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Alterations of Plasma and Brain Tryptophan in Hepatic Encephalopathy: A Study in Humans and in Experimental Animals

  • F. Salerno
  • M. Dell’Oca
  • P. Incerti
  • F. Uggeri
  • E. Beretta

Summary

The role of tryptophan in the pathogenesis of hepatic encephalopathy has been investigated both in humans and in experimental animals with a model of chronic liver failure. In a group of 149 patients with liver cirrhosis, it was shown that plasma free tryptophan (the amino acid not bound to albumin) significantly rose when liver function was impaired. This increase was well correlated to the grade of hepatic encephalopathy. The ratio free tryptophan/neutral amino acids showed a comparable behavior. Additionally, free tryptophan markedly decreased in patients recovered from encephalopathy after infusion of an amino acid solution rich in branched chain amino acids. In rats with porto-caval anastomosis brain tryptophan significantly increased to a much larger extent than plasma free tryptophan did. An enhanced activity of the transport system specific for neutral amino acids through the blood brain barrier was confirmed and, at least partly, ascribed to the hyperinsulinemia present after portocaval anastomosis. Serotonin brain levels showed a relatively small increase compared to tryptophan and 5-hydroxyindolacetic acid, implying that tryptophan-hydroxylase could be proportionately inhibited in such experimental model of chronic liver disease.

Keywords

Hepatic Encephalopathy Hepatic Coma Chronic Liver Failure Unconjugated Bilirubin Tryptophan Concentration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    J. Ono, D. G. Hutson, R. S. Dombro, J. U. Levi, A. Livingstone, and R. Zeppa, Tryptophan and hepatic coma, Gastroenterology 74: 196 (1978).PubMedGoogle Scholar
  2. 2.
    A. Cascino, C. Cangiano, V. Calcaterra, F. Rossi-Fanelli, and L. Capocaccia, Plasma amino acid imbalance in patients with liver disease, Am. J. Dig. Dis. 23: 591 (1978).PubMedCrossRefGoogle Scholar
  3. 3.
    F. Salerno, F. S. Dioguardi, and R. Abbiati, Tryptophan and hepatic coma, Gastroenterology 75: 769 (1978).PubMedGoogle Scholar
  4. 4.
    W. H. Oldendorf, Brain uptake of radiolabelled amino acids, amines and hexoses after arterial injection, Am. J. Physiol. 221: 1629 (1971).PubMedGoogle Scholar
  5. 5.
    J. Perez-Cruet, T. Chase,and D. L. Murphy, Dietary regulations of brain tryptophan metabolism by plasma ratio of free tryptophan and neutral amino acids in humans, Nature (Lond.) 248: 693 (1974).CrossRefGoogle Scholar
  6. 6.
    W. H. Oldendorf and J. Szabo, Amino acid assignment to one of three blood-brain barrier amino acid carriers, Am. J. Physiol. 230: 94 (1976).PubMedGoogle Scholar
  7. 7.
    R. J. Baldessarini and J. E. Fischer, Serotonin metabolism in rat brain after surgical diversion of the portal venous circulation, Nature (New Biol.) 245: 25 (1973).CrossRefGoogle Scholar
  8. 8.
    D. W. Woolley, “The Biochemical Bases of Psychoses or the Serotonin Hypothesis about Mental Disease,” John Wiley and Sons, New York (1962).Google Scholar
  9. 9.
    B. Smith and D. J. Prockop, Central-nervous-system effects of ingestion of L-tryptophan by normal subjects, N. Eng. J. Med. 267: 1338 (1962).CrossRefGoogle Scholar
  10. 10.
    K. Ogihara, T. Mozai,and S. N. Hirai, T.yptophan as cause of hepatic coma, N. Eng. J. Med. 275: 1255 (1966).Google Scholar
  11. 11.
    C. Hirayama, Tryptophan metabolism in liver disease, Clin. Chim. Acta 32: 191 (1971).CrossRefGoogle Scholar
  12. 12.
    F. Rossi-Fanelli, H. Freund, R. Krause, A. R. Smith, J. H. James, S. Castorina-Ziparo,and J. E. Fischer, 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 (1982).PubMedGoogle Scholar
  13. 13.
    R. D. Adams and J. M. Foley, Neurological disorder associated with liver disease, Res. Publ. Assoc. Res. Nerv. Ment. Dis. 32: 198 (1958).Google Scholar
  14. 14.
    J. E. Fischer, H. M. Rosen, A. M. Ebeid, J. H. James, J. M. Keaney,and P. B. Soeters, The effect of normalization of plasma amino acids in hepatic encephalopathy in man, Surgery 78: 276 (1976).Google Scholar
  15. 15.
    W. D. Denkla and H. K. Dewey, The determination of tryptophan concentration in plasma, liver and urine, J. Lab. Clin. Med. 69: 160 (1967).Google Scholar
  16. 16.
    A. Tagliamonte, G. Biggio, L. Vargiu,and G. L. Cessa, Free tryptophan in serum controls brain tryptophan levels and serotonin synthesis, Life Sci. 12: 277 (1973).Google Scholar
  17. 17.
    E. Stefanini and G. Biggio, A simple method for determination of free tryptophan in serum, Riv. Farmacol. Ter. 6: 49 (1975).Google Scholar
  18. 18.
    S. Laurell and G. Tibbling, Colorimetric microdetermination of free fatty acids in plasma, Clin. Chim. Acta 16: 57 (1967).CrossRefGoogle Scholar
  19. 19.
    G. E.Miller and J. D. Rice Jr., Determination of the concentration of blood ammonia by use of cation exchange resin, J. Lab. Clin. Med. 60: 170 (1962).Google Scholar
  20. 20.
    J. M. Funovics, M. G. Cummings, L. Shuman, J. H. Jmes,and J. E. Fischer, An improved nonsuture method for portocaval anastomosis in the rat, Surgery 77: 661 (1975).PubMedGoogle Scholar
  21. 21.
    G. Curzon and A. R. Green, Rapid method for the determination of 5-hydroxytryptamine and 5-hydroxyindolacetic acid in small regions of rat brain, Br. J. Pharmacol. 39: 653 (1970).PubMedGoogle Scholar
  22. 22.
    G. Marchesini, M. Zoli, C. Dondi, L. Cecchini, A. Angiolini, F. B. Bianchi,and E. Pisi, Prevalence of subclinical hepatic encephalopathy in cirrhotics and relationship to plasma amino acid imbalance, Dig. Dis. Sci. 25: 763 (1980).Google Scholar
  23. 23.
    M. L. Zeneroli, C. Cremonini, F. Licari, G. Pinelli, C. Gollini, L. Pranzini,and E. Ventura, Effect of short-term fasting on plasma tryptophan in liver cirrhosis, Ital. J. Gastroenterol. 13: 186 (1981).Google Scholar
  24. 24.
    D. G. Hutson, J. Ono, R. S. Dombro, J. U. Levi, A. Livingstone, and R. Zeppa, A longitudinal study of tryptophan involvement in hepatic coma, Am. J. Surgery 137: 235 (1979).CrossRefGoogle Scholar
  25. 25.
    R. H. McMenamy and J. L. Oncley, The specific binding of tryptophan to serum albumin, J. Biol. Chem. 233: 1436 (1958).PubMedGoogle Scholar
  26. 26.
    G. Marchesini, M. Zoli, A. Angiolini, C. Dondi, F. B. Bianchi, and E. Pisi, Muscle protein breakdown in liver cirrhosis and the role of altered carbohydrate metabolism, Hepatology 1: 294 (1981).PubMedCrossRefGoogle Scholar
  27. 27.
    F. Fiaccadori, F. Ghinelli, G. Pedretti, G. Pelosi, D. Sacchini, and G. Spadini, Negative nitrogen balance in cirrhotics, La Ricerca Clin. Lab. 11: 259 (1981).Google Scholar
  28. 28.
    S. A. Adibi, A. L. Drash,and E. D. Livi, Hormone and amino acid levels in altered nutritional states, J. Lab. Clin. Med. 76: 722 (1970).PubMedGoogle Scholar
  29. 29.
    J. C. Fernando, P. J. Knott, and G. Curzon, The relevance of both plasma free tryptophan and insulin to rat brain tryptophan concentrations, J. Neurochem. 27: 343 (1976).PubMedCrossRefGoogle Scholar
  30. 30.
    J. H. James, P. M. Herlin, L. Edwards, C. A. Nachbauer,and J. E. Fischer, Effect of infusing the branched-chain amino acids on concentrations of amino acids in plasma and brain and on brain catecholamines after total hepatectomy in the rat, Life Sci. 30: 1361 (1982).PubMedCrossRefGoogle Scholar
  31. 31.
    D. L. Bloxam and G. Curzon, A study of proposed determinants of brain tryptophan concentration in rats after portocaval anastomosis or sham operation, J. Neurochem. 34: 1255 (1978).CrossRefGoogle Scholar
  32. 32.
    S. Lai, A. Aronoff, E. Garelis, T. L. Sourkes, S. Young,and C. E. de la Vega, Cerebrospinal fluid homovanillic acid, 5-hydroxyindolacetic acid, lactic acid and pH before and after probenecid in hepatic coma, Clin. Neurosurg. 22: 142 (1975).Google Scholar
  33. 33.
    L. M. Neckers, G. Biggio, E. Moja,and J. L. Meek, Modulation of brain tryptophan hydroxylase activity by brain tryptophan content, J. Pharmacol. Exp. Ther. 201: 110 (1977).Google Scholar
  34. 34.
    C. B. Lamers, J. E. Morley, P. Poitras, B. Sharp, H. E. Carlson, J. M. Hershman,and J. H. Walsh, Immunological and biological studies on cholecystokinin in rat brain, Am. J. Physiol. 239: E232 (1980).Google Scholar
  35. 35.
    J. H. James, J. Escourrou,and J. E. Fischer, Blood-brain amino acid transport activity is increased after portocaval anastomosis, Science 200: 1395 (1978).Google Scholar
  36. 36.
    J. H. James, B. Jeppsson, V. Ziparo,and J. E. Fischer, Hyperammonemia, plasma amino acid imbalance and blood-brain amino acid transport: a unified theory of portal-systemic encephalopathy, Lancet 2: 772 (1979).PubMedCrossRefGoogle Scholar
  37. 37.
    M. G. DeMontis, M. C. Olianas, B. Haber, and A. Tagliamonte, Increase in large neutral amino acid transport into brain by insulin, J. Neurochem. 30: 121 (1978).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • F. Salerno
    • 1
  • M. Dell’Oca
    • 1
  • P. Incerti
    • 1
  • F. Uggeri
    • 2
  • E. Beretta
    • 2
  1. 1.Clinica Medica IIIUniversità di MilanoMilanoItaly
  2. 2.Clinica Chirurgica VUniversità di MilanoMilanoItaly

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