Abstract
BackgroundHepatocellular carcinoma (HCC) develops in some patients who achieve sustained virological response (SVR) against hepatitis C virus (HCV) infection via anti-HCV therapy. To examine the pathogenesis of HCC development after HCV eradication, histopathological changes and clinical markers were evaluated in SVR patients.MethodsOf 654 SVR patients treated with interferon (IFN)-based therapies, 34 patients who had undergone liver biopsy before initiating IFN therapy and after SVR achievement were enrolled: 11 patients with HCC and 23 patients without HCC (male/female, 9/2 and 8/15, respectively: age, 58 ± 5 and 54 ± 11 years, respectively). We compared the clinical and histopathological factors between the two groups. Immunohistochemistry for Cytoglobin (CYGB) and α smooth muscle actin (α-SMA) was also performed.ResultsAt baseline, prior to initiating the IFN-based therapy, there were significant differences between the SVR-non-HCC and SVR-HCC groups in the male gender, HBc antibody positivity, prothrombin activity, and histological inflammatory grade. Histopathological evaluation, using the new Inuyama classification system, revealed an improvement in the inflammatory grade, from 2.1 ± 0.6 to 1.0 ± 0.6 (p < 0.0001), whereas the fibrosis stage remained unchanged, from 2.3 ± 0.9 to 2.0 ± 1.2 (p = 0.2749), during the 97 ± 72-month observation period in the SVR-HCC group. Both the grade and stage scores were significantly improved in the SVR-non-HCC group. The area of collagen deposition, evaluated using Sirius red staining, showed a marked decrease, from 18.6 ± 7.6% to 7.7 ± 4.6%, in the SVR-non-HCC group, with no change in the SVR-HCC group. CYGB- and α-SMA-positive hepatic stellate cells (HSCs), indicative of the HSC activated phenotype, remained in the fibrotic tissue of livers among patients in the SVR-HCC group.ConclusionStagnation of fibrosis regression is associated with a high risk for HCC after SVR. HSC activation may inhibit improvement in fibrosis after SVR and potentially contribute to hepatocarcinogenesis.
Highlights
Hepatitis C virus (HCV) infection is a critical factor in the occurrence of hepatocellular carcinoma (HCC)
Using liver tissue samples from patients with chronic hepatitis and cirrhosis caused by hepatitis C virus (HCV) infection, we previously demonstrated that CYGB is a unique marker of human hepatic stellate cells (HSCs) that is negligibly expressed in portal myofibroblasts, which are positive for αSMA, thy-1, and fibulin 2 [29]
We showed that stagnation of fibrosis improvement is a risk factor for Hepatocellular carcinoma (HCC) after sustained virological response (SVR)
Summary
Hepatitis C virus (HCV) infection is a critical factor in the occurrence of hepatocellular carcinoma (HCC). HCV infection becomes chronic in 80% of cases, with a 10–20% risk of developing cirrhosis over 20 years [1,2,3]. It is reasonable to speculate that the eradication of HCV prevents HCC development in HCV-infected patients. Previous studies have confirmed that interferon (IFN)-based anti-viral therapy reduces the incidence of HCC, in patients who achieve sustained viral response (SVR) [4,5,6]. Hepatocellular carcinoma (HCC) develops in some patients who achieve sustained virological response (SVR) against hepatitis C virus (HCV) infection via anti-HCV therapy. To examine the pathogenesis of HCC development after HCV eradication, histopathological changes and clinical markers were evaluated in SVR patients
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