Hepatocerebral Interactions

  • Daniel F. Schafer


All the assaults by alcohol on the central nervous system are not direct. In a still mysterious manner, chronic alcohol ingestion is associated with the development of inflammatory and fibrotic liver disease which, if it becomes severe enough, adversely affects brain function. The common name for this neurologic dysfunction associated with advanced liver disease is “hepatic coma.” The recognition and definition of this syndrome have a long and tangled history which is beyond the scope of this chapter. The interested student can consult the monograph by Conn and Lieberthal1 for the details concerning the experimental work on this topic until the mid 1970s.


Hepatic Encephalopathy Fulminant Hepatic Failure Hepatic Coma Acute Hepatic Failure Blood Ammonia Level 
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  1. 1.
    Conn HO, Lieberthal MM: The hepatic coma syndromes and lactulose. Baltimore, Williams and Wilkins Co, 1979Google Scholar
  2. 2.
    Adams RD, Foley JM: The neurological disorder associated with liver disease. Assoc Res New Ment Dis Proc 32: 198–237, 1953Google Scholar
  3. 3.
    Eck NV: Ligature of the portal vein. Med J St Petersburg 130: 1–2, 1877Google Scholar
  4. 4.
    Balo J, Korpassy B: The encephalitis of dogs with Eck fistula fed on meat. Arch Pathol 13: 80–87, 1932Google Scholar
  5. 5.
    McDermott WV, Adams RD: Episodic stupor associated with an Eck fistula in man with particular reference to ammonia metabolism. J Clin Invest 33: 1–14, 1954PubMedCrossRefGoogle Scholar
  6. 6.
    Kirlan RK, Sollenberger RD, Palubinskas AJ, et al: Portal—systemic encephalopathy due to a congenital portocaval shunt. Am J Radiol 139: 1013–1015, 1982Google Scholar
  7. 7.
    Summerskill WHJ, Davidson EA, Sherlock S, et al: The neuropsychiatrie syndrome associated with hepatic cirrhosis and an extensive portal collateral circulation. Q J Med 25: 245–266, 1956PubMedGoogle Scholar
  8. 8.
    Victor M, Adams RD, Cole M: The acquired (non-Wilsonian) type of chronic hepatocerebral degeneration. Medicine 44: 345–396, 1965PubMedCrossRefGoogle Scholar
  9. 9.
    Zieve L, Mendelson DF, Goepfert M: Shunt encephalomyelopathy. Ann Intern Med 53: 53–60, 1960PubMedCrossRefGoogle Scholar
  10. 10.
    Fessel JM, Conn HO: An analysis of the causes and prevention of hepatic coma. Gastroenterology 62: 191, 1972Google Scholar
  11. 11.
    Sherlock S, Senewiratne B, Scott A, et al: Complications of diuretic therapy in hepatic cirrhosis. Lancet 1:1049–1053, 1966Google Scholar
  12. 12.
    Duffy TE, Plum F: Hepatic encephalopathy, in Arias I, Popper H, Schachter D, et al (eds): The Liver: Biology and Pathobiology. New York, Raven Press, 1982, pp 693–715Google Scholar
  13. 13.
    Caronna J, Shaw D, Cartlidge N, et al: The outcome of medical coma: Prediction by bedside assessment of physical signs. Arch Neurol 32: 349–357, 1975Google Scholar
  14. 14.
    Teasdale G, Jennett B: Assessment of coma and impaired consciousness. Lancet 2: 81–84, 1974PubMedCrossRefGoogle Scholar
  15. 15.
    Trey C, Davidson CC: The management of fulminant hepatic failure. Prog Liver Dis 3: 292–298, 1970Google Scholar
  16. 16.
    Levy DE, Bates D, Caronna JJ, et al: Prognosis in nontraumatic coma. Ann Intern Med 94: 293–301, 1981PubMedCrossRefGoogle Scholar
  17. 17.
    Plum F, Hindfelt B: The neurological complications of liver disease, in Vinken PG, Bruyn GW (eds): Handbook of Clinical Neurology, Vol 31. New York, Elsevier, 1977, pp 349–377Google Scholar
  18. 18.
    Fisher CJ, Faloon WW: Blood ammonia levels in hepatic cirrhosis; their control by the oral administration of neomycin. N Engl J Med 256: 1030–1034, 1957PubMedCrossRefGoogle Scholar
  19. 19.
    Pilbeam CM, Anderson RM, Bhathal PS: The brain in experimental portal-systemic encephalopathy. J Pathol 140: 331–345, 1983PubMedCrossRefGoogle Scholar
  20. 20.
    Olefsky JM: Insulin resistance in humans. Gastroenterology 83: 1313–1321, 1982PubMedGoogle Scholar
  21. 21.
    Owen 0E, Trapp VE, Reichard GA, et al: Nature and quantity of fuels consumed in patients with alcoholic cirrhosis. J Clin Invest 72: 1821–1832, 1983Google Scholar
  22. 22.
    Conn HO, Daughaday WH: Cirrhosis and diabetes. V. Serum growth hormone levels in Laennec’s cirrhosis. J Lab Clin Med 76: 678–688, 1970PubMedGoogle Scholar
  23. 23.
    Riggio O, Merli M, Cangiano C, et al: Glucose intolerance in liver cirrhosis. Metabolism 31: 627–637, 1982PubMedCrossRefGoogle Scholar
  24. 24.
    Walshe JM: Disturbances of amino acid metabolism following liver injury: A study by means of paper chromatography. Q J Med 22: 483–505, 1953PubMedGoogle Scholar
  25. 25.
    lob V, Coon WW, Sloan M: Altered clearance of free amino acids from plasma of patients with cirrhosis of the liver. J Surg Res 6: 233–239, 1966CrossRefGoogle Scholar
  26. 26.
    Rosen HM, Yoshimura N, Hodgman JM, et al: Plasma amino acid patterns in hepatic encephalopathy of differing etiology. Gastroenterology 72: 483–487, 1977PubMedGoogle Scholar
  27. 27.
    Morgan MY, Milson JP, Sherlock S: Plasma ratio of valine, leucine and isoleucine to phenylalanine and tyrosine in liver disease. Gut 19: 1068–1073, 1978PubMedCrossRefGoogle Scholar
  28. 28.
    Ono J, Hutson DG, Dombro RS, et al: Tryptophan and hepatic coma. Gastroenterology 74: 196–200, 1978PubMedGoogle Scholar
  29. 29.
    Chapman ML, Janowitz HD: Chronic portal—systemic encephalopathy after ileostomy and colonic resection. Lancet 1:1064–1065. 1966Google Scholar
  30. 30.
    Parkes JD, Murray-Lyon IM, Williams R: Neuropsychiatrie and electroencephalographic changes after transplantation of the liver. Q J Med 39: 515–519, 1970PubMedGoogle Scholar
  31. 31.
    Crossley IR, Williams R: Progress in the treatment of portosystemic encephalopathy. Gut 25: 85–98, 1984PubMedCrossRefGoogle Scholar
  32. 32.
    Hahn M, Massen O, Nenki M, et al: Die Ecksche Fistel swischen der unteren Hohlvene and der Pfortader and ihre Folgen fur den Organismus. Arch Exp Pathol Pharmakol 32: 161–270, 1893CrossRefGoogle Scholar
  33. 33.
    Van Caulaert C, Deviller C, Halff M: Le taux de l’ammoniemie dans certaines affections hepatiques. Compt Rend Soc Biol 111: 735–740, 1932Google Scholar
  34. 34.
    Kirk E: Amino acid and ammonia metabolism in liver diseases. Acta Med Scand 77: 1–147, 1936Google Scholar
  35. 35.
    Cohn R, Castell DO: The effect of acute hyperammonemia on the electroencephalogram. J Lab Clin Med 68: 195–205, 1966PubMedGoogle Scholar
  36. 36.
    Msall M, Batshaw ML, Suss R, et al: Neurologic outcome in children with inborn errors of urea synthesis: Outcome of urea-cycle enzymopathies. N Engl J Med 310: 1500–1505, 1984PubMedCrossRefGoogle Scholar
  37. 37.
    Hamberger A, Jacobsson 1, Molin SO, et al: Regulation of glutamate biosynthesis and release by pathophysiological levels of ammonium ions, in DiChiara G, Gessa G (eds): Glutamate as a Neurotransmitter. Raven Press, New York, 1981, pp 115–126Google Scholar
  38. 38.
    Ferenci P, Pappas SC, Munson PJ, et al: Changes in glutamate receptors on synaptic membranes associated with hepatic encephalopathy or hyperammonemia in the rabbit. Hepatology 4: 25–29, 1984PubMedCrossRefGoogle Scholar
  39. 39.
    Pappas SC, Ferenci P, Schafer DF, et al: Visual evoked potentials in a rabbit model of hepatic encephalopathy. ll. Comparison of hyperammonemic encephalopathy, post-ictal coma, and coma induced by synergistic neurotoxins. Gastroenterology 86: 546–551, 1984PubMedGoogle Scholar
  40. 40.
    Schafer DF, Pappas SC, Brody LE, et al: Visual evoked potentials in a rabbit model of hepatic encephalopathy. I. Sequential changes and comparisons with drug-induced comas. Gastroenterology 86: 540–545, 1984PubMedGoogle Scholar
  41. 41.
    Zieve L, Doizaki WM: Brain and blood methanethiol and ammonia concentrations in experimental hepatic coma and coma due to injections of various combinations of these substances. Gastroenterology 79: 1070, 1980Google Scholar
  42. 42.
    Zeneroli ML, Ventura E, Baraldi M, et al: Visual evoked potentials in encephalopathy induced by galactosamine, ammonia, dimethyldisulfide and octanoic acid. Hepatology 2: 532–538, 1982PubMedCrossRefGoogle Scholar
  43. 43.
    Zeneroli ML, Penne A, Parrinello G, et al: Comparative evaluation of visual evoked potentials in experimental hepatic encephalopathy and in pharmacologically induced coma-like states in rat. Life Sci 28: 1507–1515, 1981PubMedCrossRefGoogle Scholar
  44. 44.
    Zieve L: Mechanism of hepatic coma. Hepatology 1: 360–365, 1981PubMedCrossRefGoogle Scholar
  45. 45.
    James JH, Ziparo V, Jeppsson B, et al: Hyperammonemia, plasma amino acid imbalance and blood-brain amino acid transport: a unified theory of portal-systemic encephalopathy. Lancet 2: 772–775, 1979PubMedCrossRefGoogle Scholar
  46. 46.
    Zieve L, Olsen RL: Can hepatic coma be caused by a reduction of brain noradrenaline and dopamine? Gut 18: 688–691, 1977PubMedCrossRefGoogle Scholar
  47. 47.
    Cuilleret G, Pomier-Layrargues G, Pons F, et al: Changes in brain catecholamine levels in human cirrhotic hepatic encephalopathy. Gut 21: 565–569, 1980PubMedCrossRefGoogle Scholar
  48. 48.
    Blitzer BL, Waggoner JG, Jones EA, et al: A model of fulminant hepatic failure in the rabbit. Gastroenterology 74: 664–671, 1978PubMedGoogle Scholar
  49. 49.
    Olsen RW: Drug interactions at the GABA receptor—ionophore complex. Ann Rev Pharmacol Toxicol 22: 245–277, 1982CrossRefGoogle Scholar
  50. 50.
    Paul SM, Marangos PJ, Skolnick P: The benzodiazepine GABA—chloride ionophore receptor complex: Common site of minor tranquilizer action. Biol. Psychiatry 16: 213–239, 1981PubMedGoogle Scholar
  51. 51.
    Schafer DF, Waggoner JG, Jones EA: Sera from rabbits in acute hepatic coma inhibit the binding of [3HPy-aminobutyric acid to neural membranes. Gastroenterology 78: 1320, 1980Google Scholar
  52. 52.
    Schafer DF, Fowler JM, Brody LE, et al: Acute hepatic coma and inhibitory neurotransmission: The enteric bacterial flora as a source of -y-aminobutyric acid. Gastroenterology 79: 1052, 1980Google Scholar
  53. 53.
    Gerber JC, Hare TA: Gamma-aminobutyric acid in peripheral tissue with emphasis on the endocrine pancreas. Diabetes 28: 1073–1076, 1979PubMedCrossRefGoogle Scholar
  54. 54.
    Schafer DF, Fowler JM, Jones EA: Colonic bacteria: A source of y-aminobutyric acid in blood. Proc Soc Exp Biol Med 167: 301–303, 1981PubMedGoogle Scholar
  55. 55.
    Miller MW, in The Pfizer Handbook of Microbial Metabolites. New York, McGraw-Hill, 1961Google Scholar
  56. 56.
    Ferenci P, Covell D, Schafer DF, et al: Metabolism of the inhibitory neurotransmitter -yaminobutyric acid in a rabbit model of fulminant hepatic failure. Hepatology 3: 507–512, 1983PubMedCrossRefGoogle Scholar
  57. 57.
    Ferenci P, Schafer DF, Kleinberg G, et al: Serum levels of gamma-aminobutyric acid-like activity in acute and chronic hepatocellular disease. Lancet 2: 811–814, 1983PubMedCrossRefGoogle Scholar
  58. 58.
    Schafer DF, Thakur AK, Jones EA: Increased y-aminobutyric acid receptors associated with acute hepatic encephalopathy in rabbits. Clin Res 28: 485A, 1980Google Scholar
  59. 59.
    Schafer DF, Fowler JM, Munson PJ, et al: Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure. J Lab Clin Med 102: 870–880, 1983PubMedGoogle Scholar
  60. 60.
    Baraldi M, Zeneroli ML: Experimental hepatic encephalopathy: Changes in the binding of yaminobutyric acid. Science 216: 427–429, 1982PubMedCrossRefGoogle Scholar
  61. 61.
    Tran VT, Snyder SH, Major LF, et al: GABA receptors are increased in the brains of alcoholics. Ann Neurol 9: 289–292, 1981PubMedCrossRefGoogle Scholar
  62. 62.
    Ferenci P, Riederer P, Jellinger K, et al: Changes in y-aminobutyric acid receptors in patients with hepatic encephalopathy. Gastroenterology 84: 1371, 1983Google Scholar
  63. 63.
    Ferenci P, Pappas SC, Munson PJ, et al: Changes in the status of neurotransmitter receptors in a rabbit model of hepatic encephalopathy. Hepatology 4: 186–191, 1984PubMedCrossRefGoogle Scholar
  64. 64.
    Lefkowitz RJ, Caron MG, Stiles GL: Mechanisms of membrane—receptor regulation: Biochemical, physiological and clinical insights derived from studies of the adrenergic receptors. N Engl J Med 310: 1570–1579, 1984PubMedCrossRefGoogle Scholar
  65. 65.
    Ferenci P, Jacobs R, Pappas SC, et al: Enzymes of cerebral GABA metabolism and synaptosomal GABA uptake in acute liver failure in the rabbit. Evidence for decreased cerebral GABAtransaminase activity. J Neurochem 42: 1487–1490, 1984PubMedCrossRefGoogle Scholar
  66. 66.
    Sykes C, Prestwich S, Horton R: Chronic administration of the GABA-transaminase inhibitor ethanolamine-o-sulphate leads to up-regulation of GABA binding sites. Biochem Pharmacol 33: 387–393, 1984PubMedCrossRefGoogle Scholar
  67. 67.
    Lynch G, Bandry M: The biochemistry of memory: A new and specific hypothesis. Science 224: 1057–1063, 1984PubMedCrossRefGoogle Scholar
  68. 68.
    Livingstone AS, Potvin M, Goresky CA, et al: Changes in the blood—brain barrier in hepatic coma after hepatectomy in the rat. Gastroenterology 73: 697–704, 1977PubMedGoogle Scholar
  69. 69.
    Horowitz ME, Schafer DF, Molnar P, et al: Increased blood-brain transfer in a rabbit model of acute liver failure. Gastroenterology 84: 1003–1011, 1983.PubMedGoogle Scholar
  70. 70.
    Heflin PM, James JH, Nachbauer CA, et al: Effect of total hepatectomy and administration of branched-chain amino acids on regional norepinephrine, dopamine, and amino acids in rat brain. Ann Surg 198: 172–177, 1983CrossRefGoogle Scholar
  71. 71.
    Cardelli-Cangiano P, Cangiano C, James JH, et al: Effect of ammonia on amino acid uptake by brain microvessels. J Biol Chem 259: 5295–5300, 1984PubMedGoogle Scholar
  72. 72.
    Goldstein GW: The role of brain capillaries in the pathogenesis of hepatic encephalopathy. Hepatology 4: 565–567, 1984PubMedCrossRefGoogle Scholar
  73. 73.
    Schafer DF, Jones EA: Hepatic encephalopathy and the y-aminobutyric acid neurotransmitter system. Lancet 1:18–20, 1982Google Scholar
  74. 74.
    Schafer DF, Jones EA: Potential neural mechanisms of the pathogenesis of hepatic encephalopathy, in Popper H, Schaffner F (eds): Progress in Liver Diseases, Vol 7. New York, Grune and Stratton, 1982, pp 615–617Google Scholar
  75. 75.
    Hepatic encephalopathy today. Lancet 1: 489–491, 1984Google Scholar
  76. 76.
    Roberts E: The -y-aminobutyric acid (GABA) system and hepatic encephalopathy. Hepatology 4: 342–345, 1984PubMedCrossRefGoogle Scholar
  77. 77.
    Tarter RE, Hegedus AM, Van Thiel DH, et al: Nonalcoholic cirrhosis associated with neuro-psychological dysfunction in the absence of overt evidence of hepatic encephalopathy. Gastroenterology 86: 1421–1427, 1984PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1985

Authors and Affiliations

  • Daniel F. Schafer
    • 1
  1. 1.Department of Internal MedicineUniversity of Nebraska Medical Center and Liver Study Unit, Veterans Administration Medical CenterOmahaUSA

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