Role of Toxins and Synergism in Hepatic Encephalopathy

  • Leslie Zieve
Part of the Experimental Biology and Medicine book series (EBAM, volume 22)


The foremost hypothesis of pathogenesis of hepatic encephalopathy recognizes that in hepatic failure, toxins with coma-inducing potential accumulate and depress neuronal function by affecting fundamental neurophysiologic processes such as postsynaptic inhibition and excitation, and fundamental metabolic processes such as mitochondrial electron transfer and microsomal Na+, K+-ATPase activity. While accumulating, the toxins interact synergistically with each other and with various augmenting endogenous metabolic abnormalities to intensify their cellular effects. Specific toxins that both accumulate with hepatic failure and induce encephalopathy and coma in experimental animals are ammonia, methanethiol, fatty acids, and phenols (Figure 1). By interacting synergistically, they have neurological effects that are out of proportion to their individual abnormalities. Of these toxins, ammonia is the most important and has the most cumulative evidence for its role as an etiologic factor. However, the relative importance of each toxin may vary with the pathologic process.


Hepatic Encephalopathy Hepatic Failure Visual Evoke Potential Fulminant Hepatic Failure Octanoic Acid 
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  1. Baraldi, M, Pinelli, G, Ricci, P, Zeneroli ML: Toxins in hepatic encephalopathy: the role of the synergistic effect of ammonia, mercaptans and short chain fatty acids. Arch. Toxicol., Suppl. 7:103–105, 1984a.Google Scholar
  2. Baraldi, M, Zeneroli, ML, Ventura, E, et al: Supersensitivity of benzodiazepine receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat: reversal by a benzodiazepine antagonist. Clinical Science 67: 167–175, 1984b.Google Scholar
  3. Challenger, F, and Walshe, JM: Methyl mercaptan in relation to foetor hepaticus. Bioch. J. 59:372–375, 1955.Google Scholar
  4. Chen, S, Zieve, L, Mahadevan V: Mercaptans and dimethyl sulfide in the breath of patients with cirrhosis of the liver. J. Lab. Clin. Med. 75:628–635, 1970.PubMedGoogle Scholar
  5. Conn, HO and Lieberthal, MM: The Hepatic Coma Syndromes and Lactulose. Williams and Wilkins Co. Baltimore. 1979.Google Scholar
  6. Hourani, BT, Hamlin EM, Reynolds, TB: Cerebrospinal fluid glutamine as a measure of hepatic encephalopathy. Arch. Int. Med. 127:1033–1036, 1971.CrossRefGoogle Scholar
  7. McClain, CJ, Zieve, L, Doizaki, WM, et al: Blood methanethiol in alcoholic liver disease with and without hepatic encephalopathy. Gut 21:318–323, 1980.PubMedCrossRefGoogle Scholar
  8. Muting, D: New aspects on the pathogenesis of hepatic encephalopathy. Liver Research 39:38–41, 1968.Google Scholar
  9. Oei, LT, Kuys, J, Lombarts, AJP, et al: Cerebrospinal fluid glutamine levels and EEG findings in patients with hepatic encephalopathy. Clin. Neurol. Neurosurg. 81:59–63, 1979.PubMedCrossRefGoogle Scholar
  10. Phear, EA, Reubner, B, Sherlock, S, et al: Methionine toxicity in liver disease and its prevention by Chlortetracycline. Clin. Sci. 15:93–117, 1956.PubMedGoogle Scholar
  11. Raabe, W and Lin, S: Pathophysiology of ammonia intoxication. Experimental Neurology 87:519–532, 1985.PubMedCrossRefGoogle Scholar
  12. 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, 1982.PubMedCrossRefGoogle Scholar
  13. Zieve, FJ, Zieve, L, Doizaki WM, Gilsdorf, RB: Synergism between ammonia and fatty acids in the production of coma: Implications for hepatic coma. J. Pharmacol. Exp. Ther. 191:10–16, 1974.PubMedGoogle Scholar
  14. Zieve, L, Doizaki, WM, Zieve, FJ: 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, 1974.PubMedGoogle Scholar
  15. Zieve, L, Doizaki, WM, Lyftogt, C: 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, 1984.PubMedGoogle Scholar
  16. Zieve, L: Encephalopathy due to short- and medium-chain fatty acids. In DW McCandless, Ed. Cerebral Energy Metabolism and Metabolic Encephalopathy. Plenum Press. New York. 1985. pp 163–177.Google Scholar
  17. Zieve, L and Brunner, G: Encephalopathy due to mercaptans and Phenols. In DW McCandless, Ed. Cerebral Energy Metabolism and Metabolic Encephalopathy. Plenum Press. New York. 1985. pp 179–201.Google Scholar
  18. Zieve, L. Hepatic encephalopathy. In L. Schiff and ER Schiff, Eds. Diseases of the Liver, 6th edition. JB Lippincott Co. Philadelphia. 1987a. pp 925–948.Google Scholar
  19. Zieve, L. Pathogenesis of hepatic encephalopathy. Metabolic Brain Disease 2:147–165, 1987b.CrossRefGoogle Scholar

Copyright information

© The Humana Press Inc. 1989

Authors and Affiliations

  • Leslie Zieve
    • 1
  1. 1.University of MinnesotaMinneapolisUSA

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