Metabolic Brain Disease

, Volume 24, Issue 1, pp 147–157 | Cite as

Gut ammonia production and its modulation

  • Manuel Romero-GómezEmail author
  • María Jover
  • J. Jorge Galán
  • A. Ruiz
Original Paper


Systemic hyperammonemia has been largely found in patients with cirrhosis and hepatic encephalopathy, and ammonia plays a major role in the pathogenesis of hepatic encephalopathy. However, controversial points remain: a) the correlation between plasma ammonia levels and neurophysiological impairment. The lack of correlation between ammonia levels and grade of hepatic encephalopathy in some cases has been considered a weakness of the ammonia hypothesis, but new methods for ammonia measurements and the implication of systemic inflammation in the modulation of ammonia neurotoxicity could explain this gap; b) the source of ammonia production. Hyperammonemia has been considered as derived from urea breakdown by intestinal bacteria and the majority of treatments were targeted against bacteria-derived ammonia from the colon. However, some data suggest an important role for small intestine ammonia production: 1) the hyperammonemia after porto-caval shunted rats has been found similar in germ-free than in non-germ-free animals. 2) In cirrhotic patients the greatest hyperammonemia was found in portal drained viscera and derived mainly from glutamine deamination. 3) The amount of time required to increase of ammonia (less than one hour) after oral glutamine challenge supports a small intestine origin of the hyperammonemia. As the main source of ammonia in cirrhotics derives from portal drained viscera owing to glutamine deamidation, increased glutaminase activity in the intestine seems to be responsible for systemic hyperammonemia. Lastly, some genetic alterations in the glutaminase gene such as the haplotype TACC could modulate intestinal ammonia production and the risk of overt hepatic encephalopathy in cirrhotics.


Hepatic encephalopathy Phosphate-activated glutaminase Oral glutamine challenge Psychometric tests Hyperammonemia 


  1. Albrecht J, Norenberg MD (2006) Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 44:788–794PubMedCrossRefGoogle Scholar
  2. Bernal W, Donaldson P, Underhill J, Wendon J, Williams R (1998) Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure. J Hepatol 29:53–59PubMedCrossRefGoogle Scholar
  3. Campos J, Gonzalez-Quintela A, Quinteiro C, Gude F, Perez LF, Torre JA, Vidal C (2005) The −159C/T polymorphism in the promoter region of the CD14 gene is associated with advanced liver disease and higher serum levels of acute-phase proteins in heavy drinkers. Alcohol Clin Exp Res 29:1206–1213PubMedCrossRefGoogle Scholar
  4. Cauli O, Rodrigo R, Piedrafita B, Boix J, Felipo V (2007) Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts. Hepatology 46:514–519PubMedCrossRefGoogle Scholar
  5. Corvera S, Garcia-Sainz JA (1983) Hormonal stimulation of mitochondrial glutaminase. Effects of vasopressin, angiotensin II, adrenaline and glucagons. Biochem J 210:957–960PubMedGoogle Scholar
  6. Curthoys NP, Watford M (1995) Regulation of glutaminase activity and glutamine metabolism. Annu Rev Nutr 15:133–59PubMedCrossRefGoogle Scholar
  7. Elgadi KM, Meguid RA, Qian M, Souba WW, Abcouwer SF (1999) Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing. Physiol Genomics 1:51–62PubMedGoogle Scholar
  8. Gabuzda GJ Jr, Phillips GB, Davidson CS (1952) Reversible toxic manifestations in patients with cirrhosis of the liver given cation-exchange resins. N Engl J Med 246:124–130PubMedCrossRefGoogle Scholar
  9. Hashimoto N, Ashida H, Kotoura Y, Nishioka A, Nishiwaki M, Utsunomiya J (1993) Analysis of hepatic encephalopathy after distal splenorenal shunt—PTP image and pancreatic hormone kinetics. Hepatogastroenterology 40:360–364PubMedGoogle Scholar
  10. Häussinger D, Laubenberger J, vom Dahl S, Ernst T, Bayer S, Langer M, Gerok W, Hennig J (1994) Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterology 107:1475–1480PubMedGoogle Scholar
  11. Hawkins RA, Jessy J, Mans AM, Chedid A, DeJoseph MR (1994) Neomycin reduces the intestinal production of ammonia from glutamine. Adv Exp Med Biol 368:125–134PubMedGoogle Scholar
  12. Jalan R, Kapoor D (2004) Reversal of diuretic-induced hepatic encephalopathy with infusion of albumin but not colloid. Clin Sci (Lond) 106:467–474CrossRefGoogle Scholar
  13. James LA, Lunn PG, Elia M (1988) Glutamine metabolism in the gastrointestinal tract of the rat assessed by the relative activity of gutaminase (EC and glutamine synthetase (EC Br J Nutrition 79:365-372CrossRefGoogle Scholar
  14. James LA, Lunn PG, Middleton S, Elia M (1998) Distribution of glutaminase and glutamine synthase activities in the human gastrointestinal tract. Clin Sci 94:313-319PubMedGoogle Scholar
  15. Jover M, Díaz D, Collantes-de-Terán L, Córpas R, Fontiveros E, Parrado J, Bautista JD, Romero-Gómez M (2005) Glutaminase activity is implicated in the pathogenesis of hyperammonemia in porto-caval shunted rats. J Hepatol 42(suppl 1):168AGoogle Scholar
  16. Lewontin RC, Kojima K (1960) The evolutionary dynamics of complex olymorphisms. Evolution 14:450–462Google Scholar
  17. Lockwood AH (2004) Blood ammonia levels and hepatic encephalopathy. Metab Brain Dis 19:345–349PubMedCrossRefGoogle Scholar
  18. Lockwood AH (2007) Controversies in ammonia metabolism: implications for hepatic encephalopathy. Metab Brain Dis 22:285–289PubMedCrossRefGoogle Scholar
  19. Malaguarnera M, Greco F, Barone G, Gargante MP, Malaguarnera M, Toscano MA (2007) Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Dig Dis Sci 52:3259–3265PubMedCrossRefGoogle Scholar
  20. Modi WS, Pollock DD, Mock BA, Banner C, Renauld JC, Van Snick J (1991) Regional localization of the human glutaminase (GLS) and interleukin-9 (IL9)genes by in situ hybridization. Cytogenet Cell Genet 57:114–116PubMedCrossRefGoogle Scholar
  21. Nance FC, Kline DG (1971) Eck’s fistula encephalopathy in germ-free dogs. Ann Surg 174:856–861PubMedCrossRefGoogle Scholar
  22. Olde Damink SW, Jalan R, Redhead DN, Hayes PC, Deutz NE, Soeters PB (2002) Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS. Hepatology 36:1163–1171PubMedCrossRefGoogle Scholar
  23. 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(3):188–193 Feb 15PubMedCrossRefGoogle Scholar
  24. Romero Gomez M, Bautista JD, Grande L, Ramos Guerrero RM, Sanchez Munoz D (2004) New concepts in the physiopathology of hepatic encephalopathy and therapeutic prospects. Gastroenterol Hepatol 27(Suppl 1):40–48PubMedGoogle Scholar
  25. Romero-Gomez M (2005) Role of phosphate-activated glutaminase in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 20:319–325PubMedCrossRefGoogle Scholar
  26. Romero-Gomez M, Grande L, Camacho I (2004a) Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy. Hepatology 39:939–943PubMedCrossRefGoogle Scholar
  27. Romero-Gomez M, Ramos-Guerrero R, Grande L, de Teran LC, Corpas R, Camacho I, Bautista JD (2004b) Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy. J Hepatol 41:49–54PubMedCrossRefGoogle Scholar
  28. Romero-Gómez M, Hoyas E, Viloria MM, Jover M, Córpas R, Collantes-de-Terán L, Camacho I, Cruz M, Bautista JD (2005) Oral glutamine challenge response is regulated by portal hypertension and systemic inflammatory response. J Hepatol 42(suppl 1):182AGoogle Scholar
  29. Shawcross DL, Davies NA, Williams R, Jalan R (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 40:247–254PubMedCrossRefGoogle Scholar
  30. Sherlock S (1987) Chronic portal-systemic encephalopathy: update 1987. Gut 28:1043–1048PubMedCrossRefGoogle Scholar
  31. Taylor L, Liu X, Newsome W, Shapiro RA, Srinivasan M, Curthoys NP (2001) Isolation and characterization of the promoter region of the rat kidney-type glutaminase gene. Biochim Biophys Acta 1518:132–136PubMedGoogle Scholar
  32. Warren KS, Newton WL (1959) Portal and peripheral blood Ammonia concentrations in germ-free and convencional guinea pigs. Am J Pysiol 197:717–720Google Scholar
  33. Weber FJL, Veach GL (1979) The importance of the small intestine in gut ammonium production in the fasting dog. Gastroenterology 77:235–240PubMedGoogle Scholar
  34. Wong D, Dorovini-Zis K, Vincent SR (2004) Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier. Exp Neurol 190:446–455PubMedCrossRefGoogle Scholar
  35. Wright G, Jalan R (2007) Ammonia and inflammation in the pathogenesis of hepatic encephalopathy: Pandora’s box? Hepatology 46:291–294PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Manuel Romero-Gómez
    • 1
    Email author
  • María Jover
    • 1
  • J. Jorge Galán
    • 2
  • A. Ruiz
    • 2
  1. 1.Unit for the Clinical Management of Digestive Diseases & ciberehdHospital Universitario de Valme, Universidad de SevillaSevillaSpain
  2. 2.Structural genomicsNeocodexS.A., SevillaSpain

Personalised recommendations