Abstract
Hepatic iron accumulation is generally increased in the chronic hepatitis C (CHC) liver; however, the precise mechanism of such accumulation remains unclear. We evaluated iron absorption from the gastrointestinal tract of patients with CHC and control participants. We measured the expression of a panel of molecules associated with duodenal iron absorption and serum hepcidin levels to determine the mechanism of iron accumulation in the CHC liver. We enrolled 24 patients with CHC and 9 patients with chronic gastritis without Helicobacter pylori infection or an iron metabolism disorder as control participants. An oral iron absorption test (OIAT) was administered which involved a dosage of 100 mg of sodium ferrous citrate. Serum level of hepcidin-25 was measured by liquid chromatography-tandem mass spectrometry. Ferroportin 1 (FPN) mRNA was measured by RT-PCR and FPN protein was analyzed by western blot. Samples were obtained from duodenum biopsy tissue from each CHC patient and control participant. Caco-2/TC7 cells were incubated in Costar transwells (0.4 μm pores). The OIAT showed significantly greater iron absorption in CHC patients than control participants. Serum hepcidin-25 in the CHC group was significantly lower than in the control group. Compared with control participants, duodenal FPN mRNA expression in CHC patients was significantly upregulated. The FPN mRNA levels and protein levels increased significantly in Caco-2/TC7 cell monolayers cultured in transwells with hepcidin. Lower serum hepcidin-25 levels might upregulate not only FPN protein expression but also mRNA expression in the duodenum and cause iron accumulation in patients with CHC.
Highlights
Hepatic iron overload has long been known to develop in patients with chronic hepatitis C (CHC) [1]
We previously revealed that excess free iron in hepatocytes promotes the production of reactive oxygen species (ROS) causing damage to hepatocytes and hepatic fibrosis and increases the level of 8-hydroxy-2-deoxyguanosine (8-OH-dG), a mutagenic base, in the liver, resulting in the development of hepatocellular carcinoma (HCC)
Despite the increased transferrin saturation (Tf sat) levels before the administration of sodium ferrous citrate (SFC), iron absorption was upregulated in CHC patients
Summary
Hepatic iron overload has long been known to develop in patients with chronic hepatitis C (CHC) [1]. We previously revealed that excess free iron in hepatocytes promotes the production of reactive oxygen species (ROS) causing damage to hepatocytes and hepatic fibrosis and increases the level of 8-hydroxy-2-deoxyguanosine (8-OH-dG), a mutagenic base, in the liver, resulting in the development of hepatocellular carcinoma (HCC). We found that iron reduction therapy in combination with phlebotomy and a low iron diet improved hepatitis and hepatic fibrosis while normalizing the elevated 8-OH-dG level [2]. We found that long-term iron depletion significantly reduced the incidence of HCC in patients with CHC (F2/F3 grade) [3]. Intestinal iron absorption is mainly from the duodenum. Hepcidin is a 2.7 kDa peptide consisting of 25 amino acids that is produced
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