Int J Med Sci 2018; 15(5):466-474. doi:10.7150/ijms.23147

Research Paper

Persistent Hepatic Inflammation Plays a Role in Hepatocellular Carcinoma After Sustained Virological Response in Patients with HCV Infection

Kazushige Nirei1✉, Tatsuo Kanda1, Hitomi Nakamura1, Shunichi Matsuoka1, Tadatoshi Takayama2, Masahiko Sugitani3, Mitsuhiko Moriyama1

1. Division of Gastroenterology and Hepatology, Department of Internal Medicine
2. Department of Digestive Surgery and
3. Department of Pathology, Nihon University School of Medicine

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Nirei K, Kanda T, Nakamura H, Matsuoka S, Takayama T, Sugitani M, Moriyama M. Persistent Hepatic Inflammation Plays a Role in Hepatocellular Carcinoma After Sustained Virological Response in Patients with HCV Infection. Int J Med Sci 2018; 15(5):466-474. doi:10.7150/ijms.23147. Available from

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Objective: Hepatitis C virus (HCV) infection has long been treated with interferon therapy (IFN). Currently, more than 90% of IFN-treated patients show a sustained virological response (SVR) when also treated with ribavirin and/or a protease inhibitor. Histological inflammation and fibrosis improve in IFN-treated patients, which indicates HCV clearance. IFN also reduces the incidence of hepatocellular carcinoma (HCC). However, a small proportion of patients with SVR develop HCC. To investigate the causes of hepatic carcinogenesis after SVR, we compared the liver histological findings before IFN to those after the development of HCC.

Patients and methods: In total, 602 patients infected with type C chronic hepatitis or with liver cirrhosis who received IFN therapy during the period from 1992 through 2015 were included in this study. We assessed 14 of the 287 patients who achieved an SVR.

Results: HCC was diagnosed by computed tomography, angiography or liver biopsy. The longest time from the SVR until HCC detection was 16.5 years, and the mean was 7.2±4.6 years. Nine of the 14 patients underwent surgery and one radiofrequency ablation. The histological findings of 10 patients were available for comparison. The comparison of the histological findings before treatment with those after the HCC diagnosis revealed an amelioration of liver fibrosis and other inflammatory changes. All ten patients showed improvements in fibrosis and steatosis. However, we observed that mild inflammatory change persisted from 1.8 years to 16.5 years after the confirmation of SVR in all cases.

Conclusion: We suspect that persistent histological inflammation is one of the factors contributing to hepatocarcinogenesis (i.e., HCC development) even after successful treatment.

Keywords: Chronic Hepatitis C, Sustained Virological Response, Hepatocellular Carcinoma, Histological Fibrosis, Persistent Histological Inflammation.