REF-1415 · Moretti et al., 2015 · Blood · Paper · PubMed

Is a bigger iron dose better?

Not per milligram: in iron-depleted young women doses of 60 mg or more raised hepcidin for 24 h and cut the next day's absorption 35-45%; 6× the dose gave 3× the iron. Absorption only, not ferritin.

Main caveat: Abstract only; the publisher's free copy returned a bot check and was not tried further.
moderate evidenceMeasured on non-athletes and recreational people

Moretti and colleagues (ETH Zürich and partners) asked how long and how much an oral iron dose raises hepcidin, and whether that rise lowers absorption from the next dose. They recruited 54 nonanaemic young women with plasma ferritin ≤20 µg/L.

In a dose-finding part (studies 1 and 2, n = 25 and 16), labelled ferrous sulphate (40, 60, 80, 160 or 240 mg of iron as 57Fe, 58Fe or 54Fe) was given at 8:00 fasting on 1 or 2 consecutive days; in study 3 (n = 13), three 60-mg doses were given within 24 hours (twice-daily dosing).

Twenty-four hours after doses of 60 mg or more, serum hepcidin was raised and fractional absorption of the next dose fell by 35-45%. With increasing dose, fractional absorption decreased while absolute absorption increased: going from 40 to 240 mg (six times the dose) raised the iron absorbed only from 6.7 to 18.1 mg.

Three doses within 24 hours (two mornings and an afternoon) did not deliver significantly more iron than the two morning doses.

The authors conclude that lower doses (40-80 mg) and avoiding twice-daily dosing maximise fractional absorption, and that the hepcidin time course supports alternate-day supplementation, whose longer-term effects needed testing — which the same group later did (REF-970; REF-1416).

Our reading: the dose-response behind the clinical first-line dose (REF-1411 cites it) and the reason the base's high-end treatment figure needs framing; it measures efficiency per milligram, not how fast stores refill.

Protocol

Participants: n = 54 nonanaemic young women with plasma ferritin ≤20 µg/L (25 + 16 + 13 across three studies).
Studies 1 and 2 (dose finding): 40-, 60-, 80-, 160- or 240-mg labelled iron as ferrous sulphate at 8:00 fasting on 1 or on 2 consecutive days.
Study 3 (twice-daily dosing): three 60-mg doses within 24 hours (two mornings and an afternoon).
Outcomes: serum hepcidin; fractional and absolute iron absorption from isotope incorporation.
Registration: NCT01785407 and NCT02050932.
Funding and interests: PubMed lists "Research Support, Non-U.S. Gov't" without naming the funder; no conflict-of-interest statement in the abstract record. One affiliation is Hepcidinanalysis.com (Radboud University Medical Centre), as printed.

Key Results

Next-day effect: 24 hours after doses ≥60 mg, serum hepcidin was increased (P < .01) and fractional iron absorption decreased by 35% to 45% (P < .01).
Dose-response: with increasing dose, fractional absorption decreased (P < .001) and absolute absorption increased (P < .001).
Six times the dose, three times the iron: 40 to 240 mg gave 6.7 to 18.1 mg absorbed.
Twice-daily dosing: total iron absorbed from 3 doses (2 mornings and an afternoon) was not significantly greater than from 2 morning doses.
Not in the abstract: absorption figures for each dose, hepcidin values, side effects, results by baseline ferritin.

Mechanisms

Measured: an iron dose of 60 mg or more raises serum hepcidin that is still raised 24 hours later, and the next dose is absorbed less.
Authors' interpretation: the iron-induced hepcidin rise limits absorption from successive daily and twice-daily doses; the duration of the response supports alternate-day dosing.
Inference: exercise raises hepcidin too, peaking hours after a long session (REF-1418; REF-1421; PHYS-36); how the two add up in an athlete was not tested here.
Inference: fractional and absolute absorption point in different directions — a larger dose is less efficient yet still delivers more iron in total — so this study alone cannot say which dose refills stores fastest; REF-1416 tested schedules over months.

Practical Application

Is a bigger iron dose better? Not per milligram: in iron-depleted young women doses of 60 mg or more raised hepcidin for 24 h and cut the next day's absorption 35-45%; 6× the dose gave 3× the iron. Absorption only, not ferritin.
Dose framing for the base: the authors' efficient range is 40-80 mg once; the BSG's clinical first line is 50-100 mg once daily (REF-1411); the Swiss consensus gives 40-60 mg once daily (REF-1410). The 100-200 mg/day that SYNTH-67 quotes from REF-748 for treating deficiency is the high end — REF-748 also gives it for altitude blocks — and higher doses still deliver more iron in total. The dose is the prescriber's; the assistant reports what the studies show.
Split doses: a second dose the same day added nothing significant here (study 3); REF-970 found the same for 120 mg split in two.
Alternate days: this study gives the mechanism; the outcome trials show the same ferritin at the same total dose with fewer GI effects, over twice the time (REF-1416); in runners, the same ferritin gain over the same 8 weeks with fewer severe GI complaints on alternate days, which per REF-1416's description meant half the iron (REF-1417, B-).
What it does not show: a ferritin, haemoglobin, fatigue or performance outcome; effects in men, athletes or anaemic patients; effects with food or after training.

Limitations

Abstract only; the publisher's free copy returned a bot check and was not tried further.
Absorption, not status: one or two days of dosing; no ferritin or haemoglobin change.
Who: young, nonanaemic, iron-depleted women; no men, no athletes, no training.
Design details (allocation of doses, per-dose results) are not in the abstract.
Fasting doses of ferrous sulphate at 8:00; other times, forms and food were not tested.
Funding and interests: funder not named in the record; no conflict statement in the record.
How this entry was checked and changed
Why this level

(from the abstract) — controlled absorption studies of up to 25 women each (rubric B+ for a controlled crossover with at least 15), graded as the same group's REF-970; the outcome is absorption and hepcidin, not ferritin, haemoglobin or symptoms, and how doses were allocated is not described in the abstract