Hepcidin/ferroportin expression levels involve efficacy of pegylated-interferon plus ribavirin in hepatitis C virusinfected liver

AIM:To investigate the relationship between the ironmetabolism-related gene expression profiles and efficacy of antiviral therapy in chronic hepatitis C patients.METHODS:The hepatic expression profile of ironmetabolism-related genes was analyzed and its association with virological response to pegylated-interferon plus ribavirin combination therapy was evaluated.A hundred patients with chronic hepatitis C(genotype1b,n = 50; genotype 2,n = 50) were enrolled and retrospectively analyzed.Liver biopsy samples were subjected to quantitative polymerase chain reaction for iron-metabolismrelated genes and protein expression(Western blotting analysis) for ferroportin.As a control,normal liver tissue was obtained from 18 living donors of liver transplantation.Serum hepcidin level was measured by sensitive liquid chromatography/electrospray ionization tandem mass spectrometry.RESULTS:Iron overload is associated with liver damage by increasing oxidative stress and hepatitis C virus(HCV)is reported to induce iron accumulation in hepatocytes in vivo.Conversely,iron administration suppresses HCV replication in vitro.Therefore,the association between HCV infection and iron metabolism remains unclear.Compared with controls,patients had significantly higher gene expression for transferrin,iron-regulatoryproteins 1 and 2,divalent metal transporter 1,and ferroportin,but similar for transferrin receptors 1 and2,and hepcidin.When the expression profiles were compared between sustained virological response(SVR)and non-SVR patients,the former showed significantly lower transcription and protein expression of hepcidin and ferroportin.Expression of hepcidin-regulating genes,BMPR1,BMPR2,and hemojuvelin,was significantly increased,whereas BMP2 was decreased in HCV-infected liver.BMPR2 and hemojuvelin expression was significantly lower in the SVR than non-SVR group.HCV infection affects the expression of iron-metabolism-related genes,leading to iron accumulation in hepatocytes.CONCLUSION:Decreased expression of hepcidin and ferroportin in SVR patients indicates the importance of hepatocytic iron retention for viral response during pegylated-interferon plus ribavirin treatment.

Association of ITPA polymorphism with outcomes of peginterferon-α plus ribavirin combination therapy

AIM:To analyzed the association between inosine triphosphatase(ITPA)(rs1127354) genotypes and sustained virological response(SVR) rates in peginterferon(Peg-IFN)α + ribavirin(RBV) treatment.METHODS:Patients who underwent Peg-IFNα + RBV combination therapy were enrolled(n = 120) and they had no history of other IFN-based treatments.Variation in hemoglobin levels during therapy,cumulative reduction of RBV dose,frequency of treatment withdrawal,and SVR rates were investigated in each ITPA genotype.RESULTS:In patients with ITPA CC genotype,hemoglobin decline was significantly greater and the percentage of patients in whom total RBV dose was < 60% of standard and/or treatment was withdrawn was significantly higher compared with CA/AA genotype.However,SVR rates were equivalent between CC and CA/AA genotypes,and within a subset of patients with Interleukin 28B(IL28B)(rs8099917) TT genotype,SVR rates tended to be higher in patients with ITPA CC genotype,although the difference was not significant.CONCLUSION:ITPA CC genotype was a disadvantageous factor for Peg-IFNα + RBV treatment in relation to completion rates and RBV dose.However,CC genotype was not inferior to CA/AA genotype for SVR rates.When full-length treatment is accomplished,it is plausible that more SVR is achieved in patients with ITPA CC variant,especially in a background of IL28B TT genotype.