Metabolic Brain Disease

, Volume 28, Issue 2, pp 217–220 | Cite as

Branched-chain amino acids and muscle ammonia detoxification in cirrhosis

  • Gitte Dam
  • Peter Ott
  • Niels Kristian Aagaard
  • Hendrik Vilstrup
Original Paper


Branched-chain amino acids (BCAA) are used as a therapeutic nutritional supplement in patients with cirrhosis and hepatic encephalopathy (HE). During liver disease, the decreased capacity for urea synthesis and porto-systemic shunting reduce the hepatic clearance of ammonia and skeletal muscle may become the main alternative organ for ammonia detoxification. We here summarize current knowledge of muscle BCAA and ammonia metabolism with a focus on liver cirrhosis and HE. Plasma levels of BCAA are lower and muscle uptake of BCAA seems to be higher in patients with cirrhosis and hyperammonemia. BCAA metabolism may improve muscle net ammonia removal by supplying carbon skeletons for formation of alfa-ketoglutarate that combines with two ammonia molecules to become glutamine. An oral dose of BCAA enhances muscle ammonia metabolism but also transiently increases the arterial ammonia concentration, likely due to extramuscular metabolism of glutamine. We, therefore, speculate that the beneficial effect of long term intake of BCAA on HE demonstrated in clinical studies may be related to an improved muscle mass and nutritional status rather than to an ammonia lowering effect of BCAA themselves.


BCAA Cirrhosis Muscle metabolism TCA-cycle Ammonia 


Conflict of interest

The authors declare that they have no conflicts of interest


  1. Atherton PJ, Smith K, Etheridge T, Rankin D, Rennie MJ (2010) Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells. Amino Acids 38:1533–1539. doi: 10.1007/s00726-009-0377-x PubMedCrossRefGoogle Scholar
  2. Bessman SP, Bradley JE (1955) Uptake of ammonia by muscle; its implications in ammoniagenic coma. N Engl J Med 253:1143–1147PubMedCrossRefGoogle Scholar
  3. Chatauret N, Desjardins P, Zwingmann C, Rose C, Rao KV, Butterworth RF (2006) Direct molecular and spectroscopic evidence for increased ammonia removal capacity of skeletal muscle in acute liver failure. J Hepatol 44:1083–1088PubMedCrossRefGoogle Scholar
  4. Clemmesen JO, Kondrup J, Ott P (2000) Splanchnic and leg exchange of amino acids and ammonia in acute liver failure. Gastroenterology 118:1131–1139PubMedCrossRefGoogle Scholar
  5. Dam G, Keiding S, Munk OL, Ott P, Buhl M, Vilstrup H, Bak LK, Waagepetersen HS, Schousboe A, Moller N, Sorensen M (2011) Branched-chain amino acids increase arterial ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects. Am J Physiol Gastrointest Liver Physiol 301:269–277CrossRefGoogle Scholar
  6. Ferrando AA, Williams BD, Stuart CA, Lane HW, Wolfe RR (1995) Oral branched-chain amino acids decrease whole-body proteolysis. J Parenter Enter Nutr 19:47–54CrossRefGoogle Scholar
  7. Fischer JE, Rosen HM, Ebeid AM, James JH, Keane JM, Soeters PB (1976) The effect of normalization of plasma amino acids on hepatic encephalopathy in man. Surgery 80:77–91PubMedGoogle Scholar
  8. Ganda OP, Ruderman NB (1976) Muscle nitrogen metabolism in chronic hepatic insufficiency. Metabolism 25:427–435PubMedCrossRefGoogle Scholar
  9. Hayashi M, Ohnishi H, Kawade Y, Muto Y, Takahashi Y (1981) Augmented utilization of branched-chain amino acids by skeletal muscle in decompensated liver cirrhosis in special relation to ammonia detoxication. Gastroenterol Jpn 16:64–70PubMedGoogle Scholar
  10. Holecek M (2010) Three targets of branched-chain amino acid supplementation in the treatment of liver disease. Nutrition 26:482–490PubMedCrossRefGoogle Scholar
  11. Horst D, Grace ND, Conn HO, Schiff E, Schenker S, Viteri A, Law D, Atterbury CE (1984) Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial. Hepatology 4:279–287PubMedCrossRefGoogle Scholar
  12. Iob V, Coon WW, Sloan M (1966) Altered clearance of free amino acids from plasma of patients with cirrhosis of the liver. J Surg Res 6:233–239PubMedCrossRefGoogle Scholar
  13. Leweling H, Breitkreutz R, Behne F, Staedt U, Striebel JP, Holm E (1996) Hyperammonemia-induced depletion of glutamate and branched-chain amino acids in muscle and plasma. J Hepatol 25:756–762PubMedCrossRefGoogle Scholar
  14. Marchesini G, Forlani G, Zoli M, Angiolini A, Scolari MP, Bianchi FB, Pisi E (1979) Insulin and glucagon levels in liver cirrhosis. Relationship with plasma amino acid imbalance of chronic hepatic encephalopathy. Dig Dis Sci 24:594–601PubMedCrossRefGoogle Scholar
  15. Marchesini G, Bianchi GP, Vilstrup H, Checchia GA, Patrono D, Zoli M (1987) Plasma clearances of branched-chain amino acids in control subjects and in patients with cirrhosis. J Hepatol 4:108–117PubMedCrossRefGoogle Scholar
  16. Marchesini G, Dioguardi FS, Bianchi GP, Zoli M, Bellati G, Roffi L, Martines D, Abbiati R (1990) Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. The Italian Multicenter Study Group. J Hepatol 11:92–101PubMedCrossRefGoogle Scholar
  17. Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, Rossi Fanelli F, Abbiati R, Italian BCAA Study Group (2003) Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 124:1792–1801PubMedCrossRefGoogle Scholar
  18. Morgan MY, Milsom JP, Sherlock S (1978) Plasma ratio of valine, leucine and isoleucine to phenylalanine and tyrosine in liver disease. Gut 19:1068–1073PubMedCrossRefGoogle Scholar
  19. Müting D, Wortman V (1956) Amino acid metabolism in liver diseases. Dtsch Med Wochenschr 81:1853–1856PubMedCrossRefGoogle Scholar
  20. Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H, Long-Term Survival Study Group (2005) Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 3:705–713PubMedCrossRefGoogle Scholar
  21. 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
  22. Shinnick FL, Harper AE (1976) Branched-chain amino acid oxidation by isolated rat tissue preparations. Biochim Biophys Acta 437:477–486PubMedCrossRefGoogle Scholar
  23. Tischler ME, Desautels M, Goldberg AL (1982) Does leucine, leucyl-tRNA, or some metabolite of leucine regulate protein synthesis and degradation in skeletal and cardiac muscle? J Biol Chem 257:1613–1621PubMedGoogle Scholar
  24. Tomiya T, Inoue Y, Yanase M, Arai M, Ikeda H, Tejima K, Nagashima K, Nishikawa T, Fujiwara K (2002) Leucine stimulates the secretion of hepatocyte growth factor by hepatic stellate cells. Biochem Biophys Res Commun 297:1108–1111PubMedCrossRefGoogle Scholar
  25. Windmueller HG, Spaeth AE (1974) Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem 249:5070–5079PubMedGoogle Scholar
  26. Yamato M, Muto Y, Yoshida T, Kato M (1995) Clearance rate of plasma branched-chain amino acids correlates significantly with blood ammonia level in patients with liver cirrhosis. 3:91–96Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Gitte Dam
    • 1
  • Peter Ott
    • 1
  • Niels Kristian Aagaard
    • 1
  • Hendrik Vilstrup
    • 1
  1. 1.Department of Medicine V (Hepatology and Gastroenterology)Aarhus University HospitalC AarhusDenmark

Personalised recommendations