Recent advances in our understanding of the physiologic actions of PTH and vitamin D have clarified certain aspects of the pathogenesis, classification, and management of hypoparathyroidism. Central to pathogenesis and categorization is the recognition that hypoparathyroidism may result from PTH deficiency, ineffectiveness, or resistance, with a resultant inability to stimulate adenylate cyclase in target tissues. This aberration in adenylate cyclase activity impairs certain physiologic responses such as renal phosphate excretion and renal calcium reabsorption that are required for proper calcium homeostasis. Also critical is the subnormal production of 1α,25-dihydroxycholecalciferol (1,25-DHCC). Although the precise mechanism for the deficiency of 1,25-DHCC remains unclear, one may hypothesize that in hormone-deficient or hormone-ineffective hypoparathyroidism, decreased synthesis results from the absence of the two recognized stimuli for 1α-hydroxylase-bioactive PTH and hypophosphatemia. Provision of either one of these stimuli would then be expected to restore 1,25-DHCC to normal levels, which could explain the calcemic response to PTH in these patients. There is some evidence that the synthesis of 1,25-DHCC may be "primarily" affected in PTH-resistant hypoparathyroidism, and thus may be unresponsive to any of the known stimuli. It remains conceivable, however, that during normocalcemic phases, such patients may improve their renal cyclic AMP and phosphaturic responses to PTH, with associated improvement in 1,25-DHCC synthesis. Certain acquired forms of PTH resistance such as hypomagnesemia and end-stage renal disease may also be associated with defective 1-hydroxylation. Whether occurring primarily or as a secondary process, the subnormal production of 1,25-DHCC may influence calcium and skeletal metabolism directly or by modifying response to PTH. The availability of 1,25-DHCC provides an effective and physiologically meaningful mode of therapy for most cases of hypoparathyroidism.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism