AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hypercalcemia is a disorder that most commonly results from malignancy or primary hyperparathyroidism. 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, or lung cancer and is caused by increased osteoclastic activity within the bone. 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.

Frequency

United States

Hypercalcemia is a fairly common metabolic emergency. Between 20 and 30% 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). 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 US, 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Symptoms of hypercalcemia depend on the underlying cause of the disease, the time over which it develops, 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
  • Headache
• 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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Pheochromocytoma
Immobilization
Addison disease
Inflammatory disorders
Rhabdomyolysis
Paget disease
Parenteral nutrition

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Confirmatory tests: Changes in serum protein concentrations alter the total serum calcium level but do not affect the unbound fraction. Calcium level reported by the laboratory usually represents the bound and unbound calcium. When calcium levels are reported as high or low, the physician must be able to calculate the actual level of calcium. A common formula is as follows:
• Corrected total calcium (mg/dL) = (measured total calcium mg/dL) + 0.8 (4.4 - measured albumin g/dL)

  The average normal albumin level is 4.4. The reference range for corrected value of calcium is approximately 9-10.6 mg/dL.

• • The corrected calcium value is useful in most situations, but individual variation can occur.
  • If the corrected serum calcium level still is not accurate, it is possible to measure the free calcium ion activity (ie, ionized calcium level).
• Other nonspecific laboratory abnormalities commonly found in patients with hypercalcemia result from disordered renal function. Patients commonly have significant azotemia at presentation.
• Hypercalcemia may produce ECG abnormalities related to altered trans-membrane potentials that affect conduction time. QT interval shortening is common, and, in some cases, the PR interval is prolonged. At very high levels, the QRS interval may lengthen, T waves may flatten or invert, and a variable degree of heart block may develop. Digoxin effects are amplified.
• After a diagnosis of hypercalcemia is established, the next step is to determine the cause. Initial testing is directed at malignancy, hyperparathyroidism, and hyperthyroidism, the most common causes of hypercalcemia.
• • The measurement of circulating PTH in the serum is the most direct and sensitive measure of parathyroid function. A reference range is 2-6 mol/L. A nonsuppressed PTH level in the presence of hypercalcemia suggests a diagnosis of primary hyperparathyroidism. If the PTH level is suppressed in the face of an elevated calcium level, hyperparathyroidism is unlikely.
  • Parathyroid hormone-related peptide (PTHrP) is thought to mediate the hypercalcemia that develops with many malignancies. Assays to measure this peptide are available.
  • Measurement of calcitriol is difficult but can be accomplished. This laboratory value is useful in diagnosing hypercalcemia secondary to a granulomatous disease such as sarcoidosis.
  • Other electrolytes also may be disturbed in hypercalcemia. Serum phosphate levels tend to be low or normal in primary hyperparathyroidism and hypercalcemia of malignancy. Phospate levels are elevated in hypercalcemia secondary to vitamin D–related disorders or thyrotoxicosis. Serum chloride levels usually are higher than 102 mEq/L in hyperparathyroidism and less than this value in other forms of hypercalcemia.

Imaging Studies

• No imaging studies definitively diagnose hypercalcemia.
• Consider hypercalcemia in patients with multiple nonspecific complaints and an associated lung mass.
• If laboratory evidence of primary hyperparathyroidism is present, CT scan of the head, MRI, ultrasound, or nuclear parathyroid scans may be helpful. Preoperative diagnostic imaging is essential in patients with previous neck surgery.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Prehospital care is primarily supportive with management of the ABCs. If a patient has a history of hypercalcemia and displays evidence of acute hypercalcemia, immediately begin IV hydration.

Emergency Department Care

The treatment of hypercalcemia depends on the level, the chronicity, and the underlying cause of the problem. In mild-to-moderate elevations of calcium, few treatment options may be available in the ED. A physical evaluation to help delineate the source of the elevation is always appropriate, as is a subsequent timely follow-up visit.

• Initial goals of treatment
• • Stabilization and reduction of the calcium level
  • Adequate hydration
  • Increased urinary calcium excretion
  • Inhibition of osteoclast activity in the bone
  • Discontinuation of pharmacologic agents associated with hypercalcemia
  • Treatment of the underlying cause (when possible)
• The initial step in the care of severely hypercalcemic patients is hydration with saline. Hydration helps decrease the calcium level through dilution. The expansion of extracellular volume also increases the renal calcium clearance. The rate of fluid therapy is based upon the following:
• • Degree of hypercalcemia
  • Severity of dehydration
  • Ability of the patient to tolerate rehydration - Vigilance to prevent volume overload is critical.
  • Hydration is ineffective in patients with kidney failure because diuresis is impossible. Dialysis is necessary to correct hypercalcemia in patients with renal failure.
• Loop diuretics
• • A loop diuretic (eg, furosemide) may be used with hydration to increase calcium excretion. This may also prevent volume overload during therapy.
  • In contrast to loop diuretics, avoid thiazide diuretics because they increase the reabsorption of calcium.
• Bisphosphates - These agents will inhibit osteoclast activity for up to a month.

Consultations

• Patients with renal failure or heart failure may not be able to tolerate fluid hydration or some of the other medications. Patients in this group who present with severe elevations of calcium may require urgent dialysis. Consult a nephrologist immediately in such cases.
• Patients with primary hyperparathyroidism may require surgery to eliminate the condition, but surgery usually does not need to be performed on an urgent basis.
• Patients with malignancy may require surgery, chemotherapy, or radiation treatment. Appropriate consultation should be undertaken.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Several classifications of medications are used to treat elevations of serum calcium. Some can be used in acute life-threatening elevations, while others are used to help control calcium elevations after the acute event has been treated. Agents that help treat hypercalcemia include plicamycin (also known as Mithracin), calcitonin, gallium nitrate, intravenous phosphate, bisphosphates, and glucocorticoids.

Drug Category: Bisphosphonates

These compounds are analogs of pyrophosphate that act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals. These agents prevent osteoclast attachment to bone matrix and interfere with osteoclast recruitment and viability.

Drug Category: Antidote, Hypercalcemia

Inhibit RNA synthesis in osteoclasts and effective in treatment of hypercalcemia.

Drug Category: Phosphate salts

Use of IV phosphate is very effective in lowering serum calcium levels most likely because of a precipitation phenomenon. Significant risk exists with use of this agent. This agent is reserved for hypercalcemia unresponsive to other agents.

Drug Category: Corticosteroids

While these agents do not treat hypercalcemia directly, they are useful for treating hypercalcemia caused by vitamin D toxicity, certain malignancies (eg, multiple myeloma, lymphoma), sarcoidosis, and other granulomatous diseases. These agents generally are not effective in patients with solid tumors or primary hyperparathyroidism. Several different glucocorticoids may be used.

Drug Category: Calcimimetic Agent

Binds to and modulates the parathyroid calcium-sensing receptor, increases sensitivity to extracellular calcium, and reduces parathyroid hormone secretion.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Serum calcium level generally responds to fluids and Lasix; however, this therapy has no effect on the principle pathologic process causing hypercalcemia. Additional therapy must be added to the temporizing treatment described above.
• Treatment of the underlying disease must be addressed.

Further Outpatient Care

• Patients with primary hyperparathyroidism who present with symptoms of severe or moderate elevations of calcium levels should be referred for parathyroidectomy. This referral may be urgent, depending on the severity of the hypercalcemia.
• Patients with mild-to-moderate elevations of calcium who have no symptoms may be evaluated on an outpatient basis and usually are treated medically. For those patients with malignancy as the cause of their hypercalcemia, a cure may not be possible.
• The ideal scenario finds a treatable underlying cause for hypercalcemia and allows the physician to attend to this primary process. If this is accomplished, the patient may not need therapy for the hypercalcemia itself.
• The drug regimen most appropriate for each individual depends on the cause of the elevation and usually is not managed by the ED physician.
• Patients may require ongoing treatment for calcium elevation.
• This type of treatment can be frustrating and difficult, and it is not always successful.

Transfer

• Transfer may be considered in a number of situations.
• • If a patient presents with severe hypercalcemia and renal failure, emergency dialysis is necessary. Consider transfer if this is unavailable at the initial treatment center.
  • If no intensivist or physician familiar with the inpatient treatment of hypercalcemia is available, consider transferring patients with normal kidney function who are being treated for severe hypercalcemia.

Deterrence/Prevention

• Avoid prolonged bedrest for patients known to have rapid bone turnover.
• Consider elective surgical procedures for patients with Paget disease after therapy has been initiated for calcium elevation. Mobilize patients as quickly as possible to minimize bone loss.
• Worsening hypercalcemia is common in patients with known metastatic disease who are too ill to ambulate. This should be anticipated and treated before the patient becomes symptomatic.
• Patients at risk for hypercalcemia should have scheduled appointments with ongoing evaluation to monitor for development or progression of the disease.
• Avoid salt restriction, diuretics, and other causes of volume depletion and dehydration in patients with active or potential hypercalcemia.

Prognosis

• The prognosis of patients with hypercalcemia depends upon the etiology of the elevation.
• • Prognosis is very poor with malignancy that has progressed into development of hypercalcemia.
  • Prognosis is excellent when the underlying cause is treatable and treatment is initiated promptly.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider hypercalcemia in differential diagnosis of a patient with vague nonspecific complaints may result in delay of diagnosis.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med. Apr 2004;32(4 Suppl):S146-54. [Medline].
• Bilezikian JP. Clinical review 51: Management of hypercalcemia. J Clin Endocrinol Metab. Dec 1993;77(6):1445-9. [Medline].
• Bilezikian JP. Management of acute hypercalcemia. N Engl J Med. Apr 30 1992;326(18):1196-203. [Medline].
• Blomqvist CP. Malignant hypercalcemia--a hospital survey. Acta Med Scand. 1986;220(5):455-63. [Medline].
• Dent DM, Miller JL, Klaff L, Barron J. The incidence and causes of hypercalcaemia. Postgrad Med J. Sep 1987;63(743):745-50. [Medline].
• Edelson GW, Kleerekoper M. Hypercalcemic crisis. Med Clin North Am. Jan 1995;79(1):79-92. [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. Dec 1991;73(6):1309-15. [Medline].
• Kiang DT, Loken MK, Kennedy BJ. Mechanism of the hypocalcemic effect of mithramycin. J Clin Endocrinol Metab. Feb 1979;48(2):341-4. [Medline].
• Kinirons MT. Newer agents for the treatment of malignant hypercalcemia. Am J Med Sci. Jun 1993;305(6):403-6. [Medline].
• Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. Jan 27 2005;352(4):373-9. [Medline].
• Thirlwell C, Brock CS. Emergencies in oncology. Clin Med. Jul-Aug 2003;3(4):306-10. [Medline].

Article Last Updated: Dec 19, 2007