Laboratory Workup for Hypercalcemia
The essential initial laboratory panel for hypercalcemia includes intact parathyroid hormone (iPTH), serum creatinine, phosphorus, magnesium, albumin (for corrected calcium), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D—with iPTH being the single most critical test to distinguish PTH-dependent from PTH-independent causes. 1, 2, 3
First-Line Mandatory Tests
Confirm and Quantify Hypercalcemia
- Total serum calcium should be measured fasting to establish the diagnosis 2, 3
- Ionized calcium should be measured simultaneously, as total calcium can be inaccurate due to protein binding 2, 4
- Serum albumin is essential to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 2, 3
- Classify severity as mild (>10 to <11 mg/dL), moderate (11 to 12 mg/dL), or severe (>14 mg/dL) to determine urgency 1, 2, 5
Critical Diagnostic Tests
- Intact parathyroid hormone (iPTH) is the most important initial test—elevated or inappropriately normal iPTH indicates primary hyperparathyroidism, while suppressed iPTH (<20 pg/mL) points to other causes 1, 2, 3, 5
- Serum creatinine and blood urea nitrogen to assess renal function, as hypercalcemia causes nephrocalcinosis and renal impairment 1, 2, 3
- Serum phosphorus helps differentiate causes—hyperparathyroidism typically shows low phosphorus, while malignancy shows variable levels 1, 2
- Serum magnesium should be measured as deficiency affects calcium homeostasis 1, 2
Second-Line Tests Based on iPTH Results
If PTH is Suppressed (<20 pg/mL)
- Parathyroid hormone-related protein (PTHrP) should be measured to identify humoral hypercalcemia of malignancy 1, 2, 6
- 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D must be measured together—their relationship provides critical diagnostic information for vitamin D intoxication or granulomatous disease 1, 2, 3
If PTH is Elevated or Inappropriately Normal
- 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D should be measured together to exclude vitamin D deficiency before diagnosing primary hyperparathyroidism 1, 2
- Urine calcium/creatinine ratio to differentiate familial hypocalciuric hypercalcemia (low urinary calcium) from primary hyperparathyroidism (elevated urinary calcium) 2
Critical Pitfalls to Avoid
Albumin-Related Errors
- Hyperalbuminemia masks true calcium status—always calculate corrected calcium or measure ionized calcium directly 2
- Total calcium alone is often inaccurate; ionized calcium measurement increases diagnostic accuracy 4
PTH Interpretation Errors
- In patients with chronic kidney disease, interpret iPTH cautiously as secondary hyperparathyroidism may coexist with other hypercalcemia causes 1, 3
- PTH concentrations are 20% higher in vitamin D-deficient individuals, so vitamin D status must be assessed before diagnosing primary hyperparathyroidism 1
- PTH values are higher in Black individuals, increase with age due to declining GFR, and are elevated in obese patients 1
Vitamin D Testing Errors
- Never measure vitamin D metabolites in isolation—always measure both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together, as their relationship is diagnostically crucial 1, 2
- In sarcoidosis, 1,25-dihydroxyvitamin D is elevated due to increased 1α-hydroxylase production in granulomas, while 25-hydroxyvitamin D is typically low 1, 3
Dehydration Confounding
- Dehydration concentrates blood components and can falsely elevate calcium levels 1, 2
- Check serum osmolality (>300 mOsm/kg indicates dehydration) and recheck calcium after adequate hydration 1, 2
Special Clinical Scenarios
Malignancy-Associated Hypercalcemia
- If PTHrP is elevated with suppressed PTH, pursue comprehensive oncological workup even if initial CT scans are unrevealing, as lymphoma may be missed on CT 7
- Approximately 90% of hypercalcemia cases are due to primary hyperparathyroidism or malignancy 5