Retrospective Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 21, 2015; 21(11): 3291-3299
Published online Mar 21, 2015. doi: 10.3748/wjg.v21.i11.3291
Hepcidin/ferroportin expression levels involve efficacy of pegylated-interferon plus ribavirin in hepatitis C virus-infected liver
Motoyuki Kohjima, Tsuyoshi Yoshimoto, Munechika Enjoji, Nobuyoshi Fukushima, Kunitaka Fukuizumi, Tsukasa Nakamura, Miho Kurokawa, Nao Fujimori, Yusuke Sasaki, Yasushi Shimonaka, Yusuke Murata, Susumu Koyama, Ken Kawabe, Kazuhiro Haraguchi, Yorinobu Sumida, Naohiko Harada, Masaki Kato, Kazuhiro Kotoh, Makoto Nakamuta
Motoyuki Kohjima, Tsuyoshi Yoshimoto, Nobuyoshi Fukushima, Kunitaka Fukuizumi, Tsukasa Nakamura, Miho Kurokawa, Nao Fujimori, Ken Kawabe, Kazuhiro Haraguchi, Yorinobu Sumida, Naohiko Harada, Makoto Nakamuta, Department of Gastroenterology and Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
Munechika Enjoji, Yusuke Murata, Susumu Koyama, Health Care Center, Fukuoka University, Fukuoka 814-0180, Japan
Yusuke Sasaki, Yasushi Shimonaka, Product Research Department, Chugai Pharmaceutical Co., Ltd., Tokyo 103-8324, Japan
Masaki Kato, Kazuhiro Kotoh, Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan
Author contributions: Kohjima M, Nakamuta M and Enjoji M designed the research; and all of the authors performed the research; Kohjima M and Enjoji M wrote the paper.
Supported by grants from Research Program of Intractable Disease provided by the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-Aid for Clinical Research from the National Hospital Organization of Japan.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Munechika Enjoji, MD, PhD, Health Care Center, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Telephone: +81-92-8716631 Fax: +81-92-8630389
Received: September 3, 2014
Peer-review started: September 4, 2014
First decision: October 14, 2014
Revised: October 22, 2014
Accepted: December 8, 2014
Article in press: December 8, 2014
Published online: March 21, 2015

AIM: To investigate the relationship between the iron-metabolism-related gene expression profiles and efficacy of antiviral therapy in chronic hepatitis C patients.

METHODS: The hepatic expression profile of iron-metabolism-related genes was analyzed and its association with virological response to pegylated-interferon plus ribavirin combination therapy was evaluated. A hundred patients with chronic hepatitis C (genotype1b, n = 50; genotype 2, n = 50) were enrolled and retrospectively analyzed. Liver biopsy samples were subjected to quantitative polymerase chain reaction for iron-metabolism-related genes and protein expression (Western blotting analysis) for ferroportin. As a control, normal liver tissue was obtained from 18 living donors of liver transplantation. Serum hepcidin level was measured by sensitive liquid chromatography/electrospray ionization tandem mass spectrometry.

RESULTS: Iron overload is associated with liver damage by increasing oxidative stress and hepatitis C virus (HCV) is reported to induce iron accumulation in hepatocytes in vivo. Conversely, iron administration suppresses HCV replication in vitro. Therefore, the association between HCV infection and iron metabolism remains unclear. Compared with controls, patients had significantly higher gene expression for transferrin, iron-regulatory proteins 1 and 2, divalent metal transporter 1, and ferroportin, but similar for transferrin receptors 1 and 2, and hepcidin. When the expression profiles were compared between sustained virological response (SVR) and non-SVR patients, the former showed significantly lower transcription and protein expression of hepcidin and ferroportin. Expression of hepcidin-regulating genes, BMPR1, BMPR2, and hemojuvelin, was significantly increased, whereas BMP2 was decreased in HCV-infected liver. BMPR2 and hemojuvelin expression was significantly lower in the SVR than non-SVR group. HCV infection affects the expression of iron-metabolism-related genes, leading to iron accumulation in hepatocytes.

CONCLUSION: Decreased expression of hepcidin and ferroportin in SVR patients indicates the importance of hepatocytic iron retention for viral response during pegylated-interferon plus ribavirin treatment.

Keywords: Chronic hepatitis C, Iron-metabolism, Hepcidin, Ferroportin, Interferon

Core tip: The first showing the relationship between expression of iron-metabolism-related genes and response to pegylated-interferon (PEG-IFN) and ribavirin (RBV) therapy in patients with chronic hepatitis C. The expression of hepcidin and ferroportin in the liver before therapy was significantly lower in sustained virological response (SVR) patients than non-SVR patients. The expression of hepcidin was positively correlated with that of ferroportin. The variation in hepatic expression profile in iron-metabolism-related genes is important for the response to PEG-IFN + RBV treatment.