- Dietary iron absorption from biofortified potatoes is higher in high altitude residents than in matched sea level counterparts. - Our data suggests chronic upregulation of iron absorption at altitude occurs independently of the hepcidin-erythroferrone axis. Acute high-altitude hypoxia increases erythropoietin (EPO) and erythroferrone (ERFE), which suppresses hepcidin and enhances iron absorption to support erythropoiesis. Whether these responses to acute exposure persist in long-term acclimatized individuals remains unclear. We conducted a prospective comparative study in 80 healthy Peruvian women (plasma ferritin <30 μg/L) who had lived for ≥5 years at high altitude (Huancavelica, 3670 m, n=40) or sea level (Lima, n=40). The groups were matched for age, body size, plasma ferritin and altitude-adjusted hemoglobin (Hb). Participants consumed ten standardized iron-biofortified potato-based meals, each labeled with 57 FeSO 4 , twice daily for five consecutive days. We measured iron and erythropoiesis-related biomarkers and assessed cumulative fractional iron absorption (FIA) by measuring isotopic incorporation into red blood cells 14 days later. High-altitude residents had significantly higher EPO concentrations (13.6 vs. 4.4 IU/L) and unadjusted Hb concentrations (15.0 vs. 11.8 g/dL) (for both, P<0.01), consistent with chronic hypoxic stimulation of erythropoiesis. There were no differences in altitude-adjusted Hb, plasma ferritin, ERFE, or hepcidin between groups. FIA was higher at altitude (15.8%) compared to sea level (9.3%, P<0.05). At altitude, FIA correlated with intestinal fatty acid binding protein (ρ=0.343, P<0.05), a marker of enterocyte injury. Long-term residence at high altitude is associated with 3-fold higher EPO concentrations and ∼70% greater dietary iron absorption, without changes in ERFE or hepcidin. This suggests chronic adaptation to altitude increases iron absorption through hypoxia-mediated pathways in the gut, independent of hepcidin. This may be associated with increased iron requirements in high-altitude populations. ( ClinicalTrials.gov . NCT05500014)
Moretti et al. (Thu,) studied this question.