What is the initial lab workup for hypercalcemia?

Initial Laboratory Workup for Hypercalcemia

The initial laboratory workup for hypercalcemia should include serum intact parathyroid hormone (iPTH), parathyroid hormone-related protein (PTHrP), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D measurements to determine the underlying cause. 1

Core Laboratory Tests

• Serum calcium (total and ionized): Confirm hypercalcemia and assess severity. Corrected calcium calculation should be used when albumin is abnormal to rule out pseudo-hypercalcemia 1
• Intact parathyroid hormone (iPTH): The most important initial test to differentiate PTH-dependent (elevated or inappropriately normal PTH) from PTH-independent causes (suppressed PTH) 2
• Serum phosphate: Typically low in primary hyperparathyroidism and variable in malignancy-associated hypercalcemia 3
• Serum creatinine: To assess kidney function, which may be impaired by hypercalcemia 1

Additional First-Line Tests

• 25-hydroxyvitamin D: To evaluate vitamin D status, as deficiency can mask primary hyperparathyroidism 1, 2
• 1,25-dihydroxyvitamin D: Elevated in granulomatous diseases and some lymphomas 1
• Parathyroid hormone-related protein (PTHrP): Important when malignancy is suspected as a cause 1, 4
• Complete blood count: To assess for anemia, which is common in malignancy but not in primary hyperparathyroidism 3
• Serum albumin: For accurate interpretation of total calcium levels 1, 5

Diagnostic Approach Based on PTH Results

Elevated or Inappropriately Normal PTH

• Suggests primary hyperparathyroidism (PHPT) 6, 1
• Additional tests to consider:
  • 24-hour urinary calcium excretion: To differentiate PHPT from familial hypocalciuric hypercalcemia 5
  • Serum chloride: May show hyperchloremic metabolic acidosis in PHPT 3

Suppressed PTH (<20 pg/mL depending on assay)

• Indicates PTH-independent hypercalcemia 2
• Additional tests based on clinical suspicion:
  • PTHrP: For malignancy-associated hypercalcemia 4
  • 1,25-dihydroxyvitamin D: For granulomatous diseases or lymphomas 1
  • Thyroid function tests: For thyrotoxicosis 5
  • Serum and urine protein electrophoresis: For multiple myeloma 4

Important Considerations

• PTH assays differ in the antibodies used and consequently the extent to which PTH fragments are measured, which can affect results 6
• PTH is more stable in EDTA plasma than in serum and at 4°C than at room temperature 6
• Several biological factors can influence PTH concentration, including race, age, BMI, and vitamin D status 6
• Sampling site and time can affect PTH measurements; central blood has higher PTH concentrations than peripheral blood 6

Common Pitfalls to Avoid

• Relying solely on total calcium without considering albumin levels or measuring ionized calcium 5
• Failing to recognize that vitamin D deficiency can mask primary hyperparathyroidism by normalizing calcium levels 2
• Not considering medication-induced hypercalcemia (thiazide diuretics, lithium, calcium supplements, vitamin D) 2, 5
• Using inappropriate reference intervals for PTH that don't account for vitamin D status 5
• Overlooking familial hypocalciuric hypercalcemia, which can mimic primary hyperparathyroidism but requires different management 7

By systematically approaching the laboratory workup of hypercalcemia with these tests, clinicians can efficiently determine the underlying cause and guide appropriate management.