What is the workup for hypercalcemia?

From the Guidelines

The workup for hypercalcemia should begin with confirming the elevated calcium level through repeat testing, including ionized calcium if available, and a comprehensive history and physical examination, as recommended by recent guidelines 1. The initial evaluation should focus on symptoms like fatigue, confusion, constipation, and bone pain. Laboratory tests should include parathyroid hormone (PTH) level, phosphorus, vitamin D levels (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D), complete blood count, comprehensive metabolic panel, and urinary calcium excretion.

• If PTH is elevated, primary hyperparathyroidism is likely, while suppressed PTH suggests malignancy-related hypercalcemia or vitamin D toxicity, as noted in a study on PTH measurement 1.
• Additional tests may include serum and urine protein electrophoresis to evaluate for multiple myeloma, thyroid function tests, and PTH-related protein (PTHrP) if malignancy is suspected.
• Imaging studies like neck ultrasound for parathyroid adenomas, bone scan or skeletal survey for bone metastases, and chest X-ray to screen for lung cancer may be indicated based on initial findings, as outlined in the ACR appropriateness criteria for parathyroid adenoma 1. For severe hypercalcemia (>14 mg/dL) or symptomatic patients, immediate treatment with IV fluids (normal saline at 200-300 mL/hour), calcitonin (4 IU/kg every 12 hours), bisphosphonates (zoledronic acid 4 mg IV or pamidronate 60-90 mg IV), and possibly hemodialysis should be initiated while completing the diagnostic workup, as this approach prioritizes morbidity, mortality, and quality of life outcomes.
• The choice of PTH assay may impact clinical decisions, particularly in cases of secondary hyperparathyroidism or after parathyroid surgery, as highlighted in a review of PTH measurement guidelines 1.
• However, for primary hyperparathyroidism, the type of PTH assay used is less likely to affect diagnosis or management, according to a study on clinical guidelines and PTH measurement 1.

From the FDA Drug Label

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3. 0 mmol/L]) is 4 mg. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i. e., saline hydration, with or without loop diuretics).

The work up for hypercalcemia includes assessing serum creatinine prior to treatment and considering the severity and symptoms of tumor-induced hypercalcemia.

• Key steps in the work up include:
  • Assessing serum creatinine
  • Evaluating the severity and symptoms of hypercalcemia
  • Initiating vigorous saline hydration to restore urine output to about 2 L/day
  • Considering conservative measures such as saline hydration with or without loop diuretics for mild or asymptomatic hypercalcemia 2

From the Research

Diagnostic Approach

• The diagnostic workup of hypercalcemia requires a thorough patient history, a focused clinical examination, and a step-by-step laboratory diagnostic approach 3.
• Measurement of serum calcium and parathyroid hormone (PTH) levels is essential to detect the exact etiology of hypercalcemia 4, 3.
• Primary hyperparathyroidism and malignancy-related hypercalcemia are responsible for about 90% of all hypercalcemia cases, and these two pathologies should always be considered in the diagnostic approach 4, 5, 3, 6.

Initial Evaluation

• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, distinguishing PTH-dependent from PTH-independent causes 4.
• An elevated or normal PTH concentration is consistent with primary hyperparathyroidism, while a suppressed PTH level indicates another cause 4.
• Discontinuation of any medication likely to be involved in iatrogenic hypercalcemia should be considered in the initial workup 7.

Treatment

• The chosen treatments and their speed of introduction depend mainly on the severity of hypercalcemia 7.
• Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate 4, 5.
• Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas) 4, 5.
• Denosumab and dialysis may be indicated in patients with kidney failure 4, 5.