Interferon can block telomere erosion and in rare cases result in hepatocellular carcinoma development with telomeric repeat binding factor 1 overexpression in chronic hepatitis C.

PURPOSE: The purpose of this study was to evaluate whether IFN therapy for chronic hepatitis C could overcome telomere reduction in the liver, a possible risk factor for hepatocellular carcinoma (HCC) development. EXPERIMENTAL DESIGN: Relative telomeric repeat content (RTC) in the liver was measured before and after IFN therapy in 21 chronic hepatitis C cases. Liver samples were obtained at average intervals of 12, 75, and 32 months in eight complete responders (CRs) and one biochemical responder (BR), four CRs in whom HCC developed after an eradication of hepatitis C virus, and eight nonresponders, respectively. Telomeric repeat binding factor 1 (TRF1) was immunostained in specimens from CRs and a BR. RESULTS: Although the average RTC of 0.96 +/- 0.14 (mean +/- SD) significantly decreased to 0.85 +/- 0.12 after IFN therapy in nonresponders (P = 0.023), the value of 0.91 +/- 0.14 before IFN therapy in CRs and a BR increased significantly to 1.0 +/- 0.085 (P = 0.031). TRF1 expression was barely detectable and attenuated after IFN therapy, except in CRs developing HCC, in which frequent staining appeared, and the RTC evidently decreased from 0.97 +/- 0.11 to 0.63 +/- 0.0092 in corresponding noncancerous liver tissues. CONCLUSIONS: It is strongly suggested that successful IFN therapy blocks telomere erosion, except in rare cases in which telomere reduction continues with overexpression of TRF1. Successive RTC evaluation in the liver may distinguish a risky case from a clinically cured one.

Interchromosomal telomere length variation.

Despite the recent discovery of interchromosomal telomere length variation, a role for heterogeneity in telomere maintenance has yet to be established. This study aimed to clarify relative telomere length differences between chromosomes. Combined chromosomal sorting and telomeric repeat content analysis in GM130B cells, the relative telomeric repeat content in each chromosome, were calculated. Each chromosome could be isolated except for chromosomes 1 and 2 and chromosomes 9 to 12, which were isolated in a group. Telomere length was correlated with the size of the corresponding chromosome. Concomitant relative telomeric repeat content analysis in each chromosome and terminal restriction fragment analysis using the whole genome revealed that the terminal restriction fragments of each chromosome were heterogenously distributed through the smear of the fragments. This is the first description of an association between telomere length and chromosome size.

Sustained biochemical remission after interferon treatment may closely be related to the end of treatment biochemical response and associated with a lower incidence of hepatocarcinogenesis.

Clinical background and incidence of hepatocellular carcinoma (HCC) of patients with chronic hepatitis C who obtained biochemical remission without eradication of virus (biochemical response) after interferon (IFN) treatment was retrospectively analyzed for 755 patients. Annual incidence of HCC was significantly lower in the patients with biochemical response and sustained response than that of the patients that did not show these responses. Logistic regression analysis showed that only the normalization of alanine aminotransferase (ALT) value at the end of IFN treatment was a significant factor for biochemical response. Annual incidence of HCC was significantly lower in the patients who obtained normalization of ALT values at the end of treatment than those who did not. Patients who were younger, who had a lower level of activity and fibrosis indices in histology, higher platelet count, and who were given more higher total dose of IFN were more likely to attain normalization of ALT levels at the end of treatment, and this was related to biochemical response. Low incidence of HCC in patients who obtained normalization of ALT values at the end of treatment was likely because they were in the earlier stage of chronic hepatitis. Active treatment of chronic hepatitis C with interferon in the early phase of the disease may bring about a biochemical response in some patients, even if sustained virological response is not obtained.

Interferon inhibits progression of liver fibrosis and reduces the risk of hepatocarcinogenesis in patients with chronic hepatitis C: a retrospective multicenter analysis of 652 patients.

A retrospective multicenter analysis of 652 patients with chronic hepatitis C who have been treated with interferon (IFN) was performed to assess the effects of IFN on the clinical course and development of HCC. During a mean follow-up of 54.8 months, hepatocellular carcinoma (HCC) developed in 7.0% of the patients. The rate was significantly higher in the patients who did not respond to IFN treatment than in those with sustained virological response and those who obtained a normalization of alanine aminotransferase levels despite the presence of HCV RNA (incomplete response) (P < 0.01). Using multivariate Cox's proportional hazard model, alcohol abuse (P < 0.05) and a higher level of fibrosis (P < 0.05) before treatment were the significant background factors associated with HCC development in the patients who did not respond to IFN. Interestingly, a significant increase in the rate of HCC development occurred in patients who had a histological finding of progressive fibrosis (F3). In addition, patients with low histological staging scores were likely to have an incomplete response, even if a sustained virological response was not obtained. IFN produced an improvement in histological activity and fibrosis stage in the second biopsy specimens irrespective of the clinical outcome when compared against untreated subjects.