What are the initial diagnostic lab tests for hypercalcemia (elevated calcium levels in the blood)?

Initial Diagnostic Laboratory Tests for Hypercalcemia

The essential first-line laboratory tests for hypercalcemia are serum calcium (total and ionized), albumin, and intact parathyroid hormone (iPTH), which distinguishes PTH-dependent from PTH-independent causes and guides all subsequent testing. 1, 2

First-Line Laboratory Panel

Core Tests (Order Immediately)

• Serum calcium - both total and ionized calcium should be measured, as total calcium can be inaccurate due to protein binding variations 1, 3
• Albumin - required to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 4
• Intact parathyroid hormone (iPTH) - this is the single most important test, as it differentiates PTH-dependent causes (elevated or inappropriately normal PTH) from PTH-independent causes (suppressed PTH <20 pg/mL) 1, 2
• Serum creatinine and blood urea nitrogen - essential to assess renal function and guide treatment decisions 1, 4
• Serum phosphorus - typically low in primary hyperparathyroidism, may be elevated in other causes 1, 4
• Serum magnesium - can affect PTH secretion and calcium metabolism 1, 4

Critical Sampling Considerations

• Obtain fasting samples - calcium levels can be transiently elevated for several hours after calcium-containing meals or supplements, leading to false diagnoses 5
• Use EDTA plasma for PTH measurement - PTH is most stable in EDTA plasma at 4°C rather than serum at room temperature 6
• Avoid prolonged tourniquet application - venous stasis causes hemoconcentration and falsely elevates the bound calcium fraction 5

Second-Line Tests (Based on PTH Results)

If PTH is Elevated or Inappropriately Normal (PTH-Dependent)

• 25-hydroxyvitamin D - vitamin D deficiency causes secondary hyperparathyroidism and must be excluded before diagnosing primary hyperparathyroidism 6, 7
• 1,25-dihydroxyvitamin D - measure both 25-OH and 1,25-(OH)2 vitamin D levels together, as their relationship provides critical diagnostic information 8
• Urine calcium-to-creatinine ratio - helps distinguish familial hypocalciuric hypercalcemia (low ratio) from primary hyperparathyroidism (normal to high ratio) 4

If PTH is Suppressed (PTH-Independent)

• Parathyroid hormone-related protein (PTHrP) - elevated in malignancy-associated hypercalcemia, which accounts for approximately 90% of cases along with primary hyperparathyroidism 1, 2
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D - to evaluate for vitamin D intoxication or granulomatous diseases like sarcoidosis (low 25-OH with elevated 1,25-(OH)2) 1, 6

Severity Classification

Classify hypercalcemia severity to guide urgency of workup and treatment 1, 4:

• Mild: Total calcium >10.5 mg/dL to <12 mg/dL (>5.0 to <5.5 mEq/L) - typically asymptomatic
• Moderate: Total calcium 12-14 mg/dL (5.5-6.0 mEq/L) - may have polyuria, polydipsia, nausea, confusion
• Severe: Total calcium >14 mg/dL (>6.0 mEq/L) - mental status changes, bradycardia, acute renal failure

Common Pitfalls to Avoid

• Do not rely solely on total calcium - hyperalbuminemia can mask true calcium status and hypoalbuminemia can falsely suggest hypercalcemia; always calculate corrected calcium or measure ionized calcium 4, 3
• Do not order parathyroid imaging before confirming biochemical diagnosis - imaging is for surgical planning in confirmed primary hyperparathyroidism, not for diagnosis 6
• Do not interpret PTH in isolation - PTH assays differ by up to 47% between different generations, and biological factors (race, age, BMI, vitamin D status) influence PTH concentration 6
• Do not diagnose primary hyperparathyroidism without excluding vitamin D deficiency - PTH reference values are 20% lower in vitamin D-replete individuals, and deficiency causes secondary hyperparathyroidism 6
• Recognize that PTH biological variation is substantial - differences must exceed 54% between measurements to be clinically significant in healthy individuals 6

Special Population Considerations

• Chronic kidney disease patients - interpret PTH levels cautiously as secondary hyperparathyroidism can coexist with other causes; consider dialysate calcium adjustments 1, 6
• Pediatric patients - also check vitamin D concentrations (both 25-OH and 1,25-(OH)2) and consider genetic causes 1
• Suspected sarcoidosis - baseline serum calcium testing is recommended even without symptoms, as hypercalcemia occurs in approximately 6% of patients 8