Changes of liver fibrosis in chronic hepatitis C patients with no response to interferon-α therapy: including quantitative assessment by a morphometric method

Abstract

The aim of this study was to evaluate the antifibrotic effect of interferon (IFN)-alpha in chronic hepatitis C (CH-C) patients with no response to IFN-alpha therapy. We studied 76 patients (46 men, 30 women; mean age, 55.6 years) who received IFN-alpha intramuscularly, at a total close of 480 to 880MU for 6 months (group A). As a control group, we studied 50 patients (32 men and 18 women; mean age, 58.5 years) with CH-C who received medication other than IFN (ie, Strong-Neo-Minophagen C, ursodeoxycholic acid, and a herbal medicine, Sho-saiko-to [TJ-9]) and who had persistent alanine aminotransferase (ALT) elevation (group B). All patients were subdivided into three subgroups according to different patterns of ALT changes during the observation period, ie, (a) persistent ALT level < 60IU/ 1 (below about twice the upper limit of the normal range), (b) persistent ALT level > or = 60IU/1, (c) ALT levels other than (a) and (b). Liver biopsy was performed within 6 months prior to IFN therapy and more than 6 months after IFN therapy, while two liver biopsies were performed during therapy in group B. Liver fibrosis was compared between two specimens by staging. When the fibrosis stage was the same in the two specimens, we determined whether the fibrosis had improved or worsened by comparing the fibrotic ratio, ie, the ratio of the area of fibrosis to the area of the entire liver tissue specimen, calculated using computed graphic software. Serum aminoterminal peptide of type III procollagen (PIIIP) levels were measured on the day of the liver biopsy and their mean yearly changes were compared between the two groups. Improvement of liver fibrosis was found in 12% to 30% of patients in each ALT subgroup and in 24% of all patients in group A and there were no significant differences in liver fibrosis in comparison with findings in of group B when assessed by staging alone. However, these percentages rose to 59% to 75% and 66%, respectively, when liver fibrosis was assessed by the fibrotic ratio together with staging, resulting in a significant difference in fibrosis between groups A and B in total (P < 0.01). The mean yearly changes in serum PIIIP levels in each subgroup and in all patients in group A were below zero, indicating a tendency to improvement of fibrosis after IFN therapy, while these changes in group B were all above zero, except for subgroup (c). Improvement of fibrosis after IFN therapy was found in 15 of 24 patients (64%) whose ALT changes had the same pattern before and after IFN therapy, although no significant difference was noted between improved and worsened patients. These results suggest that IFN-alpha may have an antifibrotic effect even in CH-C patients with no overt response to IFN-alpha therapy, compared with the effect of medications other than IFN.

Comparative Study of the High Molecular Mass Fraction and Low Molecular Mass Fraction of Sho-saiko-to in a Murine Immunologically Induced Liver Injury Model.

“…Sho-saiko-to has been used for the treatment of various infectious diseases such as chronic viral hepatitis, [1][2][3] and it has been shown that Sho-saiko-to has immunomodulating activity, [4][5][6][7][8] antiinflammatory effects, [9][10][11] and antihepatitis activity. [12][13][14] Previously, we demonstrated that the immunomodulating actions of Sho-saiko-to, such as augmentation of macrophage function and mitogenic activity, were mainly due to its polysaccharide fractions in vivo.…”

Monotherapy with Pegylated Interferon Alpha‐2a in Hemodialyzed Patients with Chronic Hepatitis C

“…Indeed, it has been shown by some authors that even in nonresponding patients HCV-related cirrhosis progression may be lowered by IFN therapy. 23,24 Further studies should be done to assess the possibility of a benefi cial effect of PEG-IFN standard treatment in nonresponders and even of low-dose, long-term therapy. Combination treatment with PEG IFN alpha-2a and ribavirin is hampered by the augmented risk of severe anemia in this category of patients.…”

Adenovirus-mediated gene transfer of interferon α improves dimethylnitrosamine-induced liver cirrhosis in rat model

“…We examined whether hepatic INF-a expression could improve liver fibrosis in a DMN-injected rat, because the antifibrotic effect of IFN-a protein has been shown in experimental animal models and clinical studies. [6][7][8][9][10][11][12][13] The AxCA-rIFN-treated rats survived significantly longer than the rats injected with either AxCA-lacZ or PBS (P¼0.0001), and five of nine IFN-a-transduced rats survived more than 100 days ( Figure 3). Histological examination clearly revealed less fibrous connective tissue components in Glisson's sheath and pseudolobule formations in the livers of control and AxCA-rIFNtransduced rats than in the liver of the AxCA-lacZtransduced rats, in which the extensive formation of fibrotic septa and thickened reticulin fibers joining central areas were observed (Figures 1a, 4a and b).…”

“…In addition to the antiviral effect, several lines of evidence suggested that IFN-a is also effective in curtailing LC in experimental animal models and clinical studies. [6][7][8][9][10][11][12][13] IFN-a is therefore expected to be particularly powerful in preventing the development of LC in patients with HCV infection.…”