Iron deficiency, with or without anemia, is extremely frequent worldwide, representing a major public health problem. In the United States, the prevalence of iron deficiency (defined by the log ratio of transferrin receptor to ferritin) in women ages 12 to 19 years and 20 to 49 years is approximately 9 percent for both age groups according to National Health and Nutrition Examination Study data (2003-2006). Its treatment includes addressing the underlying cause and replacing the iron deficit. However, exactly who benefits from correction and how best to administer iron remain open questions. In clinical practice, oral iron supplementation at various doses and dosing intervals is the most common replacement route, complicated by poor absorption and gastrointestinal adverse effects that contribute to nonadherence in up to 50 percent of patients.1
Hepcidin (Hamp) is the key regulator of mammalian systemic iron balance. It acts on the iron export protein ferroportin causing its internalization and degradation.2 High hepcidin levels inhibit intestinal dietary iron absorption and macrophage red blood cell (RBC) iron recycling.3-5 Iron supplementation acutely increases circulating plasma hepcidin levels.6 This physiology was elegantly tested in a short-term clinical study: Women with depleted iron stores and without anemia (ferritin ≤ 20 ng/mL) received various doses and frequencies of oral iron administered for two to three days. Higher or more frequent doses of iron raised circulating hepcidin levels and reduced subsequent fractional iron absorption.7
To address whether this effect on hepcidin levels and iron absorption occurs and persists during long-term supplementation, Dr. Nicole Stoffel and colleagues conducted two open-label randomized controlled trials assessing iron absorption in iron-depleted women (serum ferritin level ≤ 25 μg/L; ages 18 to 40 years). Within-individual comparisons were performed. The primary outcomes of both studies were iron bioavailability (total and fractional iron absorption, measured by radiolabeled-iron incorporation into RBCs) and serum hepcidin levels. In the first study, 40 women were randomly assigned to either 60 mg of oral iron (as FeSO4) administered each morning for 14 days, or the same dose on alternate days for 28 days. At the end of treatment (14 or 28 days, for the consecutive- and alternate-day groups, respectively), geometric mean cumulative fractional iron absorptions were 16.3 percent in the consecutive-day group versus 21.8 percent in the alternate-day group (p=0.0013), and cumulative total iron absorption was 131.0 mg in the consecutive-day group versus 175.3 mg in the alternate-day group (p=0.0010). During the first 14 days of supplementation in both groups, serum hepcidin level was higher in the consecutive-day group than the alternate-day group (p=0.0031). There was a trend toward decreased nausea in the every-other-day group.
In the second study, women were assigned to two groups stratified by comparable serum ferritin levels. One group received 120 mg of oral iron each morning (n=10), and the other received 60 mg orally in the morning and 60 mg orally in the evening (n=10), for three consecutive days. Fourteen days after the final dose, the groups each crossed over to the other regimen. No significant differences were seen in fractional or total iron absorption between the two dosing schemes. Twice-daily divided doses resulted in a higher serum hepcidin concentration than once-daily dosing (p=0.013).
Nicely informed by basic iron physiology, this study suggests that alternate-day, rather than twice-daily, dosing of oral iron can overcome the hepcidin-mediated block of iron absorption. While not addressed in this study, patient tolerability to and compliance with oral iron might improve with this approach. Additional studies are needed to determine whether this observation holds in iron-deficient patients with anemia and in other clinical settings. If it does, this simple strategy could transform the therapy for this common medical condition.
Tolkien Z, Stecher L, Mander AP, et al. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One. 2015;10:e0117383.
Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-2093.
Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004;117:285-297.
Pak M, Lopez MA, Gabayan V, et al. Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006;108:3730-3735.
Vokurka M, Krijit J, Sulc K, et al. Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Physiol Res. 2006;55:667-674.
Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271-1276.
Moretti D, Goede JS, Zeder C, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126:1981-1989.
Conflict of Interests
Dr. Keel indicated no relevant conflicts of interest.
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