Threshold ferritin and hepcidin concentrations indicating early iron deficiency in young women based on upregulation of iron absorption

BACKGROUND: Plasma ferritin is a widely used indicator to detect iron deficiency, but the threshold ferritin that defines iron deficiency remains uncertain. Our aim was to define the ferritin concentration at which the body begins to upregulate iron absorption from the diet; this could provide a functionally-defined threshold of incipient iron deficiency. We hypothesized this threshold ferritin concentration would correspond to the threshold hepcidin concentration at which iron absorption begins to increase. METHODS: We performed a pooled analysis of our stable iron isotope studies (n = 1058) conducted from 2006 to 2019 in healthy women (age 18–50 years; mean±SD ferritin 33.7 ± 27.1 μg/L) that measured iron absorption from labeled test meals providing physiological amounts of iron. To fit relationships between iron absorption, ferritin and hepcidin, we used generalized additive modeling, and to identify thresholds, we estimated the first derivatives of the fitted trend to assess inflection points in these relationships. FINDINGS: Hepcidin increased linearly with increasing ferritin over the entire range of ferritin values. Iron absorption began to increase below a threshold hepcidin value of 3.09 (95%CI: 2.80, 3.38) nmol/l, above which iron absorption remained stable. Iron absorption began to increase below a threshold ferritin value of 51.1 (95%CI: 49.1, 53.1) µg/l, above which iron absorption remained stable. The latter two findings were internally consistent in that, in the relationship between hepcidin and ferritin, a hepcidin of ~3 nmol/l corresponded to a ferritin of ~51 µg/l. INTERPRETATION: Based on physiological upregulation of iron absorption, a threshold ferritin of <50 µg/L, corresponding to a threshold hepcidin of <3 nmol/l, indicates incipient iron deficiency in young women.