Neurochemical Research

, Volume 39, Issue 3, pp 593–598

Glutamine in the Pathogenesis of Hepatic Encephalopathy: The Trojan Horse Hypothesis Revisited

  • Kakulavarapu V. Rama Rao
  • Michael D. Norenberg


Hepatic encephalopathy (HE) is major neuropsychiatric disorder occurring in patients with severe liver disease and ammonia is generally considered to represent the major toxin responsible for this condition. Ammonia in brain is chiefly metabolized (“detoxified”) to glutamine in astrocytes due to predominant localization of glutamine synthetase in these cells. While glutamine has long been considered innocuous, a deleterious role more recently has been attributed to this amino acid. This article reviews the mechanisms by which glutamine contributes to the pathogenesis of HE, how glutamine is transported into mitochondria and subsequently hydrolyzed leading to high levels of ammonia, the latter triggering oxidative and nitrative stress, the mitochondrial permeability transition and mitochondrial injury, a sequence of events we have collectively termed as the Trojan horse hypothesis of hepatic encephalopathy.


Ammonia Astrocytes Glutamine Glutaminase Hepatic encephalopathy l-Histidine 6-Diazo-5-oxo-l-norleucine (DON) Mitochondrial permeability transition Oxidative stress 


  1. 1.
    Williams R (1973) Hepatic encephalopathy. J R Coll Physicians Lond 8:63–74PubMedGoogle Scholar
  2. 2.
    Jones EA, Weissenborn K (1997) Neurology and the liver. J Neurol Neurosurg Psychiatr 63:279–293PubMedCrossRefGoogle Scholar
  3. 3.
    Capocaccia L, Angelico M (1991) Fulminant hepatic failure. Clinical features, etiology, epidemiology, and current management. Dig Dis Sci 36:775–779PubMedCrossRefGoogle Scholar
  4. 4.
    Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N (1995) Fulminant hepatic failure: summary of a workshop. Hepatology 21:240–252PubMedGoogle Scholar
  5. 5.
    Escorsell A, Mas A, de la Mata M (2007) Acute liver failure in Spain: analysis of 267 cases. Liver Transpl 13:1389–1395PubMedCrossRefGoogle Scholar
  6. 6.
    Lee WM, Squires RH Jr, Nyberg SL, Doo E, Hoofnagle JH (2008) Acute liver failure: summary of a workshop. Hepatology 47:1401–1415PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Lee WM (1994) Acute liver failure. Am J Med 96:3S–9SPubMedCrossRefGoogle Scholar
  8. 8.
    Norenberg MD (1987) The role of astrocytes in hepatic encephalopathy. Neurochem Pathol 6:13–33PubMedCrossRefGoogle Scholar
  9. 9.
    Martinez-Hernandez A, Bell KP, Norenberg MD (1977) Glutamine synthetase: glial localization in brain. Science 195:1356–1358PubMedCrossRefGoogle Scholar
  10. 10.
    Hourani BT, Hamlin EM, Reynolds TB (1971) Cerebrospinal fluid glutamine as a measure of hepatic encephalopathy. Arch Intern Med 127:1033–1036PubMedCrossRefGoogle Scholar
  11. 11.
    Record CO, Buxton B, Chase RA, Curzon G, Murray-Lyon IM, Williams R (1976) Plasma and brain amino acids in fulminant hepatic failure and their relationship to hepatic encephalopathy. Eur J Clin Invest 6:387–394PubMedCrossRefGoogle Scholar
  12. 12.
    McConnell JR, Antonson DL, Ong CS, Chu WK, Fox IJ, Heffron TG, Langnas AN, Shaw BW Jr (1995) Proton spectroscopy of brain glutamine in acute liver failure. Hepatology 22:69–74PubMedCrossRefGoogle Scholar
  13. 13.
    Norenberg MD, Rao KV, Jayakumar AR (2005) Mechanisms of ammonia-induced astrocyte swelling. Metab Brain Dis 20:303–318PubMedCrossRefGoogle Scholar
  14. 14.
    Norenberg MD, Jayakumar AR, Rama Rao KV, Panickar KS (2007) New concepts in the mechanism of ammonia-induced astrocyte swelling. Metab Brain Dis 22:219–234PubMedCrossRefGoogle Scholar
  15. 15.
    O’Grady JG, Williams R (1986) Management of acute liver failure. Schweiz Med Wochenschr 116:541–544PubMedGoogle Scholar
  16. 16.
    Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R (2000) The systemic inflammatory response syndrome in acute liver failure. Hepatology 32:734–739PubMedCrossRefGoogle Scholar
  17. 17.
    Haussinger D, Schliess F (2005) Astrocyte swelling and protein tyrosine nitration in hepatic encephalopathy. Neurochem Int 47:64–70PubMedCrossRefGoogle Scholar
  18. 18.
    Haussinger D, Gorg B (2010) Interaction of oxidative stress, astrocyte swelling and cerebral ammonia toxicity. Curr Opin Clin Nutr Metab Care 13:87–92PubMedCrossRefGoogle Scholar
  19. 19.
    Norenberg MD, Rama Rao KV, Jayakumar AR (2009) Signaling factors in the mechanism of ammonia neurotoxicity. Metab Brain Dis 24:103–117PubMedCrossRefGoogle Scholar
  20. 20.
    Albrecht J, Norenberg MD (2006) Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 44:788–794PubMedCrossRefGoogle Scholar
  21. 21.
    Rama Rao KV, Jayakumar AR, Norenberg MD (2012) Glutamine in the pathogenesis of acute hepatic encephalopathy. Neurochem Int 61:575–580PubMedCrossRefGoogle Scholar
  22. 22.
    Pearlman DM (1957) Ammonia metabolism and hepatic coma. NY State J Med 57:3162–3166Google Scholar
  23. 23.
    Walshe JM, De Carli L, Davidson CS (1958) Some factors influencing cerebral ammonia production in relation to hepatic coma. Clin Sci (Lond) 17:27–36Google Scholar
  24. 24.
    McDermot W (1958) The role of ammonia intoxication in hepatic coma. Bull N Y Acad Med 34:357–365Google Scholar
  25. 25.
    Warren KS, Schenker S (1964) Effect of an inhibitor of glutamine synthesis (methionine sulfoximine) on ammonia toxicity and metabolism. J Lab Clin Med 64:442–449PubMedGoogle Scholar
  26. 26.
    Hawkins RA, Jessy J (1991) Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis. Biochem J 277(Pt 3):697–703PubMedGoogle Scholar
  27. 27.
    Takahashi H, Koehler RC, Hirata T, Brusilow SW, Traystman RJ (1992) Restoration of cerebrovascular CO2 responsivity by glutamine synthesis inhibition in hyperammonemic rats. Circ Res 71:1220–1230PubMedCrossRefGoogle Scholar
  28. 28.
    Takahashi H, Koehler RC, Brusilow SW, Traystman RJ (1991) Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am J Physiol 261:H825–H829PubMedGoogle Scholar
  29. 29.
    Blei AT, Olafsson S, Therrien G, Butterworth RF (1994) Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis. Hepatology 19:1437–1444PubMedCrossRefGoogle Scholar
  30. 30.
    Willard-Mack CL, Koehler RC, Hirata T, Cork LC, Takahashi H, Traystman RJ, Brusilow SW (1996) Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 71:589–599PubMedCrossRefGoogle Scholar
  31. 31.
    Norenberg MD, Bender AS (1994) Astrocyte swelling in liver failure: role of glutamine and benzodiazepines. Acta Neurochir Suppl (Wien) 60:24–27Google Scholar
  32. 32.
    Brusilow SW (2002) Hyperammonemic encephalopathy. Medicine (Baltimore) 81:240–249CrossRefGoogle Scholar
  33. 33.
    Lockwood AH, Yap EW, Rhoades HM, Wong WH (1991) Altered cerebral blood flow and glucose metabolism in patients with liver disease and minimal encephalopathy. J Cereb Blood Flow Metab 11:331–336PubMedCrossRefGoogle Scholar
  34. 34.
    Cordoba J, Crespin J, Gottstein J, Blei AT (1999) Mild hypothermia modifies ammonia-induced brain edema in rats after portacaval anastomosis. Gastroenterology 116:686–693PubMedCrossRefGoogle Scholar
  35. 35.
    Chatauret N, Zwingmann C, Rose C, Leibfritz D, Butterworth RF (2003) Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study. Gastroenterology 125:815–824PubMedCrossRefGoogle Scholar
  36. 36.
    Zwingmann C, Chatauret N, Rose C, Leibfritz D, Butterworth RF (2004) Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia. Brain Res 999:118–123PubMedCrossRefGoogle Scholar
  37. 37.
    Jayakumar AR, Rao KV, Murthy ChR, Norenberg MD (2006) Glutamine in the mechanism of ammonia-induced astrocyte swelling. Neurochem Int 48:623–628PubMedCrossRefGoogle Scholar
  38. 38.
    Desjardins P, Du T, Jiang W, Peng L, Butterworth RF (2012) Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: role of glutamine redefined. Neurochem Int 60:690–696PubMedCrossRefGoogle Scholar
  39. 39.
    Tofteng F, Hauerberg J, Hansen BA, Pedersen CB, Jorgensen L, Larsen FS (2006) Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure. J Cereb Blood Flow Metab 26:21–27PubMedCrossRefGoogle Scholar
  40. 40.
    Michalak A, Rose C, Butterworth J, Butterworth RF (1996) Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 24:908–913PubMedCrossRefGoogle Scholar
  41. 41.
    Zieminska E, Dolinska M, Lazarewicz JW, Albrecht J (2000) Induction of permeability transition and swelling of rat brain mitochondria by glutamine. Neurotoxicology 21:295–300PubMedGoogle Scholar
  42. 42.
    Rama Rao KV, Jayakumar AR, Norenberg MD (2003) Induction of the mitochondrial permeability transition in cultured astrocytes by glutamine. Neurochem Int 43:517–523PubMedCrossRefGoogle Scholar
  43. 43.
    Murthy CR, Rama Rao KV, Bai G, Norenberg MD (2001) Ammonia-induced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res 66:282–288PubMedCrossRefGoogle Scholar
  44. 44.
    Albrecht J, Zielinska M, Norenberg MD (2010) Glutamine as a mediator of ammonia neurotoxicity: a critical appraisal. Biochem Pharmacol 80:1303–1308Google Scholar
  45. 45.
    Rama Rao KV, Reddy PV, Tong X, Norenberg MD (2010) Brain edema in acute liver failure: inhibition by l-histidine. Am J Pathol 176:1400–1408Google Scholar
  46. 46.
    Ruszkiewicz J, Fresko I, Hilgier W, Albrecht J (2012) Decrease of glutathione content in the prefrontal cortical mitochondria of rats with acute hepatic encephalopathy: prevention by histidine. Metab Brain Dis (in press)Google Scholar
  47. 47.
    Brusilow SW, Koehler RC, Traystman RJ, Cooper AJ (2010) Astrocyte glutamine synthetase: importance in hyperammonemic syndromes and potential target for therapy. Neurotherapeutics 7:452–470PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Kanamori K, Ross BD (1995) In vivo activity of glutaminase in the brain of hyperammonaemic rats measured by 15 N nuclear magnetic resonance. Biochem J 305(Pt 1):329–336PubMedGoogle Scholar
  49. 49.
    Wurdig S, Kugler P (1991) Histochemistry of glutamate metabolizing enzymes in the rat cerebellar cortex. Neurosci Lett 130:165–168PubMedCrossRefGoogle Scholar
  50. 50.
    Schousboe A, Hertz L, Svenneby G, Kvamme E (1979) Phosphate activated glutaminase activity and glutamine uptake in primary cultures of astrocytes. J Neurochem 32:943–950PubMedCrossRefGoogle Scholar
  51. 51.
    Kvamme E, Svenneby G, Hertz L, Schousboe A (1982) Properties of phosphate activated glutaminase in astrocytes cultured from mouse brain. Neurochem Res 7:761–770PubMedCrossRefGoogle Scholar
  52. 52.
    Hogstad S, Svenneby G, Torgner IA, Kvamme E, Hertz L, Schousboe A (1988) Glutaminase in neurons and astrocytes cultured from mouse brain: kinetic properties and effects of phosphate, glutamate, and ammonia. Neurochem Res 13:383–388PubMedCrossRefGoogle Scholar
  53. 53.
    Kvamme E, Nissen-Meyer LS, Roberg BA, Torgner IA (2008) Novel form of phosphate activated glutaminase in cultured astrocytes and human neuroblastoma cells, PAG in brain pathology and localization in the mitochondria. Neurochem Res 33:1341–1345PubMedCrossRefGoogle Scholar
  54. 54.
    Olalla L, Gutierrez A, Jimenez AJ, Lopez-Tellez JF, Khan ZU, Perez J, Alonso FJ, de la Rosa V, Campos-Sandoval JA, Segura JA, Aledo JC, Marquez J (2008) Expression of the scaffolding PDZ protein glutaminase-interacting protein in mammalian brain. J Neurosci Res 86:281–292PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Kakulavarapu V. Rama Rao
    • 1
  • Michael D. Norenberg
    • 1
    • 2
    • 3
  1. 1.Department of PathologyUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Biochemistry and Molecular BiologyUniversity of Miami Miller School of MedicineMiamiUSA
  3. 3.Veterans Affairs Medical CenterMiamiUSA

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