Hypercalcemia in Emergency Medicine
- Author: Thomas E Green, DO, MPH, FACOEP, FACEP; Chief Editor: Romesh Khardori, MD, PhD, FACP more...
Hypercalcemia is a disorder that most commonly results from malignancy or primary hyperparathyroidism.[1, 2, 3] 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.
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.
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.
Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med. 2004 Apr. 32(4 Suppl):S146-54. [Medline].
Dent DM, Miller JL, Klaff L, Barron J. The incidence and causes of hypercalcaemia. Postgrad Med J. 1987 Sep. 63(743):745-50. [Medline].
Edelson GW, Kleerekoper M. Hypercalcemic crisis. Med Clin North Am. 1995 Jan. 79(1):79-92. [Medline].
Cho KC. Electrolyte & Acid-Base Disorders. Papadakis MA, McPhee SJ, Rabow MW, eds. CURRENT Medical Diagnosis & Treatment 2013. New York, NY: McGraw-Hill; 2013. Chapter 21.
Disorder of Calcium Metabolism. Alpern RJ, Moe OW, Caplan M, eds. Seldin and Giebisch's The Kidney. 5th ed. Elsevier; 2013. 2273-309.
Blomqvist CP. Malignant hypercalcemia--a hospital survey. Acta Med Scand. 1986. 220(5):455-63. [Medline].
Hypercalcemia. Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper, JE, eds. Abeloff's Clinical Oncology. 5th ed. Churchill Livingstone; 2014. 581-90.
Mundy GR, Guise TA. Hypercalcemia of malignancy. Am J Med. 1997 Aug. 103(2):134-45. [Medline].
Khosla S. Hypercalcemia and Hypocalcemia. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012. Chapter 46.
Lindner G, Felber R, Schwarz C, Marti G, Leichtle AB, Fiedler GM, et al. Hypercalcemia in the ED: prevalence, etiology, and outcome. Am J Emerg Med. 2013 Apr. 31(4):657-60. [Medline].
Tsao YT, Lee SW, Hsu JC, Ho FM, Wang WJ. Severe hypercalcemia in nonobstructive pyelonephritis with acute renal failure: hit or miss?. Am J Emerg Med. 2012 Oct. 30(8):1665.e5-7. [Medline].
AlZahrani A, Sinnert R, Gernsheimer J. Acute kidney injury, sodium disorders, and hypercalcemia in the aging kidney: diagnostic and therapeutic management strategies in emergency medicine. Clin Geriatr Med. 2013 Feb. 29(1):275-319. [Medline].
Grill V, Ho P, Body JJ, et al. Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab. 1991 Dec. 73(6):1309-15. [Medline].
Diaz Guardiola P, Vega Pinero B, Alameda Hernando C, Pavon de Paz I, Iglesias Bolanos P, Guijarro de Armas G. [Primary hyperparathyroidism. An alternative to the surgery.]. Endocrinol Nutr. 2009 Mar. 56(3):132-5. [Medline].
Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005 Jan 27. 352(4):373-9. [Medline].