Different vitamin D substrate-product relationship after oral vitamin D supplementation in familial benign hypercalcemia, primary hyperparathyroidism, and healthy controls

Context: In healthy subjects and in patients with primary hyperparathyroidism (PH), the administration of a low dose of 25(OH)D (25 mu g/day) increases the serum levels of both 25(OH)D and 1,25(OH)(2)D. It is unknown whether this relationship is present in patients affected by familial benign hypocalciuric hypercalcemia (FBH). Objective: To evaluate the different vitamin D substrate-product relationship after oral vitamin D supplementation in familial benign hypercalcemia, PH, and healthy controls. Design: We evaluated the main physiological regulators of 1a-hydroxylase and the substrate-product relationship of 25(OH)D and 1,25(OH) 2D in 20 patients with PH, 25 with FBH, and 122 healthy sex-and age-matched controls before and after administration of 25(OH)D for 2 weeks. Results: 25(OH)D increased significantly in all subjects, whereas 1,25(OH)(2)D serum levels increased significantly in PH patients and healthy controls but not in patients with FBH. Therefore, a significant positive substrate-product relationship of 25(OH)D-1,25(OH)(2)D was found in PH and healthy controls, but not in FBH. Monomeric calcitonin (hCT-M) was significantly lower at baseline and after 25(OH)D supplementation in the FBH group compared with the other two groups. Conclusions: The lack of 1,25(OH)(2)D increase in FBH may be due to a direct inhibitory effect on 1a-hydroxylase of hypercalcemia per se, increased metabolic clearance of 1,25(OH)(2)D, or a decreased stimulus of 1a-hydroxylase related to persistently low levels of hCT.