Effects of oral branched-chain amino acids on hepatic encephalopathy and outcome in patients with liver cirrhosis

Nutrition in Clinical Practice

Volumn 28, Issue 5, 2013, Pages 580-588

  Kawaguchi, Takumi ^a   Taniguchi, Eitaro ^a   Sata, Michio ^a  

^a KURUME UNIVERSITY SCHOOL OF MEDICINE   (Japan)

Author keywords

ammonia; branched chain amino acids; cognitive impairment; end stage liver disease; hepatic encephalopathy; liver diseases; nutrition therapy

Indexed keywords

ACETYL COENZYME A; ADENOSINE TRIPHOSPHATE; AMMONIA; BRANCHED CHAIN AMINO ACID; INSULIN; ISOLEUCINE; LEUCINE; LEVACECARNINE; MAMMALIAN TARGET OF RAPAMYCIN; ORNITHINE ASPARTATE; SUCCINYL COENZYME A; VALINE; ZINC;

AMMONIA BLOOD LEVEL; BLOOD BRAIN BARRIER; CITRIC ACID CYCLE; COGNITIVE DEFECT; DAILY LIFE ACTIVITY; DETOXIFICATION; DIET SUPPLEMENTATION; DRUG EFFICACY; END STAGE LIVER DISEASE; ENERGY YIELD; GLUCOSE METABOLISM; HEPATIC ENCEPHALOPATHY; HUMAN; HYPERAMMONEMIA; INTRACELLULAR SIGNALING; LIVER CIRRHOSIS; NEUROPSYCHOLOGICAL TEST; OUTCOME ASSESSMENT; PROGNOSIS; PROTEIN INTAKE; PSYCHOMOTOR ACTIVITY; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECURRENCE RISK; REVIEW; RISK FACTOR; SKELETAL MUSCLE; TRAFFIC ACCIDENT;

AMMONIA; BRANCHED CHAIN AMINO ACIDS; COGNITIVE IMPAIRMENT; END-STAGE LIVER DISEASE; HEPATIC ENCEPHALOPATHY; LIVER DISEASES; NUTRITION THERAPY;

ADMINISTRATION, ORAL; AMINO ACIDS; AMINO ACIDS, BRANCHED-CHAIN; AMMONIA; DIETARY SUPPLEMENTS; HEPATIC ENCEPHALOPATHY; HUMANS; LIVER CIRRHOSIS; MUSCLE, SKELETAL; ZINC;

EID: 84884300560     PISSN: 08845336     EISSN: 19412452     Source Type: Journal    
DOI: 10.1177/0884533613496432     Document Type: Review

References (152)

1. Kawaguchi T, Izumi N, Charlton MR, Sata M. Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 2011 ; 54 (3). 1063-1070
2. Charlton M. Branched-chain amino acid enriched supplements as therapy for liver disease. J Nutr. 2006 ; 136: 295S - 298S
3. 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 (7). 1792-1801
4. 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 (7). 705-713
5. Plauth M, Schutz T. Branched-chain amino acids in liver disease: new aspects of long known phenomena. Curr Opin Clin Nutr Metab Care. 2011 ; 14 (1). 61-66
6. Yoshizawa F. New therapeutic strategy for amino acid medicine: notable functions of branched chain amino acids as biological regulators. J Pharmacol Sci. 2012 ; 118 (2). 149-155
7. Paul HS, Adibi SA. Activation of hepatic branched chain alpha-keto acid dehydrogenase by a skeletal muscle factor. J Biol Chem. 1982 ; 257 (21). 12581-12588
8. Damuni Z, Merryfield ML, Humphreys JS, Reed LJ. Purification and properties of branched-chain alpha-keto acid dehydrogenase phosphatase from bovine kidney. Proc Natl Acad Sci U S A. 1984 ; 81 (14). 4335-4338
9. Holecek M. Three targets of branched-chain amino acid supplementation in the treatment of liver disease. Nutrition. 2010 ; 26 (5). 482-490
10. Tischler ME, Desautels M, Goldberg AL. Does leucine, leucyl-tRNA, or some metabolite of leucine regulate protein synthesis and degradation in skeletal and cardiac muscle?. J Biol Chem. 1982 ; 257 (4). 1613-1621
11. Kimball SR, Jefferson LS. Regulation of protein synthesis by branched-chain amino acids. Curr Opin Clin Nutr Metab Care. 2001 ; 4 (1). 39-43
12. Yoshizawa F. Regulation of protein synthesis by branched-chain amino acids in vivo. Biochem Biophys Res Commun. 2004 ; 313 (2). 417-422
13. Sener A, Malaisse WJ. The stimulus-secretion coupling of amino acid-induced insulin release: insulinotropic action of branched-chain amino acids at physiological concentrations of glucose and glutamine. Eur J Clin Invest. 1981 ; 11 (6). 455-460
14. Tappy L, Acheson K, Normand S, et al. Effects of infused amino acids on glucose production and utilization in healthy human subjects. Am J Physiol. 1992 ; 262 (6 Pt 1). E826 - E33
15. Nishitani S, Takehana K, Fujitani S, Sonaka I. Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol. 2005 ; 288 (6). G1292 - G1300
16. Kawaguchi T, Nagao Y, Matsuoka H, Ide T, Sata M. Branched-chain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease. Int J Mol Med. 2008 ; 22 (1). 105-112
17. Takeshita Y, Takamura T, Kita Y, et al. Beneficial effect of branched-chain amino acid supplementation on glycemic control in chronic hepatitis C patients with insulin resistance: implications for type 2 diabetes. Metabolism. 2012 ; 61 (10). 1388-1394
18. Cota D, Proulx K, Smith KA, et al. Hypothalamic mTOR signaling regulates food intake. Science. 2006 ; 312 (5775). 927-930
19. She P, Reid TM, Bronson SK, et al. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab. 2007 ; 6 (3). 181-194
20. Su Y, Lam TK, He W, et al. Hypothalamic leucine metabolism regulates liver glucose production. Diabetes. 2012 ; 61 (1). 85-93
21. Anthony JC, Yoshizawa F, Anthony TG, et al. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J Nutr. 2000 ; 130 (10). 2413-2419
22. Anthony TG, Anthony JC, Yoshizawa F, Kimball SR, Jefferson LS. Oral administration of leucine stimulates ribosomal protein mRNA translation but not global rates of protein synthesis in the liver of rats. J Nutr. 2001 ; 131 (4). 1171-1176
23. Lynch CJ, Patson BJ, Anthony J, et al. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Am J Physiol Endocrinol Metab. 2002 ; 283 (3). E503 - E513
24. Doi M, Yamaoka I, Nakayama M, et al. Isoleucine, a blood glucose-lowering amino acid, increases glucose uptake in rat skeletal muscle in the absence of increases in AMP-activated protein kinase activity. J Nutr. 2005 ; 135 (9). 2103-2108
25. Doi M, Yamaoka I, Nakayama M, Sugahara K, Yoshizawa F. Hypoglycemic effect of isoleucine involves increased muscle glucose uptake and whole body glucose oxidation and decreased hepatic gluconeogenesis. Am J Physiol Endocrinol Metab. 2007 ; 292 (6). E1683 - E1693
26. Peyrollier K, Hajduch E, Blair AS, Hyde R, Hundal HS. L-leucine availability regulates phosphatidylinositol 3-kinase, p70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin (mTOR) pathway in the L-leucine-induced up-regulation of system A amino acid transport. Biochem J. 2000 ; 350 (Pt 2). 361-368
27. Lam VW, Poon RT. Role of branched-chain amino acids in management of cirrhosis and hepatocellular carcinoma. s1The 6 Japan Society of Hepatology Single Topic Conference: Liver Failure: Recent Progress and Pathogenesis to Management ; 2008 Iwate, Japan ; 2008. S107.
28. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004 ; 165 (5). 1499-1508
29. Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007 ; 102 (3). 570-576
30. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy - definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002 ; 35 (3). 716-721
31. Dhiman RK, Saraswat VA, Sharma BK, et al. Minimal hepatic encephalopathy: consensus statement of a working party of the Indian National Association for Study of the Liver. J Gastroenterol Hepatol. 2010 ; 25 (6). 1029-1041
32. Bajaj JS, Cordoba J, Mullen KD, et al. Review article: the design of clinical trials in hepatic encephalopathy - an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther. 2011 ; 33 (7). 739-747
33. Kato A, Watanabe Y, Sawara K, Suzuki K. Diagnosis of sub-clinical hepatic encephalopathy by Neuropsychological Tests (NP-tests). Hepatol Res. 2008 ; 38: S122 - S127
34. Sawara K, Desjardins P, Chatauret N, et al. Alterations in expression of genes coding for proteins of the neurovascular unit in ischemic liver failure. Neurochem Int. 2009 ; 55 (1-3). 119-123
35. Kato A, Suzuki K, Kaneta H, et al. Regional differences in cerebral glucose metabolism in cirrhotic patients with subclinical hepatic encephalopathy using positron emission tomography. Hepatol Res. 2000 ; 17 (3). 237-245
36. Ciecko-Michalska I, Wojcik J, Wyczesany M, et al. Cognitive evoked response potentials in patients with liver cirrhosis without diagnosis of minimal or overt hepatic encephalopathy. A pilot study. J Physiol Pharmacol. 2012 ; 63 (3). 271-276
37. Seo YS, Yim SY, Jung JY, et al. The Psychometric Hepatic Encephalopathy Score for the detection of minimal hepatic encephalopathy in Korean patients with liver cirrhosis. J Gastroenterol Hepatol. 2012 ; 27 (11). 1695-1704
38. Kawaguchi T, Taniguchi E, Sata M. Motor vehicle accidents: how should cirrhotic patients be managed?. World J Gastroenterol. 2012 ; 18 (21). 2597-2599
39. Bajaj JS, Pinkerton SD, Sanyal AJ, Heuman DM. Diagnosis and treatment of minimal hepatic encephalopathy to prevent motor vehicle accidents: a cost-effectiveness analysis. Hepatology. 2012 ; 55 (4). 1164-1171
40. Taniguchi E, Kawaguchi T, Sakata M, et al. Lipid profile is associated with the incidence of cognitive dysfunction in viral cirrhotic patients: a data-mining analysis. Hepatol Res. 2013 ; 43 (4). 418-424
41. Ferenci P, Ebner J, Zimmermann C, et al. Overestimation of serum concentrations of gamma-aminobutyric acid in patients with hepatic encephalopathy by the gamma-aminobutyric acid-radioreceptor assay. Hepatology. 1988 ; 8 (1). 69-72
42. Clausen MR, Mortensen PB, Bendtsen F. Serum levels of short-chain fatty acids in cirrhosis and hepatic coma. Hepatology. 1991 ; 14 (6). 1040-1045
43. Basile AS, Jones EA. Ammonia and GABA-ergic neurotransmission: interrelated factors in the pathogenesis of hepatic encephalopathy. Hepatology. 1997 ; 25 (6). 1303-1305
44. Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997 ; 337 (7). 473-479
45. Matsuda Y, Fujita T, Hada T, Higashino K. Comparative study on the correlation of plasma gamma-aminobutyric acid and pipecolic acid with liver function in patients with liver cirrhosis. Hepatol Res. 2000 ; 18 (2). 132-140
46. Katayama K. Ammonia metabolism and hepatic encephalopathy. Hepatol Res. 2004 ; 30 (S). 73-80
47. Lighthouse J, Naito Y, Helmy A, et al. Endotoxinemia and benzodiazepine-like substances in compensated cirrhotic patients: a randomized study comparing the effect of rifaximine alone and in association with a symbiotic preparation. Hepatol Res. 2004 ; 28 (3). 155-160
48. Sato S, Tateishi K, Kato A, et al. Marked depression of brain cholecystokinin and vasoactive intestinal polypeptide levels in Eck fistula dogs. Regul Pept. 1989 ; 25 (1). 111-121
49. Tateishi K, Sato S, Kato A, et al. Reduced somatostatin-like immunoreactivity in the brain of dogs with an Eck fistula. Regul Pept. 1987 ; 18 (5-6). 277-286
50. Tateishi K, Sato S, Kato A, et al. Reduced somatostatin-28-(1-12)-like immunoreactivity in cerebral cortex of dogs with an Eck fistula and somatostatin molecular forms in brain. Regul Pept. 1988 ; 23 (3). 247-259
51. Hayashi S, Watanabe A, Shiota T, et al. Effects of intraduodenal feeding of a branched-chain amino acid-rich solution on ammonia-induced encephalopathy in liver-injured rats. Gastroenterol Jpn. 1982 ; 17 (6). 538-541
52. Suzuki K, Kato A, Iwai M. Branched-chain amino acid treatment in patients with liver cirrhosis. Hepatol Res. 2004 ; 30 (S). 25-29
53. Chadalavada R, Sappati Biyyani RS, Maxwell J, Mullen K. Nutrition in hepatic encephalopathy. Nutr Clin Pract. 2010 ; 25 (3). 257-264
54. Kato A, Suzuki K. How to select BCAA preparations. Hepatol Res. 2004 ; 30: 30-35
55. Schafer K, Winther MB, Ukida M, et al. Influence of an orally administered protein mixture enriched in branched chain amino acids on the chronic hepatic encephalopathy (CHE) of patients with liver cirrhosis. Z Gastroenterol. 1981 ; 19 (7). 356-362
56. Eriksson LS, Persson A, Wahren J. Branched-chain amino acids in the treatment of chronic hepatic encephalopathy. Gut. 1982 ; 23 (10). 801-806
57. Sieg A, Walker S, Czygan P, et al. Branched-chain amino acid-enriched elemental diet in patients with cirrhosis of the liver. A double blind crossover trial. Z Gastroenterol. 1983 ; 21 (11). 644-650
58. Ichida T, Shibasaki K, Muto Y, et al. Clinical study of an enteral branched-chain amino acid solution in decompensated liver cirrhosis with hepatic encephalopathy. Nutrition. 1995 ; 11: 238-244
59. Horst D, Grace ND, Conn HO, et al. Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial. Hepatology. 1984 ; 4 (2). 279-287
60. Marchesini G, Dioguardi FS, Bianchi GP, et al. 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. 1990 ; 11 (1). 92-101
61. Bianchi GP, Marchesini G, Zoli M, et al. Oral BCAA supplementation in cirrhosis with chronic encephalopathy: effects on prolactin and estradiol levels. Hepatogastroenterology. 1992 ; 39 (5). 443-446
62. Kato A, Tanaka H, Kawaguchi T, et al. Nutritional Management contributes to improvement in minimal hepatic encephalopathy and quality of life in patients with liver cirrhosis; a preliminary, prospective open-label study. Hepatol Res. 2013 ; 43 (5). 452-458
63. Plauth M, Egberts EH, Hamster W, et al. Long-term treatment of latent portosystemic encephalopathy with branched-chain amino acids. A double-blind placebo-controlled crossover study. J Hepatol. 1993 ; 17 (3). 308-314
64. Les I, Doval E, Garcia-Martinez R, et al. Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study. Am J Gastroenterol. 2011 ; 106 (6). 1081-1088
65. Bajaj JS, Saeian K, Schubert CM, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology. 2009 ; 50 (4). 1175-1183
66. Wilkinson DJ, Smeeton NJ, Watt PW. Ammonia metabolism, the brain and fatigue; revisiting the link. Prog Neurobiol. 2010 ; 91 (3). 200-219
67. Holecek M. Relation between glutamine, branched-chain amino acids, and protein metabolism. Nutrition. 2002 ; 18 (2). 130-133
68. Leweling H, Breitkreutz R, Behne F, et al. Hyperammonemia-induced depletion of glutamate and branched-chain amino acids in muscle and plasma. J Hepatol. 1996 ; 25 (5). 756-762
69. Johansen ML, Bak LK, Schousboe A, et al. The metabolic role of isoleucine in detoxification of ammonia in cultured mouse neurons and astrocytes. Neurochem Int. 2007 ; 50 (7-8). 1042-1051
70. Rose CF. Ammonia-lowering strategies for the treatment of hepatic encephalopathy. Clin Pharmacol Ther. 2012 ; 92 (3). 321-331
71. Skowronska M, Albrecht J. Alterations of blood brain barrier function in hyperammonemia: an overview. Neurotox Res. 2012 ; 21 (2). 236-244
72. Bianchi G, Marzocchi R, Lorusso C, Ridolfi V, Marchesini G. Nutritional treatment of chronic liver failure. s1The 6 Japan Society of Hepatology Single Topic Conference: Liver Failure: Recent Progress and Pathogenesis to Management ; 2008 Iwate, Japan ; 2008. S93.
73. Kim SJ, Kim DG, Lee MD. Effects of branched-chain amino acid infusions on liver regeneration and plasma amino acid patterns in partially hepatectomized rats. Hepatogastroenterology. 2011 ; 58 (109). 1280-1285
74. Itou M, Kawaguchi T, Taniguchi E, et al. Branched-chain amino acid supplements reduced ascites and increased the quality of life in a patient with liver cirrhosis: a case report. Mol Med Report. 2009 ; 2 (6). 977-981
75. Yamamoto M, Iwasa M, Matsumura K, et al. Improvement of regional cerebral blood flow after oral intake of branched-chain amino acids in patients with cirrhosis. World J Gastroenterol. 2005 ; 11 (43). 6792-6799
76. Iwasa M, Matsumura K, Watanabe Y, et al. Improvement of regional cerebral blood flow after treatment with branched-chain amino acid solutions in patients with cirrhosis. Eur J Gastroenterol Hepatol. 2003 ; 15 (7). 733-737
77. Rabbani P, Prasad AS. Plasma ammonia and liver ornithine transcarbamoylase activity in zinc-deficient rats. Am J Physiol. 1978 ; 235 (2). E203 - E206
78. Moriyama M, Matsumura H, Fukushima A, et al. Clinical significance of evaluation of serum zinc concentrations in C-viral chronic liver disease. Dig Dis Sci. 2006 ; 51 (11). 1967-1977
79. Nagasue N, Kolno H, Chang YC, Nakamura T. Iron, copper and zinc levels in serum and cirrhotic liver of patients with and without hepatocellular carcinoma. Oncology. 1989 ; 46 (5). 293-296
80. Riggio O, Merli M, Capocaccia L, et al. Zinc supplementation reduces blood ammonia and increases liver ornithine transcarbamylase activity in experimental cirrhosis. Hepatology. 1992 ; 16 (3). 785-789
81. Aquilio E, Spagnoli R, Riggio D, Seri S. Effects of zinc on hepatic ornithine transcarbamylase (OTC) activity. J Trace Elem Electrolytes Health Dis. 1993 ; 7 (4). 240-241
82. Hayashi M, Ikezawa K, Ono A, et al. Evaluation of the effects of combination therapy with branched-chain amino acid and zinc supplements on nitrogen metabolism in liver cirrhosis. Hepatol Res. 2007 ; 37 (8). 615-619
83. Takuma Y, Nouso K, Makino Y, Hayashi M, Takahashi H. Clinical trial: oral zinc in hepatic encephalopathy. Aliment Pharmacol Ther. 2010 ; 32 (9). 1080-1090
84. Ndraha S, Hasan I, Simadibrata M. The effect of L-ornithine L-aspartate and branch chain amino acids on encephalopathy and nutritional status in liver cirrhosis with malnutrition. Acta Med Indones. 2011 ; 43 (1). 18-22
85. Haussinger D. Nitrogen metabolism in liver: structural and functional organization and physiological relevance. Biochem J. 1990 ; 267 (2). 281-290
86. Malaguarnera M, Risino C, Cammalleri L, et al. Branched chain amino acids supplemented with L-acetylcarnitine versus BCAA treatment in hepatic coma: a randomized and controlled double blind study. Eur J Gastroenterol Hepatol. 2009 ; 21 (7). 762-770
87. 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 (1). 27-32
88. Kawaguchi T, Taniguchi E, Itou M, et al. The pathogenesis, complications and therapeutic strategy for hepatitis C virus-associated insulin resistance in the era of anti-viral treatment. Rev Recent Clin Trials. 2010 ; 5 (3). 147-157
89. Kawaguchi T, Shiraishi K, Ito T, et al. Branched-chain Amino acids prolonged survival of patients with liver cirrhosis: a nationwide study in Japan [Abstract 1619]. Hepatology. 2012 ;:
90. Yatsuhashi H, Ohnishi Y, Nakayama S, et al. Anti-hypoalbuminemic effect of branched-chain amino acid granules in patients with liver cirrhosis is independent of dietary energy and protein intake. Hepatol Res. 2011 ; 41 (11). 1027-1035
91. Takeshita S, Ichikawa T, Nakao K, et al. A snack enriched with oral branched-chain amino acids prevents a fall in albumin in patients with liver cirrhosis undergoing chemoembolization for hepatocellular carcinoma. Nutr Res. 2009 ; 29 (2). 89-93
92. Habu D, Nishiguchi S, Nakatani S, et al. Comparison of the effect of BCAA granules on between decompensated and compensated cirrhosis. Hepatogastroenterology. 2009 ; 56 (96). 1719-1723
93. Kuwahata M, Yoshimura T, Sawai Y, et al. Localization of polypyrimidine-tract-binding protein is involved in the regulation of albumin synthesis by branched-chain amino acids in HepG2 cells. J Nutr Biochem. 2008 ; 19 (7). 438-447
94. Fukushima H, Miwa Y, Shiraki M, et al. Oral branched-chain amino acid supplementation improves the oxidized/reduced albumin ratio in patients with liver cirrhosis. Hepatol Res. 2007 ; 37 (9). 765-770
95. Togo S, Tanaka K, Morioka D, et al. Usefulness of granular BCAA after hepatectomy for liver cancer complicated with liver cirrhosis. Nutrition. 2005 ; 21 (4). 480-486
96. Sato S, Watanabe A, Muto Y, et al. Clinical comparison of branched-chain amino acid (l-Leucine, l-Isoleucine, l-Valine) granules and oral nutrition for hepatic insufficiency in patients with decompensated liver cirrhosis (LIV-EN study). Hepatol Res. 2005 ; 31 (4). 232-240
97. Nishitani S, Takehana K. Pharmacological activities of branched-chain amino acids: augmentation of albumin synthesis in liver and improvement of glucose metabolism in skeletal muscle. Hepatol Res. 2004 ; 30S: 19-24
98. Nishiguchi S, Habu D. Effect of oral supplementation with branched-chain amino acid granules in the early stage of cirrhosis. Hepatol Res. 2004 ; 30S: 36-41
99. Kuwahata M, Kuramoto Y, Tomoe Y, et al. Posttranscriptional regulation of albumin gene expression by branched-chain amino acids in rats with acute liver injury. Biochim Biophys Acta. 2004 ; 1739 (1). 62-69
100. Ijichi C, Matsumura T, Tsuji T, Eto Y. Branched-chain amino acids promote albumin synthesis in rat primary hepatocytes through the mTOR signal transduction system. Biochem Biophys Res Commun. 2003 ; 303 (1). 59-64
101. Habu D, Nishiguchi S, Nakatani S, et al. Effect of oral supplementation with branched-chain amino acid granules on serum albumin level in the early stage of cirrhosis: a randomized pilot trial. Hepatol Res. 2003 ; 25 (3). 312-318
102. Fukushima H, Miwa Y, Ida E, et al. Nocturnal branched-chain amino acid administration improves protein metabolism in patients with liver cirrhosis: comparison with daytime administration. JPEN J Parenter Enteral Nutr. 2003 ; 27 (5). 315-322
103. Tayek JA, Bistrian BR, Hehir DJ, et al. Improved protein kinetics and albumin synthesis by branched chain amino acid-enriched total parenteral nutrition in cancer cachexia. A prospective randomized crossover trial. Cancer. 1986 ; 58 (1). 147-157
104. Sugiyama K, Yu L, Nagasue N. Direct effect of branched-chain amino acids on the growth and metabolism of cultured human hepatocellular carcinoma cells. Nutr Cancer. 1998 ; 31 (1). 62-68
105. Muto Y, Sato S, Watanabe A, et al. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res. 2006 ; 35 (3). 204-214
106. Kobayashi M, Ikeda K, Arase Y, et al. Inhibitory effect of branched-chain amino acid granules on progression of compensated liver cirrhosis due to hepatitis C virus. J Gastroenterol. 2008 ; 43 (1). 63-70
107. Yoshiji H, Noguchi R, Kitade M, et al. Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol. 2009 ; 44 (5). 483-491
108. Harima Y, Yamasaki T, Hamabe S, et al. Effect of a late evening snack using branched-chain amino acid-enriched nutrients in patients undergoing hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma. Hepatol Res. 2010 ; 40 (6). 574-584
109. Iwasa J, Shimizu M, Shiraki M, et al. Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Sci. 2010 ; 101 (2). 460-467
110. Kuroda H, Ushio A, Miyamoto Y, et al. Effects of branched-chain amino acid-enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: a one-year prospective trial. J Gastroenterol Hepatol. 2010 ; 25 (9). 1550-1555
111. Yoshiji H, Noguchi R, Kaji K, et al. Attenuation of insulin-resistance- based hepatocarcinogenesis and angiogenesis by combined treatment with branched-chain amino acids and angiotensin-converting enzyme inhibitor in obese diabetic rats. J Gastroenterol. 2010 ; 45 (4). 443-450
112. Hayaishi S, Chung H, Kudo M, et al. Oral branched-chain amino acid granules reduce the incidence of hepatocellular carcinoma and improve event-free survival in patients with liver cirrhosis. Dig Dis. 2011 ; 29 (3). 326-332
113. Lee IJ, Seong J, Bae JI, et al. Effect of oral supplementation with branched-chain amino acid (BCAA) during radiotherapy in patients with hepatocellular carcinoma: a double-blind randomized study. Cancer Res Treat. 2011 ; 43 (1). 24-31
114. Ninomiya S, Shimizu M, Imai K, et al. Possible role of visfatin in hepatoma progression and the effects of branched-chain amino acids on visfatin-induced proliferation in human hepatoma cells. Cancer Prev Res (Phila). 2011 ; 4 (12). 2092-2100
115. Yoshiji H, Noguchi R, Ikenaka Y, et al. Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: a randomized control trial. Oncol Rep. 2011 ; 26 (6). 1547-1553
116. Hagiwara A, Nishiyama M, Ishizaki S. Branched-chain amino acids prevent insulin-induced hepatic tumor cell proliferation by inducing apoptosis through mTORC1 and mTORC2-dependent mechanisms. J Cell Physiol. 2012 ; 227 (5). 2097-2105
117. Ichikawa K, Okabayashi T, Maeda H, et al. Oral supplementation of branched-chain amino acids reduces early recurrence after hepatic resection in patients with hepatocellular carcinoma: a prospective study. Surg Today. 2013 ; 43: 720-726
118. Morihara D, Iwata K, Hanano T, et al. Late-evening snack with branched-chain amino acids improves liver function after radiofrequency ablation for hepatocellular carcinoma. Hepatol Res. 2012 ; 42 (7). 658-667
119. Nishikawa H, Osaki Y, Inuzuka T, et al. Branched-chain amino acid treatment before transcatheter arterial chemoembolization for hepatocellular carcinoma. World J Gastroenterol. 2012 ; 18 (12). 1379-1384
120. Okamoto M, Sakaida I, Tsuchiya M, Suzuki C, Okita K. Effect of a late evening snack on the blood glucose level and energy metabolism in patients with liver cirrhosis. Hepatol Res. 2003 ; 27 (1). 45-50
121. Sakaida I, Tsuchiya M, Okamoto M, Okita K. Late evening snack and the change of blood glucose level in patients with liver cirrhosis. Hepatol Res. 2004 ; 30S: 67-72
122. Tsuchiya M, Sakaida I, Okamoto M, Okita K. The effect of a late evening snack in patients with liver cirrhosis. Hepatol Res. 2005 ; 31 (2). 95-103
123. 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 (9). 1287-1292
124. 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 (7). 510-516
125. Korenaga K, Korenaga M, Uchida K, Yamasaki T, Sakaida I. Effects of a late evening snack combined with alpha-glucosidase inhibitor on liver cirrhosis. Hepatol Res. 2008 ; 38 (11). 1087-1097
126. Kawaguchi T, Yamagishi S, Sata M. Branched-chain amino acids and pigment epithelium-derived factor: novel therapeutic agents for hepatitis c virus-associated insulin resistance. Curr Med Chem. 2009 ; 16 (36). 4843-4857
127. 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 (1). 30-38
128. Miyake T, Abe M, Furukawa S, et al. Long-term Branched-chain amino acid supplementation improves glucose tolerance in patients with nonalcoholic steatohepatitis-related cirrhosis. Intern Med. 2012 ; 51 (16). 2151-2155
129. Takegoshi K, Nanasawa H, Itoh H, et al. Effects of branched-chain amino acid-enriched nutrient mixture on natural killer cell activity in viral cirrhosis. Arzneimittelforschung. 1998 ; 48 (6). 701-706
130. Nakamura I, Ochiai K, Imawari M. Phagocytic function of neutrophils of patients with decompensated liver cirrhosis is restored by oral supplementation of branched-chain amino acids. Hepatol Res. 2004 ; 29 (4). 207-211
131. Taniguchi E, Kawaguchi T, Shimada M, et al. Branched-chain amino acid supplementation complements conventional treatment for spontaneous bacterial peritonitis. Dig Dis Sci. 2006 ; 51 (6). 1057-1060
132. Kakazu E, Kanno N, Ueno Y, Shimosegawa T. Extracellular branched-chain amino acids, especially valine, regulate maturation and function of monocyte-derived dendritic cells. J Immunol. 2007 ; 179 (10). 7137-7146
133. Nakamura I, Ochiai K, Imai Y, Moriyasu F, Imawari M. Restoration of innate host defense responses by oral supplementation of branched-chain amino acids in decompensated cirrhotic patients. Hepatol Res. 2007 ; 37 (12). 1062-1067
134. Itou M, Kawaguchi T, Taniguchi E, et al. Heating improves poor compliance with branched chain amino acid-rich supplementation in patients with liver cirrhosis: a before-after pilot study. Mol Med Report. 2009 ; 2 (6). 983-987
135. Kakazu E, Ueno Y, Kondo Y, et al. Branched chain amino acids enhance the maturation and function of myeloid dendritic cells ex vivo in patients with advanced cirrhosis. Hepatology. 2009 ; 50 (6). 1936-1945
136. Tomiya T, Omata M, Fujiwara K. Branched-chain amino acids, hepatocyte growth factor and protein production in the liver. Hepatol Res. 2004 ; 30S: 14-18
137. Tomiya T, Omata M, Fujiwara K. Significance of branched chain amino acids as possible stimulators of hepatocyte growth factor. Biochem Biophys Res Commun. 2004 ; 313 (2). 411-416
138. Okabayashi T, Nishimori I, Sugimoto T, et al. Effects of branched-chain amino acids-enriched nutrient support for patients undergoing liver resection for hepatocellular carcinoma. J Gastroenterol Hepatol. 2008 ; 23 (12). 1869-1873
139. Koreeda C, Seki T, Okazaki K, Ha-Kawa S K, Sawada S. Effects of late evening snack including branched-chain amino acid on the function of hepatic parenchymal cells in patients with liver cirrhosis. Hepatol Res. 2011 ; 41 (5). 417-422
140. Kuwahata M, Kubota H, Kanouchi H, et al. Supplementation with branched-chain amino acids attenuates hepatic apoptosis in rats with chronic liver disease. Nutr Res. 2012 ; 32 (7). 522-529
141. Miuma S, Ichikawa T, Arima K, et al. Branched-chain amino acid deficiency stabilizes insulin-induced vascular endothelial growth factor mRNA in hepatocellular carcinoma cells. J Cell Biochem. 2012 ; 113 (10). 3113-3121
142. Nakanishi C, Doi H, Katsura K, Satomi S. Treatment with L-valine ameliorates liver fibrosis and restores thrombopoiesis in rats exposed to carbon tetrachloride. Tohoku J Exp Med. 2010 ; 221 (2). 151-159
143. Yoshiji H, Noguchi R, Ikenaka Y, et al. Combination of branched-chain amino acid and angiotensin-converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis. Mol Med Report. 2012 ; 5 (2). 539-544
144. Ohno T, Tanaka Y, Sugauchi F, et al. Suppressive effect of oral administration of branched-chain amino acid granules on oxidative stress and inflammation in HCV-positive patients with liver cirrhosis. Hepatol Res. 2008 ; 38 (7). 683-688
145. Kuwahata M, Kubota H, Katsukawa M, et al. Effect of branched-chain amino acid supplementation on the oxidized/reduced state of plasma albumin in rats with chronic liver disease. J Clin Biochem Nutr. 2012 ; 50 (1). 67-71
146. Honda M, Takehana K, Sakai A, et al. Malnutrition impairs interferon signaling through mTOR and FoxO pathways in patients with chronic hepatitis C. Gastroenterology. 2011 ; 141 (1). 128-140
147. Kawaguchi T, Torimura T, Takata A, Satomi S, Sata M. Valine, a branched-chain amino acid, reduced HCV viral load and led to eradication of HCV by interferon therapy in a decompensated cirrhotic patient: a case report. Case Rep Gastroenterol. 2012 ; 6 (3). 660-667
148. Kawamura N, Nakajima H, Takashi SI. Administration of granulated BCAA and quality of life. Hepatol Res. 2004 ; 30 (S). 42-45
149. Nakaya Y, Okita K, Suzuki K, et al. BCAA-enriched snack improves nutritional state of cirrhosis. Nutrition. 2007 ; 23 (2). 113-120
150. 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 (10). 971-978
151. Okabayashi T, Iyoki M, Sugimoto T, Kobayashi M, Hanazaki K. Oral supplementation with carbohydrate- and branched-chain amino acid-enriched nutrients improves postoperative quality of life in patients undergoing hepatic resection. Amino Acids. 2011 ; 40 (4). 1213-1220
152. 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 (2). 269-276