Pathophysiology of Hypercalcemia

Extracellular calcium is normally tightly regulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, as well as by calcium ion (Ca⁺⁺) itself. Dysregulated PTH production leading to hypercalcemia occurs most commonly in sporadic primary hyperparathryoidism (PHPT) but may also result from select genetic mutations in familial disorders. Parathyroid hormone-related protein shares molecular mechanisms of action with PTH and is the most common cause of hypercalcemia of malignancy. Other cytokines and mediators may also cause resorptive hypercalcemia once bone metastases have occurred. Less commonly, extrarenal production of calcitriol can occur in malignancies and in infectious and noninfectious inflammatory conditions and can cause hypercalcemia.