Skip to main content
Log in

Pathogenesis of hepatic encephalopathy

  • Review Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

References

  • Ahmed, K., and Thomas, B. S. (1971). The effects of long-chain fatty acids on sodium plus potassium ion-stimulated adenosine triphosphatase of rat brain.J. Biol. Chem. 246: 103–109.

    Google Scholar 

  • Ahmed, K., Zieve, L., and Quarfoth, G. (1984). Effects of methanethiol on erythrocyte membrane stabilization and on Na+, K+ -adenosine triphosphatase: Relevance to hepatic coma.J. Pharmacol. Exp. Ther. 228: 103–108.

    Google Scholar 

  • Baraldi, M., and Zeneroli, M. L. (1982). Experimental hepatic encephalopathy: Changes in the binding of γ-aminobutyric acid.Science 216: 427–429.

    Google Scholar 

  • Baraldi, M., Pinelli, G., Ricci, P., and Zeneroli, M. L. (1984a). Toxins in hepatic encephalopathy: The role of the synergistic effect of ammonia, mercaptans and short chain fatty acids.Arch. Toxicol. Suppl. 7: 103–105.

    Google Scholar 

  • Baraldi, M., Zeneroli, M. L.,et al. (1984b). Portal-systemic encephalopathy in dogs: Changes in brain GABA receptors and neurochemical correlates. In Kleinberger, G., Ferenci, P., Riederer, P., and Thaler, H. (eds.),Advances in Hepatic Encephalopathy and Urea Cycle Diseases, Karger, Basel, pp. 353–359.

    Google Scholar 

  • Baraldi, M., Zeneroli, M. L.,et al. (1984c). 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.

    Google Scholar 

  • Bassett, M. L., Mullen, K. D., Skolnick, P., and Jones, E. A. (1985). GABA and benzodiazepine receptor antagonists ameliorate hepatic encephalopathy in a rabbit model of fulminant hepatic failure.Hepatology 5: 1032.

    Google Scholar 

  • Bloxam, D. L., and Curzon, G. (1978). A study of proposed determinants of brain tryptophan concentration in rats after portocaval anastomosis or sham operation.J. Neurochem. 31: 1255–1263.

    Google Scholar 

  • Borg, J., Warter, J. M., Schlienger, J. L., Imler, M., Marescaux, C., and Mack, G. (1982). Neurotransmitter modifications in human cerebrospinal fluid and serum during hepatic encephalopathy.J. Neurol. Sci. 57: 343–356.

    Google Scholar 

  • Challenger, F., and Walshe, J. M. (1955). Methyl mercaptan in relation to foetor hepaticus.Biochem. J. 59: 372–375.

    Google Scholar 

  • Chen, S., Zieve, L., and Mahadevan, V. (1970). Mercaptans and dimethyl sulfide in the breath of patients with cirrhosis of the liver.J. Lab. Clin. Med. 75: 628–635.

    Google Scholar 

  • Conn, H. O., and Lieberthal, M. M. (1979).The Hepatic Coma Syndromes and Lactulose, William and Wilkins, Baltimore.

    Google Scholar 

  • Cummings, M. G., James, J. H., Soeters, P. B., Keane, J. M., Foster, J., and Fischer, J. E. (1976). Regional brain study of indoleamine metabolism in the rat in acute hepatic failure.J. Neurochem. 27: 741–746.

    Google Scholar 

  • Curzon, G., and Knott, P. J. (1977). Environmental, toxicological, and related aspects of tryptophan metabolism with particular reference to the central nervous system.CRC Crit. Rev. Toxicol. 5: 145–187.

    Google Scholar 

  • Curzon, G., Kantamaneni, B. D., Winch, J., Royas-Bueno, A., Murray-Lyon, I. M., and Williams, R. (1973). Plasma and brain tryptophan changes in experimental acute hepatic failure.J. Neurochem. 21: 137–145.

    Google Scholar 

  • Derr, R. F., and Zieve, L. (1973). Decreased cerebral uptake of oxygen in coma—a consequence of decreased utilization of ATP.J. Neurochem. 21: 1555–1557.

    Google Scholar 

  • Derr, R. F., and Zieve, L. (1976). Effect of fatty acids on the disposition of ammonia.J. Pharmacol. Exp. Ther. 197: 675–680.

    Google Scholar 

  • Derr, R. F., and Zieve, L. (1982). Methanethiol and fatty acids depress urea synthesis by the isolated perfused rat liver.J. Lab. Clin. Med. 100: 585–592.

    Google Scholar 

  • Dodsworfh, J. M., James, J. H., Cummings, M. C., and Fischer, J. E. (1974). Depletion of brain norepinephrine in acute hepatic coma.Surgery 75: 811–820.

    Google Scholar 

  • Drapanas, T., McMenamy, R. H., Adler, W. J., and Vang, J. O. (1965). Intermediary metabolism following hepatectomy in dogs.Ann. Surg. 162: 621–633.

    Google Scholar 

  • Fahey, J. L. (1957). Toxicity and blood ammonia rise resulting from intravenous amino acid administration in man: The protective effect of L-arginine.J. Clin. Invest. 36: 1647–1655.

    Google Scholar 

  • Faraj, B. A., Camp, V. M., Ansley, J. D., Scott, J., Ali, F. M., and Malveaux, E. J. (1981). Evidence for central hypertyraminemia in hepatic encephalopathy.J. Clin. Invest. 67: 395–402.

    Google Scholar 

  • Farber, M. O., Carlone, S., Serra, P., Capocaccia, L., Rossi-Fanelli, F., Antonini, E., and Manfredi, F. (1981). The oxygen affinity of hemoglobin in hepatic encephalopathy.J. Lab Clin. Med. 98: 135–144.

    Google Scholar 

  • Fernstermacher, J. O., Blasberg, R. G., and Patlak, C. S. (1981). Methods for quantifying the transport of drugs across brain barrier systems.Pharmacol. Ther. 14: 217–248.

    Google Scholar 

  • Ferenci, P., Zieve, L., Ebner, J., Zimmermann, Ch., and Rzepczynski, D. (1986). Postsynaptic neural membrane affinity for GABA and receptor density are unaltered in hepatic coma following portacaval shunt and hepatic artery ligation.Hepatology 6: 1143.

    Google Scholar 

  • Fischer, J. E. (1974). False neurotransmitters and hepatic coma.Res. Publ. Assoc. Nerv. Ment. Dis. 53: 53–73.

    Google Scholar 

  • Gabuzda, G. J. (1962). Hepatic coma: Clinical consideration, pathogenesis, and management. In Dock, W., and Snapper, I. (eds.),Advances in Internal Medicine, Vol. II, Chicago Year Book, Chicago, pp. 11–73.

    Google Scholar 

  • Geisler, C., Swanson, A. R., Zieve, L., and Anders, M. W. (1979). Phthalate interference in gas Chromatographic determination of long-chain fatty acids in plasma.Clin. Chem. 35: 308–310.

    Google Scholar 

  • Greenstein, J. P., Gullino, P., Winitz, M., Birnbaum, M.,et al. (1956). Studies on the metabolism of amino acids and related compoundsin vivo. I, II, III, IV.Arch. Biochem. Biophys. 64: 319–367.

    Google Scholar 

  • Hawkins, R. A., Miller, A. L., Nielsen, R. C., and Veech, R. L. (1973). The acute action of ammonia on rat brain metabolismin vivo.Biochem. J. 134: 1001–1008.

    Google Scholar 

  • Horak, W., Waldrum, R., Murray-Lyon, I. M., Schuster, E., and Williams, R. (1976). Kinetics of14Ccholic acid in fulminant hepatic failure: A prognostic test.Gastroenterology 71: 809–813.

    Google Scholar 

  • Horowitz, M. E., Schafer, D. F., Molnar, P., Jones, E. A., Blasberg, R. G., Patlak, C. S., Waggoner, J., and Fenstermacher, J. D. (1983). Increased blood-brain transfer in a rabbit model of acute liver failure.Gastroenterology 84: 1003–1011.

    Google Scholar 

  • Hortnagel, H., Lenz, K., Singer, E. A., Kleinberger, G., and Lochs, H. (1984). Substance P is markedly increased in plasma of patients with hepatic coma.Lancet 1: 480–483.

    Google Scholar 

  • Huet, P.-M., Pomier-Layrargues, G., Duguay, L., and du Souich, P. (1981). Blood-brain transport of tryptophan and phenylalanine: Effect of portacaval shunt in dogs.Am. J. Physiol. 241: G163-G169.

    Google Scholar 

  • James, J. H., Escourrou, J., and Fischer, J. E. (1978). Blood-brain neutral amino acid transport activity is increased after portacaval anastomosis.Science 200: 1395–1397.

    Google Scholar 

  • James, J. H., Jeppson, B., Ziparo, V., and Fischer, J. E. (1979). Hyperammonemia, plasma amino acid imbalance, and blood-brain amino acid transport: A unified theory of portal-systemic encephalopathy.Lancet 1: 772–775.

    Google Scholar 

  • Jones, E. A. (1983). The enigma of hepatic encephalopathy.Postgrad. Med. J. 59 (Suppl. 4): 42–54.

    Google Scholar 

  • Jones, E. A., Schafer, D. F., Ferenci, P., and Pappas, S. C. (1984). The neurobiology of hepatic encephalopathy.Hepatology 4: 1235–1242.

    Google Scholar 

  • Kleinberger, G., Ferenci, P., Riederer, P., and Thaler, H. (eds.) (1984).Advances in Hepatic Encephalopathy and Urea Cycle Diseases, Karger, Basel, pp. 232–309.

    Google Scholar 

  • Lal, S., Aronoff, A., Garelis, E., Sourkes, T. L., Young, S. N., and de la Vega, G. E. (1974). Cerebrospinal fluid homovanillic acid, 5-hydroxyindoleacetic acid, lactic acid and pH before and after probenecid in hepatic coma.Clin. Neurol. Neurosurg. 77: 142–154.

    Google Scholar 

  • Liehr, H., Grun, M., and Brunswig, D. (1976). Endotoxemia in acute hepatic failure.Acta HepatoGastroenterol. 23: 235–240.

    Google Scholar 

  • Lo, W. D., Ennis, S. R., Goldstein, G. W., McNeely, D. L., and Betz, A. L. (1987). The effects of galactosamine induced hepatic failure upon blood-brain barrier permeability.Hepatology 7: 452–456.

    Google Scholar 

  • Lockwood, A. H., McDonald, J. M., Reiman, R. E., Gelbard, A. S., Laughlin, J. S., Duffy, T. E., and Plum, F. (1979). The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia.J. Clin. Invest. 63: 449–460.

    Google Scholar 

  • Loscher, W. (1982). GABA in plasma, CSF and brain of dogs during acute and chronic treatment with γ-acetylenic GABA and valproic acid. In Okada, Y., and Roberts, E. (eds.),Problems in GABA Research from Brain to Bacteria, Exerpta Medica, Princeton, N.J., pp. 102–109.

    Google Scholar 

  • Maddison, J. E., Dodd, P. R., Johnston, G. A. R.,et al. (1987a). Brain GABA receptor binding is normal in rats with thioacetamide-induced hepatic encephalopathy despite elevated plasma GABA-like activity.Gastroenterology (in press).

  • Maddison, J. E., Dodd, P. R., Morrison, M., Johnston, G. A. R., and Farrell, G. C. (1987b). Plasma GABA, GABA-like activity and the brain GABA-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy.Hepatology (in press).

  • Maiolo, A. T., Porro, G. B., Galli, C., Sessa, M., and Polli, E. E. (1971). Brain energy metabolism in hepatic coma.Exp. Biol. Med. 4: 52–67.

    Google Scholar 

  • Mamunes, P., DeVries, G. H., Miller, C. D., and David, R. B. (1975). Fatty acid quantitation in Reye's syndrome. In Pollack, J. D. (ed.)Reye's Syndrome, Grune and Stratton, New York, pp. 245–253.

    Google Scholar 

  • Mattson, W. J., Jr., Iob, V., Sloan, M., Coon, W. W., Turcotte, J. G., and Child, CG, III (1970). Alterations of individual free ammonia acids in brain during acute hepatic coma.S.G.O. 130: 263–266.

    Google Scholar 

  • McLain, C. J., Zieve, L., Doizaki, W. M., Gilberstadt, S., and Onstad, G. R. (1980). Blood methanethiol in alcoholic liver disease with and without hepatic encephalopathy.Gut 21: 318–323.

    Google Scholar 

  • McLain, C. J., Kromhout, J. P., Elson, M. K., and VanThiel, D. (1981). Hyperprolactinemia in portal systemic encephalopathy.Digest Dis. Sci. 26: 353–357.

    Google Scholar 

  • McDermott, W. V., and Adams, R. D. (1954). Episodic stupor associated with an Eck fistula in the human with particular reference to the metabolism of ammonia.J. Clin. Invest. 33: 1–9.

    Google Scholar 

  • McMenamy, R. H., Vang, J. O., and Drapanas, T. (1965). Amino acid and α-keto acid concentrations in plasma and blood of the liverless dog.Am. J. Physiol. 209: 1046–1052.

    Google Scholar 

  • Moroni, F., Lombardi, G., Moneti, G., and Cortesini, C. (1983). The release and neosynthesis of glutamic acid are increased in experimental models of hepatic encephalopathy.J. Neurochem. 40: 850–854.

    Google Scholar 

  • Muting, D., and Reikowski, H. (1965). Protein metabolism in liver disease. In Popper, H., and Schaffner, F. (eds.),Progress in Liver Diseases, Vol. 2, Grune and Stratton, New York, pp. 84–94.

    Google Scholar 

  • Ohno, K., Pettigrew, K. D., and Rapoport, S. E. (1978). Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat.Am. J. Physiol. 235: H299-H307.

    Google Scholar 

  • O'Keefe, S. J. D., Abraham, R., El-Zayadi, A., Marshall, W., Davis, M., and Williams, R. (1981). Increased plasma tyrosine concentrations in patients with cirrhosis and fulminant hepatic failure associated with increased plasma tyrosine flux and reduced hepatic oxidation capacity.Gastroenterology 81: 1017–1024.

    Google Scholar 

  • Oldendorf, W. H. (1971). Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection.Am. J. Physiol. 221: 1629–1639.

    Google Scholar 

  • Ozawa, K., Kamiyama, Y., Kimura, K., Yamamoto, M., Aoyama, H., Yasuda, K., and Tobe, T. (1983). Contribution of the arterial blood ketone body ratio to elevated plasma amino acids in hepatic encephalopathy of surgical patients.Am. J. Surg. 146: 299–305.

    Google Scholar 

  • Phear, E. A., Reubner, B., Sherlock, S., and Summerskill, W. H. J. (1956). Methionine toxicity in liver disease and its prevention by chlortetracycline.Clin. Sci. 15: 93–117.

    Google Scholar 

  • Quarfoth, G., Ahmed, K., Foster, D., and Zieve, L. (1976). Action of methanethiol on membrane (Na+, K+)-ATPase of rat brain.Biochem. Pharmacol. 25: 1039–1044.

    Google Scholar 

  • Raabe, W., and Gumnit, R. J. (1975). Disinhibition in cat motor cortex by ammonia.J. Neurophysiol. 38: 347–355.

    Google Scholar 

  • Record, C. O., Buxton, B., Chase, R. A., Curzon, G., Murray-Lyon, I. M., and Williams, R. (1976). Plasma and brain amino acids in fulminant hepatic failure and their relationship to hepatic encephalopathy.Eur. J. Clin. Invest. 6: 387–394.

    Google Scholar 

  • Riddell, A. G., Kopple, P. N., and McDermott, W. V. (1954). The etiology of “meat intoxication” in the Eck fistula dog.Surgery 36: 675–684.

    Google Scholar 

  • Rossi-Fanelli, F., Freund, H., Krause, R., Smith, A. R., James, J. H., Castorina-Ziparo, S., and Fischer, J. E. (1982). Induction of coma in normal dogs by the infusion of aromatic amino acids and its prevention by the addition of branched-chain amino acids.Gastroenterology 83: 664–671.

    Google Scholar 

  • Rzepczynski, D., and Zieve, L. (1986). Inhibitory neuromodulators do not alter course of experimental hepatic encephalopathy.Gastroenterology 90: 1327.

    Google Scholar 

  • Rzepczynski, D., Zieve, L., Lindblad, S., and LaFontaine, D. (1986).In vivo studies of GABAergic effects in experimental hepatic encephalopathy.Hepatology 6: 902–905.

    Google Scholar 

  • Salerno, F., Malesci, A., Bonato, C., Rosati, R., and Panerai, A. E. (1984). Brain cholecystokinin and beta-endorphin immunoreactivity in rats with different experimental models of liver failure. In Kleinberger, G., Ferenci, P., Riederer, P., and Thaler, H. (eds.),Advances in Hepatic Encephalopathy and Urea Cycle Diseases, Karger, Basel, pp. 402–410.

    Google Scholar 

  • Samson, F. E., Jr., Dahl, N., and Dahl, D. R. (1956). A study on the narcotic action of the short chain fatty acids.J. Clin. Invest. 35: 1291–1298.

    Google Scholar 

  • Schafer, D. F., Fowler, J. M., Munson, P. J., Thakur, A. K., Waggoner, J. G., and Jones, E. A. (1983). Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure.J. Lab Clin. Med. 102: 870–880.

    Google Scholar 

  • Sherwin, R., Joshi, P., Hendler, R., Felig, P., and Conn, H. O. (1974). Hyperglucagonemia in Laennec's cirrhosis.N. Engl. J. Med. 290: 239–242.

    Google Scholar 

  • Smith, A. R., Rossi-Fanelli, F., Ziparo, V., James, J. H., Perelle, B. A., and Fischer, J. E. (1978). Alteration in plasma and CSF amino acids, amines and metabolites in hepatic coma.Ann. Surg. 187: 343–350.

    Google Scholar 

  • Smith, B., and Prockop, D. J. (1962). Central nervous system effects of ingestion of L-tryptophan by normal subjects.N. Engl. J. Med. 267: 1338–1341.

    Google Scholar 

  • Tyce, G. M., Flock, E. V., and Owen, C. A., Jr. (1967). 5-Hydroxyindole metabolism in the brain after hepatectomy.Biochem. Pharmacol. 16: 979–992.

    Google Scholar 

  • Vahlkamp, T., Meijer, A. J., Wilms, J., and Chamuleau, R. A. F. M. (1979). Inhibition of mitochondrial electron transfer in rats by ethanethiol and methanethiol.Clin. Sci. 56: 147–156.

    Google Scholar 

  • Visek, W. J. (1979). Ammonia metabolism, urea cycle capacity and their biochemical assessment.Nutr. Rev. 37: 273–282.

    Google Scholar 

  • Waller, R. L. (1977). Methanethiol inhibition of mitochondrial respiration.Toxicol. Appl. Pharmacol. 42: 111–117.

    Google Scholar 

  • Warren, K. S., and Schenker, S. (1960). Hypoxia and ammonia toxicity.Am. J. Physiol. 199: 1105–1108.

    Google Scholar 

  • Weber, G., Hird Convery, H. J., Lea, M. A., and Stamm, N. B. (1966). Feedback inhibition of key glycolytic enzymes in liver: Action of free fatty acids.Science 154: 1357–1360.

    Google Scholar 

  • Windus-Podehl, G., Lyftogt, C., Zieve, L., and Brunner, G. (1983). Encephalopathic effect of phenol in rats.J. Lab Clin. Med. 101: 586–592.

    Google Scholar 

  • Zieve, F. J., Zieve, L., Doizaki, W. M., and Gilsdorf, R. B. (1974). Synergism between ammonia and fatty acids in the production of coma: Implications for hepatic coma.J. Pharmacol. Exp. Ther. 191: 10–16.

    Google Scholar 

  • Zieve, L. (1962). Hepatic coma.Med Clin. N.A. 46: 507–519.

    Google Scholar 

  • Zieve, L. (1979). Hepatic encephalopathy: Summary of present knowledge with an elaboration on recent developments. In Popper, H., and Schaffner, F. (eds.)Progress in Liver Diseases, Vol. 6, Grune and Stratton, New York, pp. 327–341.

    Google Scholar 

  • Zieve, L. (1982). Hepatic encephalopathy. In Schiff, L., and Schiff, E. R. (eds.),Diseases of the Liver, J. B. Lippincott, Philadelphia, pp. 433–459.

    Google Scholar 

  • Zieve, L. (1984). Role of synergism in the pathogenesis of hepatic encephalopathy. In Capocaccia, L., Fischer, J. E., and Rossi-Fanelli, F. (eds.),Hepatic Encephalopathy in Chronic Liver Failure, Plenum Press, New York, pp. 15–23.

    Google Scholar 

  • Zieve, L. (1985). Encephalopathy due to short- and medium-chain fatty acids. In McCandless, D. W. (ed.),Cerebral Energy Metabolism and Metabolic Encephalopathy, Plenum Press, New York, pp. 163–177.

    Google Scholar 

  • Zieve, L., and Brunner, G. (1985). Encephalopathy due to mercaptans and phenols. In McCandless, D. W. (ed.),Cerebral Energy Metabolism and Metabolic Encephalopathy, Plenum Press, New York, pp. 179–201.

    Google Scholar 

  • Zieve, L., and Olsen, R. L. (1977). Can hepatic coma be caused by a reduction of brain noradrenaline or dopamine?Gut 18: 688–691.

    Google Scholar 

  • Zieve, L., Doizaki, W. M., and Zieve, F. J. (1974). Synergism between mercaptans and ammonia or fatty acids in the production of coma: A possible role for mercaptans in the pathogenesis of hepatic coma.J. Lab Clin. Med. 83: 16–28.

    Google Scholar 

  • Zieve, L., Nicoloff, D., and Doizaki, W. (1975). Effect of total hepatectomy on selected cerebral substrates and enzymes of the glycolytic pathway and Krebs cycle.Surgery 78: 414–423.

    Google Scholar 

  • Zieve, L., Doizaki, W. M., and Derr, R. F. (1979). Reversal of ammonia coma in rats by L-dopa: A peripheral effect.Gut 20: 28–38.

    Google Scholar 

  • Zieve, L., Onstad, G. R., Doizaki, W. M., Timmerman, W. R., and Palm, S. R. (1980). High brain concentrations of phenylalanine, tryptophan and methionine do not cause coma in rats or dogs.Gastroenterology 79: 1070.

    Google Scholar 

  • Zieve, L., Doizaki, W. M., and Lyftogt, C. (1984). Brain methanethiol and ammonia concentrations in experimental hepatic coma and coma induced by injections of various combinations of these substances.J. Lab Clin. Med. 104: 655–664.

    Google Scholar 

  • Zieve, L., Ferenci, P., Rzepczynski, D., Ebner, J., and Zimmermann, Ch. (1986). Benzodiazepine antagonist does not alter course of experimental hepatic encephalopathy or neural GABA receptor affinity or density.Hepatology 6: 1142.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zieve, L. Pathogenesis of hepatic encephalopathy. Metabolic Brain Disease 2, 147–165 (1987). https://doi.org/10.1007/BF00999607

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00999607

Keywords

Navigation