Synergistic Contribution of HFE H63D Mutation to Secondary Polycythemia Pathogenesis at Moderate-High Altitude: A...

Objective: This study examined whether HFE H63D carriers living at moderate-to-high altitude have a stronger secondary polycythemia phenotype than non-carriers from the same region. Methods: This retrospective cohort study included 59 patients with HFE gene mutation (heterozygous n = 49, homozygous n = 10) and 51 controls without HFE mutation (total N = 110). JAK2 V617F negativity was confirmed in all participants. Serum erythropoietin (EPO) levels were assessed in the HFE mutation group to support secondary, non-clonal erythrocytosis. Results: Hemoglobin (17.32 ± 1.29 vs. 15.11 ± 0.95 g/dL (p < 0.001), hematocrit (median 51.50 vs. 45.20; p < 0.001), and erythrocyte count (p < 0.001) were significantly higher in the HFE mutation group. Transferrin saturation was higher in the HFE mutation group than in controls (64.56 ± 2.03% vs. 36.30 ± 1.58%; p < 0.001; Cohen's d = 0.95). Serum iron was higher and total iron-binding capacity was lower in the HFE mutation group, respectively (127.58 ± 44.10 vs. 93.62 ± 29.55 µg/dL and 194.32 ± 72.41 vs. 243.36 ± 40.82 µg/dL; both p < 0.001). CRP levels were also significantly elevated (p < 0.001). No significant differences were observed between the heterozygous and homozygous HFE mutation subgroup. Conclusions: HFE H63D carriers had higher erythrocytosis-related parameters and transferrin saturation than controls. These findings suggest that HFE-related changes in iron handling may strengthen the erythrocytosis phenotype at moderate-to-high altitude. Larger prospective studies should test this association.