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Metabolic Brain Disease

, Volume 20, Issue 3, pp 193–204 | Cite as

Hepatic Encephalopathy: A Dynamic or Static Condition

  • Charmaine A. Stewart
  • Jane Cerhan
Article

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with portal hypertension. The mechanism of this disorder is still being characterized and the management has relied primarily on lowering the amount of ammonia present in the gastrointestinal tract or reversing liver disease by replacing the diseased liver. It is, however, not established that all the effects of hepatic encephalopathy are reversed by liver transplantation. In this review, we have outlined the mechanisms underlying HE and the pros and cons of reversibility of HE.

Keywords

Hepatic encephalopathy cirrhosis decompensated liver disease portosystemic encephalopathy cognition in liver disease cognitive dysfunction in liver diseases 

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References

  1. Aguilar, M.A., Minarro, J., and Felipo, V. (2000). Chronic moderate hyperammonemia impairs active and passive avoidance behavior and conditional discrimination learning in rats. Exp. Neurol. 161(2):704–713.CrossRefPubMedGoogle Scholar
  2. al Mardini, H., Harrison, E.J., Ince, P.G., Bartlett, K., and Record, C.O. (1993). Brain indoles in human hepatic encephalopathy. Hepatology 17(6):1033–1040.CrossRefPubMedGoogle Scholar
  3. Anholt, R.R., Pedersen, P.L., De Souza, E.B., and Snyder, S.H. (1986). The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane. J. Biol. Chem. 261(2):576–583.PubMedGoogle Scholar
  4. Bengtsson, F., Bugge, M., Johansen, K.H., and Butterworth, R.F. (1991). Brain tryptophan hydroxylation in the portacaval shunted rat: A hypothesis for the regulation of serotonin turnover in vivo. J. Neurochem. 56:1069–1074.PubMedGoogle Scholar
  5. Bergeron, M., Reader, T.A., Layrargues, G.P., and Butterworth, R.F. (1989). Monoamines and metabolites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Neurochem. Res. 14(9):853–859.CrossRefPubMedGoogle Scholar
  6. Blei, A. T. (1996). Brain edema—ITs relation to hepatic encephalopathy. In (C. Record and H. Al-Mardini, eds.), Advances in Hepatic Encephalopathy and Metabolism in Liver Disease, Newcastle Upon Tyne, Medical Faculty of Newcastle Upon Tyne, pp. 1259–1266.Google Scholar
  7. Bruck, R., Aeed, H., Shirin, H., Matas, Z., Zaidel, L., Avni, Y., and Halpern, Z. (1999). The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure. J. Hepatol. 31:27–38.CrossRefPubMedGoogle Scholar
  8. Burkhard, P.R., Delavelle, J., Du Pasquier, R., and Spahr, L. (2003). Chronic parkinsonism associated with cirrhosis: A distinct subset of acquired hepatocerebral degeneration. Arch. Neurol. 60(4):521–528.CrossRefPubMedGoogle Scholar
  9. Butterworth, R.F. (1998). Alterations of neurotransmitter-related gene expression in human and experimental portal-systemic encephalopathy. Metab Brain Dis. 13(4):337–349.CrossRefPubMedGoogle Scholar
  10. Chan, H., and Butterworth, R.F. (1999). Evidence for an astrocytic glutamate transporter deficit in hepatic encephalopathy. Neurochem. Res. 24(11):1397–1401.CrossRefPubMedGoogle Scholar
  11. Ciancio, A., Marchet, A., Saracco, G., Carucci, P., Lavezzo, B., Leotta, D., Capellero, B., Nobili, M., Smedile, A., and Rizzetto, M. (2002). Spectral electroencephalogram analysis in hepatic encephalopathy and liver transplantation. Liver Transpl. 8(7):630–635.CrossRefPubMedGoogle Scholar
  12. Collingridge, G., and Bliss, T. (1987). NMDA receptors-their role in long-term potentiation. Trends Neurosci. 10:288–293.CrossRefGoogle Scholar
  13. Conn, H., and Lieberthal, M.M. (1979). The Hepatic Coma Syndromes and Lactulose, Lippincott Williams & Wilkins, Baltimore.Google Scholar
  14. Corbalan, R., Hernandez-Viadel, M., Llansola, M., Montoliu, C., and Felipo, V. (2002). Chronic hyperammonemia alters protein phosphorylation and glutamate receptor-associated signal transduction in brain. Neurochem. Int. 41(2/3):103–108.CrossRefPubMedGoogle Scholar
  15. Cordoba, J., Alonso, J., Rovira, A., Jacas, C., Sanpedro, F., Castells, L., Vargas, V., Margarit, C., Kulisewsky, J., Esteban, R., and Guardia, J. (2001). 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. 35(5):598–604.CrossRefPubMedGoogle Scholar
  16. Dugovic, C., Wauquier, A., Leysen, J. E., Marrannes, R., and Janssen, P.A. (1989). Functional role of 5-HT2 receptors in the regulation of sleep and wakefulness in the rat. Psychopharmacology (Berl) 97(4):436–442.CrossRefGoogle Scholar
  17. Ferenci, P., Lockwood, A., Mullen, K., Tarter, R., Weissenborn, K., Blei, A.T., and members of the Working Party (2002). Hepatic encephalopathy–Definition, nomenclature, diagnosis, and quantification: Final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35(3):716–721.CrossRefPubMedGoogle Scholar
  18. Gilberstadt, S.J., Gilberstadt, H., Zieve, L., Buegel, B., Collier, R. O., Jr., and McClain, C.J. (1980). Psychomotor performance defects in cirrhotic patients without overt encephalopathy. Arch. Intern. Med. 140(4):519–521.CrossRefPubMedGoogle Scholar
  19. Gross, C.R., Malinchoc, M., Kim, W.R., Evans, R.W., Wiesner, R.H., Petz, J.L., Crippin, J.S., Klintmalm, G.B., Levy, M.F., Ricci, P., Therneau, T.M., and Dickson, E.R. (1999). Quality of life before and after liver transplantation for cholestatic liver disease. Hepatology 29(2):356–364.CrossRefPubMedGoogle Scholar
  20. Guerrini, V.H. (1994). Effect of antioxidants on ammonia induced CNS-renal pathobiology in sheep. Free Radic. Res. 21(1):35–43.PubMedGoogle Scholar
  21. Hermenegildo, C., Montoliu, C., Llansola, M., Munoz, M.D., Gaztelu, J.M., Minana, M.D., and Felipo, V. (1998). Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur. J. Neurosci. 10(10):3201–3209.CrossRefPubMedGoogle Scholar
  22. Hertz, L., and Bender, A. (1993). Astrocytic benzodiazepine receptors: Their possible role in the regulation of brain excitability. In (H. Kimelberg, ed.), Glial Cell Receptors, Raven Press, New York, pp. 159–181.Google Scholar
  23. Hertz, L., Yu, A.C., Kala, G., and Schousboe, A. (2000). Neuronal-astrocytic and cytosolic-mitochondrial metabolite trafficking during brain activation, hyperammonemia and energy deprivation. Neurochem. Int. 37(2/3):83–102.CrossRefPubMedGoogle Scholar
  24. Hockerstedt, K., Kajaste, S., Isoniemi, H., Muuronen, A., Raininko, R., Seppalainen, A.M., and Hillbom, M. (1990). Tests for encephalopathy before and after liver transplantation. Transpl. Proc. 22(4):1576–1578.Google Scholar
  25. Ilsley, J.E., Moffoot, A.P., and O’Carroll, R.E. (1995). An analysis of memory dysfunction in major depression. J. Affect Disord. 35(1/2):1–9.CrossRefPubMedGoogle Scholar
  26. Jayakumar, A.R., Panickar, K.S., and Norenberg, M.D. (2002). Effects on free radical generation by ligands of the peripheral benzodiazepine receptor in cultured neural cells. J. Neurochem. 83(5):1226–1234.CrossRefPubMedGoogle Scholar
  27. Jayakumar, A.R., Rama Rao, K.V., Schousboe, A., and Norenberg, M.D. (2004). Glutamine-induced free radical production in cultured astrocytes. Glia 46(3):296–301.CrossRefPubMedGoogle Scholar
  28. Kaneko, T., Shigemoto, R., and Mizuno, N. (1988). Metabolism of glutamate and ammonia in astrocyte: An immunocytochemical study. Brain Res. 457(1):160–164.CrossRefPubMedGoogle Scholar
  29. Karam, V., Castaing, D., Danet, C., Delvart, V., Gasquet, I., Adam, R., Azoulay, D., Samuel, D., and Bismuth, H. (2003). Longitudinal prospective evaluation of quality of life in adult patients before and one year after liver transplantation. Liver. Transpl. 9(7):703–711.CrossRefPubMedGoogle Scholar
  30. Larsen, F.S., Olsen, K.S., Ejlersen, E., Hansen, B.A., Paulson, O.B., and Knudsen, G.M. (1995). Cerebral blood flow autoregulation and transcranial Doppler sonography in patients with cirrhosis. Hepatology 22(3):730–736.CrossRefPubMedGoogle Scholar
  31. Layrargues, G.P., Shapcott, D., Spahr, L., and Butterworth, R.F. (1995). Accumulation of manganese and copper in pallidum of cirrhotic patients: Role in the pathogenesis of hepatic encephalopathy? Metab. Brain Dis. 10(4):353–356.CrossRefPubMedGoogle Scholar
  32. Lazeyras, F., Spahr, L., DuPasquier, R., Delavelle, J., Burkhard, P., Hadengue, A., Hochstrasser, D., Mentha, G., Giostra, E., Terrier, F., and Vingerhoets, F. (2002). Persistence of mild parkinsonism 4 months after liver transplantation in patients with preoperative minimal hepatic encephalopathy: A study on neuroradiological and blood manganese changes. Transpl. Int. 15(4):188–195.CrossRefPubMedGoogle Scholar
  33. Lockwood, A.H., Yap, E.W., and Wong, W.H. (1991). Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J. Cereb. Blood Flow Metab. 11(2):337–341.PubMedGoogle Scholar
  34. Macdonald, G.A., Frey, K.A., Agranoff, B.W., Minoshima, S., Koeppe, R.A., Kuhl, D.E., Shulkin, B.L., and Lucey, M.R. (1997). Cerebral benzodiazepine receptor binding in vivo in patients with recurrent hepatic encephalopathy. Hepatology 26(2):277–282.CrossRefPubMedGoogle Scholar
  35. Magistretti, P.J., Pellerin, L., Rothman, D.L., and Shulman, R.G. (1999). Energy on demand. Science 283(5401):496–497.CrossRefPubMedGoogle Scholar
  36. Mattarozzi, K., Stracciari, A., Vignatelli, L., D’Alessandro, R., Morelli, M.C., and Guarino, M. (2004). Minimal hepatic encephalopathy: Longitudinal effects of liver transplantation. Arch. Neurol. 61(2):242–247.CrossRefPubMedGoogle Scholar
  37. McCrea, M., Cordoba, J., Vessey, G., Blei, A.T., and Randolph, C. (1996). Neuropsychological characterization and detection of subclinical hepatic encephalopathy. Arch. Neurol. 53(8):758–763.PubMedGoogle Scholar
  38. Mechtcheriakov, S., Graziadei, I.W., Mattedi, M., Bodner, T., Kugener, A., Hinterhuber, H.H., Marksteiner, J., and Vogel, W. (2004). Incomplete improvement of visuo-motor deficits in patients with minimal hepatic encephalopathy after liver transplantation. Liver Transpl. 10(1):77–83.CrossRefPubMedGoogle Scholar
  39. Moore, K.A., Mc, L.J.R., and Burrows, G.D. (2000). Quality of life and cognitive function of liver transplant patients: A prospective study. Liver Transpl. 6(5):633–642.CrossRefPubMedGoogle Scholar
  40. Moss, H.B. (1992). Subclinical hepatic encephalopathy: Relationship between neuropsychological deficits and standard laboratory tests assessing hepatic status. Arch. Clin. Neuropsychol. 7:419–429.CrossRefPubMedGoogle Scholar
  41. Mousseau, D.D., and Butterworth, R.F. (1994). The {3H} Tryptamine Receptor in Human Brain: Kinetics, Distribution, and Pharmacologic Profile. J. Neurochem. 63:1052–1059.PubMedGoogle Scholar
  42. Mousseau, D.D., Layrargues, G.P., and Butterworth, R.F. (1994). Region-selective decreases in densities [3H] tryptamine binding sites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. J. Neurochem. 46:869–874.Google Scholar
  43. Munoz, M.D., Monfort, P., Gaztelu, J.M., and Felipo, V. (2000). Hyperammonemia impairs NMDA receptor-dependent long-term potentiation in the CA1 of rat hippocampus in-vitro. Neurochem. Res. 25:437–441.CrossRefPubMedGoogle Scholar
  44. Naegele, T., Grodd, W., Viebahn, R., Seeger, U., Klose, U., Seitz, D., Kaiser, S., Mader, I., Mayer, J. Lauchart, W., Gregor, M., and Voigt, K. (2000). MR imaging and (1)H spectroscopy of brain metabolites in hepatic encephalopathy: Time-course of renormalization after liver transplantation. Radiology 216: 683–691.PubMedGoogle Scholar
  45. Nolte, W., Wiltfang, J., Schindler, C., Munke, H., Unterberg, K., Zumhasch, U., Figulla, H.R., Werner, G., Hartmann, H., and Ramadori, G. (1998). Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: Clinical, laboratory, psychometric, and electroencephalographic investigations. Hepatology 28(5):1215–1225.CrossRefPubMedGoogle Scholar
  46. Norenberg, M., Itzhak, Y., Bender, A.S., Baker, L., Aguila-Mansilla, H.N., Zhou, B.-G., and Isaacks, R. (1998). Liver and Nervous System. Proceedings of the Falk Symposium No. 103, Falk Symposium, Freiberg, Kluwer Austin.Google Scholar
  47. O’Carroll, R.E., Couston, M., Cossar, J., Masterton, G., and Hayes, P.C. (2003). Psychological outcome and quality of life following liver transplantation: A prospective, national, single-center study. Liver Transpl. 9(7):712–720.CrossRefPubMedGoogle Scholar
  48. Pantiga, C., Rodrigo, L.R., Cuesta, M., Lopez, L., Arias, J. L., and Pujol, A. (2003). Cognitive deficits in patients with hepatic cirrhosis and in liver transplant recipients. J. Neuropsychiatr. Clin. Neurosci. 15(1):84–89.Google Scholar
  49. Parsons-Smith, B.S., Summerskill, W.H.J., Dawson, A.M., and Sherlock, S. (1957). The electroencephalograph in liver disease. Lancet. 2:867–871.CrossRefGoogle Scholar
  50. Pujol, A., Pujol, J., Graus, F., Rimola, A., Peri, J., Mercader, J.M., Garcia-Pagan, J.C., Bosch, J., Rodes, J., and Tolosa, E. (1993). Hyperintense globus pallidus on T1-weighted MRI in cirrhotic patients is associated with severity of liver failure. Neurology 43(1):65–69.PubMedGoogle Scholar
  51. Rama Rao, K.V., Jayakumar, A.R., and Norenberg, M.D. (2003). Induction of the mitochondrial permeability transition in cultured astrocytes by glutamine. Neurochem. Int. 43(4–5):517–523.CrossRefPubMedGoogle Scholar
  52. Rao, R.K., and Norenberg, M.D. (2004). Manganese induces the mitochondrial permeability transition in cultured astrocytes. J. Biol. Chem. 279(31):32333–32338.CrossRefPubMedGoogle Scholar
  53. Rao, V.L., and Butterworth, R.F. (1994). Alterations of [3H]8-OH-DPAT and [3H]ketanserin binding sites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Neurosci Lett. 182(1):69–72.CrossRefPubMedGoogle Scholar
  54. Ratcliffe, J., Longworth, L., Young, T., Bryan, S., Burroughs, A., and Buxton, M. (2002). Assessing health-related quality of life pre- and post-liver transplantation: A prospective multicenter study. Liver Transpl. 8(3):263–270.CrossRefPubMedGoogle Scholar
  55. Rehnstrom, S., Simert, G., Hansson, J.A., Johnson, G., and Vang, J. (1977). Chronic hepatic encephalopathy. A psychometrical study. Scand. J. Gastroenterol. 12(3):305–311.PubMedGoogle Scholar
  56. Rikkers, L., Jenko, P., Rudman, D., and Freides, D. (1978). Subclinical hepatic encephalopathy: Detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 75(3):462–469.PubMedGoogle Scholar
  57. Rose, C., Butterworth, R.F., Zayed, J., Normandin, L., Todd, K., Michalak, A., Spahr, L., Huet, P.M., and Pomier-Layrargues, G. (1999). Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology 117(3):640–644.PubMedGoogle Scholar
  58. Sanyal, A.J., Freedman, A.M., Luketic, V.A., Purdum, P.P., 3rd, Shiffman, M.L., Cole, P.E., Tisnado, J., and Simmons, S. (1997). Transjugular intrahepatic portosystemic shunts compared with endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage. A randomized, controlled trial. Ann. Int. Med. 126(11):849–857.PubMedGoogle Scholar
  59. Schliess, F., Gorg, B., Fischer, R., Desjardins, P., Bidmon, H.J., Herrmann, A., Butterworth, R.F., Zilles, K., and Haussinger, D. (2002). Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. Faseb J. 16(7):739–741.PubMedGoogle Scholar
  60. Schomerus, H., Hamster, W., Blunck, H., Reinhard, U., Mayer, K., and Doyle, W. (1981). Latent portasystemic encephalopathy. In nature of cerebral functional defects and their effect on fitness to drive. Digestive Diseases and Sciences 28:622–630.CrossRefGoogle Scholar
  61. Schomerus, H., and Hamster, W. (1998). Neuropsychological aspects of portal-systemic encephalopathy. Metab. Brain Dis. 13(4):361–377.CrossRefPubMedGoogle Scholar
  62. Schomerus, H., and Hamster, W. (2001). Quality of life in cirrhotics with minimal hepatic encephalopathy. Metab. Brain Dis. 16(1/2):37–41.CrossRefPubMedGoogle Scholar
  63. Shawcross, D.L., Davies, N.A., Williams, R., and Jalan, R. (2004). Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J. Hepatol. 40(2):47–254.CrossRefPubMedGoogle Scholar
  64. Spahr, L., Butterworth, R.F., Fontaine, S., Bui, L., Therrien, G., Milette, P.C., Lebrun, L.H., Zayed, J., Leblanc, A., and Pomier-Layrargues, G. (1996). Increased blood manganese in cirrhotic patients: Relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms. Hepatology 24(5):1116–1120.PubMedGoogle Scholar
  65. Suarez, I., Bodega, G., Arilla, E., and Fernandez, B. (1996). Long-term changes in glial fibrillary acidic protein and glutamine synthetase immunoreactivities in the supraoptic nucleus of portacaval shunted rats. Metab. Brain Dis. 11(4):369–379.CrossRefPubMedGoogle Scholar
  66. Tarbuck, A.F., and Paykel, E.S. (1995). Effects of major depression on the cognitive function of younger and older subjects. Psychol. Med. 25(2):285–295.PubMedGoogle Scholar
  67. Tarter, R.E., and Van Thiel, D.H. (2001). Neuropsychological dysfunction due to liver disease. In: Tarter, R.E., and Butters, M., et al. (Eds.). Medical neuropsychology (2nd ed.). Kluwer Academic Publishers, Dordrecht, Netherlands, x, 346 pp.Google Scholar
  68. Tarter, R.E., Hegedus, A.M., Van Thiel, D.H., Edwards, N., and Schade, R.R. (1987). Neurobehavioral correlates of cholestatic and hepatocellular disease: Differentiation according to disease specific characteristics and severity of the identified cerebral dysfunction. Int. J. Neurosci. 32(3/4):901–910.PubMedGoogle Scholar
  69. Tarter, R.E., Hegedus, A.M., Van Thiel, D.H., Edwards, N., and Schade, R.R. (1984). Nonalcoholic cirrhosis associated with neuropsychological dysfunction in the absence of overt evidence of hepatic encephalopathy. Gastroenterology 86(6):421–1427.PubMedGoogle Scholar
  70. Tarter, R., Hegedus, A., Van Thiel, D., Gavaler, J., and Schade, R. (1986). Hepatic dysfunction and neuropsychological test performance in alcoholics with cirrhosis. J. Studies Alcohol 47:74–77.Google Scholar
  71. Tarter, R.E., Sandford, S.L., Hays, A.L., Carra, J.P., and Van Thiel, D.H. (1989). Hepatic injury correlates with neuropsychologic impairment. Int. J. Neurosci. 44(1–2):75–82.PubMedGoogle Scholar
  72. Tarter, R.E., Switala, J.A., Arria, A., Plail, J., and Van Thiel, D.H. (1990). Subclinical hepatic encephalopathy. Comparison before and after orthotopic liver transplantation. Transplantation 50(4):632–637.PubMedGoogle Scholar
  73. Van Thiel, D.H., Schade, R.R., Starzl, T.E., Iwatsuki, S., Shaw, B.W., Jr., Gavaler, J.S., and Dugas, M. (1982). Liver transplantation in adults. Hepatology 2(5):637–640.PubMedGoogle Scholar
  74. Weissenborn, K., Ehrenheim, C., Hori, A., Kubicka, S., and Manns, M.P. (1995). Pallidal lesions in patients with liver cirrhosis: Clinical and MRI evaluation. Metab. Brain Dis. 10(3):219–231.CrossRefPubMedGoogle Scholar
  75. Weissenborn, K., Heidenreich, S., Giewekemeyer, K., Ruckert, N., Hecker, H., Young, S.N., and Lal, S. (2003). Memory function in early hepatic encephalopathy. J. Hepatol. 39(3):320–325.CrossRefPubMedGoogle Scholar
  76. Young, S.N., and Lal, S. (1980). CNS tryptamine metabolism in hepatic coma. J. Neural. Transmission 47:153–161.CrossRefGoogle Scholar

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© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Division of Gastroenterology and HepatologyMayo Clinic RochesterRochester
  2. 2.Department of Psychiatry and PsychologyMayo Clinic RochesterRochester
  3. 3.Mayo Clinic Rochester

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