation in patients with acute liver failure. J Hepatol . 1998; 28 199-203
76 Master S, Gottstein J, Blei A T. Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology . 1999; 30 876-880
77 Chung C, Gottstein J, Blei A T. Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology . 2001; 34 249-254
78 Clemmesen J O, Hansen B A, Larsen F S. Indomethacin normalizes intracranial pressure in acute liver failure: a twenty-three-year-old woman treated with indomethacin. Hepatology . 1997; 26 1423-1425
79 Larsen F S, Wendon J. Brain edema in liver failure: basic physiologic principles and management. Liver Transpl . 2002; 8 983-989
80 Rao V L, Audet R M, Butterworth R F. Increased neuronal nitric oxide synthase expression in brain following portacaval anastomosis. Brain Res . 1997; 765 169-172
81 Larsen F S, Gottstein J, Blei A T. Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema. J Hepatol . 2001; 34 548-554
82 Chung C, Gottstein J, Vaquero J. et al . Vasopressin infusion accelerates the development of brain edema in rats after portacaval anastomosis. J Hepatol . 2003; 39 193-199
83 Strauss G I, Knudsen G M, Kondrup J. et al . Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure. Gastroenterology . 2001; 121 1109-1119
84 Norenberg M D. The astrocyte in liver disease. In: Fedoroff S, Hertz L, eds. Advances in Cellular Neurobiology, Vol 2. New York: Academic Press 1981: 303-352
85 Song G, Dhodda V K, Blei A T. et al . GeneChip analysis shows altered mRNA expression of transcripts of neurotransmitter and signal transduction pathways in the cerebral cortex of portacaval shunted rats. J Neurosci Res . 2002; 68 730-737
86 Rao V L, Audet R M, Butterworth R F. Increased nitric oxide synthase activities and L-[3H]arginine uptake in brain following portacaval anastomosis. J Neurochem . 1995; 65 677-678
87 Murthy C R, Rama R ao, Bai G, Norenberg M D. Ammonia-induced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res . 2001; 66 282-288
88 Bai G, Rama Rao V K, Murthy C R. et al . Ammonia induces the mitochondrial permeability transition in primary cultures of rat astrocytes. J Neurosci Res . 2001; 66 981-991
89 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 . 2002; 16 739-741
90 O'Grady J G, Alexander G J, Hayllar K M, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology . 1989; 97 439-445
91 Cordoba J, Gottstein J, Blei A T. Chronic hyponatremia exacerbates ammonia-induced brain edema in rats after portacaval anastomosis. J Hepatol . 1998; 29 589-594
92 Davenport A, Will E J, Davison A M. Continuous versus intermittent forms of haemofiltration and/or dialysis in the management of acute renal failure in patients with defective cerebral autoregulation at risk of cerebral oedema. Contrib Nephrol . 1991; 93 225-233
93 Munoz S J, Moritz M J, Bell R. et al . Factors associated with severe intracranial hypertension in candidates for emergency liver transplantation. Transplantation . 1993; 55 1071-1074
94 Katsumura H, Kabuto M, Hosotani K. et al . The influence of total body hyperthermia on brain haemodynamics and blood-brain barrier in dogs. Acta Neurochir (Wien) . 1995; 135 62-69
95 Kodakar S K, Gopal P B, Wendon J A. Intracranial pressure is related to body temperature in acute liver failure. Liver Transpl . 2001; 7 C87
96 Kodakar S K, Gopal P B, Wendon J A. Hyperglycemia is associated with intracranial hypertension in patients with acute liver failure. Liver Transpl . 2001; 7 C21
97 Lam A M, Winn H R, Cullen B F, Sundling N. Hyperglycemia and neurological outcome in patients with head injury. J Neurosurg . 1991; 75 545-551
98 Nakakimura K, Fleischer J E, Drummond J C. et al . Glucose administration before cardiac arrest worsens neurologic outcome in cats. Anesthesiology . 1990; 72 1005-1011
99 Therrien G, Giguere J F, Butterworth R F. Increased cerebrospinal fluid lactate reflects deterioration of neurological status in experimental portal-systemic encephalopathy. Metab Brain Dis . 1991; 6 225-231
100 Tofteng F, Jorgensen L, Hansen B A. et al . Cerebral microdialysis in patients with fulminant hepatic failure. Hepatology . 2002; 36 1333-1340
101 Wijdicks E F, Plevak D J, Rakela J, Wiesner R H. Clinical and radiologic features of cerebral edema in fulminant hepatic failure. Mayo Clin Proc . 1995; 70 119-124
102 Venkatasubramanian P N, Tom B, Blei A T, Wyrwicz A M. Monitoring of brain water by chemical shift imaging during ammonia-induced brain swelling in rats after portacaval anastomosis. Artif Organs . 2001; 25 551-557
103 Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management. Semin Liver Dis . 2003; 23 271-282