Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans

Abstract

Context: In autosomal dominant hypophosphatemic rickets (ADHR), fibroblast growth factor 23 (FGF23) resists cleavage, causing increased plasma FGF23 levels. The clinical phenotype includes variable onset during childhood or adulthood and waxing/waning of hypophosphatemia. Delayed onset after puberty in females suggests iron status may be important.

Objective: Studies were performed to test the hypothesis that plasma C-terminal and intact FGF23 concentrations are related to serum iron concentrations in ADHR.

Design and setting: Cross-sectional and longitudinal studies of ADHR and a cross-sectional study in healthy subjects were conducted at an academic medical center.

Participants: Participants included 37 subjects with ADHR mutations from four kindreds and 158 healthy adult controls.

Main outcome measure: The relationships of serum iron concentrations with plasma C-terminal and intact FGF23 concentrations were evaluated.

Results: Serum phosphate and 1,25-dihydroxyvitamin D correlated negatively with C-terminal FGF23 and intact FGF23 in ADHR but not in controls. Serum iron was negatively correlated to both C-terminal FGF23 (r = -0.386; P < 0.05) and intact FGF23 (r = -0.602; P < 0.0001) in ADHR. However, control subjects also demonstrated a negative relationship of serum iron with C-terminal FGF23 (r = -0.276; P < 0.001) but no relationship with intact FGF23. Longitudinally in ADHR subjects, C-terminal FGF23 and intact FGF23 concentrations changed negatively with iron concentrations (P < 0.001 and P = 0.055, respectively), serum phosphate changed negatively with C-terminal FGF23 and intact FGF23 (P < 0.001), and there was a positive relationship between serum iron and phosphate (P < 0.001).

Conclusions: Low serum iron is associated with elevated FGF23 in ADHR. However, in controls, low serum iron was also associated with elevated C-terminal FGF23, but not intact FGF23, suggesting cleavage maintains homeostasis despite increased FGF23 expression.

Figures

Fig. 1.

Iron and FGF23. Cross-sectional plots are shown of serum iron with plasma log intact FGF23 and log C-terminal FGF23 for ADHR and control subjects. A and B, ADHR subjects; C and D, healthy controls (▵, females; □, males). To easily view the distribution of variables, different scales are used for some axes between ADHR and controls.

Fig. 2.

FGF23, phosphate, 1,25D, and alkaline phosphatase in ADHR. Cross-sectional plots are shown for ADHR relationships of plasma log C-terminal FGF23 and log intact FGF23 with serum phosphate (A snd B), alkaline phosphatase (C and D), and 1,25D (E and F) as dependent variables (▵, females; □, males).

Fig. 3.

ADHR longitudinal data: iron, FGF23, 1,25D, and phosphate. A and B, Longitudinal plots are shown for relationships of serum iron to plasma log C-terminal FGF23 (A) and plasma log intact FGF23 (B). C and D illustrate the relationships of plasma log C-terminal FGF23 and log intact FGF23 to serum phosphate, longitudinally. Note similarities in distribution with the cross-sectional graphs in Figs. 1 and 2. E and F illustrate the relationships of plasma log C-terminal FGF23 and log intact FGF23 to serum 1,25D, longitudinally. G and H, Longitudinal plot of the relationships of serum iron and serum phosphate (G) and longitudinal plots of the relationship of serum iron and 1,25D (H). For all measurements, n = 15, except 1,25D (n = 14). For each graph, the diamonds indicate the initial sample, and the lines indicate changes in parameters over sequential measurements.