Association of hepatic oxidative stress and iron dysregulation with HCC development after interferon therapy in chronic hepatitis C.
BACKGROUND
Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established.


METHODS
We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera.


RESULTS
Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (p<0.0001). Systemic and intracellular iron regulators of hepcidin and F-box and leucine-rich repeat protein 5 (FBXL5) expression levels were significantly suppressed in CHC patients (p=0.0032 and p=0.016, respectively) despite their significantly higher levels of serum iron and ferritin compared with controls. However, intracellular iron regulators of FBXL5 and iron regulatory proteins were regulated in balance with hepatic iron deposition. Significant correlations were observed among IL-6, bone morphogenetic protein 6, hepcidin and ferroportin, as regards systemic iron regulation.


CONCLUSIONS
Measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients.


BACKGROUND
UMIN 000001031.
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Shintaro
S
Nanba
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Fusao
F
Ikeda
Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
Nobuyuki
N
Baba
Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
Koichi
K
Takaguchi
Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
Tomonori
T
Senoh
Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
Takuya
T
Nagano
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Hiroyuki
H
Seki
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Yasuto
Y
Takeuchi
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Yuki
Y
Moritou
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Tetsuya
T
Yasunaka
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Hideki
H
Ohnishi
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Yasuhiro
Y
Miyake
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Akinobu
A
Takaki
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Kazuhiro
K
Nouso
Health Service Center, Okayama University, Okayama, Japan.
Yoshiaki
Y
Iwasaki
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Kazuhide
K
Yamamoto
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000378:metabolism / Q000821:virology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D019698:Hepatitis C, Chronic / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D019189:Iron Metabolism Disorders / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D008113:Liver Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000821:virology*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D018384:Oxidative Stress; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
D000998:Antiviral Agents; D015415:Biomarkers; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; C100416:peginterferon alfa-2a
CYTOPATHOLOGY; HEPATITIS; IRON METABOLISM; MOLECULAR PATHOLOGY; VIRUS