eMedicine Specialties > Emergency Medicine > Endocrine & Metabolic

Hypercalcemia

Author: Robin R Hemphill, MD, MPH, Associate Professor, Director, Quality and Safety, Department of Emergency Medicine, Emory University
Contributor Information and Disclosures

Updated: Aug 5, 2009

Introduction

Background

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.

Pathophysiology

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 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.

Clinical

History

• Symptoms of hypercalcemia depend on the underlying cause of the disease, the time over which it develops (rapid increases in calcium cause more severe symptoms), and the overall physical health of the patient.
• Mild elevations in calcium levels usually have few or no symptoms.
• Increased calcium levels may cause the following:
  • Nausea
  • Vomiting
  • Alterations of mental status
  • Abdominal or flank pain (The workup of patients with a new kidney stone occasionally reveals an elevated calcium level.)
  • Constipation
  • Lethargy
  • Depression
  • Weakness and vague muscle/joint aches
  • Polyuria, polydipsia, nocturia
  • Headache
  • Confusion
• Severe elevations in calcium levels may cause coma.
• Elderly patients are more likely to be symptomatic from moderate elevations of calcium levels.
• Hypercalcemia of malignancy may lack many of the features commonly associated with hypercalcemia caused by hyperparathyroidism. In addition, the symptoms of elevated calcium level may overlap with the symptoms of the patient's malignancy.
• Hypercalcemia associated with renal calculi, joint complaints, and ulcer disease is more likely to be caused by hyperparathyroidism.

Physical

Hypercalcemia has few physical examination findings specific to its diagnosis.

• Often it is the symptoms or signs of underlying malignancy that bring the patient with hypercalcemia to seek medical attention.
• The primary malignancy may be suggested by lung findings, skin changes, lymphadenopathy, or liver or spleen enlargement.
• Hypercalcemia can produce a number of nonspecific findings, as follows:
  • Hypertension and bradycardia may be noted in patients with hypercalcemia, but this is nonspecific.
  • Abdominal examination may suggest pancreatitis or the possibility of an ulcer.
  • Patients with long-standing elevation of serum calcium may have proximal muscle weakness that is more prominent in the lower extremities; they also may have bony tenderness to palpation.
  • Hyperreflexia and tongue fasciculations may be present.
  • Anorexia or nausea may occur.
  • Polyuria and dehydration are common.
  • Lethargy, stupor, or even coma may be observed.
• Long-standing hypercalcemia may cause band keratopathy, but this is rarely recognized in the ED.
• If hypercalcemia is caused by sarcoidosis, vitamin D intoxication, or hyperthyroidism, patients may have physical examination findings suggestive of those diseases.

Causes

Hypercalcemia is divided into PTH-mediated hypercalcemia (primary hyperparathyroidism) and non–PTH-mediated hypercalcemia.

• PTH-mediated hypercalcemia is related to increased calcium absorption from the intestine.
• Non–PTH-mediated hypercalcemia includes the following:
  • Hypercalcemia associated with malignancy: Unlike PTH-mediated hypercalcemia, the elevation of calcium that results from malignancy generally worsens until therapy is provided. Hypercalcemia caused by malignancy is the result of increased osteoclastic activity within the bone. This results from one or both of the mechanisms that follow:
    • Extensive localized bone destruction may result from osteolytic metastasis of solid tumors. Evidence indicates that many malignant cells may release local osteoclastic activating factors.
    • Increased calcium levels resulting from malignancy caused by a PTH-related protein is a second mechanism. This protein is a humeral factor that acts on the skeleton to increase bone reabsorption; it acts on the kidney to decrease excretion of calcium. The gene that produces this protein is present in many malignant tissues.
  • Granulomatous disorders: High levels of calcitriol may be found in patients with sarcoidosis and other granulomatous diseases. In these disorders, the increased level of calcitriol results from production within the macrophages, which constitute a large portion of some granulomas.
  • Iatrogenic: In some cases, elevation of calcium is a known adverse effect of appropriate dosage. In other cases, large ingestions must be taken to induce the increase in calcium levels. Obtain a complete review of current medications for patients presenting with hypercalcemia. Record any vitamin use.
• Other causes of hypercalcemia
  • Neoplasms (nonparathyroid) - Metastasis to the bone from breast, multiple myeloma, and hematologic malignancies (Breast cancer is one of the most common malignancies responsible for hypercalcemia.)
  • Nonmetastatic (humoral-induced) - Ovary, kidney, lung, head and neck, esophagus, cervix, lymphoproliferative disease, multiple endocrine neoplasia, pheochromocytoma, and hepatoma
  • Pharmacologic agents - Thiazide, calcium carbonate (antacid), hypervitaminosis D, hypervitaminosis A, lithium, milk-alkali syndrome, and theophylline toxicity
  • Endocrinopathies (nonparathyroid) -Hyperthyroidism, adrenal insufficiency, and pheochromocytoma
  • Familial hypocalciuric hypercalcemia
  • Tertiary hyperparathyroidism -Postrenal transplant and initiation of chronic hemodialysis
  • Miscellaneous - Immobilization, hypophosphatasia, primary infantile hyperparathyroidism, AIDS, and advanced chronic liver disease

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