Metabolic Brain Disease

, Volume 28, Issue 2, pp 175–178 | Cite as

Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy

  • Cristina R. Bosoi
  • Christopher F. Rose
Original Paper


Although ammonia is considered the main factor involved in the pathogenesis of hepatic encephalopathy (HE), it correlates well with the severity of HE in acute liver failure, but not in chronic liver disease. Oxidative stress is another factor believed to play a role in the pathogenesis of this syndrome; it represents an imbalance between the production and neutralization of reactive oxygen species, which leads to cellular dysfunction. In the setting of liver disease, oxidative stress represents a systemic phenomenon induced by several mechanisms: decreased antioxidant synthesis, increased systemic release of oxidant enzymes, generation of reactive oxygen species, and impaired neutrophil function. High ammonia concentrations induce cerebral oxidative stress, thus contributing to severe hepatic encephalopathy, as observed in acute liver failure. In chronic liver disease, significantly lower degrees of hyperammonemia (<500 μM) do not induce cerebral nor systemic oxidative stress. Data from both animal and human studies sustain that there is a synergistic effect between systemic oxidative stress, and ammonia that is implicated in the pathogenesis of hepatic encephalopathy.


Oxidative stress Liver disease Ammonia Hepatic encephalopathy 


  1. Battelli MG, Musiani S, Valgimigli M, Gramantieri L, Tomassoni F, Bolondi L, Stirpe F (2001) Serum xanthine oxidase in human liver disease. Am J Gastroenterol 96:1194–1199PubMedCrossRefGoogle Scholar
  2. Bosoi CR, Parent-Robitaille C, Anderson K, Tremblay M, Rose CF (2011) AST-120 (spherical carbon adsorbent) lowers ammonia levels and attenuates brain edema in bile duct-ligated rats. Hepatology 53:1995–2002PubMedCrossRefGoogle Scholar
  3. Bosoi CR, Yang X, Huynh J, Parent-Robitaille C, Jiang W, Tremblay M, Rose CF (2012) Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure. Free Radic Biol Med 52:1228–1235PubMedCrossRefGoogle Scholar
  4. Chen M-F, Mo L-R, Lin R-C, Kuo J-Y, Chang K-K, Liao C, Lu F-J (1997) Increase of resting levels of superoxide anion in the whole blood of patients with decompensated liver cirrhosis. Free Radic Biol Med 23:672–679PubMedCrossRefGoogle Scholar
  5. Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648–653PubMedCrossRefGoogle Scholar
  6. Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195–1214PubMedCrossRefGoogle Scholar
  7. Görg B, Qvartskhava N, Keitel V, Bidmon HJ, Selbach O, Schliess F, Häussinger D (2008) Ammonia induces RNA oxidation in cultured astrocytes and brain in vivo. Hepatology 48:567–579PubMedCrossRefGoogle Scholar
  8. Jiang W, Desjardins P, Butterworth RF (2009) Hypothermia attenuates oxidative/nitrosative stress, encephalopathy and brain edema in acute (ischemic) liver failure. Neurochem Int 55:124–128PubMedCrossRefGoogle Scholar
  9. Kmieć Z (2001) Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol 161, III–XIII, 1–151Google Scholar
  10. Kundra A, Jain A, Banga A, Bajaj G, Kar P (2005) Evaluation of plasma ammonia levels in patients with acute liver failure and chronic liver disease and its correlation with the severity of hepatic encephalopathy and clinical features of raised intracranial tension. Clin Biochem 38:696–699PubMedCrossRefGoogle Scholar
  11. Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, Davern TJ 2nd, Murray NG, McCashland T, Reisch JS, Robuck PR (2009) Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 137:856–864, 864.e1PubMedCrossRefGoogle Scholar
  12. Mehrotra A, Trigun SK (2012) Moderate grade hyperammonemia induced concordant activation of antioxidant enzymes is associated with prevention of oxidative stress in the brain slices. Neurochem Res 37:171–181PubMedCrossRefGoogle Scholar
  13. Montoliu C, Cauli O, Urios A, ElMlili N, Serra MA, Giner-Duran R, González-Lopez O, Del Olmo JA, Wassel A, Rodrigo JM, Felipo V (2011) 3-nitro-tyrosine as a peripheral biomarker of minimal hepatic encephalopathy in patients with liver cirrhosis. Am J Gastroenterol 106:1629–1637PubMedCrossRefGoogle Scholar
  14. Mookerjee RP, Stadlbauer V, Lidder S, Wright GAK, Hodges SJ, Davies NA, Jalan R (2007) Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 46:831–840PubMedCrossRefGoogle Scholar
  15. Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van Lente F, Arroliga AC, Mullen KD (2003) Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 114:188–193PubMedCrossRefGoogle Scholar
  16. Poon HF, Calabrese V, Scapagnini G, Butterfield DA (2004) Free radicals and brain aging. Clin Geriatr Med 20:329–359PubMedCrossRefGoogle Scholar
  17. Roche M, Rondeau P, Singh NR, Tarnus E, Bourdon E (2008) The antioxidant properties of serum albumin. FEBS Lett 582:1783–1787PubMedCrossRefGoogle Scholar
  18. Shaw S, Jayatilleke E (1990) The role of aldehyde oxidase in ethanol-induced hepatic lipid peroxidation in the rat. Biochem J 268:579–583PubMedGoogle Scholar
  19. Spahr L, Bresson-Hadni S, Amann P, Kern I, Golaz O, Frossard J-L, Hadengue A (2007) Allopurinol, oxidative stress and intestinal permeability in patients with cirrhosis: an open-label pilot study. Liver Int 27:54–60PubMedCrossRefGoogle Scholar
  20. Stadtman ER, Levine RL (2000) Protein oxidation. Ann N Y Acad Sci 899:191–208PubMedCrossRefGoogle Scholar
  21. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84PubMedCrossRefGoogle Scholar
  22. Yang H, Ramani K, Xia M, Ko KS, Li TWH, Oh P, Li J, Lu SC (2009) Dysregulation of glutathione synthesis during cholestasis in mice: molecular mechanisms and therapeutic implications. Hepatology 49:1982–1991PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM)Université de MontréalMontrealCanada

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