Evidence for a defect in the formation of 1α,25-dihydroxyvitamin D in pseudohypoparathyroidism

Abstract

The metabolic defect which accounts for the lack of response to parathyroid hormone in pseudohypoparathyroidism (PHP) has been ascribed to an abnormal adenylate cyclase system in the renal cortex and possibly in the skeleton. Previous observations indicated that in PHP osteitis fibrosa cystica may result from secondary hyperparathyroidism and that parathyroid hormone stimulates the conversion of 25-hydroxyvitamin D to 1α,25-dihydroxyvitamin D in the renal cortex. Therefore studies were carried out to examine the possibility that impaired formation of 1α, 25-dihydroxyvitamin D might contribute to or be responsible for impaired intestinal absorption of calcium, hypocalcemia and secondary hyperparathyroidism in PHP. Accordingly, the effects of 1α,25-dihydroxycholecalciferol, 1 μg/day for 12 days, on serum calcium and phosphorus, balances of calcium and phosphorus, and serum parathyroid hormone were examined in three patients with well-documented PHP. Serum 25-hydroxyvitamin D was also determined. Before treatment fecal calcium was increased, serum calcium was abnormally low, and serum parathyroid hormone and serum 25-hydroxyvitamin D were abnormally increased. With 1α,25-dihydroxycholecalciferol, fecal calcium decreased, serum and urinary calcium increased, and serum parathyroid hormone decreased to or toward the normal range. After treatment this sequence of events was reversed. These findings support the hypothesis that diminished intestinal absorption of calcium, hypocalcemia, and secondary hyperparathyroidism in PHP result from a defect in the formation of 1α,25-dihydroxyvitamin D in the kidney and indicate that 1α,25-dihydroxycholecalciferol is a new and useful specific means for treatment of the abnormal calcium metabolism in the disorder.