What is the initial workup for a patient presenting with hypercalcemia?

Initial Workup for Hypercalcemia

The initial workup for hypercalcemia must include measurement of intact parathyroid hormone (iPTH) to differentiate PTH-dependent from PTH-independent causes, along with serum calcium (total and ionized), albumin, phosphorus, creatinine, and 25-hydroxyvitamin D levels. 1

First-Line Laboratory Tests

The diagnostic algorithm begins with a focused panel of laboratory tests that will identify the underlying etiology in over 90% of cases:

Core Initial Labs (Order Immediately)

• Serum calcium - Measure both total and ionized calcium to confirm hypercalcemia and quantify severity, as ionized calcium avoids the pitfall of pseudo-hypercalcemia from hemolysis or improper sampling 1, 2, 3
• Albumin - Required to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Albumin (g/dL)], since hyperalbuminemia can mask true calcium status 2, 3
• Intact PTH (iPTH) - This is the single most important discriminating test that separates PTH-dependent causes (primary hyperparathyroidism) from PTH-independent causes (malignancy, vitamin D toxicity, granulomatous disease) 1, 4
• Serum phosphorus - Typically low in primary hyperparathyroidism and high in vitamin D toxicity, providing critical diagnostic information 1
• Serum creatinine and BUN - Essential to assess renal function, as hypercalcemia causes progressive dehydration and declining glomerular filtration rate 1, 3

Additional First-Line Tests

• 25-hydroxyvitamin D - Must be measured to evaluate for vitamin D intoxication or deficiency 1
• Magnesium - Should be measured as part of the initial electrolyte assessment 1

Diagnostic Algorithm Based on PTH Results

If PTH is Elevated or Normal (>20 pg/mL)

This pattern indicates primary hyperparathyroidism as the likely diagnosis 1, 4:

• Order renal ultrasound to assess for nephrocalcinosis or nephrolithiasis 1
• Order bone mineral density testing to evaluate for skeletal involvement 1
• Measure urine calcium/creatinine ratio if familial hypocalciuric hypercalcemia is suspected 1

If PTH is Suppressed (<20 pg/mL)

This pattern indicates PTH-independent hypercalcemia and requires immediate further workup 1:

• PTHrP (parathyroid hormone-related protein) - Measure immediately to evaluate for humoral hypercalcemia of malignancy, which is the most common cause in this scenario 1, 3
• 1,25-dihydroxyvitamin D - Measure if granulomatous disease (sarcoidosis, tuberculosis) is suspected based on clinical context 1, 3
• Chest X-ray - Perform to evaluate for lung malignancy or sarcoidosis 1
• Age-appropriate cancer screening - Expedite this evaluation, as hypercalcemia of malignancy indicates advanced disease with median survival of approximately 1 month in lung cancer 1, 3

Severity Assessment and Symptom Evaluation

Classify the severity immediately to guide urgency of treatment 2:

• Mild hypercalcemia: Total calcium 10-11 mg/dL (2.5-2.75 mmol/L) - Usually asymptomatic but may cause fatigue and constipation in 20% of patients 2, 4
• Moderate hypercalcemia: Total calcium 11-12 mg/dL (2.75-3 mmol/L) - Associated with polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia 1, 2
• Severe hypercalcemia: Total calcium >14 mg/dL (>3.5 mmol/L) - Causes mental status changes, confusion, somnolence, coma, bradycardia, hypotension, dehydration, acute renal failure 2, 4

Critical Pitfalls to Avoid

• Do not rely solely on corrected calcium - Always measure ionized calcium when available, as corrected calcium formulas can be inaccurate, particularly with significant albumin abnormalities 3
• Do not delay PTHrP measurement - If PTH is suppressed and malignancy is suspected, order PTHrP immediately as this represents a medical emergency with poor prognosis 1, 3
• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together - Measuring only one can lead to diagnostic errors, particularly in granulomatous disease where 1,25-dihydroxyvitamin D is elevated despite normal 25-hydroxyvitamin D 3
• Obtain medication history - Specifically ask about thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), and vitamin A intake 3
• Do not overlook rare causes - Consider thyroid disorders, adrenal insufficiency, and immobilization in patients with negative initial workup 1

Special Clinical Contexts

For patients with known malignancy: The diagnostic evaluation must be expedited as hypercalcemia indicates advanced disease with extremely poor prognosis 1, 3. Immediately measure PTHrP and initiate treatment while completing the workup.

For pediatric patients: Avoid vitamin D supplements in early childhood if hypercalcemia is present, and consider genetic disorders such as Williams syndrome 2, 3.