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The calcium ion plays a critical role in normal cellular function and signaling, regulating diverse physiologic processes such as neuromuscular signaling, cardiac contractility, hormone secretion, and blood coagulation. Thus, extracellular calcium concentrations are maintained within an exquisitely narrow range through a series of feedback mechanisms that involve parathyroid hormone (PTH) and the active vitamin D metabolite 1,25-dihydroxyvitamin D [1,25(OH)2D]. These feedback mechanisms are orchestrated by integrating signals between the parathyroid glands, kidney, intestine, and bone (Fig. 50-1; Chap. 402). Disorders of serum calcium concentration are relatively common and often serve as a harbinger of underlying disease. This chapter provides a brief summary of the approach to patients with altered serum calcium levels. See Chap. 403 for a detailed discussion of this topic.
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The causes of hypercalcemia can be understood and classified based on derangements in the normal feedback mechanisms that regulate serum calcium (Table 50-1). 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 in familial hypocalciuric hypercalcemia (FHH), which is an autosomal dominant syndrome most commonly involving inactivating mutations in the calcium sensor receptor (CaSR; FHH type 1), with rare families having mutations in the Gα11 protein (GNA11; FHH type 2) or the adaptor-related protein complex 2, σ-2 subunit (AP2S1; FHH type 3); all of these mutations impair extracellular calcium sensing by the parathyroid glands and the kidneys, leading to inappropriate PTH secretion and increased renal tubular calcium reabsorption. 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 ...