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Oral iron supplementation with ferrous sulfate (FeSO4) is recommended to treat ID and iron deficiency anemia (IDA).3 Because iron absorption from oral supplements tends to be low, current recommendations call for daily provision of high doses of FeSO4, in the range of 60-200 mg, preferably split into 2 or 3 daily doses.4-7 With larger iron doses,8 the proportion of the dose absorbed, termed the fractional iron absorption (FIA), decreases, and large amounts of unabsorbed iron can cause gut inflamma- tion9,10 and increase free radical production and peroxida- tion in the gut mucosa.11,12 This may result in gastrointesti- nal side effects, which are common9 and typically dose dependent.13 Furthermore, an increase in colonic iron can reduce abundances of beneficial commensal gut bacteria and increase abundances of potential enteropathogens.14,15
oral iron doses of 100 and 200 mg acutely increase SHep and this increase persists for 24 h, but not 48 h; b) FIA from both doses would be lower on the following day, but not differ from baseline 48 h post administration (alternate day dosing), suggesting there is no ‘mucosal block’; and c) FIA would be lower from the 200 mg dose than the 100 mg dose.
Methods
Subjects
We recruited healthy women participating in the blood donation drive at the University of Zürich, and we con- ducted this study at the Human Nutrition Laboratory of the ETH Zürich, Switzerland. Detailed inclusion criteria are described in the Online Supplementary Materials and Methods. In this cross-over study, we compared iron absorption from consecutive and alternate day dosing in women with IDA, using 100 and 200 mg doses of iron as ferrous sulfate (FeSO4). This study was approved by the Cantonal Ethics Committee in Zürich, Switzerland. All participants gave informed written consent.
Participants went through two study cycles of 6 days each, with 16 days in between (Figure 1). To all subjects, we administered oral doses of FeSO4 in the morning on two consecutive days (days 2 and 3) and a third dose 48 h later (day 5), each dose was labeled with 57Fe, 58Fe or 54Fe. Subjects were randomly assigned to first receive either three doses of 100 mg or three doses of 200 mg. They were given the iron dose under standardized conditions. Detailed supplement administration is described in the Online Supplementary Material and Methods. On day 1, before iron supplementation, baseline venipuncture blood samples were taken at 8:00 AM and at 4:00 PM. Iron was administered at 8:00 AM on days 2, 3 and 5. Blood sam- ples were taken at 8:00 AM (before dosing) and at 4:00 PM on days 2, 3 and 5. Additional blood samples were taken on day 4 and day 6 at 8:00 AM. Using a questionnaire, subjects were asked whether they had gastrointestinal side effects during the visits. We assessed iron absorption by measuring isotopic enrichment in red blood cells 16 days after administration of the third dose in both supple- mentation periods.23-25 Hemoglobin (Hb), SHep, iron- and inflammatory biomarkers were measured as described in the Online Supplementary Materials and Methods.
Based on previous studies in our laboratory at the ETH Zürich using iron supplements in women we expected a standard deviation (SD) of the difference between pairs of 0.18 in log FIA. The study was powered to detect a rele- vant difference of 30% in FIA on a linear scale (such as 15% and 20%), which on a log scale, corresponds to 0.125 units of log FIA. This yielded a minimal sample size of 18 subjects, assuming a power of 0.8 and an alpha of 0.05. We recruited an additional subject to account for possible attrition, and enrolled 19 women in the study.
Statisticalanalysis
We performed the statistical analyses using SPSS (IBM SPSS statistics, Version22), as described in detail in the Online Supplementary Materials and Methods. We used lin- ear mixed effect model analysis with Bonferroni corrected multiple comparisons to assess the effect of consecutive versus alternate day dosing with 100 and 200 mg on dif- ferent variables. Dose and time (reflecting the supplement
Hepcidin, the central systemic controller of iron home- ostasis in mammals is a 25-amino acid peptide mainly pro- duced by the liver, and is regulated by iron, hypoxia, inflammation and erythropoiesis.16 Hepcidin binds to fer- roportin, mainly expressed on enterocytes, hepatocytes and macrophages, leading to internalization and degrada- tion of ferroportin. Thus, high serum hepcidin (SHep) reduces dietary iron absorption and recycling of iron from senescent erythrocytes. Large oral doses of iron acutely increase SHep in a dose-dependent fashion, with the increase in SHep persisting for ~24 hours (h).8,17 The increase after iron administration is distinct18 from the nat- ural circadian increase in SHep over the day.19 We previ- ously showed that twice daily administration of 60 mg oral iron sharply augments the circadian SHep increase and results in higher SHep on the next day compared to once daily dosing with 120 mg iron.17
In iron-depleted young women given doses ≥60 mg of oral iron in the morning, SHep increases and is followed by a decrease in iron absorption on the following day.8 Consequently, alternate day dosing results in a higher FIA compared to daily dosing.8 In a study comparing iron absorption from 60 mg doses during 28 days of alternate day versus 14 days of consecutive day supplementation, FIA was significantly higher (+33%) with alternate day dosing.17 In addition, due to the acute SHep increase after an oral iron dose, splitting a dose into two daily divided doses did not increase iron absorption.17 However, these studies were conducted in iron-depleted women without anemia. Whether oral iron supplements, given at higher doses in women with IDA also induce an acute SHep increase and inhibit absorption of daily doses of iron is uncertain.20
Besides the iron-induced increase in SHep, a putative ‘mucosal block’ may decrease iron absorption from daily iron doses. According to the ‘mucosal block’ theory, ente- rocytes exposed to a large dose of iron will not absorb subsequent iron doses until they are replaced by new enterocytes after five to six days; therefore, provision of iron doses at weekly intervals might increase absorption.21 If the increase in SHep subsides after 48 h, any residual inhibition on absorption would be consistent with this view of the ‘mucosal block’. The World Health Organisation recommends weekly intermittent iron doses in women who experience significant side effects taking oral iron doses.22 Therefore, the aim of our study was to measure the magnitude and duration of the acute SHep increase after high-dose oral iron supplementation and the effect on iron absorption in women with IDA. Our hypotheses regarding women with IDA were: a) single
haematologica | 2020; 105(5)
Iron absorption from oral supplements in anemia
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