What is the initial workup for a patient presenting with hypercalcemia, considering demographics and past medical history?

Initial Workup for Hypercalcemia

The initial workup for hypercalcemia must begin with measurement of intact parathyroid hormone (iPTH), serum calcium (total and ionized), albumin, phosphorus, creatinine, and blood urea nitrogen to differentiate PTH-dependent from PTH-independent causes and assess severity. 1, 2

First-Line Laboratory Tests

The diagnostic algorithm hinges on iPTH measurement, which is the single most important test to guide further evaluation 1, 2, 3:

• Serum calcium (total and ionized) should be measured to confirm hypercalcemia and quantify severity 1
• Albumin level must be obtained to calculate corrected calcium, as total calcium measurements can be misleading when albumin is abnormal 4
• Intact PTH (iPTH) is the critical branching point in the diagnostic algorithm 1, 2
• Serum phosphorus helps differentiate causes—typically low in primary hyperparathyroidism and high in vitamin D toxicity 1
• Serum creatinine and BUN assess renal function and complications 1
• Magnesium level should be measured as part of the initial panel 1

Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C. 4 Be aware that PTH assays vary significantly between laboratories (up to 47% difference), so use assay-specific reference values 4.

Diagnostic Algorithm Based on PTH Level

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

This pattern suggests primary hyperparathyroidism 1, 4, 2:

• 25-hydroxyvitamin D must be measured to exclude vitamin D deficiency causing secondary hyperparathyroidism 4
• 24-hour urine calcium or spot urine calcium/creatinine ratio should be obtained to assess for hypercalciuria and differentiate from familial hypocalciuric hypercalcemia 1, 4
• Renal ultrasound to evaluate for nephrocalcinosis or nephrolithiasis 1
• Bone mineral density testing should be performed to assess for osteoporosis 1

If PTH is Suppressed (<20 pg/mL) (PTH-Independent)

This pattern indicates non-PTH mediated causes 1:

• PTHrP (parathyroid hormone-related protein) should be measured immediately to evaluate for humoral hypercalcemia of malignancy 1, 4
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are essential—the relationship between these two provides critical diagnostic information 1, 4
  • Low 25-OH with elevated 1,25-(OH)₂ suggests granulomatous disease (sarcoidosis, tuberculosis) due to increased 1α-hydroxylase activity 4
  • Elevated 25-OH suggests vitamin D intoxication 1
• Chest X-ray and age-appropriate cancer screening should be performed to evaluate for malignancy 1

Assessment of Severity and Symptoms

Evaluate for specific symptoms that correlate with calcium levels 1, 4:

• Mild hypercalcemia (<12 mg/dL): Usually asymptomatic but may cause fatigue, constipation, polyuria, polydipsia 2
• Moderate hypercalcemia (12-14 mg/dL): Nausea, vomiting, abdominal pain, myalgia, confusion 4
• Severe hypercalcemia (>14 mg/dL): Mental status changes, bradycardia, hypotension, severe dehydration, acute renal failure 4

Special Considerations and Common Pitfalls

Do not order parathyroid imaging (ultrasound or sestamibi scan) before confirming the biochemical diagnosis—imaging is for surgical planning, not diagnosis. 4 This is a common error that wastes resources and can lead to false-positive findings.

For patients with malignancy, expedite the diagnostic evaluation as hypercalcemia indicates advanced disease with poor prognosis (median survival approximately 1 month in lung cancer). 1, 4

Correct calcium for albumin using the formula: Corrected calcium = measured calcium + 0.8 × (4.0 - albumin). If albumin is abnormal, measure ionized calcium (normal: 4.65-5.28 mg/dL) for definitive assessment 4.

Review and discontinue causative medications: thiazide diuretics, calcium supplements, vitamin D supplements, lithium 1, 2. In patients taking vitamin D supplements with hypercalcemia, discontinue all vitamin D therapy immediately if calcium exceeds 10.2 mg/dL 4.

PTH biological variation is substantial (20% in healthy individuals), so differences must exceed 54% between measurements to be clinically significant 4. Additionally, PTH is affected by race, age, BMI, vitamin D status, and sampling site (central blood has higher PTH than peripheral) 4.

In patients with chronic kidney disease, consider secondary or tertiary hyperparathyroidism in the differential, though these typically present with normal or low calcium, not hypercalcemia 4.