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, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and magnesium. 1

First-Line Laboratory Tests

The diagnostic algorithm begins with confirming and quantifying hypercalcemia severity:

• Measure serum calcium (both total and ionized) to confirm hypercalcemia and assess severity 1, 2
• Calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4], since albumin level affects calcium binding and can mask true calcium status 2
• Classify severity as mild (>10 to <11 mg/dL), moderate (11 to 12 mg/dL), or severe (>14.0 mg/dL) to guide urgency of intervention 2, 3

Critical Initial Test: Intact PTH

Intact parathyroid hormone (iPTH) is the single most important initial test and must be obtained in every patient with confirmed hypercalcemia 1, 4:

• Elevated or normal PTH with hypercalcemia indicates PTH-dependent causes, primarily primary hyperparathyroidism 1, 3
• Suppressed PTH (<20 pg/mL) indicates PTH-independent causes such as malignancy, vitamin D toxicity, or granulomatous disease 1, 3

Additional Essential Laboratory Tests

Complete the initial panel with these measurements 1, 2:

• Serum phosphorus: Typically low in primary hyperparathyroidism, high in vitamin D toxicity 1
• Serum creatinine and BUN: Essential to assess renal function, as hypercalcemia commonly causes renal impairment 1
• Magnesium level: Required for complete electrolyte assessment 1
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D: Necessary to identify vitamin D-mediated hypercalcemia 1

Symptom Assessment

Evaluate for specific symptoms based on severity 1, 2:

• Mild to moderate hypercalcemia: Polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia, fatigue, constipation (approximately 20% of patients with mild hypercalcemia are symptomatic) 1, 3
• Severe hypercalcemia: Mental status changes, confusion, somnolence, coma, bradycardia, hypotension, dehydration, acute renal failure 2, 3

Algorithmic Approach Based on PTH Results

If PTH is Suppressed (<20 pg/mL):

• Measure PTHrP (parathyroid hormone-related protein) to evaluate for humoral hypercalcemia of malignancy, which accounts for over 90% of hypercalcemia cases along with primary hyperparathyroidism 1, 3
• Obtain chest X-ray and perform age-appropriate cancer screening, as malignancy-associated hypercalcemia indicates advanced disease with poor prognosis (median survival approximately 1 month in lung cancer) 1
• Measure 1,25-dihydroxyvitamin D if granulomatous disease (sarcoidosis, tuberculosis) is suspected 1

If PTH is Elevated or Normal:

• Perform renal ultrasound to assess for nephrocalcinosis or nephrolithiasis, which are characteristic of primary hyperparathyroidism 1
• Obtain bone mineral density testing to evaluate for skeletal involvement 1
• Measure urine calcium/creatinine ratio if hypercalciuria is suspected 1

Common Pitfalls to Avoid

• Do not rely on total calcium alone without correcting for albumin or measuring ionized calcium, as hyperalbuminemia can mask true calcium status 2
• Expedite the diagnostic evaluation in patients with suspected malignancy, as hypercalcemia may indicate advanced disease requiring urgent intervention 1
• Consider rare causes such as thyroid disorders, adrenal insufficiency, or medication-induced hypercalcemia (thiazide diuretics, calcium/vitamin D supplements, immune checkpoint inhibitors) when common causes are excluded 3
• Do not delay PTH measurement as it is the single most discriminating test and guides all subsequent diagnostic and therapeutic decisions 1, 4