Hypercalcemia from any cause can result in fatigue, depression, mental confusion, anorexia, nausea, constipation, renal tubular defects, polyuria, a short QT interval, and arrhythmias. CNS and GI symptoms can occur at levels of serum calcium >2.9 mmol/L (>11.5 mg/dL), and nephrocalcinosis and impairment of renal function occur when serum calcium is >3.2 mmol/L (>13 mg/dL). Severe hypercalcemia, usually defined as >3.7 mmol/L (>15 mg/dL), can be a medical emergency, leading to coma and cardiac arrest.
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.
Feedback mechanisms maintaining extracellular calcium concentrations within a narrow, physiologic range (8.9–10.1 mg/dL [2.2–2.5 mM]). A decrease in extracellular fluid (ECF) calcium (Ca2+) triggers an increase in parathyroid hormone (PTH) secretion (1) via the calcium sensor receptor on parathyroid cells. PTH, in turn, results in increased tubular reabsorption of calcium by the kidney (2) and resorption of calcium from bone (2) and also stimulates renal 1,25(OH)2D production (3). 1,25(OH)2D, in turn, acts principally on the intestine to increase calcium absorption (4). Collectively, these homeostatic mechanisms serve to restore serum calcium levels to normal.
TABLE 176-1CLASSIFICATION OF CAUSES OF HYPERCALCEMIA |Favorite Table|Download (.pdf) TABLE 176-1CLASSIFICATION OF CAUSES OF HYPERCALCEMIA
Solitary adenomas or rarely carcinoma
Multiple endocrine neoplasia
Familial hypocalciuric hypercalcemia
Solid tumor with humoral mediation of hypercalcemia (lung, kidney, squamous cell carcinoma)
Solid tumor with metastases (breast)
Hematologic malignancies (multiple myeloma, lymphoma, leukemia)
Vitamin D intoxication
↑ 1,25(OH)2D; sarcoidosis and other granulomatous diseases
↑ 1,25(OH)2D; impaired 1,25(OH)2D metabolism due to 24-hydroxylase deficiency
Associated with high bone turnover
Vitamin A intoxication
Associated with renal failure
Severe secondary or tertiary hyperparathyroidism
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 ...