Hypercalcemia in Emergency Medicine 

Hypercalcemia is a disorder that most commonly results from malignancy or primary hyperparathyroidism.^{[1, 2, 3]} Other causes of elevated calcium are less common and usually are not considered until malignancy and parathyroid disease are ruled out.

Hypercalcemic crisis does not have an exact definition, although marked elevation of serum calcium, usually more than 14 mg/dL, is associated with acute signs and symptoms of hypercalcemia. Treatment of the elevated calcium level may resolve the crisis.

The reference range of serum calcium levels is 8.7-10.4 mg/dL, with somewhat higher levels present in children. Approximately 40% of the calcium is bound to protein, primarily albumin, while 50% is ionized and is in physiologic active form. The remaining 10% is complexed to anions.

Plasma calcium is maintained within the reference range by a complex interplay of 3 major hormones, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (ie, calcitriol), and calcitonin. These 3 hormones act primarily at bone, kidney, and small intestine sites to maintain appropriate calcium levels.

Calcium enters the body through the small intestine and eventually is excreted via the kidney. Bone can act as a storage depot. This entire system is controlled through a feedback loop; individual hormones respond as needed to increase or decrease the serum calcium concentration.

For hypercalcemia to develop, the normal calcium regulation system must be overwhelmed by an excess of PTH, calcitriol, some other serum factor that can mimic these hormones, or a huge calcium load.

Hypercalcemia can result from a multitude of disorders. The causes are divided into PTH-mediated hypercalcemia and non–PTH-mediated hypercalcemia.

PTH-mediated hypercalcemia

Primary hyperparathyroidism originally was the disease of "stones, bones, and abdominal groans." In most primary hyperparathyroidism cases, the calcium elevation is caused by increased intestinal calcium absorption. This is mediated by the PTH-induced calcitriol synthesis that enhances calcium absorption. The increase in serum calcium results in an increase in calcium filtration at the kidney. Because of PTH-mediated absorption of calcium at the distal tubule, less calcium is excreted than might be expected. In PTH-mediated hypercalcemia, bones do not play an active role because most of the PTH-mediated osteoclast activity that breaks down bone is offset by hypercalcemic-induced bone deposition. Hypercalcemia of this disorder may remain mild for long periods because some parathyroid adenomas respond to the feedback generated by the elevated calcium levels.

Non–PTH-mediated hypercalcemia

Hypercalcemia associated with malignancy commonly is the result of multiple myeloma, breast cancer, or lung cancer and is caused by increased osteoclastic activity within the bone.^[4] The ED physician should be concerned about any patient with a history of cancer who presents with lethargy or altered mental status. Granulomatous disorders with high levels of calcitriol may be found in patients with sarcoidosis, berylliosis, tuberculosis, leprosy, coccidioidomycosis, and histoplasmosis. Iatrogenic disorders of calcium levels may increase secondary to the ingestion of many medications.^[3]

Frequency

United States

Hypercalcemia is a fairly common metabolic emergency. Between 20 and 40% of patients with cancer develop hypercalcemia at some point in their disease (this may be decreasing with the use of bisphosphates, but data are lacking), and it is the most common serious electrolyte presenting in adults with malignancies.^[5]

Primary hyperparathyroidism occurs in 25 per 100,000 persons in the general population and in 75 per 100,000 hospitalized patients. This condition is the most common cause of mild hypercalcemia, which can be treated on an outpatient basis. In the United States, more than 50,000 new cases occur each year.

Mortality/Morbidity

• Prognosis of hypercalcemia associated with malignancy is poor; the 1-year survival rate is 10-30%. In one study, 50% of patients died within 30 days of beginning treatment; 75% died within 3 months.
• Prognosis related to many of the other causes of hypercalcemia can be excellent once the underlying disease is addressed.

Sex

• The incidence of primary hyperparathyroidism is considerably higher in women. The annual incidence in women older than 65 years is 250 per 100,000.
• Elevations in calcium levels related to cancer have no sex predominance.

Age

• The incidence of primary hyperparathyroidism increases with age.
• The rate of malignancy and, thus, of malignancy-associated hypercalcemia increases with age.