Metabolic Brain Disease

, Volume 28, Issue 2, pp 201–207 | Cite as

Pathogenesis of hepatic encephalopathy: lessons from nitrogen challenges in man

Original Paper


Induction of hyperammonaemia with nitrogen challenge in man can be used to study the pathogenesis and treatment of hepatic encephalopathy complicating cirrhosis. Initially 20 g of glutamine was given orally as a flavored solution which resulted in doubling of blood ammonia concentration and this was associated with a deterioration in performance of the choice reaction time. The effect could have been due to a direct effect of glutamine rather than the ammonia generated so in subsequent experiments a glutamine free mixture of amino acids resembling the composition of haemoglobin was used (gastrointestinal bleeding is a known precipitant of hepatic encephalopathy). In Child grade B and C patients, 2–3 h after 54 g, slowing of the EEG was observed. The cerebral effects of induced hyperammonaemia were studied with diffusion weighted imaging and MR spectroscopy after giving 54 g of a mixture of threonine, serine and glycine when apparent diffusion coefficient increased. Also the change in ammonia levels correlated with the change in cerebral glutamine levels (r = 0.78, p = 0.002) suggesting intra cerebral formation of glutamine from ammonia and this may have accounted for the fall in cerebral myoinositol concentrations observed. Finally a colonic source for ammonia was confirmed by administering urea using colon coated capsules when ammonia concentrations slowly increased from 5 h after administration and rapidly after 10 h. In two patients the hyperammonaemia was ameliorated by pre treatment with Rifaximin 1200 mg per day for 1 week. Nitrogen challenge studies are thus a valuable model for studying new treatments for hepatic encephalopathy without the need to simultaneously treat precipitating factors.


Ammonia Amino acids Hepatic encephalopathy 


  1. Al Mardini H, Leonard J, Bartlett K, Lloyd S, Record CO (1988) Effect of methionine loading and endogenous hypermethioninaemia on blood mercaptans in man. Clin Chim Acta 176:83–90PubMedCrossRefGoogle Scholar
  2. Al Mardini H, Harrison EJ, Ince PG, Bartlett K, Record CO (1993) Brain indoles in human hepatic encephalopathy. Hepatology 17:1033–1040PubMedCrossRefGoogle Scholar
  3. Al Mardini H, Douglass A, Record C (2006) Amino acid challenge in patients with cirrhosis and control subjects: ammonia, plasma amino acid and EEG changes. Metab Brain Dis 21:1–10PubMedCrossRefGoogle Scholar
  4. Albrecht J, Norenberg M (2006) Glutamine: a Trojan Horse in neurotoxicity. Hepatology 44:788–794PubMedCrossRefGoogle Scholar
  5. Balata S, DaminkSW O, Ferguson K, Marshall I, Hayes PC, Deutz NE et al (2003) Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetisation transfer in cirrhosis. Hepatology 37:931–939PubMedCrossRefGoogle Scholar
  6. Basile A, Jones EA (1997) Ammonia and GABA-ergic neurotransmission: interrelated factors in the pathogenesis of hepatic encephalopathy. Hepatology 25:1303–1305PubMedCrossRefGoogle Scholar
  7. Butterworth RF (1997) Hepatic encephalopathy and brain oedema in acute hepatic failure: does glutamate play a role? Hepatology 25:1032–1034PubMedCrossRefGoogle Scholar
  8. 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 29:648–645PubMedCrossRefGoogle Scholar
  9. Cooper AJL (1990) Ammonia metabolism in normal and portacaval shunted rats. Adv ExpMed Biol 272:23–46CrossRefGoogle Scholar
  10. Cordoba S, Blei A (1997) Treatment of hepatic encephalopathy. Am J Gastroenterol 92:1429–1439PubMedGoogle Scholar
  11. Cordoba J, Alonso J, Rovira A, Jacas C, Sanpedro F, Castells L et al (2001) The development of low-grade cerebral edema in cirrhosis is supported by the evolution of 1H-magnetic resonance abnormalities after liver transplantation. J Hepatol 35:598–604PubMedCrossRefGoogle Scholar
  12. Dam G, Keiding S, Munk OL, Ott P, Vilstrup H, Bak LK et al. Hepatic Encephalopathy is Associated with Decreased Cerebral Oxygen Metabolism and Blood Flow, not Increased Ammonia Uptake. Hepatology 2012 in pressGoogle Scholar
  13. Deutz NEP, Dejong C, Soeters P (1996) Inter-organ ammonia and glutamine exchange during liver failure. In: Record CO, Al-Mardini HA (eds) Advances in hepatic encephalopathy and metabolism in liver disease. Medical Faculty, University of Newcastle Upon Tyne, UK, pp 87–99. ISBN 0947678115Google Scholar
  14. Douglass A, Al Mardini H, Record C (2001) Amino acid challenge in patients with cirrhosis: a model for the assessment of treatments for hepatic encephalopathy. J Hepatol 34:658–664PubMedCrossRefGoogle Scholar
  15. Douglass A, Al Mardini H, Oppong K, Record CO (2003) An oral tryptophan challenge in cirrhotic patients: a psychometric and analysed EEG study. Metab Brain Dis 18:179–186PubMedCrossRefGoogle Scholar
  16. Haussinger D, Schliess F (2009) Pathogenic mechanisms of hepatic encephalopathy. Gut 57:1156–1165CrossRefGoogle Scholar
  17. Hermenegildo C, Monfort P, Felipo V (2000) Activation of N-methyl-d-aspartate receptors in rat brain in vivo following acute ammonia intoxication: characterisation by in vivo brain microdialysis. Hepatology 31:709–715PubMedCrossRefGoogle Scholar
  18. Jalan R, Kapoor D (2003) Enhanced renal ammonia excretion following volume expansion in patients with well compensated cirrhosis of the liver. Gut 52:1041–1045PubMedCrossRefGoogle Scholar
  19. Jalan R, Olde Damink SWM, Lui HF, Glabus M, Deutz NEP, Hayes PC et al (2003) Oral amino acid load mimicking haemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver. Met Brain Dis 18:37–49CrossRefGoogle Scholar
  20. Keiding S, Sorensen M, Bender D, Munk O, Ott P, Vilstrup H (2006) Brain metabolism of 13N ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography. Hepatology 43:42–50PubMedCrossRefGoogle Scholar
  21. Kromhout J, McClain CJ, Zieve L, Doizaki WM, Gilberstadt S (1980) Blood mercaptan and ammonia concentrations in cirrhotics after a protein load. Am J Gastroenterol 74:507–511PubMedGoogle Scholar
  22. Lockwood AH, McDonald JM, Reiman RE, Gelbard AS, Laughlin JS, Duffy TE et al (1979) The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J Clin Invest 63:449–460PubMedCrossRefGoogle Scholar
  23. Lockwood AH, Yap EW, Wong WH (1991) Cerebral ammoniametabolism in patients with severe liver disease and minimal encephalopathy. J Cereb Blood Flow Metab 11:337–341PubMedCrossRefGoogle Scholar
  24. Mardini H, Smith FE, Record CO, Blamire A (2011) Magnetic resonance quantification of water and metabolites in the brain of cirrhotics following induced hyperammonaemia. J Hepatol 54:1154–1160PubMedCrossRefGoogle Scholar
  25. Masini A, Efrati C, Merli M, Attili A, Amodio P, Riggio O (1999) Effect of lactitol on blood ammonia in response to oral glutamine challenge in cirrhotic patients: evidence for an effect of non-absorbable disaccharides on small intestinal ammonia generation. Am J Gastroenterol 94:3323–3327PubMedCrossRefGoogle Scholar
  26. Mullen KD (2003) Pathogenesis of hepatic encephalopathy. In: Jones EA, Meijer AJ, Chamuleau R (eds) Encephalopathy and nitrogen metabolism in liver failure. Kluwer, Dordrecht, pp 177–183CrossRefGoogle Scholar
  27. Nicolao F, Efrati C, Masini A, Merli M, Attili AF, Riggio O (2003) Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy. J Hepatol 38:441–446PubMedCrossRefGoogle Scholar
  28. Olde Damink SW, Dejong CH, Deutz NE, Soeters PB (1997) Decreased plasma and tissue isoleucine levels after simulated gastrointestinal bleeding by blood gavages in chronic portacaval shunted rats. Gut 40:418–424PubMedGoogle Scholar
  29. Olde Damink SWM, Jalan R, Redhead DN, Hayes PC, Deutz NEP, Soeters PB (2002) Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS. Hepatology 36:1163–1171PubMedCrossRefGoogle Scholar
  30. Olde Damink SWM, Jalan R, Deutz NEP, Redhead DN, Dejong CHC, Hynds P et al (2003) The kidney places a major role in the hyperammonaemia seen after simulated or actual GI bleeding in patients with cirrhosis. Hepatology 37:1277–1285PubMedCrossRefGoogle Scholar
  31. Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van Lente F et al (2003) Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 114:188–193PubMedCrossRefGoogle Scholar
  32. Oppong KNW, Bartlett K, Record CO, Al Mardini H (1995) Synaptosomal glutamate transport in thioacetamide-induced hepatic encephalopathy in the rat. Hepatology 22:553–558PubMedGoogle Scholar
  33. Oppong KN, Al-Mardini H, Thick M, Record CO (1997) Oral glutamine challenge in cirrhotics pre- and post-liver transplantation: a psychometric and analysed EEG study. Hepatology 26:870–876PubMedCrossRefGoogle Scholar
  34. Plauth M, Roske AE, Romaniuk P, Roth E, Ziebig R, Lochs H (2000) Post-feeding hyperammonaemia in patients with transjugular portosystemic shunt and liver cirrhosis: role of small intestinal ammonia release and route of nutrient administration. Gut 46:849–855PubMedCrossRefGoogle Scholar
  35. Rao VL, Audet RM, Butterworth RF (1995) Selective alterations of extracellular brain amino acids in relation to function in experimental portal-systemic encephalopathy: results of an in vivo microdialysis study. J Neurochem 65:1221–1228PubMedGoogle Scholar
  36. Rees CJ, Oppong K, Al-Mardini H, Hudson M, Rose J, Record CO (2000) The effect of l-ornithine l-aspartate on patients with and without TIPS undergoing glutamine challenge: a double blind placebo controlled trial. Gut 47:571–574PubMedCrossRefGoogle Scholar
  37. Riggio O, Efrati C, Masini A, Angeloni S, Merli M (2003) Is hyperammonemia really the true cause of altered neurospsychology, brain MMR spectroscopy and magnetisation transfer after an oral amino acid load in cirrhosis? Hepatology 38:777PubMedCrossRefGoogle Scholar
  38. Riodan SM, Williams R (1997) Treatment of hepatic encephalopathy. N Eng J Med 337:473–479CrossRefGoogle Scholar
  39. Romero-Gómez M, Grande L, Camacho I, Benitez S, Irles J, Castro M (2002) Altered response to oral glutamine challenge as prognostic factor for overt episodes in patients with minimal hepatic encephalopathy. J Hepatol 37:781–787PubMedCrossRefGoogle Scholar
  40. Romero-Gomez M, Ramos-Guerrero R, Grande L, de Teran LC, Corpas R, Camacho I, Bautista JD (2004) Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy. J Hepatol 41:49–54PubMedCrossRefGoogle Scholar
  41. Rudman D, Galambos J, Smith R, Salam A, Warren W (1973) Comparison of the effect of various amino acids upon the blood ammonia concentration of patients with liver disease. Am J Clin Nutr 26:916–925PubMedGoogle Scholar
  42. Walser M, Bodenlos LJ (1959) Urea metabolism in man. J Clin Invest 38:1617–1626Google Scholar
  43. Weissenborn K, Ahl B, Fischer-Wasels D, van den Hoff J, Hecker H, Burchert W et al (2007) Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy. Gut 56:1736–1742PubMedCrossRefGoogle Scholar
  44. Wolpert E, Phillips S, Summerskill WHJ (1970) Ammonia production in the human colon. New Eng J Med 283:159–164PubMedCrossRefGoogle Scholar
  45. Wolpert E, Phillips S, Summerskill WHJ (1971) Transport of urea and ammonia production in the human colon. Lancet ii:1387–1390CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Institute of Cellular Medicine, The Medical SchoolNewcastle UniversityNewcastle u TyneUK
  2. 2.Royal Victoria InfirmaryNewcastle u TyneUK

Personalised recommendations