Accumulation of
8-hydroxy-2'-deoxyguanosine (8-OHdG) in
DNA, which may result from the continuous
reactive oxygen species (ROS) generation associated with chronic
inflammation, has been reported in various human preneoplastic lesions and in cancerous tissues. However, no direct causative relationship between the 8-OHdG formation and
carcinogenesis has been thus far demonstrated in humans. Directly proving the causality requires showing that depletion of 8-OHdG levels in tissue by interfering with ROS generation results in a reduction in
cancer.
Chronic hepatitis C virus (HCV)
infection is associated with a high risk of
hepatocellular carcinoma (HCC). Several studies on patients with chronic HCV have shown that hepatic
iron overload is attributable to liver injury and that
iron depletion improved serum
aminotransferase levels. Excess
iron is known to generate ROS within cells, which causes mutagenic lesions, such as 8-OHdG. In this study, therefore, we have evaluated whether therapeutic
iron reduction (phlebotomy and low
iron diet) with a long-term follow-up (6 years) would decrease the hepatic 8-OHdG levels and the risk of HCC development in patients with chronic HCV. Patients (34) enrolled were those who had undergone standard IFN
therapy but had no sustained response. Quantitative immunohistochemistry using the KS-400 image analyzing system and electrochemical detection was used for 8-OHdG detection. With this treatment, elevated hepatic 8-OHdG levels in patients with
chronic hepatitis C (8.3 +/- 4.6/10(5) dG) significantly decreased to almost normal levels (2.2 +/- 0.9/10(5) dG; P < 0.001) with concomitant improvement of
hepatitis severity, including
fibrosis, whereas HCV titers were unaffected. None of these patients developed HCC. Thus, long-term
iron reduction
therapy in patients with
chronic hepatitis C may potentially lower the risk of progression to HCC.