Since its discovery, hepcidin has attracted the attention of investigators because of its ability to regulate iron metabolism and exert antimicrobial activity against numerous bacteria and fungi [1
]. In the present study, the serum level of prohepcidin, a hepcidin precursor, and its relationship with iron metabolism and H. pylori
infection were evaluated. There was no relationship between prohepcidin, iron deficiency parameters, and H. pylori
Hepcidin plays a major role in the iron regulatory mechanism through inhibition of iron export from enterocytes, macrophages, and hepatocytes [5
]. Hepcidin levels increase in response to iron loading, reducing intestinal iron absorption and inhibiting iron release from stores [21
]. Meanwhile, iron deficiency produces low hepcidin levels, resulting in enhanced iron absorption and iron mobilization from stores. In addition, hepcidin is induced by inflammation, causing its sequestration in stores [7
]. The resulting iron decrease contributes to anemia in chronic disease. The relationship of hepcidin to disorders of iron metabolism has been established via the measurement of urinary hepcidin concentrations using immune-dot [7
], sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), western blot [4
], and surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) [22
]. Recent studies reported two types of hepcidin assays for the semiquantitative or quantitative determination in human serum. First, mass spectrometric assays detect the characteristic mass of the active 25-amino-acid hepcidin species or its fragments [23
]. However, these assays require access to specialized equipment and are not widely available. Second, an ELISA specific for the refolded, mature 25-amino-acid form was developed [26
]. The serum hepcidin level by ELISA was inversely correlated with iron absorption from supplemental and food-based nonheme iron sources in iron-replete healthy women [27
]. However, subsequent evaluation is required to prove the usefulness of this method.
In the present study, we measured serum prohepcidin levels; this is one of the limitations of this study. Prohepcidin is far more immunogenic than hepcidin, and a prohepcidin ELISA is commercially available. Our study failed to show any association between serum prohepcidin concentrations and iron deficiency parameters. These results are in agreement with those of previous studies in which the serum prohepcidin concentration was correlated poorly with markers of iron homeostasis, such as intestinal iron absorption [27
]. In addition, a relationship between serum concentrations of prohepcidin and those of hepcidin 25 was not found [27
]. However, another study reported a significant positive correlation between prohepcidin and hepcidin serum levels [30
An association between H. pylori
infection and IDA has been reported [8
]. Our study showed that anemia was not increased in subjects with H. pylori
infection and showed no relationship with hepcidin. This may be due to the small sample size, the fact that the study cohort was fairly uniform, and the fact that most subjects had normal iron stores. Nevertheless, our data do not support the proposal that hepcidin plays a key role in the primary mechanism of H. pylori
-induced anemia. Previous studies have demonstrated that hepcidin and prohepcidin serum levels by ELISA were not altered by H. pylori
infection or eradication even when hepcidin was detected in human gastric juice [16
]. These findings suggest that hepcidin may exert local rather than systemic functions.
Schwarz et al. recently reported a new role for hepcidin in the stomach [16
]. In this study, quantitative RT-PCR demonstrated abundant hepcidin expression in the fundus/corpus part of the glandular stomach in mice, rats, and humans. Hepcidin was localized in gastric parietal cells by immunofluorescence staining and in situ
hybridization. Gastric hepcidin expression in patients and in AGS cells was significantly upregulated during H. pylori
infection. In addition, H. pylori
eradication resulted in normalization of hepcidin expression levels. Moreover, hepcidin-knockout mice displayed decreased H+
-ATPase gene expression, significant bacterial overgrowth, and reduced gastric gene expression. These findings suggest that hepcidin regulates gastric acid production and may contribute to the development of gastric ulcers. In the present study, atrophic gastritis was found to be present in 50%. In Korea, the seroprevalence of H. pylori
was high (59.6%) in the Korean population among asymptomatic Korean adults in 2005 [33
]. In addition, the prevalence of atrophic gastritis in the antrum and body was 42.5% and 20.1%, respectively, in Korean population without significant gastroduodenal disease [34
]. We found that serum prohepcidin levels decreased in subjects with gastric atrophy, irrespective of H. pylori
infection. This finding might be explained by the loss of hepcidin-producing cells caused by gastric atrophy. However, we did not find that serum prohepcidin levels are related to the degree of atrophy. In addition, correlation between the serum prohepcidin and the parameters for anemia was not found in patient with atrophic gastritis. This can be explained by the small number of patients enrolled and by the lack of evaluation of hepcidin expression in gastric tissues. A recent study demonstrated that gastric hepcidin expression decreased in hypergastrinemic ING-mice with chronic gastric H. pylori
infection and resulted in the upregulation of the expression of various downstream iron absorption and efflux genes such as Ferroportin 1, Divalent metal transporter 1, and Transferrin receptor 1 [35
]. These findings suggest that the decrease of gastric hepcidin expression due to the loss of hepcidin-producing parietal cells may function as an iron regulator. However, further studies regarding the functional role of hepcidin and iron transporter in the gastric mucosa are required because iron is mainly absorbed in the small intestine.
Pepsinogen, an aspartic proteinase secreted mainly by gastric cells, is classified immunologically as pepsinogen I (PG I) and pepsinogen II (PG II). Whereas PG I is secreted only from the gastric fundic mucosa, PG II is secreted from the cardiac, fundic, and antral mucosae of the stomach [36
]. The effects of gastric atrophy on serum PG concentrations are lower PG I and stable or increased PG II levels, and this results in a lower PG I/II ratio [37
]. Gastrin is another valid tool for detection of gastric body mucosal atrophy, and increased serum gastrin is a regular feature of atrophic body gastritis due to the loss of negative feedback by gastric acidity [38
]. Further study is needed to evaluate the relationships between hepcidin and gastric mucosal atrophy using the gastrin and/or pepsinogen I/II ratio.
In conclusion, our data suggest that serum prohepcidin levels were not altered by H. pylori infection. Serum prohepcidin levels decreased in patients with atrophic gastritis, irrespective of H. pylori infection. It suggests that hepcidin may decrease due to gastric atrophy, a condition that causes a loss of hepcidin-producing parietal cells. Further studies with a larger number of atrophic gastritis patients are necessary to better investigate the relationship between hepcidin and atrophic gastritis.