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. 2008 Feb 12;98(3):580-6.
doi: 10.1038/sj.bjc.6604204. Epub 2008 Jan 29.

Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C

H Tanaka  1 , N Fujita, R Sugimoto, N Urawa, S Horiike, Y Kobayashi, M Iwasa, N Ma, S Kawanishi, S Watanabe, M Kaito, Y Takei
Affiliations

Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C

H Tanaka et al. Br J Cancer. .

Abstract

Although the oxidative stress frequently occurs in patients with chronic hepatitis C, its role in future hepatocellular carcinoma (HCC) development is unknown. Hepatic 8-hydroxydeoxyguanosine (8-OHdG) was quantified using liver biopsy samples from 118 naïve patients who underwent liver biopsy from 1995 to 2001. The predictability of 8-OHdG for future HCC development and its relations to epidemiologic, biochemical and histological baseline characteristics were evaluated. During the follow-up period (mean was 6.7+/-3.3 years), HCC was identified in 36 patients (30.5%). Univariate analysis revealed that 16 variables, including 8-OHdG counts (65.2+/-20.2 vs 40.0+/-23.5 cells per 10(5) microm2, P<0.0001), were significantly different between patients with and without HCC. Cox proportional hazard analysis showed that the hepatic 8-OHdG (P=0.0058) and fibrosis (P=0.0181) were independent predicting factors of HCC. Remarkably, 8-OHdG levels were positively correlated with body and hepatic iron storage markers (vs ferritin, P<0.0001 vs hepatic iron score, P<0.0001). This study showed that oxidative DNA damage is associated with increased risk for HCC and hepatic 8-OHdG levels are useful as markers to identify the extreme high-risk subgroup. The strong correlation between hepatic DNA damage and iron overload suggests that the iron content may be a strong mediator of oxidative stress and iron reduction may reduce HCC incidence in patients with chronic hepatitis C.

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Figures

Figure 1
Figure 1
8-Hydroxydeoxyguanosine immunohistochemical staining in liver tissue from chronic hepatitis C and control (simple fatty liver) patients. (A) In the liver of chronic hepatitis C patient, 8-OHdG immunoreactivity was strongly observed throughout the whole acinus (PA=portal area) and mainly in the nuclei of hepatocytes and Kupffer cells (arrows in (A)). (B) In the liver of control (simple fatty liver), immunoreactivity of 8-OHdG was weak in the nuclei of hepatocytes. Scale bar, 100 μm in (A) and (B).
Figure 2
Figure 2
Comparison between 8-OHdG counts in patients who developed HCC (N=36) and those who remained free of HCC (non-HCC, N=82) during the follow-up period. Baseline 8-OHdG counts were significantly higher in the HCC group than in the non-HCC group in patients with chronic hepatitis C.
Figure 3
Figure 3
Cumulative incidence of HCC in 118 patients with chronic hepatitis C. Incidence curves were determined using the Kaplan–Meier method and statistical analysis was performed using the long-rank test. (A) Cumulative incidence of HCC divided by degrees of hepatic 8-OHdG expression levels. (B) Cumulative incidence of HCC divided by degrees of histological hepatic fibrosis staging score.
Figure 4
Figure 4
Correlations between hepatic 8-OHdG staining and serum ferritin levels (A), and TIS in hepatic tissues (B), in 118 patients with chronic hepatitis C.
See this image and copyright information in PMC

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