Hypercalcemia Workup

Updated: Apr 26, 2023
  • Author: Mahendra Agraharkar, MD, MBBS, FACP, FASN; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Approach Considerations

Malignancy is one of the most common causes and must be excluded. Hyperparathyroidism and other causes of hypercalcemia can coexist with malignancy. If calcium levels have been mildly elevated for months or years, malignancy is an unlikely cause.

Hypercalcemia from malignancy usually is rapidly progressive; thus, rapidly rising calcium levels should increase suspicion of malignancy. If calcium levels have been elevated for an unknown duration, the patient should be evaluated for the presence of malignancy. Breast, lung, and kidney cancers should be considered, as should multiple myeloma, lymphoma, and leukemia. Testing in such cases might include a peripheral blood smear and/or serum and urine immunofixation electrophoresis. Biopsy samples may be taken from a solid tumor or from bone marrow for tissue histology studies.

Hyperparathyroidism is the most common cause of hypercalcemia in the population at large and usually is mild, asymptomatic, and sustained for years. Immunoreactive parathyroid hormone (PTH) and ionized calcium should be simultaneously measured. PTH levels should be suppressed in hypercalcemia; thus, the combination of normal PTH levels and elevated calcium levels suggests mild hyperparathyroidism. Hyperparathyroidism may be part of multiple endocrine neoplasia type 1, (ie, Wermer syndrome).

Other causes of hypercalcemia usually can be distinguished or at least considered on the basis of history and physical examination findings. Measurement of serum phosphate, alkaline phosphatase, serum chloride, serum bicarbonate, and urinary calcium may be useful in some cases. Renal function should be evaluated and thyroid-stimulating hormone should be checked to help rule out hyperthyroidism. In rare cases, measurement of vitamin D and its metabolites and measurement of parathyroid hormone–related peptide (PTHrP) may be necessary.

A flowchart of investigations is depicted in the image below.

Investigations flowchart. Investigations flowchart.



Imaging Studies

Chest radiographs always should be performed to help rule out lung cancer or sarcoidosis. Other radiographs should be considered to help evaluate for possible malignancies, metastases, or Paget disease.

Mammograms should be considered to help rule out breast cancer. Computed tomography (CT) and ultrasound should be considered to help rule out renal cancer.

When a biochemical diagnosis of primary hyperparathyroidism is made, CT scan, ultrasound, magnetic resonance imaging (MRI), and radionuclide imaging of the parathyroid gland may be helpful to assist with preoperative localization.



On electrocardiography (ECG), characteristic changes in patients with hypercalcemia include shortening of the QT interval. ECG changes in patients with very high serum calcium levels include the following [21, 22, 23] :

  • Slight prolongation of the PR and QRS intervals
  • T wave flattening or inversion
  • A J wave at the end of the QRS complex
  • ST elevation mimicking acute myocardial infarction