Iron supplementation - better with intermittent low doses
Iron supplementation is important when iron storage is deficient as indicated by a low ferritin level. Even in the absence of anemia suboptimal ferritin is associated with fatigue, hair loss, restless leg syndrome, and impaired production of dopamine and serotonin. There is evidence that prescribing iron taken intermittently may result in more effective absorption due to the increased production of hepcidin in response to iron supplementation. A study published in the journal Blood (American Society of Hematology) examines the dynamics.
"Iron supplements acutely increase hepcidin, but the duration and magnitude of the increase, its dose dependence, and its effects on subsequent iron absorption have not been characterized in humans. Better understanding of these phenomena might improve oral iron dosing schedules. We investigated whether the acute iron-induced increase in hepcidin influences iron absorption of successive daily iron doses and twice-daily iron doses."
Besides the discomfort that can be associated with less advanced forms of iron supplementation, overcoming partial absorption with higher doses can cause other harms.
"The absorption of iron supplements ranges from 2% to 13% and 5% to 28% in subjects with low iron stores when consumed with and without food, respectively. Thus, a majority of the iron is unabsorbed. Although its role in the emergence of side effects is uncertain, high iron doses can potentially adversely affect the composition of the gut microbiome and increase inflammation, as assessed by fecal calprotectin levels."
Hepcidin response to iron supplementation
Hepcidin is a decisive factor in the degree of iron absorption.
"Hepcidin is the key regulator of systemic iron balance in mammals, acting in concert with intracellular iron metabolism. Iron supplementation acutely increases the circulating plasma hepcidin level, but the magnitude and duration of this increase has not been characterized in humans. Plasma hepcidin negatively correlates with iron bioavailability and has a circadian increase over the day, in association with a fall in transferrin saturation. Morning iron supplementation enhances this increase in plasma hepcidin, potentially affecting iron absorption from supplements given as divided doses in the morning and in the afternoon."
Low-dose alternate day iron may be best
The authors conducted three trials examining the effects of various dosage amounts and intervals and found an interesting reaction to iron supplementation that has great clinical significance. They demonstrated clear differences in absorption depending on dose spacing when doses are higher than 40 mg.
"In iron-depleted young women, oral iron doses of 60, 80, 160, and 240 mg Fe given in the morning acutely increased PHep [plasma hepcidin] on the same day and 24 hours later. This increase was strongly associated with decreased absorption from the second iron dose, given 24 hours after the first. Providing 60 mg of iron twice daily amplified the PHep increase and decreased the fractional absorption of both the afternoon dose and the next morning dose, so that total iron absorbed from the 3 doses (2 mornings and afternoon) was not different from that of the 2 morning doses. Although these results require confirmation in longer-term supplementation schedules, the short-term effects observed on hepcidin suggest that oral iron at doses ≥60 mg greater will result in higher fractional absorption when dosages are spaced by 48 hours. For 40 mg iron, we found borderline effects. Similarly, hepcidin profiles after supplementation indicate that increasing the interval between doses to >48 hours would not result in higher absorption than dosing at 48-hour intervals, although we did not test this directly. The WHO recommends intermittent iron supplementation in children and menstruating women, proposing as the rationale a mucosal block in enterocytes lasting for 5 to 6 days. Our data, based on the acute effect of supplements on hepcidin, suggest that 48 hours, not 5 or 6 days, is sufficient for iron absorption to return to baseline."
They conclude that, at least for young women with low iron stores who are not yet anemic, relatively low doses of iron given on alternate days may be the most effective:
"In conclusion, our data show that fractional absorption in iron-depleted women is highest at low iron doses (40-80 mg) and that acute, consecutive-day dosing results in decreased iron bioavailability. For total iron absorption, twice-daily iron supplementation seems to have limited additional effect compared with daily administration. These findings emphasize the need to study longer-term, alternate-day schedules of iron supplementation and advocate the hypothesis that low-dose iron given on alternate days may maximize fractional iron absorption, increase dosage efficacy, reduce gastrointestinal exposure to unabsorbed iron, and ultimately improve tolerance of iron supplements."
More evidence for alternate-day dosing
A study published subsequently in The Lancet Haematology asks the same questions:
"Current guidelines to treat iron deficiency recommend daily provision of ferrous iron divided through the day to increase absorption. However, daily dosing and split dosing might increase serum hepcidin and decrease iron absorption from subsequent doses. Our study aim was to compare iron absorption from oral iron supplements given on consecutive versus alternate days and given as single morning doses versus twice-daily split dosing."
They conducted two trials with varying dosages and intervals, and come to the same conclusion:
"In iron-depleted women, providing iron supplements daily as divided doses increases serum hepcidin and reduces iron absorption. Providing iron supplements on alternate days and in single doses optimises iron absorption and might be a preferable dosing regimen. These findings should be confirmed in iron-deficient anaemic patients."