What blood tests should be ordered for a patient with hypercalcemia?

Blood Tests to Order for Hypercalcemia

Order intact parathyroid hormone (iPTH) as the single most important initial test, along with serum calcium (total and ionized), albumin, phosphorus, creatinine, and magnesium; then proceed to second-line tests including 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTHrP based on the PTH result. 1, 2, 3

First-Line Laboratory Tests (Order These Initially)

Essential Core Panel

• Serum calcium (both total and ionized) to confirm and quantify hypercalcemia 1, 2, 3
• Albumin to calculate corrected calcium using the formula: corrected calcium (mg/dL) = total calcium (mg/dL) - 0.8 × [albumin (g/dL) - 4] 2, 3
• Intact parathyroid hormone (iPTH) - this is the most critical test to differentiate PTH-dependent from PTH-independent causes 1, 2, 3, 4
• Serum phosphorus - typically low in primary hyperparathyroidism and high in vitamin D toxicity 2
• Serum creatinine and blood urea nitrogen to assess renal function 1, 2, 3
• Magnesium level 1, 2

Important Sampling Considerations

• Obtain fasting samples for diagnostic purposes, as calcium supplements or calcium-containing nutrients can cause transient elevations lasting several hours 5
• Avoid prolonged venous stasis during blood draw, as this causes hemoconcentration and artificially elevates the bound calcium fraction 5

Second-Line Tests (Based on PTH Results)

If PTH is Elevated or Inappropriately Normal (Suggests Primary Hyperparathyroidism)

• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels - measure both together as their relationship provides critical diagnostic information 6, 1, 2
• Consider renal ultrasound to assess for nephrocalcinosis or nephrolithiasis 2
• Consider bone mineral density testing 2

If PTH is Suppressed (<20 pg/mL) (Suggests Non-PTH Mediated Causes)

• Parathyroid hormone-related protein (PTHrP) to evaluate for humoral hypercalcemia of malignancy 1, 2, 3, 4
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D if granulomatous disease (such as sarcoidosis) is suspected 6, 2
• Consider chest X-ray and age-appropriate cancer screening 2

Clinical Context and Pitfalls

Severity Classification

Classify hypercalcemia severity to guide urgency: mild (>10 to <11 mg/dL), moderate (11 to 12 mg/dL), or severe (>14 mg/dL) 1, 3, 4

Common Diagnostic Errors to Avoid

• Do not rely on corrected calcium formulas alone - they may be accurate only within a limited range and can introduce errors; ionized calcium is more reliable for diagnostic purposes 5
• Interpret PTH cautiously in renal insufficiency - secondary hyperparathyroidism may coexist with other causes of hypercalcemia 1, 3
• Always measure both vitamin D metabolites together (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) rather than individually, as the American Thoracic Society emphasizes their relationship provides critical diagnostic information 6, 1

Special Populations

• In suspected sarcoidosis, baseline serum calcium testing is recommended even without symptoms, as hypercalcemia occurs in approximately 6% of patients, with elevated 1,25-dihydroxyvitamin D due to increased 1α-hydroxylase production in granulomas 1, 3
• In malignancy-associated hypercalcemia, expedite the diagnostic evaluation as it may indicate advanced disease with poor prognosis (median survival approximately 1 month after discovery in lung cancer) 2

Underlying Causes

Primary hyperparathyroidism and malignancy account for more than 90% of hypercalcemia cases 4, 7