INTRODUCTION
The major factors that influence the serum calcium concentration are parathyroid hormone (PTH), vitamin D, fibroblast growth factor 23 (FGF23), the calcium ion itself [1,2], and phosphate. Low serum calcium concentrations are most often caused by disorders of PTH or vitamin D. Other causes of hypocalcemia include disorders that result in a decrease in serum ionized calcium concentration by binding of calcium within the vascular space or by its deposition in tissues, as can occur with hyperphosphatemia.The causes of hypocalcemia in adults will be reviewed here. The etiology of hypocalcemia in neonates and children and the clinical manifestations, evaluation, and treatment of hypocalcemia in adults are discussed elsewhere. (See "Etiology of hypocalcemia in infants and children" and "Clinical manifestations of hypocalcemia" and "Diagnostic approach to hypocalcemia" and "Treatment of hypocalcemia".)
CALCIUM HOMEOSTASIS
Serum calcium concentrations are normally maintained within the very narrow range that is required for the optimal activity of the many extra- and intracellular processes calcium regulates. Calcium in the blood is transported partly bound to plasma proteins (approximately 40 to 45 percent), notably albumin; partly bound to small anions such as phosphate and citrate (approximately 15 percent); and partly in the free or ionized state (approximately 40 to 45 percent). (See "Relation between total and ionized serum calcium concentrations".)Although only the ionized calcium is metabolically active (ie, subject to transport into cells), most laboratories report total serum calcium concentrations. Concentrations of total calcium in normal serum generally range between 8.5 and 10.5 mg/dL (2.12 to 2.62 mmol/L), and levels below this are considered to be consistent with hypocalcemia. The normal range of ionized calcium is 4.65 to 5.25 mg/dL (1.16 to 1.31 mmol/L).
Hypoalbuminemia — When protein concentrations (particularly albumin) fluctuate substantially, total calcium levels may vary, whereas the ionized calcium (whose level is hormonally regulated) remains relatively stable. Thus, total serum calcium concentrations may not accurately reflect the physiologically important ionized (or free) calcium concentration. As an example, in volume overload, chronic illness, and malnutrition or nephrotic syndrome (where serum protein can be reduced), total plasma calcium is low but the ionized calcium is normal. This phenomenon is called pseudohypocalcemia.