Exploring the dynamics of FGF23 in patients with Hereditary Hemochromatosis type I following iron depletive treatment: a pilot study

Purpose: Anemia, inflammation and iron deficiency are linked to Fibroblast growth factor 23 (FGF23). Aim of this study was to explore the dynamics of FGF23 in Hereditary Hemochromatosis type-I (HH1). Methods: Twenty-six consecutive patients with genetically confirmed and uncomplicated HH1 and nineteen healthy age-matched voluntary blood donors (CTR) were enrolled for the study. Intact (iFGF23) and C-terminal (cFGF23) FGF23 and iron status markers were evaluated at baseline (T0) and seven days (T7) after phlebotomy/voluntary blood donation (VBD). Bone mineral density (BMD) and vertebral fracture assessment (VFA) were also evaluated at T0. Results: Cross-sectional and longitudinal analyses failed to reveal significant differences in iFGF23 in both HH1 (T0: 54.27 ± 14.42 pg/mL; T7: 54.70 ± 15.48 pg/mL) and CTR (T0: 52.77 ± 17.63 pg/mL; T7: 53.27 ± 15.88 pg/mL) groups. Absence of significant difference was also observed for cFGF23 at baseline between the two groups (HH1, T0: 0.98 ± 0.39 pmol/L; CTR, T0: 1.18 ± 0.91 pmol/L) but not at T7 when the values (HH1, T7: 01.20 ± 0.89; CTR, T7: 1.84 ± 1.11 pmol/L) were significantly increased in CTR compared to T0 (p = 0.0003) and to HH1 (p = 0.0240). After phlebotomy/VBD, in both HH1 and CTR groups, serum levels of phosphate were unchanged from baseline while serum iron, ferritin and transferrin saturation and erythrocyte-related parameters (red blood cells, hemoglobin and hematocrit) were significantly reduced (all p  <  0.0001). Serum iron, ferritin, and transferrin saturation were significantly higher in HH1 than in CTR (p = 0.0002 for serum iron and p  <  0.0001 for both ferritin and transferrin saturation) at T7. In the CTR group, these parameters showed a trend toward iron deficiency whereas in HH1 they remained near the upper limit of the normal range, suggesting a persistent mild iron overload. Correlation and regression analyses did not show significant associations between circulating FGF23 (both iFGF23 and cFGF23) and iron status markers. BMD and VFA were not significantly different between HH1 and CTR. Furthermore, BMD and Trabecular Bone Score values were not associated with circulating FGF23 levels. Conclusion: This pilot study indicates that the serum levels of iFGF23 and cFGF23 and skeletal health evaluated through BMD and VFA do not differ between patients with uncomplicated HH1 and healthy subjects at baseline. The absence of changes in the serum levels of iFGF23 and cFGF23 in HH1 patients with uncomplicated HH1 after phlebotomy may reflect the persistence of iron overload which could counteract the physiological hypoxia-driven stimulation of FGF23 production and cleavage observed in healthy subjects after VBD.