Background: It has been reported that branched-chain amino acid (BCAA) supplementation can improve nutritional status and prevent liver-related complications in patients with decompensated cirrhosis. We investigated the effects of oral BCAA supplementation on the incidence of hepatocellular carcinoma (HCC) and liver-related events in patients with compensated and decompensated cirrhosis. Methods: We enrolled 211 patients with cirrhosis including 152 patients with Child-Pugh A cirrhosis, but no history of HCC. Of these, 56 received oral administration of 12 g/day BCAA for ≧6 months (BCAA group), and 155 were followed-up without BCAA treatment (control group). The HCC occurrence and event-free survival rates were compared between the two groups. We used a propensity score analysis to overcome selection bias of this retrospective analysis. Results: The HCC occurrence rate was significantly lower and event-free survival rate was significantly higher in the BCAA group than in the control group. Multivariate analyses showed BCAA supplementation was significantly associated with reduced incidence of HCC (hazard ratio (HR) 0.416, 95% confidence interval (CI) 0.216–0.800, p = 0.0085). BCAA supplementation also reduced the incidence of liver-related events in patients with Child-Pugh A cirrhosis, although the difference did not reach statistical significance (HR 0.585, 95% CI 0.336–1.017, p = 0.0575). Conclusions: Oral BCAA supplementation is associated with reduced incidence of HCC in patients with cirrhosis and seems to prevent liver-related events in patients with Child-Pugh A cirrhosis.

Keywords:
Hepatocellular carcinoma, Event-free survival, Liver cirrhosis, Branched-chain amino acids
1.
Moriwaki H, Miwa Y, Tajika M, Kato M, Fukushima H, Shiraki M: Branched-chain amino acids as a protein- and energy-source in liver cirrhosis. Biochem Biophys Res Commun 2004;313:405–409.
2.
Kondrup J, Muller MJ: Energy and protein requirements of patients with chronic liver disease. J Hepatol 1997;27:239–247.
3.
Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, Rossi Fanelli F, Abbiati R: Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 2003;124:1792–1801.
4.
Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H: Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 2005;3:705–713.
5.
Charlton M: Branched-chain amino acid enriched supplements as therapy for liver disease. J Nutr 2006;136:295S–298S.
6.
Umemura T, Ichijo T, Yoshizawa K, Tanaka E, Kiyosawa K: Epidemiology of hepatocellular carcinoma in Japan. J Gastroenterol 2009;44(suppl 19):102–107.
7.
Aizawa Y, Shibamoto Y, Takagi I, Zeniya M, Toda G: Analysis of factors affecting the appearance of hepatocellular carcinoma in patients with chronic hepatitis C. A long-term follow-up study after histologic diagnosis. Cancer 2000;89:53–59.
8.
Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, Inoue O, Yano M, Tanaka M, Fujiyama S, Nishiguchi S, Kuroki T, Imazeki F, Yokosuka O, Kinoyama S, Yamada G, Omata M: Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis c in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med 1999;131:174–181.
9.
Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E, Singh H, Chow WC, Ooi LL, Chow P, Khin MW, Koo WH: Management of hepatocellular carcinoma in Asia: Consensus statement from the Asian Oncology Summit 2009. Lancet Oncol 2009;10:1111–1118.
10.
Imai Y, Kawata S, Tamura S, Yabuuchi I, Noda S, Inada M, Maeda Y, Shirai Y, Fukuzaki T, Kaji I, Ishikawa H, Matsuda Y, Nishikawa M, Seki K, Matsuzawa Y: Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Osaka hepatocellular Carcinoma Prevention Study Group. Ann Intern Med 1998;129:94–99.
11.
Ghany MG, Strader DB, Thomas DL, Seeff LB: Diagnosis, management, and treatment of hepatitis c: an update. Hepatology 2009;49:1335–1374.
12.
Lok AS, Seeff LB, Morgan TR, di Bisceglie AM, Sterling RK, Curto TM, Everson GT, Lindsay KL, Lee WM, Bonkovsky HL, Dienstag JL, Ghany MG, Morishima C, Goodman ZD: Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 2009;136:138–148.
13.
Singal AK, Singh A, Jaganmohan S, Guturu P, Mummadi R, Kuo YF, Sood GK: Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis. Clin Gastroenterol Hepatol 2010;8:192–199.
14.
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;31:62–68.
15.
Murata K, Moriyama M: Isoleucine, an essential amino acid, prevents liver metastases of colon cancer by antiangiogenesis. Cancer Res 2007;67:3263–3268.
16.
Yoshiji H, Noguchi R, Kitade M, Kaji K, Ikenaka Y, Namisaki T, Yoshii J, Yanase K, Yamazaki M, Tsujimoto T, Akahane T, Kawaratani H, Uemura M, Fukui H: Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol 2009;44:483–491.
17.
Shimizu M, Shirakami Y, Iwasa J, Shiraki M, Yasuda Y, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H: Supplementation with branched-chain amino acids inhibits azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db mice. Clin Cancer Res 2009;15:3068–3075.
18.
Iwasa J, Shimizu M, Shiraki M, Shirakami Y, Sakai H, Terakura Y, Takai K, Tsurumi H, Tanaka T, Moriwaki H: Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Sci 2010;101:460–467.
19.
Kumada H, Okanoue T, Onji M, Moriwaki H, Izumi N, Tanaka E, Chayama K, Sakisaka S, Takehara T, Oketani M, Suzuki F, Toyota J, Nomura H, Yoshioka K, Seike M, Yotsuyanagi H, Ueno Y: Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan. Hepatol Res 2010;40:8–13.
20.
Fan ST, Lo CM, Lai EC, Chu KM, Liu CL, Wong J: Perioperative nutritional support in patients undergoing hepatectomy for hepatocellular carcinoma. N Engl J Med 1994;331:1547–1552.
21.
Okabayashi T, Nishimori I, Sugimoto T, Maeda H, Dabanaka K, Onishi S, Kobayashi M, Hanazaki K: Effects of branched-chain amino acids-enriched nutrient support for patients undergoing liver resection for hepatocellular carcinoma. J Gastroenterol Hepatol 2008;23:1869–1873.
22.
Poon RT, Yu WC, Fan ST, Wong J: Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a randomized trial. Aliment Pharmacol Ther 2004;19:779–788.
23.
Holecek M: Three targets of branched-chain amino acid supplementation in the treatment of liver disease. Nutrition 2010;26:482–490.
24.
Tomiya T, Omata M, Fujiwara K: Significance of branched chain amino acids as possible stimulators of hepatocyte growth factor. Biochem Biophys Res Commun 2004;313:411–416.
25.
Calder PC: Branched-chain amino acids and immunity. J Nutr 2006;136:288S–293S.
26.
Kakazu E, Ueno Y, Kondo Y, Fukushima K, Shiina M, Inoue J, Tamai K, Ninomiya M, Shimosegawa T: Branched chain amino acids enhance the maturation and function of myeloid dendritic cells ex vivo in patients with advanced cirrhosis. Hepatology 2009;50:1936–1945.
27.
Delhaye M, Louis H, Degraef C, Le Moine O, Deviere J, Gulbis B, Jacobovitz D, Adler M, Galand P: Relationship between hepatocyte proliferative activity and liver functional reserve in human cirrhosis. Hepatology 1996;23:1003–1011.
28.
Kobayashi M, Ikeda K, Arase Y, Suzuki Y, Suzuki F, Akuta N, Hosaka T, Murashima N, Saitoh S, Someya T, Tsubota A, Kumada H: Inhibitory effect of branched-chain amino acid granules on progression of compensated liver cirrhosis due to hepatitis C virus. J Gastroenterol 2008;43:63–70.
29.
Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H, Ohashi Y: 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;35:204–214.
30.
Ohno T, Tanaka Y, Sugauchi F, Orito E, Hasegawa I, Nukaya H, Kato A, Matunaga S, Endo M, Sakakibara K, Mizokami M: 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;38:683–688.
31.
El-Serag HB, Tran T, Everhart JE: Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460–468.
32.
Siegel AB, Zhu AX: Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer 2009;115:5651–5661.
33.
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;22:105–112.
34.
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:G1292–G1300.
35.
Hinault C, Mothe-Satney I, Gautier N, Lawrence JC Jr, Van Obberghen E: Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from db/db mice. FASEB J 2004;18:1894–1896.
36.
Higuchi N, Kato M, Miyazaki M, Tanaka M, Kohjima M, Ito T, Nakamuta M, Enjoji M, Kotoh K, Takayanagi R: 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;112:30–38.
37.
Sheikh MY, Choi J, Qadri I, Friedman JE, Sanyal AJ: Hepatitis C virus infection: molecular pathways to metabolic syndrome. Hepatology 2008;47:2127–2133.
38.
Nair S, Mason A, Eason J, Loss G, Perrillo RP: Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 2002;36:150–155.
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