Hepatic Encephalopathy: The Present and the Future

  • Steven Schenker
Chapter
Part of the Experimental Biology and Medicine book series (EBAM, volume 22)

Abstract

Hepatic encephalopathy may be defined as an alteration in mental state accompanying and due to liver disease. Hepatic dysfunction may be of the chronic type (i.e. cirrhosis) with spontaneous or surgically-induced portal-systemic shunting of blood (portal-systemic encephalopathy, PSE), or caused by acute liver failure (viral or toxic). Encephalopathy, in the former disorder (PSE), is usually insidious in onset, precipitated by some specific insult (i.e. gastrointestinal hemorrhage, azotemia, hypokalemic alkalosis) and is often rapidly reversible with appropriate therapy. In this regard, PSE is unique since treatment is relatively effective despite lack of complete understanding of the pathogenesis of this syndrome. Some 75 percent of such patients respond to rather simple and innocuous therapy within 72 hours and, in fact, lack of improvement is cause to reevaluate the diagnosis.

Keywords

Hepatitis Dopamine Glutamine Dexamethasone Neurol 

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References

  1. 1.
    Iwatsuki, S., Esquivel, C.O., Gordon, R.D., et al. (1985). Liver transplantation for fulminant hepatic failure. Semin. Liver Dis. 5, 325–328.PubMedCrossRefGoogle Scholar
  2. 2.
    Ringe, B., Pilchmayr, R., Lancchart, W., et al. (1986). Indications and results of liver transplantation in acute hepatic failure. Transplant. Proc. 18, 86–88.Google Scholar
  3. 3.
    Bismuth, H., Samuel, D., Gugenheim, J. (1987). Emergency liver transplantation for fulminant hepatitis. Ann. Int. Med. 107, 337–341.PubMedGoogle Scholar
  4. 4.
    Lo, W.D., Ennis, S.R., Goldstein, G.W., et al. (1987). The effects of galactosamine-induced hepatic failure upon blood/brain barrier permeability. Hepatology 7, 452–456.PubMedCrossRefGoogle Scholar
  5. 5.
    Gantz, R., Swain, M., Traber, P., et al. (1988). A role for ammonia in the brain edema of fulminant hepatic failure (FHF) in the rat. Studies in cortical brain slices. Hepatology 8, 1247.Google Scholar
  6. 6.
    Seda, H.W.M., Hughes, R.D., Gove, C.D., et al. (1984). Inhibition of rat brain Na+, K+-ATPase activity by serum from patients with fulminant hepatic failure. Hepatology 4, 74–79.PubMedCrossRefGoogle Scholar
  7. 7.
    Canalese, S., Gimson, A.E.S., Davis, C. et al (1982). Controlled trial of dexamethasone and mannitol for the cerebral edema of fulminant hepatic failure. Gut 23, 625–629.PubMedCrossRefGoogle Scholar
  8. 8.
    LaBrecque, D.R., Steele, G., Fogerty, S. et al. (1987). Purification and physical-chemical characterization of hepatic stimulator substance. Hepatology 7, 100–106.PubMedCrossRefGoogle Scholar
  9. 9.
    Michalopaulos, G., Houck, K.A., Dolan, M.L. et al. (1984). Control of hepatocyte replication by two serum factors. Cancer Res. 44, 4414–4419.Google Scholar
  10. 10.
    Francavilla, A., DiLeo, A., Polineno, L. et al. (1986). The effect of hepatic stimulatory substance isolated from regenerating hepatic cytosol and 50,000 and 300,000 subfractions in enhancing survival in experimental acute hepatic failure in rats treated with galactosamine. Hepatology 6, 1346–1351.PubMedCrossRefGoogle Scholar
  11. 11.
    Baskin, G.S., Henderson, G.I., Schenker, S. (1988). Ethanol and hepatic regeneration. Hepatology 8, 408–411.PubMedCrossRefGoogle Scholar
  12. 12.
    Alsion, M.R. (1986). Regulation of hepatic growth. Physiol. Rev. 66, 499–541.Google Scholar
  13. 13.
    Roper, S.E., Burwen, S.J., Barker, M.E., Jones, A.L. (1987). Translocation of epidermal growth factor to the hepatocyte nucleus during rat liver regeneration. Gastroenterology 92, 1243–1250.Google Scholar
  14. 14.
    Jamieson, N.V., Sandburg, R., Lindell, S. et al. (1988). Successful 24–30 hour preservation of the canine liver: a preliminary report. Transplant. Proceed. 20, 945–947.Google Scholar
  15. 15.
    Demetriou, A.A., Reisner, A., Sanchez, J. et al. (1988). Transplantation of microcarrier-attached hepatocytes into 90% partially hepatectomized rats. Hepatology 8, 1006–1009.PubMedCrossRefGoogle Scholar
  16. 16.
    Magoun, H.W. (1963). The Waking Brain, 2nd Ed., CS. Thomas, Springfield, IL.Google Scholar
  17. 17.
    Butterworth, R.F., Giguère, J.F., Michaud, J. et al. (1987). Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem. Path. 6, 1–12.CrossRefGoogle Scholar
  18. 18.
    Hindfelt, B. (1973). The effect of acute ammonia intoxication upon the brain energy state in rats pretreated with L-methionine D-L-sulphoximine. Scan. J. Clin. Lab. Invest. 31, 289–299.CrossRefGoogle Scholar
  19. 19.
    Butterworth, R.F., Lavoie, J., Pomier Layrargues, G., Giguère, J-F. (1988). Neurotransmitter changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. In Advances in Ammonia Metabolism and Hepatic Encephalopathy. P.B. Soeters, J.H.P. Wilson, A.J. Meijer, E. Holm (Eds.). Elsevier, pp. 319, 324.Google Scholar
  20. 20.
    Lockwood, A.H., Ginsberg, M.D., Rhoades, H.M., Gutierrez, M.T. (1986). Cerebral glucose metabolism after portacaval shunting in the rat. J. Clin. Invest. 78, 86–95, 1986.Google Scholar
  21. 21.
    Hawkins, R.A., Mans, A.M., Biebuyck, J.F. (1987). Changes in brain metabolism in hepatic encephalopathy. Neurochem. Pathol. 6, 35–66.PubMedCrossRefGoogle Scholar
  22. 22.
    McCandless, D.W., Schenker, S. (1981). Effect of acute ammonia intoxication on energy stores in the cerebral reticular activating system. Exp. Brain Res. 44, 325–330.PubMedCrossRefGoogle Scholar
  23. 23.
    McCandless, D.W. (1985). Octanoic acid induced coma and reticular formation energy metabolism. Brain Res. 335, 131–137.PubMedCrossRefGoogle Scholar
  24. 24.
    Norenberg, M.D. (1987). The role of astrocytes in hepatic encephalopathy. Neurochem. Pathol. 6, 13–34, 1987.Google Scholar
  25. 25.
    Albrecht, J., Wysmyk-Cybula, U., Rafalowska, V. (1985). Na+/K+-ATPase activity and GABA uptake in astroglial cell-enriched fractions and synaptosomes derived from rats in the early stages of experimental hepatogenic encephalopathy. Acta Neurol. Scand. 72, 317–320.PubMedCrossRefGoogle Scholar
  26. 26.
    Gregorios, J.B., Mozes, L.W., Norenberg, L.O.B., Norenberg, M.D. (1986). Effect of cyclic AMP on ammonia-induced alterations in primary astrocyte cultures. J. Neuropathol. Exp. Neurol. 45, 396–407.PubMedCrossRefGoogle Scholar
  27. 27.
    Cooper, A.J.L., Plum, F. (1987). Biochemistry and physiology of brain ammonia. Physiol. Rev. 67, 440–519.PubMedGoogle Scholar
  28. 28.
    Bernthal, P., Hays, A., Tarter, R.F. et al. (1987). Cerebral CT scan abnormalities in cholestatic and hepatocellular diseases and their relationship to neuropsychological test performance. Hepatology 7, 107–114.PubMedCrossRefGoogle Scholar
  29. 29.
    Gilberstadt, S., Gilberstadt, H., Zieve, L. et al. (1980). Psychomotor performance defects in cirrhotic patients without overt encephalopathy. Arch. Int. Med. 140, 519–521.CrossRefGoogle Scholar
  30. 30.
    Fischer, J.E., Baldessarini, R.J. (1976). Pathogenesis and therapy of hepatic coma. Prog. Liver Dis. 1, 363.Google Scholar
  31. 31.
    Hoyumpa, A.M., Schenker, S. (1982). Perspectives in hepatic encephalopathy. J. Lab. Clin. Med. 100, 477–487.PubMedGoogle Scholar
  32. 32.
    Zieve, L., Olsen, E.L. (1977). Can hepatic coma be caused by a reduction of brain noradrenaline or dopamine? Gut 18, 688.PubMedCrossRefGoogle Scholar
  33. 33.
    Michel, H., Solere, M., Granier, P., et al. (1980). Treatment of cirrhotic hepatic encephalopathy with L-Dopa. A controlled trial. Gastroenterology 79, 207.PubMedGoogle Scholar
  34. 34.
    Schafer, D.F., Jones, E.A. (1982). Potential neural mechanisms in the pathogenesis of hepatic encephalopathy. In: Progress in Liver Disease, H. Popper, F. Schaffner (Eds.), New York: Grune & Stratton, vol. 7, pp. 615–627.Google Scholar
  35. 35.
    Maddison, J.E., Dodd, P.R., Morrison, M. et al. (1987). Plasma GABA, GABA-like activity and the brain GABA-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy. Hepatology 7, 621–628.PubMedCrossRefGoogle Scholar
  36. 36.
    Moroni, F., Riggio, O., Carla, V. et al. (1987). Hepatic encephalopathy: lack of changes of gamma-aminobutyric acid content in plasma and cerebrospinal fluid. Hepatology 7, 816–820.PubMedCrossRefGoogle Scholar
  37. 37.
    Levy, L.J., Leek, J., Losowsky, M.S. (1987). Evidence for gamma-aminobutyric acid as the inhibitor of gamma-aminobutyric acid binding in the plasma of humans with liver disease and hepatic encephalopathy. Clin. Sci. 73, 531–534.PubMedGoogle Scholar
  38. 38.
    Lo, W.D., Ennis, S.R., Goldstein, G.W. et al. (1987). The effects of galactosamine-induced hepatic failure upon blood/brain barrier permeability. Hepatology 7, 452–456.PubMedCrossRefGoogle Scholar
  39. 39.
    Traber, P.G., Canto, M.D., Granger, D.R. et al. (1987). Electron microscopic evaluation of brain edema in rabbits with galactosamine-induce fulminant hepatic failure: ultrastructure and integrity of the blood-brain barrier. Hepatology 7, 1272–1277.PubMedCrossRefGoogle Scholar
  40. 40.
    Maddison, J.E., Dodd, P.R., Johnston, G.A.R. et al. (1987). Brain gamma-aminobutyric acid receptor binding is normal in rats with thioacetamide-induced hepatic encephalopathy despite elevated plasma gamma-aminobutyric acid-like activity. Gastroenterology 93, 1062–1068.PubMedGoogle Scholar
  41. 41.
    Lavoie, J., Giguere, J.F., Layrargues, G.P., Butterworth, R.F. (1987). Amino acid changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. J. Neurochem. 49, 692–697.PubMedCrossRefGoogle Scholar
  42. 42.
    Sykes, C., Prestwich, S., Horton, R. (1984). Chronic administration of the GABA-transaminase inhibitor ethanolamine o-sulphate leads to up-regulation of GABA binding sites. Biochem. Pharmacol. 33, 387–393.PubMedCrossRefGoogle Scholar
  43. 43.
    Schenker, S., Brady, C.E. (1988). Pathogenesis of hepatic encephalopathy. In: Hepatic Encephalopathy: Management with Lactulose and Related Carbohydrates. H.O. Conn, J. Bircher (Eds.), Medi-Ed. Press, East Lansing, MI, pp. 15–30.Google Scholar
  44. 44.
    Samson, Y., Bernau, J., Pappata, S. et al. (1987). Cerebral uptake of benzodiazepine measured by positron emission tomography in hepatic encephalopathy (correspondence). N. Engl. J. Med. 316, 414–415.PubMedCrossRefGoogle Scholar
  45. 45.
    Schafer, D.F. (1987). Hepatic coma: studies on the target organ. Gastroenterology 93, 1131–1134.PubMedGoogle Scholar
  46. 46.
    Evoniuk, G., Skolnick, P. (1988). Anion regulation of agonist and inverse agonist binding to benzodiazepine receptors. J. Neurochem. 51, 1169–1175.PubMedCrossRefGoogle Scholar
  47. 47.
    Butterworth, R.F., Lavoie, J., Giguere, J.-F., Pomier-Layrargues, G. (1988). Affinities and densities of high affinity [3H]-muscimol (GABA-A) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Hepatology 8, 1084–1088.PubMedCrossRefGoogle Scholar
  48. 48.
    Ferenci, P., Riederer, P., Jellinger, K. et al. (1988). Changes in cerebral receptors for gamma-aminobutyric acid in patients with hepatic encephalopathy. Liver 8, 225–230.PubMedGoogle Scholar
  49. 48a.
    Watkins, J.C., Evans, R.H. (1981). Excitatory amino acid transmitters. Ann. Rev. Pharmacol. Toxicol. 21, 165–204.CrossRefGoogle Scholar
  50. 49.
    Zeneroli, M.L., Iuliano, E., Racogni, G. et al (1982). Metabolism and brain uptake of gamma-aminobutyric acid in galactosamine-induced hepatic encephalopathy in rats. J. Neurochem. 38, 1219–1222.PubMedCrossRefGoogle Scholar
  51. 50.
    Wildman, J., Mohler, H., Vetler, W. et al. (1987). Diazepam and N-desmethyldiazepam are found in rat brain and adrenal and may be of plant origin. J. Neural. Transm. 70, 282–288.CrossRefGoogle Scholar
  52. 51.
    Baraldi, M., Zeneroli, M.L., Ventura, E. et al. (1984). Supersensitivity of benzodiazepine receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat: reversal by a benzodiazepine antagonist. Clin. Sci. 67, 167–175.PubMedGoogle Scholar
  53. 52.
    Bassett, M.L., Mullen, K.D., Skolnick, P. et al. (1987). Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastroenterology 93, 1069–1077.PubMedGoogle Scholar
  54. 53.
    Scollo-Lavizzari, C., Steinmann, E. (1985). Reversal of hepatic coma by benzodiazepine antagonist (Rol5–1788) (correspondence). Lancet 1, 1324.CrossRefGoogle Scholar
  55. 54.
    Bansky, G., Meier, P.J., Ziegler, W.H. et al. (1985). Reversal of hepatic coma by benzodiazepine antagonist (Rol5–1788) (correspondence). Lancet 1, 1324.Google Scholar
  56. 55.
    Baraldi, M., Zeneroli, M.L. (1982). Experimental hepatic encephalopathy: changes in the binding of gamma-aminobutyric acid. Science 216, 427.PubMedCrossRefGoogle Scholar
  57. 56.
    Mullen, K.D., Szauter, K.M., Kaminsky, K., Matuszak, S.M. (1988). Characterization of “endogenous” benzodiazepine (BZ) activity detected in human hepatic encephalopathy (HE). Hepatology 8, 1352.CrossRefGoogle Scholar
  58. 57.
    Basile, A.S., Gammal, S.H., Mullen, K.D. et al. (1988). Differential responsiveness of cerebellar Purkinje neurons to GABA and benzodiazepine receptor ligands in an animal model of hepatic encephalopathy. J. Neurosci. 8, 2414–2421.PubMedGoogle Scholar
  59. 58.
    Bakter, G., Fisch, H.V., Garkoganes, G. et al. (1987). Mechanism of the excessive sedative response to cirrhotics to benzodiazepines: model experiments with trazolan. Hepatology 7, 629–638.CrossRefGoogle Scholar
  60. 59.
    Zieve, L. (1987). Pathogenesis of hepatic encephalopathy. Metab. Brain Dis. 2, 147–165.PubMedCrossRefGoogle Scholar
  61. 60.
    Watanabe, A., Takei, N., Higashi, T. et al. (1984). Glutamic acid and glutamine levels in serum and cerebrospinal fluid in hepatic encephalopathy. Biochem. Med. 32, 225–231.PubMedCrossRefGoogle Scholar
  62. 61.
    Plum, F. and Hindfeldt, B. (1986). The neurological complications of liver disease. In: Handbook of Clinical Neurology. P.J. Vinken, G. W. Bruyn (Eds.), Elsevier, New York, pp. 349–377.Google Scholar
  63. 62.
    Soeters, P.B., van Leeuwen, P.A.M., van Berlo, C.L.H. (1988). Nitrogen metabolism in the gut. In: Hepatic Encephalopathy: Management with Lactulose and Related Carbohydrates. H.O. Conn, J. Bircher (Eds.), Medi-Ed, East Lansing, MI, pp. 31–39.Google Scholar
  64. 63.
    Lockwood, A.M., McDonald, J.M., Reiman, R.E., Gelbard, A.S. et al. (1979). The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J. Clin. Invest. 63, 449–460.PubMedCrossRefGoogle Scholar
  65. 64.
    Schenker, S., Hoyumpa, A.M. (1984). Pathophysiology of hepatic encephalopathy. Hospital Practice 19, 99–121.PubMedGoogle Scholar
  66. 65.
    Butterworth, R.F., Lavoie, J., Giguere, J.F., et al. (1987). Cerebral GABA-ergic and gluta-matergic function in hepatic encephalopathy. Neurochem. Pathol. 6, 131–144.PubMedCrossRefGoogle Scholar
  67. 66.
    Warren, K.S., Schenker, S. (1964). Effect of an inhibitor of glutamine synthesis (methionine sulfoximine) on ammonia toxicity and metabolism. J. Lab. Clin. Med. 64, 442.PubMedGoogle Scholar
  68. 67.
    Hindfelt, B., Plum, F., Duffy, T.E. (1977). Effect of acute ammonia intoxication or cerebral metabolism in rats with portacaval shunts. J. Clin. Invest. 59, 386–396.PubMedCrossRefGoogle Scholar
  69. 68.
    Yao, H., Sadoshima, S., Fujii, K. et al. (1987). Cerebrospinal fluid lactate in patients with hepatic encephalopathy. Eur. Neurol. 27, 182–187.PubMedCrossRefGoogle Scholar
  70. 69.
    Dentz, N.E.P., Chamuleau, R.A.F.M. (1988). In vivo 31NMR spectroscopy of the rat cerebral cortex during acute hepatic encephalopathy. NMR Biomed. 1, 101–106.CrossRefGoogle Scholar

Copyright information

© The Humana Press Inc. 1989

Authors and Affiliations

  • Steven Schenker
    • 1
  1. 1.Health Science Center and Audie Murphy Veterans HospitalUniversity of TexasSan AntonioUSA

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