The pathophysiologic basis of hepatic encephalopathy: Central role for ammonia and inflammation

Cellular and Molecular Life Sciences

Volumn 62, Issue 19-20, 2005, Pages 2295-2304

  Shawcross, D ^a   Jalan, R ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

Ammonia; Astrocyte; Cytokines; Hepatic encephalopathy; Inflammation

Indexed keywords

AMMONIA; CYTOKINE; GLUTAMINE; SILDENAFIL;

ASTROCYTE; BLOOD BRAIN BARRIER; BRAIN BLOOD FLOW; BRAIN EDEMA; BRAIN METABOLISM; GENE EXPRESSION; HEPATIC ENCEPHALOPATHY; HUMAN; HYPERAMMONEMIA; HYPOTHESIS; INFLAMMATION; INTRACRANIAL HYPERTENSION; LIVER CIRRHOSIS; LIVER DYSFUNCTION; LIVER FAILURE; LIVER INJURY; MENTAL DISEASE; NEUROPATHOLOGY; NEUROPSYCHIATRY; NONHUMAN; PATHOPHYSIOLOGY; PROGNOSIS; REVIEW;

AMMONIA; ASTROCYTES; HEPATIC ENCEPHALOPATHY; HUMANS; INFLAMMATION;

EID: 27144492341     PISSN: 1420682X     EISSN: 15691632     Source Type: Journal    
DOI: 10.1007/s00018-005-5089-0     Document Type: Review

References (101)

1. Hahn M., Massen O., Nencki M., Pavlov I. (1893) Die Eck'sche fistel zwischen der unteren hohlvene und der pfortader und ihre folgen für den Organismus. Arch. Exp. Pathol. Pharm. 32: 161-210
2. Nencki M. and Zaleski J. (1895) Ueber die Bestimmung des Ammoniaks in Thierischen Fluessigkeiten und Geweben. Arch. exp. pathol. pharm. 36: 385-396
3. Nencki M., Pawlow J., Zaleski J. (1896) Ueber den ammoniakgehalt des blutes under der organe und die harnstoffbildung bei den saugethieren. Arch. exp. pathol. pharm. 37: 26-51
4. Gazuba G. J. Jr, Phillips G. B., Davidson C.S. (1952) Reversible toxic manifestations in patients with cirrhosis of the liver given cation-exchange resins. N. Engl. J. Med. 246(4): 124-130
5. Phillips G., Schwartz R., Gabuzda G., Davidson C. (1952) The syndrome of impending hepatic coma in patients with cirrhosis of the liver given certain nitrogenous substances. N. Engl. J. Med. 247: 239-246
6. Sherlock S. (1958) Pathogenesis and management of hepatic coma. Am. J. Med. 24(5): 805-813
7. Stahl J. (1963) Studies of the blood ammonia in liver disease. Its diagnostic, prognostic, and therapeutic significance. Ann. Intern. Med. 58: 1-24
8. Ferenci P., Lockwood A., Mullen K., Tater R., Weissenborn K., Blei A. et al. (2002) Hepatic encephalopathy - definition, nomenclature, diagnosis and quantification: final report of the Working Party at the 11th World Congress of Gastroenterology, Vienna, 1998. Hepatology 35: 716-721
9. Amodio P., Del Piccolo F., Marchetti P., Angeli P., Iemmolo R., Caregaro L. et al. (1999) Clinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology 29(6): 1662-1667
10. Amodio P., Montagnese S., Gatta A., Morgan M. Y. (2004) Characteristics of minimal hepatic encephalopathy. Metab. Brain Dis. 19(3-4): 253-267
11. Schomerus H., Hamster W., Blunck H., Reinhard U., Mayer K., Dolle W. (1981) Latent portasystemic encephalopathy. I. Nature of cerebral functional defects and their effect on fitness to drive. Dig. Dis. Sci. 26(7): 622-630
12. Sen S., Williams R., Jalan R. (2002) The pathophysiological basis of acute-on-chronic liver failure. Liver Suppl. 2: 5-13
13. Norenberg M. (1988) Hepatic Encephalopathy: studies with astrocyte cultures. In: The Biochemical Pathology of Astrocytes. Norenberg M., Hertz L. and Schousboe A. (eds.). Alan R. Liss, New York; pp. 451-464
14. Butterworth R.F, Giguere J.F., Michaud J., Lavoie J., Layrargues G.P. (1987) Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem. Pathol. 6(1-2): 1-12
15. Desjardins P., Bandeira P., Rao V. L., Butterworth R. F. (1999) Portacaval anastomosis causes selective alterations of peripheral-type benzodiazepine receptor expression in rat brain and peripheral tissues. Neurochem. Int. 35(4): 293-299
16. Chan H, Butterworth RF. Evidence for an astrocytic glutamate transporter deficit in hepatic encephalopathy. Neurochem. Res. 24(11): 1397-1401
17. Belanger M., Desjardins P., Chatauret N., Butterworth R. F. (2002) Loss of expression of glial fibrillary acidic protein in acute hyperammonemia. Neurochem. Int. 41(2-3): 155-160
18. McCarty J. H. (2005) Cell biology of the neurovascular unit: implications for drug delivery across the blood-brain barrier. Assay Drug Dev. Technol. 3(1): 89-95
19. Lockwood A., Yap E., Wong W. (1991) Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J. Cereb. Blood Flow Metab. 11: 337-341
20. Hamm S., Dehouck B., Kraus J., Wolburg-Buchholz K., Wolburg H., Risau W. et al. (2004) Astrocyte mediated modulation of blood-brain barrier permeability does not correlate with a loss of tight junction proteins from the cellular contacts. Cell Tissue Res. 315(2): 157-166
21. Bassett M. L., Mullen K. D., Scholz B., Fenstermacher J. D., Jones E. A. (1990) Increased brain uptake of gamma-aminobutyric acid in a rabbit model of hepatic encephalopathy. Gastroenterology 98(3): 747-757
22. Michalak A., Rose C., Butterworth J., Butterworth R. F. (1996) Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 24(4): 908-913
23. Schafer D. F., Fowler J. M., Munson P. J., Thakur A. K., Waggoner J. G, Jones E. A. (1983) Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure. J. Lab. Clin. Med. 102(6): 870-880
24. Ahboucha S., Butterworth R. F. (2004) Pathophysiology of hepatic encephalopathy: a new look at GABA from the molecular standpoint. Metab. Brain Dis. 19(3-4): 331-343
25. Butterworth R. F. (2002) Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab. Brain Dis. 17(4): 221-227
26. Lockwood A. H., McDonald J. M., Reiman R. E., Gelbard A. S., Laughlin J. S., Duffy T. E. et al. (1979) The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J. Clin. Invest. 63(3): 449-460
27. Dejong C., Kampman M., Deutz N., Soeters P. (1992) Cerebral cortex ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat. J. Neurochem. 59: 1071-1079
28. Clemmesen J., Larsen F., Kondrup J., Hansen B., Ott P. (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29: 648-653
29. Haussinger D., Kircheis G., Fischer R., Schleiss F., vom Dahl S. (2000) Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low grade oedema? J. Hepatol. 32: 1035-1038
30. Cordoba J., Alonso J., Rovira A., Jacas C., Sanpedro F., Castells L. et al. (2001) The development of low-grade cerebral oedema in cirrhosis is supported by the evolution of 1H-magnetic resonance abnormalities after liver transplantation. J. Hepatol. 35: 598-604
31. Balata S., Olde Damink S., Ferguson K., Marshall I., Hayes P., Deutz N. et al. (2003) Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis. Hepatology 37: 931-939
32. Shawcross D. L., Balata S., Olde Damink S. W., Hayes P. C., Wardlaw J., Marshall I. et al. (2004) Low myo-inositol and high glutamine levels in brain are associated with neuropsychological deterioration after induced hyperammonemia. Am. J. Physiol. Gastrointest. Liver Physiol. 287(3): G503-G509
33. Cordoba J., Gottstein J., Blei A. (1998) Chronic hyponatremia exacerbates ammonia-induced brain oedema in rats after portacaval anastomosis. Hepatology 29(4): 589-594
34. Szerb J. C., Butterworth R. F. (1992) Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Prog. Neurobiol. 39(2): 135-153
35. Rose C., Kresse W., Kettenmann H. (2005) Acute insult of ammonia leads to calcium-dependent glutamate release from cultured astrocytes: an effect of pH. J. Biol. Chem.
36. Michalak A., Rose C., Butterworth J., Butterworth R. F. (1996) Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 24(4): 908-913
37. Albrecht J., Jones E.A. (1999) Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. J. Neurol. Sci. 170(2): 138-146
38. Jones E.A. (2003) Potential mechanisms of enhanced GABA-mediated inhibitory neurotransmission in liver failure. Neurochem.Int. 43(4-5): 509-516
39. Ahboucha S., Pomier-Layrargues G., Butterworth R. F. (2004) Increased brain concentrations of endogenous (non-benzodiazepine) GABA-A receptor ligands in human hepatic encephalopathy. Metab. Brain. Dis. 19(3-4): 241-251
40. Erceg S., Monfort P., Hernandez-Viadel M., Rodrigo R., Montoliu C., Felipo V. (2005) Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology 41(2): 299-306
41. Lai J. C., Cooper A. J. (1986) Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution and effects of inhibitors. J. Neurochem. 47(5): 1376-1386
42. Hindfelt B., Plum F., Duffy T. (1977) Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts. J. Clin. Invest. 59(3): 386-396
43. Yao H., Sadoshima S., Fujii K., Kusuda K., Ishitsuka T., Tamaki K. et al. (1987) Cerebrospinal fluid lactate in patients with hepatic encephalopathy. Eur. Neurol. 27(3): 182-187
44. Therrien G., Giguere J. F., Butterworth R. F. (1991) Increased cerebrospinal fluid lactate reflects deterioration of neurological status in experimental portal-systemic encephalopathy. Metab. Brain Dis. 6(4): 225-231
45. Zwingmann C., Chatauret N., Leibfritz D., Butterworth R. F. (2003) Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study. Hepatology 37(2): 420-428
46. Desjardins P., Belanger M., Butterworth R. F. (2001) Alterations in expression of genes coding for key astrocytic proteins in acute liver failure. J. Neurosci. Res. 66(5): 967-971
47. Bergeron M., Reader T. A., Layrargues G. P., Butterworth R. F. (1989) Monoamines and metabolites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Neurochem. Res. 14(9): 853-859
48. Norenberg M. D. (1996) Astrocytic-ammonia interactions in hepatic encephalopathy. Semin. Liver Dis. 16(3): 245-253
49. Rama Rao K. V., Chen M., Simard J. M., Norenberg M. D. (2003) Increased aquaporin-4 expression in ammonia-treated cultured astrocytes. Neuroreport 14(18): 2379-2382
50. Manley G. T., Binder D. K., Papadopoulos M. C., Verkman A. S. (2004) New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice. Neuroscience 129(4): 983-991
51. Rao V., Butterworth R. (1998) Neuronal nitric oxide synthase and hepatic encephalopathy. Metab. Brain Dis. 13: 175-189
52. Mulligan S. J., MacVicar B. A. (2004) Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431(7005): 195-199
53. Jalan R., Olde Damink S. W., Hayes P. C., Deutz N. E., Lee A. (2004) Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. J. Hepatol. 41(4): 613-620
54. Vaquero J., Chung C., Blei A. T. (2004) Cerebral blood flow in acute liver failure: a finding in search of a mechanism. Metab. Brain Dis. 19(3-4): 177-194
55. Magistretti P. J., Pellerin L., Rothman D. L., Shulman R. G. (1999) Energy on demand. Science 283(5401): 496-497
56. Master S., Gottstein J., Blei A. T. (1999) Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 30(4): 876-880
57. Guevara M., Bru C., Gines P., Fernandez-Esparrach G., Sort P., Bataller R. et al. (1998) Increased cerebrovascular resistance in cirrhotic patients with ascites. Hepatology 28(1): 39-44
58. Ahl B, Weissenborn K, van den HJ, Fischer-Wasels D, Kostler H, Hecker H et al. Regional differences in cerebral blood flow and cerebral ammonia metabolism in patients with cirrhosis. Hepatology 2004;40(1):73-9.
59. Jalan R., Olde Damink S., Lui H., Glabus M., Deutz N., Hayes P. et al. (2003) Oral amino acid load mimicking haemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver. Metab. Brain Dis. 18: 37-49
60. Fong Y., Tracey K. J., Moldawer L. L., Hesse D. G., Manogue K. B., Kenney J. S. et al. (1989) Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia. J. Exp. Med. 170(5): 1627-1633
61. de Vries H. E., Blom-Roosemalen M. C., van Oosten M., de Boer A. G., van Berkel T. J., Breimer D. D. et al. (1996) The influence of cytokines on the integrity of the blood-brain barrier in vitro. J. Neuroimmunol. 64(1): 37-43
62. Falsig J., Latta M., Leist M. (2004) Defined inflammatory states in astrocyte cultures: correlation with susceptibility towards CD95-driven apoptosis. J. Neurochem. 88(1): 181-193
63. Didier N., Romero I. A., Creminon C., Wijkhuisen A., Grassi J., Mabondzo A. (2003) Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability. J: Neurochem: 86(1): 246-254
64. Licinio J., Wong M. (1997) Pathways and mechanisms for cytokine signalling of the central nervous system. J. Clin. Invest. 100: 2941-2947
65. Hosoi T., Okuma Y., Nomura Y. (2002) The mechanisms of immune-to-brain communication in inflammation as a drug target. Curr. Drug Targets Inflamm. Allergy 1(3): 257-262
66. Sharshar T., Gray F., Lorin de la Grandmaison G., Hopkinson N., Ross E., Dorandeau A. et al. (2003) Apoptosis of neurons in cardiovascular autonomie centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 363: 1799-1805
67. Hu S., Sheng W., Ehrlich L., Peterson P., Chao C. (2000) Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation 7:153-159
68. Oh Y. J., Francis J. W., Markelonis G. J., Oh T. H. (1992) Interleukin-1-beta and tumor necrosis factor-alpha increase peripheral-type benzodiazepine binding sites in cultured polygonal astrocytes. J. Neurochem. 58(6): 2131-2138
69. Duchini A., Govindarajan S., Santucci M., Zampi G., Hofman F. M. (1996) Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J. Investig. Med. 44(8): 474-482
70. Schiltz J. C., Sawchenko P. E. (2003) Signaling the brain in systemic inflammation: the role of perivascular cells. Front. Biosci. 8: s1321-s1329
71. Korcok J., Wu F., Tyml K., Hammond R. R., Wilson J. X. (2002) Sepsis inhibits reduction of dehydroascorbic acid and accumulation of ascorbate in astroglial cultures: intracellular ascorbate depletion increases nitric oxide synthase induction and glutamate uptake inhibition. J. Neurochem. 81(1): 185-193
72. Schliess F., Gorg B., Fischer R., Desjardins P., Bidmon H. J., Herrmann A. et al. (2002) Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. FASEB J. 16(7): 739-741
73. Murthy C. R. K., Bai G., Dombro R. S. and Norenberg M. D. (2000) Ammonia-induced swelling in primary cultures of rat astrocytes: Role of free radicals. Soc. Neurosci. Abstr. 26: 1893
74. Sonnewald U., Westergaard N., Jones P., Taylor A., Bachelard H. S., Schousboe A. (1996) Metabolism of [U-13C5] glutamine in cultured astrocytes studied by NMR spectroscopy: first evidence of astrocytic pyruvate recycling. J. Neurochem. 67(6): 2566-2572
75. Yudkoff M., Nissim I., Pleasure D. (1988) Astrocyte metabolism of [15N]glutamine: implications for the glutamine-glutamate cycle. J. Neurochem. 51(3): 843-850
76. Tan K. H., Harrington S., Purcell W. M., Hurst R. D. (2004) Peroxynitrite mediates nitric oxide-induced blood-brain barrier damage. Neurochem. Res. 29(3): 579-587
77. Rama Rao K. V., Jayakumar A. R., Norenberg M. D. (2003) Induction of the mitochondrial permeability transition in cultured astrocytes by glutamine. Neurochem. Int. 43(4-5): 517-523
78. Marcaida G., Felipo V., Hermenegildo C., Minana M. D., Grisolia S. (1992) Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors. FEBS Lett. 296(1): 67-68
79. Rao K. V., Norenberg M. D. (2001) Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Metab. Brain Dis. 16(1-2): 67-78
80. Guerrini V. H. (1994) Effect of antioxidants on ammonia induced CNS-renal pathobiology in sheep. Free Radic. Res. 21(1): 35-43
81. Jalan R., Olde Damink S. W., Deutz N. E., Hayes P. C., Lee A. (2004) Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology 127(5): 1338-1346
82. Globus M. Y., Alonso O., Dietrich W. D., Busto R., Ginsberg M. D. (1995) Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J. Neurochem. 65(4): 1704-1711
83. Takada Y., Ishiguro S., Fukunaga K., Gu M., Tangiguchi H., Seino K.-I. et al. (2001) Increased intracranial pressure in a porcine model of fulminant hepatic failure using amatoxin and endotoxin. J. Hepatol. 34: 825-831
84. Sen S., Rose C., Davies N., Williams R., Butterworth R., Revhaug A. and Jalan R. (2003) Albumin dialysis reduces brain water and intracranial pressure in acute liver failure: a randomised controlled study in a pig model. Hepatology 38: 540 A
85. Rolando N., Wade J., Davalos M., Wendon J., Philpott-Howard J., Williams R. (2000) The systemic inflammatory response syndrome in acute liver failure. Hepatology 32: 734-739
86. Vacquero J., Polson J., Chung C., Helenowski I., Schiodt F., Reisch J. et al. (2003) Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology 125: 755-764
87. Jalan R., Olde Damink S. W., Hayes P. C., Deutz N. E., Lee A. (2004) Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. J. Hepatol. 41(4): 613-620
88. Jalan R., Olde Damink S. W. M., Lee A., Hayes P. C. and Williams R. (2003) Brain production of inflammatory cytokines in patients with acute liver failure and uncontrolled intracranial hypertension. Hepatology 38: 548A
89. Jalan R., Olde Damink S. W. M., Sen S., Mookerjee R. P, Hayes P. C. and Deutz N. E. P. (2004) Arginine, citrulline and nitric oxide metabolism in patients with liver failure and the effect of intervention with hypothermia, MARS and transplantation. Hepatology 40: 636 A
90. Aggarwal S., Kramer D., Yonas H., Obrist W., Kang Y., Martin M. et al. (1994) Cerebral hemodynamic and metabolic changes in fulminant hepatic failure: a retrospective study. Hepatology 19(1): 80-87
91. Jalan R., Olde Damink S., Deutz N., Lee A., Hayes P. (1999) Treatment of uncontrolled intracranial hypertension in acute liver failure with moderate hypothermia. Lancet 354: 1164-1168
92. Jalan R., Pollok A., Shah S. H., Madhavan K., Simpson K. J. (2002) Liver derived pro-inflammatory cytokines may be important in producing intracranial hypertension in acute liver failure. J. Hepatol. 37(4): 536-538
93. Brunk U. T. (1989) On the origin of lipofuscin; the iron content of residual bodies, and the relation of these organelles to the lysosomal vacuome. A study on cultured human glial cells. Adv. Exp. Med. Biol. 266: 313-320
94. Rao V. L., Audet R. M., Butterworth R. F. (1995) Increased nitric oxide synthase activities and L-[3H]arginine uptake in brain following portacaval anastomosis. J. Neurochem. 65(2): 677-678
95. Vaquero J., Chung C., Cahill M. E., Blei A. T. (2003) Pathogenesis of hepatic encephalopathy in acute liver failure. Semin. Liver Dis. 23(3): 259-269
96. Larsen F., Gottstein J., Blei A. (2001= Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema. J. Hepatol. 34: 548-554
97. Shawcross D. L. and Jalan R. (2004) Systemic inflammation determines baseline and ammonia-induced neuropsychological deterioration in cirrhosis. Hepatology 40 (4 Suppl. 1): A310
98. Shawcross D., Davies N., Williams R., Jalan R. (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J. Hepatol. 40(2): 247-254
99. Sen S., Davies N. A., Mookerjee R. P., Cheshire L. M., Hodges S. J., Williams R. et al. (2004) Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study. Liver Transpl. 10(9): 1109-1119
100. Liu Q., Duan Z. P., Ha dK., Bengmark S., Kurtovic J., Riordan S. M. (2004) Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 39(5): 1441-1449
101. Clemmesen J. O., Hansen B. A., Larsen F. S. (1997) Indomethacin normalizes intracranial pressure in acute liver failure: a twenty-three-year-old woman treated with indomethacin. Hepatology 26(6): 1423-1425