Clinical Information

Fibroblast growth factor 23 (FGF23) is a major regulator of phosphate (phosphorus) homeostasis. FGF23 is secreted primarily by bone, followed by thymus, heart, brain and, in low levels, by several other tissues. High serum phosphate (phosphorus) concentrations stimulate FGF23 expression and secretion through a yet poorly understood mechanism. Only intact FGF23 is considered bioactive. Intact FGF23 interacts with a specific receptor on renal tubular cells, decreasing expression of type IIa sodium/phosphate cotransporters, resulting in decreased phosphate reabsorption. In addition, gene transcription of 1-alpha-hydroxylase is downregulated, reducing bioactive 1,25-dihydroxy vitamin D, thereby further decreasing phosphate reabsorption. Eventually, falling serum phosphate concentrations lead to diminished FGF23 secretion, closing the feedback loop.

Measurement of FGF23 can assist in diagnosis and management of disorders of phosphate and bone metabolism in patients with either normal or impaired kidney function. When FGF23 levels are pathologically elevated in individuals with normal kidney function, hypophosphatemia, with or without osteomalacia, ensues. This can occur in rare, usually benign, mixed connective tissue tumors that contain characteristic complex vascular structures, osteoclast-like giant cells, cartilaginous elements, and dystrophic calcifications. These neoplasms secrete FGF23 ectopically and autonomously (tumor-induced osteomalacia; TIO). In less than one-fourth of cases, a different benign or malignant soft tissue tumor type or, extremely rarely, a carcinoma may be the cause of paraneoplastic FGF23 secretion. In either scenario, complete removal of the tumor cures the TIO.

Hypophosphatemia and skeletal abnormalities are also observed in X-linked hypophosphatemia (XLH) and autosomal dominant hypophosphatemic rickets (ADHR). In XLH, variants in the PHEX (phosphate-regulating neutral endopeptidase) gene, which encodes a cell-surface-bound protein-cleavage enzyme, affect bioactive FGF23 secretion. Although the pathogenesis of XLH is not fully understood, animal studies indicate that loss of PHEX function results in enhanced secretion of FGF23.

In ADHR, FGF23 variants render the protein resistant to proteolytic cleavage, thereby increasing FGF23 levels. However, not all FGF23 variants increase renal phosphate secretions. Variants that impair FGF23 signaling, rather than increase its protease resistance, are associated with the syndrome of familial tumoral calcinosis (ectopic calcifications) with hyperphosphatemia.

In patients with kidney failure, FGF23 contributes to renal osteodystrophy. The patient's kidneys can no longer excrete sufficient amounts of phosphate. This leads to marked increases in FGF23 secretion as a compensatory response, aggravating the 1,25-dihydroxy vitamin D deficiency of renal failure and the consequent secondary hyperparathyroidism.

In circulation, intact FGF-23 is cleaved to generate 2 biologically inactive fragments: a N-terminal fragment and a C-terminal fragment. FGF23 has a rapid clearance and short half-life, which ranges between 46 and 58 min for intact and C-terminal fragments, respectively. Different types of FGF-23 immunoassays are available: those targeting the intact form (iFGF23) and those detecting C-terminal fragments (cFGF23). Various studies have suggested that iFGF23 assays are more sensitive than cFGF23 for the detection of FGF23 concentrations in patients with TIO and patients with XLH. In addition, iFGF23 concentrations are not affected by iron deficiency, which may lead to false-positive results when using cFGF23 assays.