Effects of branched-chain amino acids and zinc-enriched nutrients on prognosticators in HCV-infected patients: A multicenter randomized controlled trial

Kawaguchi,Takumi; Nagao,Yumiko; Abe,Kazumichi; Imazeki,Fumio; Honda,Koichi; Yamasaki,Kazumi; Miyanishi,Koji; Taniguchi,Eitaro; Kakuma,Tatsuyuki; Kato,Junji; Seike,Masataka; Yokosuka,Osamu; Ohira,Hiromasa; Sata,Michio

doi:10.3892/mmr.2014.2943

Effects of branched-chain amino acids and zinc-enriched nutrients on prognosticators in HCV-infected patients: A multicenter randomized controlled trial

Authors:
- Takumi Kawaguchi
- Yumiko Nagao
- Kazumichi Abe
- Fumio Imazeki
- Koichi Honda
- Kazumi Yamasaki
- Koji Miyanishi
- Eitaro Taniguchi
- Tatsuyuki Kakuma
- Junji Kato
- Masataka Seike
- Osamu Yokosuka
- Hiromasa Ohira
- Michio Sata
View Affiliations

Affiliations: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830‑0011, Japan, Department of Digestive Disease and Information, Kurume University School of Medicine, Kurume 830‑0011, Japan, Department of Gastroenterology and Rheumatology, Fukushima Medical University, Fukushima 960‑1295, Japan, Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan, Department of Gastroenterology, Faculty of Medicine, Oita University, Yuhu 879‑5593, Japan, Narao Medical Center, Shinkamigoto 853‑3101, Japan, Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo 060‑8543, Japan, Biostatistics Center, Kurume University, Kurume 830‑0011, Japan
Published online on: November 13, 2014 https://doi.org/10.3892/mmr.2014.2943
Pages: 2159-2166

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Branched‑chain amino acids (BCAAs) and trace element deficiencies are associated with poor prognosis in hepatitis C virus (HCV)‑infected patients. The aim of this study was to investigate the effects of BCAA and zinc‑enriched supplementation on prognostic factors in HCV‑infected patients. Fifty‑three HCV‑infected patients were enrolled in this multicenter randomized controlled trial. The patients were assigned to either the placebo (n=27) or supplement group (n=26; 6,400 mg/day BCAAs and 10 mg/day zinc) and were followed up for 60 days. Primary outcomes were prognostic factors for chronic liver disease, including the serum BCAA‑to‑tyrosine ratio (BTR), zinc levels and α‑fetoprotein (AFP) levels. There were no significant differences in any of the prognostic factors between the placebo and supplement groups at baseline. In the supplement group, the BTR and zinc levels were significantly increased compared with the placebo group (BTR: 5.14±1.59 vs. 4.23±1.14, P=0.0290; zinc: 76±11 vs. 68±11 µg/dl, P=0.0497). No significant differences were observed in AFP levels between the groups in the whole analysis. However, a stratification analysis showed a significant reduction in ΔAFP levels in the supplement group, with elevated AFP levels compared with the other groups (‑2.72±3.45 ng/ml, P=0.0079). It was demonstrated that BCAA and zinc‑enriched supplementation increased the BTR and zinc levels in the HCV‑infected patients. Furthermore, the supplementation reduced the serum AFP levels in patients who had elevated serum AFP levels at baseline. Thus, BCAA and zinc‑enriched supplementation may prolong the survival of HCV‑infected patients by improving amino acid imbalance and zinc deficiency, and by partly downregulating AFP.

View Figures

View References

1	Kawaguchi T, Izumi N, Charlton MR and Sata M: Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 54:1063–1070. 2011. View Article : Google Scholar : PubMed/NCBI
2	Kawaguchi T, Taniguchi E and Sata M: Effects of oral branched-chain amino acids on hepatic encephalopathy and outcome in patients with liver cirrhosis. Nutr Clin Pract. 28:580–588. 2013. View Article : Google Scholar : PubMed/NCBI
3	Ishikawa T, Kubota T, Horigome R, Kimura N, Honda H, Iwanaga A, et al: Branched-chain amino acids to tyrosine ratio (BTR) predicts intrahepatic distant recurrence and survival for early hepatocellular carcinoma. Hepatogastroenterology. 60:2013.PubMed/NCBI
4	Kawaguchi T, Shiraishi K, Ito T, Suzuki K, Koreeda C, Ohtake T, et al: Branched-chain amino acids prevent hepatocarcinogenesis and prolong survival of patients with cirrhosis. Clin Gastroenterol Hepatol. in press. 2014. View Article : Google Scholar
5	Auld DS, Kawaguchi H, Livingston DM and Vallee BL: RNA-dependent DNA polymerase (reverse transcriptase) from avian myeloblastosis virus: a zinc metalloenzyme. Proc Natl Acad Sci USA. 71:2091–2095. 1974. View Article : Google Scholar : PubMed/NCBI
6	Kumar R, Manning J, Spendlove HE, Kremmidiotis G, McKirdy R, Lee J, et al: ZNF652, a novel zinc finger protein, interacts with the putative breast tumor suppressor CBFA2T3 to repress transcription. Mol Cancer Res. 4:655–665. 2006. View Article : Google Scholar : PubMed/NCBI
7	Moriyama M, Matsumura H, Fukushima A, Ohkido K, Arakawa Y, Nirei K, et al: Clinical significance of evaluation of serum zinc concentrations in C-viral chronic liver disease. Dig Dis Sci. 51:1967–1977. 2006. View Article : Google Scholar : PubMed/NCBI
8	Katayama K, Sakakibara M, Imanaka K, Ohkawa K, Matsunaga T, Naito M, et al: Effect of zinc supplementation in patients with type C liver cirrhosis. O J Gas. 1:22–28. 2011.
9	Matsumura H, Nirei K, Nakamura H, Arakawa Y, Higuchi T, Hayashi J, et al: Zinc supplementation therapy improves the outcome of patients with chronic hepatitis C. J Clin Biochem Nutr. 51:178–184. 2012.PubMed/NCBI
10	Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, et al: Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol. 3:705–713. 2005. View Article : Google Scholar : PubMed/NCBI
11	Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato 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. 35:204–214. 2006.PubMed/NCBI
12	Kawaguchi T, Nagao Y, Matsuoka H, Ide T and Sata M: Branched-chain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease. Int J Mol Med. 22:105–112. 2008.PubMed/NCBI
13	Kawaguchi T, Taniguchi E, Itou M, Sumie S, Oriishi T, Matsuoka H, et al: Branched-chain amino acids improve insulin resistance in patients with hepatitis C virus-related liver disease: report of two cases. Liver Int. 27:1287–1292. 2007.PubMed/NCBI
14	Nagao Y, Kawaguchi T, Ide T and Sata M: Effect of branched-chain amino acid-enriched nutritional supplementation on interferon therapy in Japanese patients with chronic hepatitis C virus infection: a retrospective study. Virol J. 9:2822012. View Article : Google Scholar : PubMed/NCBI
15	Nagao Y, Kawaguchi T, Kakuma T, Ide T and Sata M: Post-marketing surveillance study for efficacy and safety of Aminofeel^®, a branched chain amino acids-enriched supplement including zinc. J New Rem & Clin. 60:198–215. 2011.(In Japanese).
16	Nagao Y, Matsuoka H, Kawaguchi T and Sata M: Aminofeel^® improves the sensitivity to taste in patients with HCV-infected liver disease. Med Sci Monit. 16:PI7–P12. 2010.PubMed/NCBI
17	Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, 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. 165:1499–1508. 2004. View Article : Google Scholar : PubMed/NCBI
18	Dupont WD and Plummer WD Jr: Power and sample size calculations. A review and computer program. Control Clin Trials. 11:116–128. 1990. View Article : Google Scholar : PubMed/NCBI
19	Suzuki K, Koizumi K, Ichimura H, Oka S, Takada H and Kuwayama H: Measurement of serum branched-chain amino acids to tyrosine ratio level is useful in a prediction of a change of serum albumin level in chronic liver disease. Hepatol Res. 38:267–272. 2008. View Article : Google Scholar
20	Riggio O, Merli M, Capocaccia L, Caschera M, Zullo A, Pinto G, et al: Zinc supplementation reduces blood ammonia and increases liver ornithine transcarbamylase activity in experimental cirrhosis. Hepatology. 16:785–789. 1992. View Article : Google Scholar : PubMed/NCBI
21	Chavez-Tapia NC, Cesar-Arce A, Barrientos-Gutierrez T, Villegas-Lopez FA, Mendez-Sanchez N and Uribe M: A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy. Nutr J. 12:742013. View Article : Google Scholar : PubMed/NCBI
22	Hagiwara A, Nishiyama M and 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. 227:2097–2105. 2012. View Article : Google Scholar
23	Nakao K and Ichikawa T: Recent topics on alpha-fetoprotein. Hepatol Res. 43:820–825. 2013. View Article : Google Scholar : PubMed/NCBI
24	Xie Z, Zhang H, Tsai W, Zhang Y, Du Y, Zhong J, et al: Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver. Proc Natl Acad Sci USA. 105:10859–10864. 2008. View Article : Google Scholar : PubMed/NCBI
25	Nakanishi C, Doi H, Katsura K and Satomi S: Treatment with L-valine ameliorates liver fibrosis and restores thrombopoiesis in rats exposed to carbon tetrachloride. Tohoku J Exp Med. 221:151–159. 2010. View Article : Google Scholar : PubMed/NCBI
26	Zhang Y, Guo K, LeBlanc RE, Loh D, Schwartz GJ and Yu YH: Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes. 56:1647–1654. 2007. View Article : Google Scholar : PubMed/NCBI
27	Ikehara O, Kawasaki N, Maezono K, Komatsu M and Konishi A: Acute and chronic treatment of L-isoleucine ameliorates glucose metabolism in glucose-intolerant and diabetic mice. Biol Pharm Bull. 31:469–472. 2008. View Article : Google Scholar : PubMed/NCBI
28	Ishida H, Kato T, Takehana K, Tatsumi T, Hosui A, Nawa T, et al: Valine, the branched-chain amino acid, suppresses hepatitis C virus RNA replication but promotes infectious particle formation. Biochem Biophys Res Commun. 437:127–133. 2013. View Article : Google Scholar : PubMed/NCBI
29	Kugelmas M: Preliminary observation: oral zinc sulfate replacement is effective in treating muscle cramps in cirrhotic patients. J Am Coll Nutr. 19:13–15. 2000. View Article : Google Scholar : PubMed/NCBI
30	Sako K, Imamura Y, Nishimata H, Tahara K, Kubozono O and Tsubouchi H: Branched-chain amino acids supplements in the late evening decrease the frequency of muscle cramps with advanced hepatic cirrhosis. Hepatol Res. 26:327–329. 2003. View Article : Google Scholar : PubMed/NCBI