Accumulation of 8-n itroguanine in the liver of chronic hepatitis C patients without sustained virological response after completion of interferon therapy

Abstract

To the Editor: Nitric oxide has been suggested to play a crucial role in chronic inflammation-mediated carcinogenesis.1,2 We previously reported that nucleic acid damage by reactive nitrogen and oxygen species in the liver of patients with chronic hepatitis C (CHC) may contribute to inflammation-related hepatocellular carcinogenesis.3 We demonstrated that 8-nitroguanine is a useful biomarker for evaluating the severity of hepatitis C virus (HCV)induced chronic inflammation in relation to hepatocellular carcinoma (HCC), and that interferon (IFN) therapy decreases the accumulation of 8-nitroguanine in the liver. In addition, we evaluated the association between 8-nitroguanine accumulation and the time interval following the completion of IFN therapy during a second biopsy in nonresponders (NR). In the NR group (n = 12), the number of 8-nitroguanine-positive and 8-hydroxy-2′deoxyguanosine (8-OHdG)-positive hepatocytes before treatment with IFN [26.5 (9.0–170.0)/105μm2 and 37.8 (10.0–113.7)/ 105μm2, respectively; data are expressed as median and range] did not decrease after IFN therapy [36.3 (8.7–62.6)/105μm2 and 76.2 (11.3–99.3)/105μm2, respectively]. Each NR patient showed a different duration of 8-nitroguanine accumulation after IFN therapy. The number of 8-nitroguanine-positive hepatocytes tended to increase after IFN therapy [before, 26.5 (9.0–170.0)/ 105μm2; after, 36.3 (8.7–62.6)/105μm2], and the time interval following IFN therapy was significantly correlated with the number of 8-nitroguanine-positive hepatocytes (r = 0.635, P = 0.0351). However, the number of 8-OHdG-positive hepatocytes was not correlated with the time interval following IFN therapy (Fig. 1). This result suggests that improvement of liver inflammation by IFN therapy in NR patients persists for several years. Several clinical studies have suggested a preventive effect of IFN on HCC development in patients with HCV-related cirrhosis4 and CHC.5–8 Ikeda et al.6 reported that the rate of HCC in IFN-treated and -untreated patients with CHC is 2.1% and 4.8% in the fifth year, and 7.6% and 12.4% in the tenth year, respectively (P = 0.0036). In the IFN-treated NR group, the rate of HCC increases during the time following the completion of IFN therapy.4–7 The relationship between 8-nitroguanine accumulation and time after IFN therapy in NR patients supports the idea that temporary reduction of chronic inflammation in the liver by IFN therapy decreases the production of reactive nitrogen species. Accumulation of 8-nitroguanine in the liver increases during the time following completion of IFN treatment (Fig. 1). Arase et al.7 reported that long-term IFN therapy in patients with chronic HCV infection is effective in preventing hepatocarcinogenesis. Long-term IFN therapy in patients may decrease the accumulation of 8-nitroguanine in the liver. Our present study showed that IFN therapy induced temporary suppression of 8-nitroguanine accumulation even in the NR group, suggesting that IFN therapy may prevent hepatocarcinogenesis in HCV-induced chronic inflammation.