Symptoms referable to hypercalcemia itself are very nonspecific; they include vomiting, constipation, polydipsia and polyuria, and mental confusion. Coma may develop in severe cases. There may be renal stones or soft tissue calcification. Hypercalcemia is most often detected on routine multitest biochemical screening panels, either in asymptomatic persons or incidental to symptoms from some disease associated with hypercalcemia (see the box on this page). In asymptomatic persons, primary hyperparathyroidism (PHPT) accounts for about 60% of cases. In hospital admissions, however, malignancy is the etiology for 40%-50% of cases and PHPT accounts for about 15%.

Regulation of Serum Calcium Levels

Regulation of serum calcium levels is somewhat complex. The major control mechanism is parathyroid hormone (PTH). Normally, parathyroid secretion of PTH is regulated by a feedback mechanism involving the blood calcium level. A decreased serum calcium level induces increased secretion of PTH, whereas an acute increase of the

Selected Etiologies of Hypercalcemia

Relatively common

Neoplasia (noncutaneous)
Bone primary
Acute leukemia
Nonbone solid tumors
Squamous nonpulmonary
Neoplasm secretion of parathyroid hormone-related protein (PTHrP, “ectopic PTH”)
Primary hyperparathyroidism (PHPT)
Thiazide diuretics
Tertiary (renal) hyperparathyroidism
Spurious (artifactual) hypercalcemia
Serum protein elevation
Lab technical problem

Relatively uncommon

Neoplasia (less common tumors)
Immobilization (mostly seen in children and adolescents)
Diuretic phase of acute renal tubular necrosis
Vitamin D intoxication
Milk-alkali syndrome
Addison’s disease
Lithium therapy
Idiopathic hypercalcemia of infancy
Theophylline toxicity

serum calcium level decreases secretion of PTH. PTH has a direct action on bone, increasing bone resorption and release of bone calcium and phosphorus. In addition, PTH increases the activity of the activating enzyme cyclic adenosine monophosphate (AMP) in the proximal tubules of the kidney, which increases conversion of calcidiol (25-hydroxyvitamin D) to calcitriol (1,25-dihydroxy-vitamin D). Calcitriol has metabolic effects that help to increase serum calcium levels, such as increased renal reabsorption of calcium, increased GI tract absorption of calcium, and the drawing out of some calcium from bone. On the other hand, an increased calcitriol level also initiates a compensatory series of events that prevents the calcium-elevating system from overreacting. An increased calcitriol level inhibits renal tubule phosphate reabsorption, which results in loss of phosphorus into the urine. This leads to a decreased serum phosphate level, which, in turn, inhibits production of calcitriol. The actions of PTH, phosphate, and calcitriol produce a roughly reciprocal relationship between serum calcium and phosphate levels, with elevation of one corresponding to a decrease of the other. Both PTH (through cyclic AMP) and phosphate act on the same enzyme (25-OH-D 1 a-hydroxylase), which converts calcidiol to calcitriol.

Besides PTH, a hormone called “calcitonin” has important, although subsidiary, effects on calcium metabolism. Calcitonin is produced in the thyroid gland, and secretion is at least partially regulated by serum calcium levels. Acute elevation of serum calcium leads to increased calcitonin secretion. Calcitonin inhibits bone resorption, which decreases withdrawal of calcium and phosphorus and produces a hypocalcemic and hypophosphatemic effect that opposes calcium-elevating mechanisms.