Association of Hepcidin mRNA Expression With Hepatocyte Iron Accumulation and Effects of Antiviral Therapy in Chronic Hepatitis C Infection

Abstract

Background:Iron overload is frequently observed in patients with chronic hepatitis C (CHC) and is associated with the increased risk of liver fibrosis and carcinogenesis. Hepcidin is a regulator of iron homeostasis and a component of innate immunity. Based on experimental studies, iron overload might be a result of low hepcidin synthesis in CHC.Objectives:The aim of this case-control study was to assess hepcidin mRNA expression in liver tissue of patients with CHC in terms of iron metabolism parameters, hemochromatosis (HFE) gene mutations, disease activity, and efficacy of antiviral treatment with pegylated interferon and ribavirin.Patients and Methods:A total of 31 patients with CHC, who were qualified for antiviral therapy, were compared with 19 patients with chronic hepatitis B (CHB). In both groups, liver function tests and serum iron parameters were assayed and hepcidin mRNA expression was measured in liver specimens using real time PCR with normalization to reference genes mRNA of stable expression.Results:Patients with CHC had lower hepcidin mRNA expression and more frequently iron deposits in hepatocytes than subjects with CHB did. In CHC group, hepcidin mRNA expression was positively correlated with alanine aminotransferase activity and serum iron concentration. Low expression of hepcidin had no correlation with tissue iron overload in those with CHC. In univariate analysis, HCV viral load and efficacy of antiviral treatment were not significantly associated with hepcidin mRNA expression.Conclusions:Further studies on the role of hepcidin in pathogenesis of CHC are needed to assess the potency of its use in antiviral treatment.

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

“…Few studies have mentioned such an association, with no clear reference to viral load levels in chronic HCV patients and contradictory data concerning the relationship between HCV viraemia and hepcidin expression. 12,24,56 On the other hand, our observation hints at a putative differential regulation of hepcidin by the virus depending on its replication capacity and, in that respect, is in accordance with the hepcidin levels observed in our in vitro model.…”

“…We have previously showed that HCV core induces HAMP gene expression in hepatoma cells 23 and this may also apply to early HCV infection. Conversely, upon established infection, hepcidin expression dropped in our in vitro model and in patient sera, 12,13 in step with studies from chronic HCV patients with low intrahepatic HAMP mRNA 24 and decreased serum hepcidin, 12,13 and earlier in vitro RNA data. 25,26 Secreted protein expression was also increased throughout infection, albeit not as dramatically as mRNA.…”

The iron homeostasis network and hepatitis C virus – a new challenge in the era of directly acting antivirals

“…Positive correlation of hepcidin expression with liver iron stores or serum iron concentration was observed and that corresponded to the physiological mechanisms of iron homeostasis regulation. [17][18][19] It could not explain causal relationship between iron overload and hepcidin inhibition in CHC. Changes in hepcidin synthesis, including lower serum levels in CHC patients compared to patients with other liver diseases, indicated rather a need to understand the role of this "iron regulator" in the context of disorders of the innate immune response in HCV infection.…”

“…Changes in hepcidin synthesis, including lower serum levels in CHC patients compared to patients with other liver diseases, indicated rather a need to understand the role of this "iron regulator" in the context of disorders of the innate immune response in HCV infection. 19,20 This thesis partially may be explained by results of studies which reported inhibition of HCV replication caused by HAMP silencing in HCV replicon models. 21,22 On the contrary a direct antiviral activity of hepcidin against HCV replication in cell culture was also proved.…”

Relationship between Hepatitis C Virus Infection and Iron Overload

“…It is generally accepted that HCV alters iron metabolism by reducing the level of hepcidin. [134142434445464748] Fujita et al . [43] measured hepcidin messenger RNA (mRNA) levels in liver samples from 56 patients with HCV infection, and revealed that the expression of hepcidin is strongly correlated with serum ferritin and the degree of iron deposition in liver tissues.…”