Insights & Discussion
The hepcidin-ferroportin iron regulatory pathway prevents iron overload, creating an inherent limit on gastrointestinal iron absorption, and hence affects the efficacy of oral iron supplementation.
The methodology adopted in this study involved investigating the pathophysiology of iron absorption alongside reviewing existing evidence relating to different preparations of oral iron. Different dosing protocols were compared, including daily low dose and every other day protocols, in an attempt to bypass the limitations imposed by the body's own regulatory systems and maximize absorption while minimizing side effects. The formulation, dosing strategy, and patient selection for oral vs. intravenous iron supplementation were also studied.
The results demonstrated that the body's inherent iron regulation pathway, named the hepcidin-ferroportin pathway, has evolved to prevent iron overload, which subsequently places an inherent limit on gastrointestinal iron uptake; this has significant implications for the efficacy of oral iron supplementation. Furthermore, excess unabsorbed iron proved to be responsible for various side effects often associated with oral iron supplementation, such as dyspepsia and constipation. This underlines the challenges posed by the body's own iron management system when dealing with iron deficiency through oral iron supplements.
Discover Related Insights
A lower dose of iron amino acid chelate was not as effective as the standard iron salts dose in increasing ferritin levels in a predominantly iron-replete female Cambodian population.
2023 The Journal of Nutrition Is a Lower Dose of More Bioavailable Iron (18-mg Ferrous Bisglycinate) Noninferior to 60-mg Ferrous Sulfate in Increasing Ferritin Concentrations While Reducing Gut Inflammation and Enteropathogen Detection in Cambodian Women? A Randomized Controlled Noni Fischer JAJ, Pei LX, Elango R, Hou K, Goldfarb DM, Karakochuk CD
Clinical Study Iron Deficiency
The research used a double-blind, randomized placebo-controlled noninferiority trial conducted in Cambodia. Participating nonpregnant women, aged 18-45, were randomly assigned either 60mg ferrous sulfate, 18mg ferrous bisglycinate or a placebo for 12 weeks. Baseline and 12-week post blood and fecal samples were collected from the participants and used to measure ferritin and fecal calprotectin levels as well as to detect the presence of enteropathogens.
The study found that mean ferritin concentration was higher at 12 weeks in those receiving ferrous sulfate dose compared to those receiving a lower dose of ferrous bisglycinate and a placebo. No significant changes were observed across the groups in terms of fecal calprotectin concentrations or detection of enteropathogens. Therefore, it was concluded that the 18mg dose of ferrous bisglycinate was not as effective as the 60mg ferrous sulfate dose in increasing ferritin concentrations.
Iron supplementation with ferrous bisglycinate in Cambodian women of reproductive age may increase the abundance of certain bacteria, including potential enteric pathogens.
2023 Microbiology Spectrum The Effect of Oral Iron Supplementation on Gut Microbial Composition: a Secondary Analysis of a Double-Blind, Randomized Controlled Trial among Cambodian Women of Reproductive Age Finlayson-Trick E, Nearing J, Fischer JAJ, Ma Y, Wang S, Krouen H, et al.
Randomised Controlled Trial Iron Deficiency
The study involved a secondary analysis of a double-blinded, randomized controlled trial examining the impact of two different oral iron supplements, ferrous sulfate and ferrous bisglycinate, or placebo on the gut microbiomes in Cambodian women of reproductive age (WRA) over a period of 12 weeks. Stool samples were provided by the participants at the beginning and end of the study for gut microbial analysis. This analysis consisted of 16S rRNA gene sequencing and targeted real-time PCR.
In terms of results, it was found that iron supplementation did not significantly change the overall diversity of the gut microbiome in these predominantly iron-replete Cambodian WRA. However, ferrous bisglycinate did lead to an increase in the relative abundance of and showed a trend of an increase for another strain of bacteria, Escherichia. Furthermore, the presence of a virulence gene associated with enteropathogenic Escherichia coli was detected in a greater quantity in the stool samples of those who took ferrous sulfate. This suggests that while the overall biodiversity of the gut microbiome remained stable, certain potential pathogen-associated bacterial populations may have increased due to the iron supplementation.
Ferrous bisglycinate, an innovative amino acid iron chelate, showed increased absorption and fewer gastrointestinal side effects when used as an iron supplement in pregnant women.
2023 Nutrition Reviews The effects of oral ferrous bisglycinate supplementation on hemoglobin and ferritin concentrations in adults and children: a systematic review and meta-analysis of randomized controlled trials Fischer JAJ, Cherian AM, Bone JN, Karakochuk CD
Meta-Analysis Iron Deficiency
Methodology: The team carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) through a comprehensive survey of electronic databases and grey literature up to July 17, 2020, to ascertain the impacts of ferrous bisglycinate versus other iron supplements on hemoglobin and ferritin levels and gastrointestinal (GI) adverse events. Exercises were undertaken to calculate averages from these trials which involved pregnant women and children and these average estimates were communicated as standardized mean differences. The rate of occurrence for GI adverse events was determined using Poisson generalized linear mixed-effects models. Studies involving other subjects (men and non-pregnant women) were evaluated on an individual basis.
Discussion of Results: The results reveal fermentable bisglycinate demonstrating an advantage over other iron supplements. Among the pregnant women involved in the trials, those using this supplement had higher hemoglobin levels after 4-20 weeks of administration. Additionally, these women reported reduced GI adverse events. Although the observed increase in ferritin levels was not marked as significant, it depicted an upward trend. However, no notable differences were detected in either hemoglobin or ferritin concentrations in children using ferrous bisglycinate.
Iron deficiency promotes a shift towards a more glycolytic metabolism, without detectable effect on mitochondrial bioenergetics, which can be corrected with iron supplements.
2022 Scientific Reports Abnormal whole-body energy metabolism in iron-deficient humans despite preserved skeletal muscle oxidative phosphorylation Frise MC, Holdsworth DA, Johnson AW, Chung YJ, Curtis MK, Cox PJ, et al.
Experimental Study Iron Deficiency Skeletal Muscle
The methodology of this prospective, case-control, clinical physiology study involved two series of testing. Thirteen iron-deficient individuals and thirteen iron-replete control participants were chosen for the study, and they underwent P-magnetic resonance spectroscopy of their exercising calf muscles to investigate the differences in oxidative phosphorylation. This testing was followed by a whole-body cardiopulmonary exercise test. After these assessments, individuals were given an intravenous infusion, which was randomised to be either iron or saline.
The results showed no significant influence of either baseline iron levels or the intravenous iron infusion on the high-energy phosphate metabolism. In the case of submaximal cardiopulmonary exercise, the rate of decline in blood lactate concentration was slower for the iron deficient group, which shows signs of abnormal energy metabolism on a whole-body level. Remarkably, this anomaly was corrected after an intravenous iron infusion. Furthermore, the intravenous iron also increased the lactate threshold during maximal cardiopulmonary exercise by around 10%, no matter what the baseline iron status of the individual was.
The body begins to upregulate iron absorption at a ferritin concentration of less than 50 µg/L, indicating an incipient iron deficiency in young women.
2021 EClinicalMedicine Threshold ferritin and hepcidin concentrations indicating early iron deficiency in young women based on upregulation of iron absorption Galetti V, Stoffel NU, Sieber C, Zeder C, Moretti D, Zimmermann MB
Cohort Study Ferritin Hepcidin Iron Absorption
In the methodology, this study utilizes a pooled analysis of stable iron isotope studies conducted between 2006 and 2019 on healthy women aged 18 to 50. These studies quantified iron absorption from meals providing physiological quantities of iron. A mathematical model known as generalized additive modeling was employed to ascertain the relationships between iron absorption, ferritin, and a molecule called hepcidin. By estimating the first derivatives of the trend created by the model, inflection points (or thresholds) in these relationships were established.
The results revealed that hepcidin increased in a linear fashion parallel to ferritin. Iron absorption increased when hepcidin reached a threshold value and when a threshold ferritin value was detected, beyond which iron absorption remained stable. An auxiliary validation within the results found that a hepcidin of approximately 3 nmol/l corresponded to a ferritin level of approximately 51 µg/l. These findings collectively suggest that if the body's ferritin concentration falls below 50 µg/L—corresponding to a hepcidin level of less than 3 nmol/l—the body will respond by absorbing more iron from the diet, signaling an emerging iron deficiency.
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