High-altitude residence increases dietary iron absorption in young women: a prospective stable isotope study in Peru

Key Findings:

• Increased Absorption: Women living at high altitudes absorbed ~70% more iron from biofortified potatoes compared to those at sea level (15.8% vs. 9.3%).
• Mechanism: The study found that high-altitude residents had 3-fold higher Erythropoietin (EPO) concentrations. Interestingly, this increased absorption occurred without changes in hepcidin or erythroferrone (ERFE) levels.
• Hypoxia-Mediated: The results suggest that chronic adaptation to altitude increases iron absorption through hypoxia-mediated pathways directly in the gut, rather than the traditional hepcidin-regulated axis.
• Nutritional Implications: This finding highlights potentially higher iron requirements for populations living in high-altitude regions to support chronic hypoxic stimulation of erythropoiesis.

ABSTRACT

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 ⁵⁷FeSO₄, 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)