The causes of hypercalcemia can be understood and classified based on derangements in the normal feedback mechanisms that regulate serum calcium (Table 46-1). Excess PTH production, which is not appropriately suppressed by increased serum calcium concentrations, occurs in primary neoplastic disorders of the parathyroid glands (parathyroid adenomas; hyperplasia; or, rarely, carcinoma) that are associated with increased parathyroid cell mass and impaired feedback inhibition by calcium. Inappropriate PTH secretion for the ambient level of serum calcium also occurs with heterozygous inactivating calcium sensor receptor (CaSR) mutations, which impair extracellular calcium sensing by the parathyroid glands and the kidneys, resulting in familial hypocalciuric hypercalcemia (FHH). Although PTH secretion by tumors is extremely rare, many solid tumors produce PTH-related peptide (PTHrP), which shares homology with PTH in the first 13 amino acids and binds the PTH receptor, thus mimicking effects of PTH on bone and the kidney. In PTHrP-mediated hypercalcemia of malignancy, PTH levels are suppressed by the high serum calcium levels. Hypercalcemia associated with granulomatous disease (e.g., sarcoidosis) or lymphomas is caused by enhanced conversion of 25(OH)D to the potent 1,25(OH)2D. In these disorders, 1,25(OH)2D enhances intestinal calcium absorption, resulting in hypercalcemia and suppressed PTH. Disorders that directly increase calcium mobilization from bone, such as hyperthyroidism or osteolytic metastases, also lead to hypercalcemia with suppressed PTH secretion as does exogenous calcium overload, as in milk-alkali syndrome, or total parenteral nutrition with excessive calcium supplementation.