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, magnesium, creatinine, BUN, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTHrP if malignancy is suspected. 1, 2, 3

Essential First-Line Laboratory Tests

The diagnostic algorithm begins with these mandatory tests:

• Serum calcium: Measure both total and ionized calcium to confirm hypercalcemia and quantify severity 1, 2
• Albumin: Required to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 2, 3
• Intact PTH (iPTH): This is the single most important test to guide your differential diagnosis 1, 3, 4
• Serum phosphorus: Typically low in primary hyperparathyroidism and high in vitamin D toxicity 1, 2
• Creatinine and BUN: Essential to assess renal function and guide treatment decisions 1, 2
• Magnesium: Must be measured as part of the initial panel 1, 2
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D: Required to evaluate vitamin D-mediated causes 1, 2, 3

Clinical Assessment of Severity

Before ordering labs, assess symptom severity to determine urgency:

• Mild hypercalcemia (10-11 mg/dL): Usually asymptomatic but may cause fatigue and constipation in 20% of patients 3, 4
• Moderate hypercalcemia (11-12 mg/dL): Look for polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, myalgia, and dehydration 1, 2, 3
• Severe hypercalcemia (>14 mg/dL): Expect mental status changes, bradycardia, hypotension, acute renal failure, somnolence, and potentially coma 2, 4

Algorithmic Approach Based on PTH Level

If PTH is Elevated or Inappropriately Normal

This pattern indicates primary hyperparathyroidism 1, 3, 5:

• Order renal ultrasound to assess for nephrocalcinosis or nephrolithiasis 1
• Obtain bone mineral density testing 1
• Expect to find hypophosphatemia and hyperchloremic metabolic acidosis 3, 5
• Note that calcium levels are typically <12 mg/dL with duration >6 months 5

If PTH is Suppressed (<20 pg/mL)

This indicates non-PTH mediated causes and requires immediate additional workup 1, 3:

• Measure PTHrP immediately to evaluate for humoral hypercalcemia of malignancy 1, 2, 3
• Order chest X-ray and age-appropriate cancer screening 1
• Measure 1,25-dihydroxyvitamin D if granulomatous disease (sarcoidosis, lymphoma) is suspected 1, 3
• Obtain urine calcium/creatinine ratio if hypercalciuria is suspected 1

Critical pitfall: Malignancy-associated hypercalcemia typically presents with rapid onset, higher calcium levels (often >12 mg/dL), marked anemia, and carries a poor prognosis with median survival of approximately 1 month after discovery in lung cancer patients 1, 5, 6. This requires expedited evaluation. 1

Key Diagnostic Distinctions

Primary hyperparathyroidism versus malignancy can be differentiated by these patterns 5:

• Hyperparathyroidism: Lower calcium (<12 mg/dL), longer duration (>6 months), kidney calculi present, hyperchloremic metabolic acidosis, no anemia 5
• Malignancy: Rapid onset, higher calcium levels, severe symptoms, marked anemia, never kidney calculi or metabolic acidosis 5, 6

Common Pitfalls to Avoid

• Hyperalbuminemia can mask true calcium status: Always calculate corrected calcium or measure ionized calcium directly 2
• Don't overlook rare causes: Consider granulomatous diseases, thyroid disorders, adrenal insufficiency, medications (thiazides, vitamin D/A supplements), and newer associations with SGLT2 inhibitors, immune checkpoint inhibitors, and denosumab discontinuation 1, 4
• Assess acid-base status: This affects interpretation of calcium levels 7
• In patients with Bence-Jones proteinuria: Ensure adequate hydration before any contrast studies or nephrotoxic interventions 8