This study shows that iron status is the primary determinant of urinary hepcidin concentrations among pregnant women dwelling in a rural community of Bangladesh. To our knowledge, this is the first study to report urinary hepcidin levels in pregnancy, and it provides insights into factors involved in the regulation of iron metabolism during pregnancy. The four main factors that are thought to be involved in the upregulation of hepcidin are iron status, erythropoiesis, hypoxia, and inflammation.5,7,12
Elevated hepcidin limits the availability of iron for erythropoiesis by reducing iron absorption in the gut and limiting iron release from splenic macrophages and the liver.3
Therefore, hepcidin levels are generally higher in iron-replete individuals, during accelerated erythropoiesis, in non-hypoxic states, and in individuals with evidence of inflammation. We chose indicators that would allow us to examine, as closely as possible, these aspects of iron metabolism and their relationships with hepcidin in a free-living population at risk of iron deficiency and anemia. Among pregnant women in Bangladesh, urinary hepcidin levels were linearly related with iron stores over a wide range of serum ferritin concentrations. To a lesser degree, tissue iron deficiency (elevated TfR) was associated with lower hepcidin concentrations. However, urinary hepcidin levels were not associated with Hb concentrations and the signal for erythropoietic activity (EPO), and the association of hepcidin with inflammatory markers was modest.
It is noteworthy that women in this study were in the first trimester of pregnancy, when the demand of the body for iron is relatively low due to the cessation of menstruation. Iron requirements increase through the second and third trimesters of pregnancy to support the expansion of the red blood cell mass and tissue development of the placenta and fetus. Future work is needed to characterize changes in hepcidin in relation to iron status as pregnancy progresses and iron deficiency becomes more acute.
It is also notable that, while mild infections are common during pregnancy in this area of Bangladesh, among these community-dwelling pregnant women, CRP and AGP were not commonly elevated. Thus, the ranges of values in inflammatory markers against which to relate hepcidin were limited compared to other studies. Interleukin-6 (IL-6), which was not measured here but which is involved in the acute phase response, is thought to be directly involved in the upregulation of hepcidin.3
However, the relationship between IL-6 and hepcidin has mostly been studied previously in subjects with more severe inflammation than was apparent here; that is, in subjects with acute sepsis,19
and in healthy volunteers challenged with IL-6 or lipopolysaccharide.22,23
Although hepcidin is thought to be a major regulator of the anemia of chronic inflammation, such a role had yet to be shown definitively in a population-based study of community-dwelling adults. In this setting, AGP but not CRP showed a modest association with urinary hepcidin. The differential findings between AGP and CRP suggest that the choice of inflammatory marker is crucial for the interpretation of iron status indicators in population-based studies and may be explained by the fact that CRP rises and falls more rapidly in response to infection and inflammation than AGP.21
The findings from this study are consistent with observations of Nemeth and colleagues in which serum ferritin was significantly correlated with urinary hepcidin in a mixed sample of study subjects that consisted of patients with anemia of inflammation, compensated hereditary hemochromatosis, iron overload, iron deficiency anemia, and healthy donors.23
Other studies of hepcidin specific to pregnancy include a rat model in which liver hepcidin expression declined throughout pregnancy as iron stores declined. The decline in liver hepcidin expression was associated with increases in duodenal iron transport proteins DMT1, dcytb, and Ireg1, implying an association of declining hepcidin with increased iron requirements and enhanced iron absorption.24
Although there is considerable interest in evaluating the role of hepcidin in iron metabolism in a variety of population groups, currently the techniques for assessing bioactive hepcidin are not widely available and appear to be limited to mass spectrometric methods such as that utilized in this study. The relationship between plasma prohepcidin hormone has been explored using a commercial assay, and no association of iron or anemia status with plasma prohepcidin was demonstrated, suggesting that the commercial assay for plasma prohepcidin may not identify the active form of the hormone.25
This study provides insight into the role of hepcidin in iron deficiency associated with pregnancy. Hepcidin is likely to be a key regulator of iron metabolism during pregnancy, and this study provides strong evidence that iron status in particular influences hepcidin concentrations among pregnant women of Bangladesh. Future studies are needed with larger sample sizes and longitudinal study designs to characterize changes in hepcidin over time, and a wider panel of indicators to capture the multifactorial etiologies of iron deficiency and anemia during pregnancy and their as-yet unidentified associations with hepcidin concentrations.