Author: Prof. Anna-Maria Borissova
Abstract:
The phosphate balance depends primarily upon gastrointestinal absorption and renal excretion. Several hormones and metabolic pertubations are able to modulate phosphate reabsorption by the kidney. Among these PTH, PTHrP, calcitonin, glucocorticoids and phosphate loading inhibit renal phosphate reabsorption. In contrast, IGF-1, insulin, thyroid hormone, 1,25(OH)2D and phosphate deprivation stimulate renal phosphate reabsorption. More recently the study of disorders of renal phosphate wasting has revealed the important functions of FGF23 (a novel member of the fibroblast growth factor family) with respect to renal Pi homeostasis. The common target for this hormonal regulation is the renal proximal tubular cell. The kidney is the primary regulatory site for phosphate homeostasis. Aberrant phosphate metabolism results most commonly from altered renal Pi handling. The vast majority of the primary diseases are phosphate losing disorders in which renal Pi wasting and hypophosphatemia predominate and osteomalacia and rickets are characteristic presenting symptoms. The serum calcium concentration in affected subjects is normal. Circulating PTH levels may be normal to modestly elevated in untreatec patients, but treatment with phosphate salts may aggravate this tendency such that persistent secondary hyperparathyroidism may occur. Prior to the initiation of therapy, serum 25(OH)D levels are normal, and serum 1,25(OH)2D levels are in the low normal range.
X-linked hypophosphatemic rickets/osteomalacia (XLH) is the most common “vitamin D resistant” disease in man. Analysis of data identified PHEX (for phosphate regulating gene with homologies to endopeptidases located on the X chromosome) as the gene mutated in XLH. The mean circulating FGF23 (a hypophosphatemic factor) concentrations are greater in XLH patients than in control samples. Immunohistochemistry studies suggest that PHEX is most abundant on the cell surface of the osteocyte.
Autosomal Dominant Hypophosphatemic Rickets (ADHR) is a result of specific mutations in FGF23 which disrupt a protease recognition site, and the resultant mutant molecule is thereby protected from proteolysis, and resultant elevated circulating levels of FGF23 are the likely cause of the renal Pi wasting.
The study of some tumors associated with rickets and/or osteomalacia led to the identification and isolation of FGF23 – product of Tumor-Induced Osteomalacia (TIO). The FGF23 is a direct regulator of phosphate homeostasis at the renal level, and also has the effect of downregulating metabolism of vitamin D to its active form.
There are two major phosphate regulating hormones in the body – firstly PTH (primarily responsive to serum Calcium levels), which also serves to increase Ca levels via an increase in circulating 1,25(OH)2D, and secondly, FGF23 (primarily responsive to phosphate), which counters PTH’s calcemic effect by reducing 1,25(OH)2D levels.
Treatment – pharmacologic amounts of vitamin D were used in combination with phosphate supplements to counter the exacerbation of hyperparathyroidism observed in this setting.
Keywords: FGF23, hypophosphatemia, ricket/ osteomalacia.
