Journal of Gastroenterology

, Volume 53, Issue 3, pp 427–437 | Cite as

Supplementation with branched-chain amino acids ameliorates hypoalbuminemia, prevents sarcopenia, and reduces fat accumulation in the skeletal muscles of patients with liver cirrhosis

  • Yoichiro Kitajima
  • Hirokazu Takahashi
  • Takumi Akiyama
  • Kenichiro Murayama
  • Shinji Iwane
  • Takuya Kuwashiro
  • Kenichi Tanaka
  • Seiji Kawazoe
  • Naofumi Ono
  • Takahisa Eguchi
  • Keizo Anzai
  • Yuichiro EguchiEmail author
Original Article—Liver, Pancreas, and Biliary Tract



Liver cirrhosis induces marked metabolic disorders, protein-energy malnutrition, and sarcopenia. The objective of the study reported here was to investigate the effects of dietary branched-chain amino acids (BCAAs) on systemic glucose metabolism, skeletal muscle, and prognosis of patients with liver cirrhosis.


Japanese patients with liver cirrhosis (n = 21) were enrolled into a longitudinal study in which their diets were supplemented with BCAAs. We evaluated glucose metabolism and analyzed the skeletal muscle area index (SAI) and intramuscular adipose tissue content (IMAC) using computed tomography.


After 48 weeks of supplementation with BCAAs, there were no changes in glucose metabolism and skeletal muscle findings. In patients with ameliorated hypoalbuminemia, IMAC was significantly decreased and SAI was preserved concomitant with decreasing 90- and 120-min post-challenge plasma glucose levels (P < 0.01 each). In patients without increased albumin levels, IMAC was significantly increased and the SAI was significantly decreased (P < 0.01 each). Liver-related event-free survival rates for 72 months were 63.6% in patients with decreased IMAC and 20.0% in patients with increased IMAC.


Amelioration of hypoalbuminemia associated with BCAA supplementation correlated with decreased fat accumulation in skeletal muscle, maintenance of skeletal muscle mass, and improved glucose sensitivity, all factors which may contribute to improving the survival of patients with liver cirrhosis.


Branched-chain amino acids Skeletal muscle steatosis Sarcopenia Liver cirrhosis 



We thank the medical staff at Eguchi Hospital and Professor Kyuichi Tanikawa (International Institute for Liver Research) for excellent advice. This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (2010) (#22590741 to Y.E.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

535_2017_1370_MOESM1_ESM.pptx (243 kb)
Supplementary material 1 (PPTX 242 kb)
535_2017_1370_MOESM2_ESM.doc (104 kb)
Supplementary material 2 (DOC 104 kb)


  1. 1.
    Gross CR, Malinchoc M, Kim WR, et al. Quality of life before and after liver transplantation for cholestatic liver disease. Hepatology. 1999;29:356–64.CrossRefPubMedGoogle Scholar
  2. 2.
    Marchesini G, Bianchi G, Merli M, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology. 2003;124:1792–801.CrossRefPubMedGoogle Scholar
  3. 3.
    Muto Y, Sato S, Watanabe A, et al. Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol. 2005;3:705–13.CrossRefPubMedGoogle Scholar
  4. 4.
    Plauth M, Merli M, Kondrup J, et al. ESPEN guidelines for nutrition in liver disease and transplantation. Clin Nutr. 1997;16:43–55.CrossRefPubMedGoogle Scholar
  5. 5.
    Greco AV, Mingrone G, Benedetti G, et al. Daily energy and substrate metabolism in patients with cirrhosis. Hepatology. 1998;27:346–50.CrossRefPubMedGoogle Scholar
  6. 6.
    Tajika M, Kato M, Mohri H, et al. Prognostic value of energy metabolism in patients with viral liver cirrhosis. Nutrition. 2002;18:229–34.CrossRefPubMedGoogle Scholar
  7. 7.
    Moriwaki H, Miwa Y, Tajika M, et al. Branched-chain amino acids as a protein- and energy-source in liver cirrhosis. Biochem Biophys Res Commun. 2004;313:405–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Hidaka H, Nakazawa T, Kutsukake S, et al. The efficacy of nocturnal administration of branched-chain amino acid granules to improve quality of life in patients with cirrhosis. J Gastroenterol. 2013;48:269–70.CrossRefPubMedGoogle Scholar
  9. 9.
    Muto Y, Sato S, Watanabe A, et al. Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol. 2005;3:705–13.CrossRefPubMedGoogle Scholar
  10. 10.
    Marchesini G, Bianchi G, Merli M, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology. 2003;124:1792–801.CrossRefPubMedGoogle Scholar
  11. 11.
    Urata Y, Okita K, Korenaga K, et al. The effect of supplementation with branched-chain amino acids in patients with liver cirrhosis. Hepatol Res. 2007;37:510–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Tabaru A, Shirohara H, Moriyama A, et al. Effects of branched-chain-enriched amino acid solution on insulin and glucagon secretion and blood glucose level in liver cirrhosis. Scand J Gastroenterol. 1998;33:853–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Kawaguchi T, Taniguchi E, Itou M, et al. Branched-chain amino acids improve insulin resistance in patients with hepatitis C virus-related liver disease: report of two cases. Liver Int. 2007;27:1287–92.PubMedGoogle Scholar
  14. 14.
    Nishitani S, Takehana K, Fujitani S, et al. Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1292–300.CrossRefPubMedGoogle Scholar
  15. 15.
    Lautz HU, Selberg O, Körber J, et al. Protein-calorie malnutrition in liver cirrhosis. Clin Investig. 1992;70(6):478–86.CrossRefPubMedGoogle Scholar
  16. 16.
    Kachaamy T, Bajaj JS, Heuman DM. Muscle and mortality in cirrhosis. Clin Gastroenterol Hepatol. 2012;10(2):100–2.CrossRefPubMedGoogle Scholar
  17. 17.
    Kitajima Y, Eguchi Y, Ishibashi E, et al. Age-related fat deposition in multifidus muscle could be a marker for nonalcoholic fatty liver disease. J Gastroenterol. 2010;45:218–24.CrossRefPubMedGoogle Scholar
  18. 18.
    Kitajima Y, Hyogo H, Sumida Y, et al. The severity of nonalcoholic steatohepatitis is associated with substitution of adipose tissue in skeletal muscle. J Gastroenterol Hepatol. 2013;28(9):1507–14.CrossRefPubMedGoogle Scholar
  19. 19.
    Plauth M, Cabré E, Campillo B, et al. ESPEN guidelines on parenteral nutrition: hepatology. Clin Nutr. 2009;28:436–44.CrossRefPubMedGoogle Scholar
  20. 20.
    Haffner SM, Kennedy E, Gonzalez C, et al. A prospective analysis of the HOMA model. The Mexico City Diabetes Study. Diabetes Care. 1996;19:1138–41.CrossRefPubMedGoogle Scholar
  21. 21.
    Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402–10.CrossRefPubMedGoogle Scholar
  22. 22.
    Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123:745–50.CrossRefPubMedGoogle Scholar
  23. 23.
    Piekarski J, Goldberg HI, Royal SA, et al. Difference between liver and spleen CT number in the normal adult: its usefulness in predicting the presence of diffuse liver disease. Radiology. 1980;137:727–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Yoshizumi T, Nakamura T, Yamane M, et al. Abdominal fat: standardized technique for measurement at CT. Radiology. 1999;211:283–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Janssen I, Baumgartner RN, Ross R, et al. Skeletal muscle cutpoints associated with elevated physical disability risk in older men and women. Am J Epidemiol. 2004;159(4):413–21.CrossRefPubMedGoogle Scholar
  26. 26.
    Mourtzakis M, Prado CM, Lieffers JR, et al. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab. 2008;33(5):997–1006.CrossRefPubMedGoogle Scholar
  27. 27.
    Ling CH, de Craen AJ, Slagboom PE, et al. Accuracy of direct segmental multi-frequency bioimpedance analysis in the assessment of total body and segmental body composition in middle-aged adult population. Clin Nutr. 2011;30(5):610–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Janssen I, Heymsfield SB, Baumgartner RN, et al. Estimation of skeletal muscle mass by bioelectrical impedance analysis. J Appl Physiol. 2000;89(2):465–71.CrossRefPubMedGoogle Scholar
  29. 29.
    Kawaguchi T, Izumi N, Charlton MR, et al. Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 2011;54:1063–70.CrossRefPubMedGoogle Scholar
  30. 30.
    Ijichi C, Matsumura T, Tsuji T, et al. Branched-chain amino acids promote albumin synthesis in rat primary hepatocytes through the mTOR signal transduction system. Biochem Biophys Res Commun. 2003;303:59–64.CrossRefPubMedGoogle Scholar
  31. 31.
    Nishitani S, Ijichi C, Takehana K, et al. Pharmacological activities of branched-chain amino acids: specificity of tissue and signal transduction. Biochem Biophys Res Commun. 2004;313:387–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Matsumura T, Morinaga Y, Fujitani S, et al. Oral administration of branched-chain amino acids activates the mTOR signal in cirrhotic rat liver. Hepatol Res. 2005;33:27–32.CrossRefPubMedGoogle Scholar
  33. 33.
    Hayashi M, Ohnishi H, Kawade Y, et al. Augmented utilization of branched-chain amino acids by skeletal muscle in decompensated liver cirrhosis in special relation to ammonia detoxication. Gastroenterol Jpn. 1981;16:64–70.PubMedGoogle Scholar
  34. 34.
    Higuchi N, Kato M, Miyazaki M, et al. Potential role of branched-chain amino acids in glucose metabolism through the accelerated induction of the glucose-sensing apparatus in the liver. J Cell Biochem. 2011;112:30–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Nishimura J, Masaki T, Arakawa M, et al. Isoleucine prevents the accumulation of tissue triglycerides and upregulates the expression of PPARalpha and uncoupling protein in diet-induced obese mice. J Nutr. 2010;140:496–500.CrossRefPubMedGoogle Scholar
  36. 36.
    Arakawa M, Masaki T, Nishimura J, et al. The effects of branched-chain amino acid granules on the accumulation of tissue triglycerides and uncoupling proteins in diet-induced obese mice. Endocr J. 2011;58:161–70.CrossRefPubMedGoogle Scholar
  37. 37.
    Nakaya Y, Okita K, Suzuki K, et al. BCAA-enriched snack improves nutritional state of cirrhosis. Nutrition. 2007;23:113–20.CrossRefPubMedGoogle Scholar
  38. 38.
    Ichikawa T, Naota T, Miyaaki H, et al. Effect of an oral branched chain amino acid-enriched snack in cirrhotic patients with sleep disturbance. Hepatol Res. 2010;40:971–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Nishitani S, Matsumura T, Fujitani S, et al. Leucine promotes glucose uptake in skeletal muscles of rats. Biochem Biophys Res Commun. 2002;299:693–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Müller MJ, Böker KH, Selberg O. Metabolism of energy-yielding substrates in patients with liver cirrhosis. Metabolism of energy-yielding substrates in patients with liver cirrhosis. Clin Investig. 1994;72(8):568–79.CrossRefPubMedGoogle Scholar
  41. 41.
    Campillo B, Bories PN, Pornin B, et al. Influence of liver failure, ascites, and energy expenditure on the response to oral nutrition in alcoholic liver cirrhosis. Nutrition. 1997;13(7–8):613–21.CrossRefPubMedGoogle Scholar
  42. 42.
    Selberg O, Böttcher J, Tusch G, et al. Identification of high- and low-risk patients before liver transplantation: a prospective cohort study of nutritional and metabolic parameters in 150 patients. Hepatology. 1997;25(3):652–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Englesbe MJ, Patel SP, He K, et al. Sarcopenia and mortality after liver transplantation. J Am Coll Surg. 2010;211:271–8.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kamachi S, Mizuta T, Otsuka T, et al. Sarcopenia is a risk factor for the recurrence of hepatocellular carcinoma after curative treatment. Hepatol Res. 2016;46(2):201–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Campillo B, Fouet P, Bonnet JC, et al. Submaximal oxygen consumption in liver cirrhosis. Evidence of severe functional aerobic impairment. J Hepatol. 1990;10(2):163–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Román E, Torrades MT, Nadal MJ, et al. Randomized pilot study: effects of an exercise programme and leucine supplementation in patients with cirrhosis. Dig Dis Sci. 2014;59(8):1966–75.CrossRefPubMedGoogle Scholar
  47. 47.
    Nishida Y, Ide Y, Okada M, et al. Effects of home-based exercise and branched-chain amino acid supplementation on aerobic capacity and glycemic control in patients with cirrhosis. Hepatol Res. 2017;47(3):E193–200.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2017

Authors and Affiliations

  • Yoichiro Kitajima
    • 1
    • 3
  • Hirokazu Takahashi
    • 1
  • Takumi Akiyama
    • 1
  • Kenichiro Murayama
    • 1
  • Shinji Iwane
    • 1
  • Takuya Kuwashiro
    • 1
  • Kenichi Tanaka
    • 1
  • Seiji Kawazoe
    • 4
  • Naofumi Ono
    • 3
  • Takahisa Eguchi
    • 3
  • Keizo Anzai
    • 1
  • Yuichiro Eguchi
    • 2
    Email author
  1. 1.Division of Metabolism and Endocrinology, Faculty of MedicineSaga UniversitySagaJapan
  2. 2.Liver CenterSaga Medical SchoolSagaJapan
  3. 3.Department of Clinical GastroenterologyEguchi HospitalOgiJapan
  4. 4.Hepatobiliary and Pancreatology Division, Department of Internal MedicineSaga Prefectural Hospital Kosei-kanSagaJapan

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