Duodenal Ferroportin Is Up-Regulated in Patients with Chronic Hepatitis C

Abstract

Hepatitis C virus (HCV) infection is a leading cause of liver-related mortality. Chronic hepatitis C (CHC) is frequently associated with disturbances in iron homeostasis, with serum iron and hepatic iron stores being elevated. Accumulating evidence indicates that chronic HCV infection suppresses expression of hepatic hepcidin, a key mediator of iron homeostasis, leading to iron overload conditions. Since hepcidin mediates degradation of ferroportin, a basolateral transporter involved in the release of iron from cells, diminished hepcidin expression probably leads to up-regulation of ferroportin-1 (Fpn1) in patients with CHC. In this study, we determined the protein levels of duodenal Fpn1, and found that its expression was significantly up-regulated in patients with CHC. The expression of duodenal Fpn1 is negatively correlated with mRNA levels of hepcidin, and positively correlated with serum iron parameters. Although iron is a critical factor for growth of a variety of pathogenic bacteria, our results suggest that iron overload in blood does not increase the infection rate of bacteria in patients with CHC.

Relationship between Hepatitis C Virus Infection and Iron Overload

“…This suggests that HCV proteins may directly lead to increased duodenal iron absorption, macrophage iron release, and hepatic iron accumulation. [42] Elevated duodenal FPN levels[47] and a significant relationship between HCV and hepcidin[48] in CHC patients were also found by other studies. All of these studies suggest that hepcidin may play a pivotal role in the pathogenesis of iron overload in patients with CHC.…”

“…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.…”

Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

“…Hepcidin production and its antiviral action may be reduced by HCV. Low serum hepcidin levels may in turn increase duodenal absorption of iron by up‐regulating duodenal ferroportin, and the increased intracellular iron content may suppress HCV replication in a negative feedback loop . The net effect of these counterbalancing actions may depend on the relative strength of the inherent response to raise hepcidin levels in response to iron overload and the prowess of HCV to circumvent the antiviral action of hepcidin by suppressing transcriptional activity of the HAMP gene …”

Impact of iatrogenic iron overload on the course of hepatitis C in the dialysis population: A plea for caution

“…Serum hepcidin has been shown to be lower in the cohorts of Italian and Greek patients with hepatitis C and liver hepcidin production has been shown to be lower in Japanese patients with hepatitis C than in patients with other liver diseases . Due to the suppression of hepcidin, ferroportin is upregulated in the duodenum of HCV‐infected patients, leading to unregulated intestinal iron absorption, as seen in genetic hemochromatosis and thalassemia . Thus, decreased hepcidin‐mediated degradation of ferroportin constitutes one of the main pathophysiological mechanism responsible for superimposed hepatic iron overload in HCV‐infected patients …”

“…[36][37][38] Due to the suppression of hepcidin, ferroportin is upregulated in the duodenum of HCVinfected patients, leading to unregulated intestinal iron absorption, as seen in genetic hemochromatosis and thalassemia. 39 Thus, decreased hepcidin-mediated degradation of ferroportin constitutes one of the main pathophysiological mechanism responsible for superimposed hepatic iron overload in HCV-infected patients. 40…”