Iron and fibroblast growth factor 23 in X-linked hypophosphatemia

Abstract

Background Excess fibroblast growth factor 23 (FGF23) causes hypophosphatemia in autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH). Iron status influences C-terminal FGF23 (incorporating fragments plus intact FGF23) in ADHR and healthy subjects, and intact FGF23 in ADHR. We hypothesized that in XLH serum iron would inversely correlate to C-terminal FGF23, but not to intact FGF23, mirroring the relationships in normal controls. Methods Subjects included 25 untreated outpatients with XLH at a tertiary medical center and 158 healthy adult controls. Serum iron and plasma intact FGF23 and C-terminal FGF23 were measured in stored samples. Results Intact FGF23 was greater than the control mean in 100% of XLH patients, and >2SD above the control mean in 88%, compared to 71% and 21% respectively for C-terminal FGF23. In XLH, iron correlated negatively to log-C-terminal FGF23 (r= −0.523, p<0.01), with a steeper slope than in controls (p<0.001). Iron was not related to log-intact FGF23 in either group. The log-ratio of intact FGF23 to C-terminal FGF23 was higher in XLH (0.00 ± 0.44) than controls (−0.28 ± 0.21, p<0.01), and correlated positively to serum iron (controls r= 0.276, p<0.001; XLH r= 0.428, p<0.05), with a steeper slope in XLH (p<0.01). Conclusion Like controls, serum iron in XLH is inversely related to C-terminal FGF23 but not intact FGF23. XLH patients are more likely to have elevated intact FGF23 than C-terminal FGF23. The relationships of iron to FGF23 in XLH suggest altered regulation of FGF23 cleaving may contribute to maintaining hypophosphatemia around an abnormal set-point.

Fibroblast growth factor is associated to left ventricular mass index, anemia and low values of transferrin saturation

“…This may suggest that cleavage maintains homeostasis despite increased FGF-23 expression 10,38 . Similar results were also obtained in patients with X-linked hypophosphatemia 39 . In studies in children and the elderly population also a relationship between FGF-23 and low serum iron level was detected 40,41 .…”

Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets

“…Recently however, evidence is accumulating from laboratory observations (13), the ADHR mouse model (14) and adults with ADHR (10) that low iron status may increase FGF23 expression in patients with ADHR, indicating that changes in iron status could cause the typical waxing/waning ADHR phenotype. Inverse relationships between serum iron status and C-terminal (but not intact) FGF23 concentrations have also been demonstrated in healthy adults (10,15,16), children (17), and patients with XLH (18).…”

A Practical Clinical Approach to Paediatric Phosphate Disorders

“…By contrast, in XLH patients, low iron levels are associated with further increases in circulating FGF23 fragments, but intact FGF23 concentrations and hypophosphataemia are not influenced by serum iron [44] . Interestingly, some forms of intravenous iron administered to iron-deficient subjects without ADHR may also cause transient elevations in intact FGF23, hypophosphataemia, and osteomalacia if administered repeatedly [45][46][47][48] . FGF23-mediated hypophosphataemia also occurs due to abnormal FGF23 production in TIO, fibrous dysplasia of bone (FD), and linear sebaceous naevus syndrome.…”