Interferon-α2b therapy reduces liver fibrosis in chronic non-A, non-B hepatitis: A quantitative histological evaluation

Manabe, Noboru; Chevallier, M.; Chossegros, P.; Causse, Xavier; Guérret, Sylviane; Trépo, C.; Grimaud, Jean‐Alexis

doi:10.1002/hep.1840180610

Cited by 129 publications

(72 citation statements)

References 22 publications

(25 reference statements)

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“…20,23,33 Furthermore, 158 patients (65%) were treated with IFN-␥ 1b in the course of this study, but because there was no difference between these and placebo-treated patients (Tables 3 and 4), we combined the data from all 245 patients for the analyses. Even though our patients had been treated with potentially antifibrotic agents, the findings in this cohort are quite similar to those in the small groups of untreated patients reported by Manabe et al 32 and Kage et al 5 Extrapolating the reported data, Manabe et al 32 found an average increase in fibrosis of approximately 52% per year in 16 patients, Kage et al 5 found 55% per year in 25 patients, and we found 58% per year in 245 patients, despite the differences in patients and in the baseline levels of fibrosis. This implies that in patients with chronic hepatitis C, the average amount of hepatic collagen doubles in approximately 2 years, and if this is true at all degrees of fibrosis, then the fibrous tissue may actually increase exponentially rather than linearly.…”

Section: Discussionsupporting

confidence: 91%

“…Four published studies have used morphometry to study changes in hepatic fibrosis after alpha interferon therapy, 20,23,32,33 and one has used morphometry to study disease progression in untreated patients with chronic hepatitis C. 5 In an early interferon alpha-2b trial, Manabe et al 32 measured collagen content in 59 patients, 43 treated with interferon and 16 treated with placebo. Mean collagen content of the liver biopsies decreased in the interferon-treated patients, but mean collagen increased by 26% in those treated with placebo for 24 weeks.…”

Section: Discussionmentioning

confidence: 99%

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Progression of fibrosis in advanced chronic hepatitis C: Evaluation by morphometric image analysis

et al. 2007

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Fibrosis progression in chronic liver disease has usually been evaluated by liver biopsy using insensitive semiquantitative numerical scores. An alternative to this is to measure fibrous tissue quantitatively using morphometric image analysis. The aim of this study was to quantify fibrosis progression in a cohort of patients with treatment-refractory chronic hepatitis C enrolled in a placebo-controlled clinical trial of interferon gamma-1b (IFN-␥ 1b) for the treatment of advanced hepatic fibrosis. We used morphometry to quantify the amount of fibrous tissue in liver biopsies performed at baseline and after 48 weeks in 245 patients who had paired unfragmented, adequate-sized specimens and correlated the results with clinical and laboratory parameters. Eighty-seven patients were treated with placebo and 158 with IFN-␥ 1b. No effect of the drug on fibrosis was found in the trial, and so data from all 245 patients were combined for analysis. At baseline, 78% had cirrhosis; 22%, bridging fibrosis. The mean morphometrically determined collagen content increased by 58% between baseline and 48 weeks. There were statistically significant but weak correlations of fibrosis with platelet count, albumin, bilirubin, INR, and hyaluronic acid; however, changes in these did not correlate with or predict changes in fibrosis in the liver biopsy. Conclusion: In advanced chronic hepatitis C, fibrosis increases at a rapid pace that can only be detected by morphometry. This technique can be used in future therapeutic trials of agents to inhibit fibrosis progression. (HEPATOLOGY 2007;45:886-894.)

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Progression of fibrosis in advanced chronic hepatitis C: Evaluation by morphometric image analysis

et al. 2007

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“…Serum transaminase activities were measured according to standard procedures using commercial kits with normal values as indicated by the manufacturer. The following secondary efficacy criteria were also recorded: changes in histological lesions assessed according to Knodell et al 10 and to the French Metavir cooperative study group 11 ; changes in the liver collagen content as assessed on needle liver biopsy slides of sufficient size according to Jimenez et al, 12 as reported previously 13,14 ; sustained biochemical response, i.e., normal serum transaminase activities from week 48 to week 72; changes in serum albumin, serum bilirubin, prothrombin, and serum ␣-fetoprotein; and changes in portal venous pressure gradient. Histological evaluations were performed on coded paired liver slides by a single histopathologist, who was unaware of the treatment received and of the order of the slides.…”

Section: Methodsmentioning

confidence: 99%

Treatment of hepatitis C virus-related cirrhosis: A randomized, controlled trial of interferon alfa-2b versus no treatment

Valla¹,

Chevallier

Marcellin³

et al. 1999

Hepatology

202

151

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To examine the effects of interferon (IFN) therapy on clinical, biochemical, and histological features in patients with compensated hepatitis C virus (HCV)-related cirrhosis, we have conducted a randomized, controlled trial of IFN therapy versus observation. Eight centers included a total of 99 patients with biopsy-proven cirrhosis. IFN-␣2b, 3 million units three times per week, or no antiviral therapy was given for 48 weeks. Twenty-three patients dropped out. End-of-treatment biochemical response was not observed in any of the 39 controls but was observed in 6 of the 47 treated patients (P F .02); sustained biochemical response was obtained in only 2 treated patients. Controls and treated patients did not significantly differ with regard to the changes in serum level of albumin, bilirubin, ␣-fetoprotein, in plasma prothrombin, in histological activity, or liver collagen content. During trial or follow-up (160 ؎ 57 weeks), hepatocellular carcinoma developed in 9 controls and 5 treated patients (NS); decompensation of cirrhosis occurred in 5 controls and 7 treated patients. Seven controls and 10 treated patients died. In conclusion, in patients with compensated HCV-related cirrhosis, a 48-week course of IFN therapy is safe and is able to induce end-of-treatment biochemical response in a significant proportion of patients. However, a 48-week course of IFN therapy usually fails to achieve sustained response and, within the limit of this study, did not significantly improve the 3-year outcome. Therefore, a longer course of IFN therapy or combination therapy with ribavirin should be evaluated in patients with HCV-related cirrhosis. (HEPATOLOGY 1999;29:1870-1875.)Cirrhosis is a common complication of chronic hepatitis C, affecting approximately 20% of patients followed up for more than 10 years. 1 Currently identified risk factors for cirrhosis in hepatitis C virus (HCV)-infected patients are age at contamination, duration of infection, degree of histological activity, and alcohol consumption. 2,3 Natural history of HCVrelated cirrhosis is jeopardized by a high incidence of hepatocellular carcinoma (up to 5% per year) 4-7 and hepatic decompensation (up to 25% at 4 years). 4,6,7 Mortality rate is about 15% to 20% at 4 years. HCV-related cirrhosis accounts for 30% of liver transplantation in adults. 1 A treatment able to halt the progression of liver disease once cirrhosis is established but not yet complicated would be of great interest. Current data on the efficacy of interferon (IFN) therapy in patients with HCV-related cirrhosis are conflicting. Cirrhosis is a marker of a poor response to IFN therapy. 8 However, when genotype and serum viral load are taken into account, it is unclear that cirrhosis has any independent value in predicting a poor response to IFN therapy. 8 It has been recently suggested that IFN therapy can prevent the subsequent development of hepatocellular carcinoma, 9 but this contention is not supported by all studies. [5][6][7] In addition, the effects of IFN therapy on mortality rate and probab...

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“…Sections were stained with hematoxylin-eosin for routine histology and with Sirius red (saturated picric acid in distilled water containing 0.1% (w/v) Sirius red F3B (BDH Chemicals Ltd., Poole, United Kingdom) to allow visualization of fibrosis (Manabe et al, 1993). After Sirius red staining, the sections were not counterstained.…”

Section: Processing Of Rat Liver Tissuementioning

confidence: 99%

Cellular Retinol-Binding Protein-1 Expression and Modulation during In Vivo and In Vitro Myofibroblastic Differentiation of Rat Hepatic Stellate Cells and Portal Fibroblasts

Uchio¹,

Tuchweber

Manabe

et al. 2002

Laboratory Investigation

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103

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SUMMARY:Cellular retinol-binding protein-1 (CRBP-1) is involved in vitamin A metabolism because it mediates both retinol esterification to retinyl esters and retinol oxidation to retinal and retinoic acid. CRBP-1 is highly expressed in the liver, particularly in hepatic stellate cells (HSC). In this study, we investigated the liver expression of CRBP-1 during experimental fibrogenesis. We also studied the regulation of CRBP-1 expression in cultured HSC and portal fibroblasts, two fibroblastic cell types involved in liver fibrogenesis. Fibrosis was induced in rats by carbon tetrachloride (CCl 4 ) or bile duct ligation. Immunohistochemical staining was performed for CRBP-1 and ␣-smooth muscle (SM) actin, an activation marker of fibrogenic cells. CRBP-1 and ␣-SM actin expression was studied by Western blotting and/or Northern blot in primary cultures of HSC isolated by conventional methods and in portal fibroblasts that were obtained by outgrowth from the biliary tree after enzymatic digestion. In normal liver, contrary to HSC, portal fibroblasts did not express CRBP-1. After CCl 4 injury, CRBP-1 expression was maintained in myofibroblastic ␣-SM actin-positive HSC. After bile duct ligation, portal fibroblasts (which proliferated around ductular structures) acquired expression of both CRBP-1 and ␣-SM actin. During HSC activation in culture, CRBP-1 expression gradually increased until Day 5 when ␣-SM actin expression was obvious. Cultured portal fibroblasts developed both CRBP-1 and ␣-SM actin expression. In both cell populations, transforming growth factor-␤1 treatment increased CRBP-1 expression. Thus, in normal liver, CRBP-1 expression was different among fibroblastic cells, a finding that adds to the concept of heterogeneity of liver fibrogenic cells. Furthermore, during myofibroblastic differentiation, HSC that lost their stores of retinol maintained a high level of CRBP-1 expression, whereas portal fibroblasts acquired CRBP1 expression. Together, these data suggest a correlation between CRBP-1 expression and myofibroblastic differentiation. (Lab Invest 2002, 82:619 -628).

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Interferon-α2b therapy reduces liver fibrosis in chronic non-A, non-B hepatitis: A quantitative histological evaluation

Cited by 129 publications

References 22 publications

Progression of fibrosis in advanced chronic hepatitis C: Evaluation by morphometric image analysis

Progression of fibrosis in advanced chronic hepatitis C: Evaluation by morphometric image analysis

Treatment of hepatitis C virus-related cirrhosis: A randomized, controlled trial of interferon alfa-2b versus no treatment

Cellular Retinol-Binding Protein-1 Expression and Modulation during In Vivo and In Vitro Myofibroblastic Differentiation of Rat Hepatic Stellate Cells and Portal Fibroblasts

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