Best Practice & Research Clinical Endocrinology & Metabolism
4Disorders of phosphate metabolism—pathomechanisms and management of hypophosphataemic disorders
Section snippets
Renal handling of phosphate—physiology and pathophysiology
Pi re-absorption in the proximal tubule is mediated by Na+-dependent secondary active transport mechanisms3, i.e. Pi travels against an electrochemical gradient into the proximal tubular epithelial cell mediated by a sodium (Na) phosphate (Pi) co-transporter (NPT). The energy for this transport comes from the concentration gradient of sodium and ultimately from the action of the sodium pump. The influx of Pi from the tubular lumen into the epithelial cells is rate-limiting and the target for
Tumour-induced osteomalacia (oncogenic osteomalacia)
Tumour-induced osteomalacia (TIO) is a rare condition usually characterized by generalized pain and muscle weakness (for unknown reasons the latter is not a feature of XLH and ADHR). Otherwise, TIO mimics the clinical phenotype of XLH or ADHR. It was first described by McCance in 1947.5 It develops in patients with predominantly benign tumours of mesenchymal origin, often located in the skeleton.6 Occasionally, malignant tumours have been reported.7 Non-malignant tumours associated with this
X-linked hypophosphataemia
X-linked hypophosphataemia (XLH) is characterized by growth retardation, rachitic and osteomalacic bone disease, hypophosphataemia, impaired proximal tubular re-absorption of Pi and inappropriately normal concentrations of 1,25(OH)2D3 (which should be upregulated in the presence of low Pi). The disorder shows an X-linked mode of inheritance. XLH is more frequent than the alternative and phenotypically more variable hereditary hypophosphataemic condition, i.e. ADHR.
Clarification of the
Autosomal dominant hypophosphataemic rickets (ADHR)
ADHR has a phenotype similar to that of XLH, although the clinical presentation tends to be variable because of incomplete penetrance and variable age of onset. The condition is less common than XLH. Because of the autosomal dominant mode of inheritance, male-to-male transmission is seen. Again, an international collaborative effort recently identified the responsible gene by positional cloning.35 The gene encodes FGF-23, the product also responsible for TIO.21., 22., 23. Important for the
Hereditary hypophosphataemic rickets with hypercalciuria (HHRH)
While HHRH replicates many features of the phenotype of XLH and ADHR, it is distinguished by appropriately increased plasma concentrations of 1,25(OH)2D3. This is presumably the explanation of why this condition is also associated with hypercalciuria. This rare condition was first identified in a Bedouin family36, but may also occur sporadically. Homozygous NPT-2a −/− mice have a phenotype resembling HHRH. Loss-of-function mutations of the NTP-2a co-transporter were proposed as plausible
Hypothesis on the underlying pathophysiology of phosphaturic disorders
Figure 1 summarizes the most common hypotheses offered to explain the phenotypic similarities and known molecular findings in TIO, XLH and ADHR.20., 39., 40. The phenotypic similarities suggest a common metabolic pathway.
It is certain that TIO is characterized by overproduction of FGF-23 which is phosphaturic. The role of other peptides, frizzled-related probe 4 and mepg, secreted by the tumour, is currently uncertain.
The defect in autosomal dominant hypophospataemic rickets (ADHR) behaves like
Patient management
In patients with TIO resection of a tumour is the treatment of choice.6 If the tumour cannot be found, despite the novel radio indium octreotide scintigraphic technique26, or if the tumour is unresectable because of its location, chronic administration of phosphate and calcitriol is indicated (details see below). There is also some preliminary experience with the administration of octreotide.26 Oral phosphate administration may cause gastrointestinal intolerance and diarrhoea. In that case,
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