Interpretation

Increased fibroblast growth factor 23 (FGF23) concentrations are present in individuals with renal phosphate-wasting diseases such as autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), X-linked hypophosphatemia rickets (XLH) and tumor induced osteomalacia (TIO). Clinically, FGF23 measurement is useful in the differential diagnosis of these hypophosphatemic diseases since the patient presents with high FGF23 levels along with hypophosphatemia. In other causes of hypophosphatemia, such as vitamin D deficiency, FGF23 levels are low. In FGF23-producing tumors, a decrease in FGF23 concentrations following surgery is a reliable indication of complete tumor resection.

Intact FGF23 concentrations are elevated in patients with TIO or XLH. However, intact FGF23 concentrations within the reference interval do not exclude the disease and should be interpreted in the setting of phosphate concentrations (ie, an FGF23 concentration in the upper level of the reference interval in the context of hypophosphatemia might be indicative of XLH). In ADHR, FGF23 concentrations are not consistently elevated, and the severity of renal phosphate-wasting may wax and wane; FGF23 concentrations are normal during quiescent periods when serum phosphate levels are normal, and they are elevated during active, hypophosphatemic phases of the disease.(1) FGF23 concentrations are influenced by factors such as phosphate intake and vitamin D therapy. Therefore, intact FGF23 levels are most informative in untreated patients.

In the setting of hypophosphatemia, an elevated FGF23 may be indicative of FGF23-mediated hypophosphatemia. In a Mayo Clinic study, using the Medfrontier (Minaris Medical Co, Ltd, Tokyo, Japan) and a cut-off of greater than or equal to 59 pg/mL, corresponding to the upper limit of the reference interval, intact FGF23 concentrations were elevated in 90% and 84% of TIO and XLH hypophosphatemia patients, respectively. In the TIO and XLH patients where the intact FGF23 concentration was not above the reference interval, the intact FGF23 concentrations were at the upper end of the reference interval and much higher than observed in the patients with FGF23-independent hypophosphatemia. In contrast in the patients with FGF23-independent hypophosphatemia, intact FGF23 concentrations were significantly lower than what was observed in the healthy cohort and the normophosphatemic patients.(2) A study using the same assay and a cut-off of 30.0 pg/mL, reported 100% sensitivity and 82% specificity for the differential diagnosis of FGF23-related hypophosphatemia rickets/osteomalacia without vitamin D deficiency versus non-FGF23-related hypophosphatemia.(3)