Usually, hypercalcemia is reported as elevation of total plasma calcium levels rather than ionized calcium levels. Approximately 50% of total calcium is protein bound, and the total calcium level will vary with protein-binding capacity. This phenomenon may rarely result in pseudohypercalcemia—for example, in patients with hyperalbuminemia secondary to dehydration and in some patients with multiple myeloma. More commonly, lowering of total calcium levels is observed in patients with low levels of binding proteins (hypoalbuminemia). This physiology requires that the total plasma calcium level be corrected for the albumin level. Normal calcium levels may range from 8.5 to 10.5 mg/day, assuming an albumin level of 4.5 g/dL. The calcium concentration [Ca] usually changes by 0.8 mg/dL for every 1.0-g/dL change in plasma albumin concentration. Thus, this formula estimates the actual total plasma calcium level:
Corrected [Ca] = Total [Ca] + (0.8 × [4.5 − albumin level])
Acidosis decreases the amount of calcium bound to albumin, whereas alkalosis increases the bound fraction of calcium. A small amount of calcium (about 6%) is complexed to anions such as citrate and sulfate. The remainder is ionized calcium that is biologically active.
The most common causes of hypercalcemia, affecting 90% of all patients, are primary hyperparathyroidism (HPT) and malignancy. Other causes are summarized in Box 1.
Box 1: Causes of Hypercalcemia
Primary hyperparathyroidism
Sporadic
Familial
Hypercalcemia of malignancy
Osteolytic hypercalcemia
Humoral hypercalcemia of malignancy
Ectopic production of calcitriol (by lymphoma)
Hypercalcemia of granulomatous disease
Chronic renal failure with aplastic bone disease
Tertiary hyperparathyroidism
Acute renal failure
Familial hypercalcemic hypocalciuria
Lithium-associated hypercalcemia
Vitamin D intoxication
Other causes
Increased calcium intake
Pheochromocytoma
Congenital lactase deficiency
Hyperthyroidism
Vitamin A intoxication
Thiazides
Milk-alkali syndrome
Immobilization
Theophylline