Brain energy metabolism in acute liver failure: studies using NMR spectroscopy

  • C. Zwingmann
  • N. Chatauret
  • D. Leibfritz
  • R. F. Butterworth

Abstract

Hyperammonemia (HA) occurs in acute liver failure (ALF). When severe, ALF leads to hepatic encephalopathy (HE) (fulminant hepatic failure, FHF), which can progress to coma. Brain edema, a serious neurological complication of ALF, which may lead to increased intracranial pressure and subsequent brain herniation, remains a major cause of death in ALF.1 Evidence points to a key role for ammonia in ALF, and an ammonia-induced failure of brain energy metabolism was one of the earliest mechanisms proposed to explain the pathogenesis of HE.2 Although changes in metabolite concentrations (e.g. amino acids) have been frequently found in patients with HE and animal models of acute HE, whether or not brain energy failure occurs in ALF is still controversial, and the significance of metabolic changes in the brain in the pathogenesis of neurological complications of ALF has been repeatedly questioned. Evidence from patients with ALF, animal models of ALF, and cell culture studies suggest that ammonia directly interferes with cerebral energy metabolism in several ways, including glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain. In addition, impaired energy production caused by the metabolism of ammonia to glutamine may also contribute to brain energy failure, which may play a role in the pathogenesis of brain edema in ALF.

Keywords

Lactate Adenosine Pyruvate Glutamine NMDA 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Blei AT. Cerebral edema and intracranial hypertension in acute liver failure: distinct aspects of the same problem. Hepatology 1991; 13: 376–379.PubMedCrossRefGoogle Scholar
  2. 2.
    Bessmann SP and Bessmann AN. The cerebral and peripheral uptake of ammonia in liver disease with an hypothesis for the mechanism of hepatic coma. J Clin Invest 1955; 34: 622–628.CrossRefGoogle Scholar
  3. 3.
    Mans AM, DeJoseph MR and Hawkins RA. Metabolic abnormalities and grade of encephalopathy in acute hepatic failure. J Neurochem 1994; 63: 1829–1938.PubMedCrossRefGoogle Scholar
  4. 4.
    Huang ZH, Murakami T, Okochi A, Yumoyo R, Nagai J and Takano M. Expression and function of P-glycoprotein in rats with CCMnduced acute hepatic failure. J Pharm Pharmacol 2001; 53: 873–881.PubMedCrossRefGoogle Scholar
  5. 5.
    Friolet R, Colombo JP, Lazeyras F, Aue WP, Kretschmer R, Zimmermann A and Bachmann C. In vivo 31P NMR spectroscopy of energy rich phosphates in the brain of the hyperammonemic rat. Biochem Biophys Res Commun 1989; 159: 815–820.PubMedCrossRefGoogle Scholar
  6. 6.
    Holmin T, Agardh CD, Alinder G, Herlin P and Hultberg B. The influence of total hepatectomy on cerebral energy state, ammonia-related amino acids of the brain and plasma amino acids in the rat. Eur J Clin Invest 1983; 13:215–220.PubMedCrossRefGoogle Scholar
  7. 7.
    Deutz NEP, De Graaf AA, De Haan JG, Bovée WMMJ and Chamuleau RAFM. In vivo brain 1H-NMR spectroscopy (1-NMRS) during acute hepatic encephalopathy (HE). In: Soeters PB, Wilson JHP, Meijer AJ and Holm E (Eds). Advances in Ammonia Metabolism and Hepatic Encephalopathy. Amsterdam: Excerpta Media 1988: 439–446.Google Scholar
  8. 8.
    Bates TE, Williams SR, Kauppinen RA and Gadian DG. Observation of cerebral metabolites in an animal model of acute liver failure in vivo: a 1H and NMR study. J Neurochem 1989; 53: 102–110.PubMedCrossRefGoogle Scholar
  9. 9.
    Fitzpatrick SM, Hetherington HP, Behar KL and Shulman RG. Effects of acute hyperammonemia on cerebral amino acid metabolism and pHi in vivo, measured by 1H and 31P nuclear magnetic resonance. J Neurochem 1989; 52: 741–749.PubMedCrossRefGoogle Scholar
  10. 10.
    Martinez-Hernandez A, Bell KP and Norenberg MD. Glutamine synthetase: glial localization in brain. Science 1977; 195: 1356–1358.PubMedCrossRefGoogle Scholar
  11. 11.
    Cooper AJ, McDonald JM, Gelbard AS, Gledhill RF and Duffy TE. The metabolic fate of 13N-labeled ammonia in rat brain. J Biol Chem 1979; 254: 4982–4992.PubMedGoogle Scholar
  12. 12.
    Norenberg MD and Martinez-Hernandez A. Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 1979; 161: 303–310.PubMedCrossRefGoogle Scholar
  13. 13.
    Swain M, Butterworth RF and Blei AT. Ammonia and related amino acids in the pathogenesis of brain edema in acute ischemic liver failure in rats. Hepatology 1992; 15: 449–453.PubMedCrossRefGoogle Scholar
  14. 14.
    Michalak A, Rose C, Butterworth J and Butterworth RF. Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental ALF. Hepatology 1996; 24: 908–913.PubMedCrossRefGoogle Scholar
  15. 15.
    Peeling J, Shoemaker L, Gauthier T, Benarroch A, Sutherland GR and Minuk GY. Cerebral metabolic and histological effects of thioacetamide-induced liver failure. Am J Physiol 1993; 265: G572–578.PubMedGoogle Scholar
  16. 16.
    Record CO, Buxton B, Chase RA, Curzon G, Murray-Lyon IM and Williams R. Plasma and brain amino acids in fulminant hepatic failure and their relationship to hepatic encephalopathy. Eur J Clin Invest 1976; 6: 387–394.PubMedCrossRefGoogle Scholar
  17. 17.
    Norenberg MD and Bender AS. Astrocyte swelling in liver failure: role of glutamine and benzodiazepines. Acta Neurochir Suppl (Wien) 1994; 60: 24–27.Google Scholar
  18. 18.
    Bosman DK, Deutz NE, Maas MA, van Eijk HM, Smit JJ, de Haan JG and Chamuleau RA. Amino acid release from cerebral cortex in experimental acute liver failure, studied by in vivo cerebral cortex microdialysis. J Neurochem 1992; 59: 591–599.PubMedCrossRefGoogle Scholar
  19. 19.
    Gupta RK, Saraswat VA, Poptani H, Dhiman RK, Kohli A, Gujral RB and Naik SR. Magnetic resonance imaging and localized in vivo proton spectroscopy in patients with fulminant hepatic failure. Am J Gastroenterol 1993; 88: 670–674.PubMedGoogle Scholar
  20. 20.
    McConnell JR, Antonson DL, Ong CS, Chu WK, Fox U, Heffron TG, Langnas AN and Shaw BW Jr. Proton spectroscopy of brain glutamine in acute liver failure. Hepatology 1995; 22: 69–74.PubMedCrossRefGoogle Scholar
  21. 21.
    Olafsson S, Gottstein J and Blei AT. Brain edema and intracranial hypertension in rats after total hepatectomy. Gastroenterology 1995; 108: 1097–1103.PubMedCrossRefGoogle Scholar
  22. 22.
    Cooper AJ and Lai JC. Cerebral ammonia metabolism in normal and hyperammonemic rats. Neurochem Pathol 1987; 6:67–95.PubMedCrossRefGoogle Scholar
  23. 23.
    Diaz-Munoz M and Tapia R. Functional changes of brain mitochondria during experimental hepatic encephalopathy. Biochem Pharmacol 1989; 38: 3835–3841.PubMedCrossRefGoogle Scholar
  24. 24.
    Hindfelt B, Plum F and Duffy TE. Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts. J Clin Invest 1977; 59: 386–396.PubMedCrossRefGoogle Scholar
  25. 25.
    Felipo V, Hermenegildo C, Montoliu C, Liansola M and Minana MD. Neurotoxicity of ammonia and glutamate: molecular mechanisms and prevention. Neurotoxicology 1998; 19: 675–681.PubMedGoogle Scholar
  26. 26.
    Kosenko E, Kaminsky Y, Grau E, Minana MD, Marcaida G, Grisolia S and Felipo V. Brain ATP depletion induced by acute ammonia intoxication in rats is mediated by activation of the NMDA receptor and Na+,K(+)-ATPase. J Neurochem 1994; 63: 2172–2178.PubMedCrossRefGoogle Scholar
  27. 27.
    Tofteng F and Larsen FS. Monitoring extracellular concentrations of lactate, glutamate, and glycerol by in vivo microdialysis in the brain during liver transplantation in ALF. Liver Transpl 2002; 8: 302–305.PubMedCrossRefGoogle Scholar
  28. 28.
    Staub F, Baethmann A, Peters J, Weigt H and Kempski O. Effects of lactacidosis on glial cell volume and viability. J Cereb Blood How Metab 1990; 10: 866–876.CrossRefGoogle Scholar
  29. 29.
    Chatauret N, Rose C, Themen G and Butterworth RF. Mild hypothermia prevents cerebral edema and CSF lactate accumulation in acute liver failure. Metab Brain Dis 2001; 16: 95–102.PubMedCrossRefGoogle Scholar
  30. 30.
    Lowry OH and Passonneau JV. Kinetic evidence for multiple binding sites on phosphofructokinase. J Biol Chem 1966; 241: 2268–2279.PubMedGoogle Scholar
  31. 31.
    Gruetter R, Novotny EJ, Boulware SD, Rothman DL, Mason GF, Shulman Gl, Shulman RG and Tamborlane WV. Direct measurement of brain glucose concentrations in humans by 13C NMR spectroscopy. Proc Natl Acad Sei USA 1992; 89: 1109–1112.CrossRefGoogle Scholar
  32. 32.
    Gruetter R, Novotny EJ, Boulware SD, Mason GF, Rothman DL, Shulman GI, Prichard JW and Shulman RG. Localized 13C NMR spectroscopy in the human brain of amino acid labeling from D-[1-13C]glucose. J Neurochem 1994; 63: 1377–1385.PubMedCrossRefGoogle Scholar
  33. 33.
    Sibson NR, Dhankhar A, Mason GF, Behar KL, Rothman DL and Shulman RG. In vivo 13C NMR measurements of cerebral glutamine synthesis as evidence for glutamate-glutamine cycling. Proc Natl Acad Sei USA 1997; 94: 2699–2704.CrossRefGoogle Scholar
  34. 34.
    Cerdan S, Kunnecke B and Seelig J. Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro 13C NMR. J Biol Chem 1990; 265: 12916–12926.PubMedGoogle Scholar
  35. 35.
    Pfeuffer J, Tkac I, Choi IY, Merkle H, Ugurbil K, Garwood M and Gruetter R. Localized in vivo 1H NMR detection of neurotransmitter labeling in rat brain during infusion of [l-13C]D-glucose. Magn Reson Med 1999; 41: 1077–1083.PubMedCrossRefGoogle Scholar
  36. 36.
    Bachelard H and Badar-Goffer R. NMR spectroscopy in neurochemistry. J Neurochem 1993; 61: 412–429.PubMedCrossRefGoogle Scholar
  37. 37.
    Brand A, Gil S, Leibfritz D and Yavin E. Direct administration and utilization of [l-13C]glucose by fetal brain and liver tissues under normal and ischemic conditions: 1H, 31P, and 13C NMR studies. J Neurosci Res 1998; 54: 97–108.PubMedCrossRefGoogle Scholar
  38. 38.
    Zwingmann C, Brand A, Richter-Landsberg C and Leibfritz D. Multinuclear NMR spectroscopy studies on NHUCl-induced metabolic alterations and detoxification processes in primary astrocytes and glioma cells. Dev Neurosci 1998; 20: 417–426.PubMedCrossRefGoogle Scholar
  39. 39.
    Zwingmann C, Flogel U, Pfeuffer J and Leibfritz D. Effects of ammonia exposition on glioma cells: changes in cell volume and organic osmolytes studied by diffusion-weighted and high-resolution NMR spectroscopy. Dev Neurosci 2000; 22: 463–471.PubMedCrossRefGoogle Scholar
  40. 40.
    Shank RP, Bennett GS, Freytag SO and Campbell GL. Pyruvate carboxylase: an astrocyte-speciflc enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res 1985; 329: 364–367.PubMedCrossRefGoogle Scholar
  41. 41.
    Desjardins P, Belanger M and Butterworth RF. Alterations in expression of genes coding for key astrocytic proteins in acute liver failure. J Neurosci Res 2001; 66: 967–971.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2003

Authors and Affiliations

  • C. Zwingmann
    • 1
  • N. Chatauret
    • 1
  • D. Leibfritz
    • 2
  • R. F. Butterworth
    • 1
  1. 1.Neuroscience Research UnitCHUM Hopital Saint-LucMontrealCanada
  2. 2.Department of Organic ChemistryUniversity of BremenBremenGermany

Personalised recommendations