The regulation of the calcium homeostasis is depicted in Fig. 176-1. The causes of hypercalcemia are listed in Table 176-1. Hyperparathyroidism and malignancy account for >90% of cases.

Primary hyperparathyroidism is a generalized disorder of bone metabolism due to increased secretion of parathyroid hormone (PTH) by an adenoma (80%) or rarely a carcinoma in a single gland, or by parathyroid hyperplasia (15%). Familial hyperparathyroidism may be part of multiple endocrine neoplasia type 1 (MEN 1), which also includes pituitary and pancreatic islet tumors, or of MEN 2A, in which hyperparathyroidism occurs with pheochromocytoma and medullary carcinoma of the thyroid.

Hypercalcemia associated with malignancy is often severe and difficult to manage. Mechanisms for this include excess production and release of PTH-related protein (PTHrP) in lung, kidney, and squamous cell carcinoma (humoral hypercalcemia of malignancy); local bone destruction in myeloma and breast carcinoma; activation of lymphocytes leading to release of cytokines in myeloma and lymphoma; or an increased synthesis of 1,25(OH)₂D in lymphoma.

Several other conditions have been associated with hypercalcemia. These include sarcoidosis and other granulomatous diseases, which lead to increased synthesis of 1,25(OH)₂D; vitamin D intoxication from chronic ingestion of large vitamin doses (50-100 × physiologic requirements); lithium therapy, which results in hyperfunctioning of the parathyroid glands; and familial hypocalciuric hypercalcemia (FHH) due autosomal dominant inheritance of an inactivating mutation in the calcium-sensing receptor, which results in inappropriately normal or even high secretion of PTH, despite hypercalcemia and enhanced renal calcium resorption. Severe secondary hyperparathyroidism associated with end-stage renal disease may progress to tertiary hyperthyroidism, in which PTH hypersecretion becomes autonomous, causes hypercalcemia, and is no longer responsive to medical therapy.