Hypercalcemia is a disorder that most commonly results from malignancy or primary hyperparathyroidism. [1, 2, 3, 4] Other, less common, causes of elevated calcium include increased intake or absorption, granulomatous disease, immobilization, and thiazide diuretic use. However, the primary diagnostic approach should be to first rule out underlying malignancy and parathyroid disease. 
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 varies among laboratories but generally is 8.7-10.4 mg/dL, with somewhat higher levels present in children. Approximately 50% of calcium is bound to protein, primarily albumin, and the remaining 50% is ionized and is in physiologic active form. 
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.
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. Hypercalcemia of this disorder may remain mild for long periods because some parathyroid adenomas respond to the feedback generated by the elevated calcium levels.
Malignancy-associated hypercalcemia occurs in up to 20-30% of patients at some course within their disease. Most episodes occur with advanced disease and patients typically have a poor prognosis (with up to a 50% 30-day mortality). There are two generally recognized forms of this disorder, one in which hypercalcemia is the result of tumor secretion of a humoral factor (usually PTHrP) and one is the result of excessive bone metastases.  Common malignancies include multiple myeloma, breast cancer, or lung cancer. Multiple factors for osteolysis are responsible for this action, which is produced by or in response to the myeloma cells in the marrow. These are collectively referred to osteoclast-activating factors. 
Multiple endocrine neoplasia (MEN) are a group of disorders associated with hyperfunction of two or more endocrine glands and can be a cause of hypercalcemia (which may be milder and even asymptomatic). Finally, tamoxifen-linked hypercalcemia is hypercalcemia in association with the use of estrogen or antiestrogen therapy for therapy for carcinoma of the breast. The severity of hypercalcemia is variable, but it can be fatal. The mechanism by which tamoxifen and similar agents cause hypercalcemia is unclear but prostaglandins may be the main mediator of the response.  Other causes that are non-malignancy-related include milk-alkali syndrome (which involves large intake of calcium in association with volume contraction, systemic alkalosis and renal insufficiency) and medication-induced hypercalcemia (especially chronic lithium therapy). 
The emergency 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. 
Hypercalcemia is a fairly common metabolic emergency. Between 20-40% 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. 
A study by Gastanaga et al estimated that between 2009 and 2013, 2.0-2.8% of all cancer patients in the United States were affected by hypercalcemia of malignancy, with the highest rates of such hypercalcemia found in multiple myeloma patients (7.5-10.2% between 2010 and 2012), and the lowest rates found in patients with prostate cancer (1.4-2.1% between 2011 and 2012). 
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.
A Scottish study, by McNeilly et al, estimated that in a general hospital setting, the rate of sustained hypercalcemia (hypercalcemia on 2 or more consecutive days) is 1 in 500 children, with the greatest frequency found in neonates. Etiologies varied with age among pediatric patients. 
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.
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.
The incidence of primary hyperparathyroidism increases with age.
The rate of malignancy and, thus, of malignancy-associated hypercalcemia increases with age.
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