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

Initial Workup for Hypercalcemia

The initial workup for a patient presenting with hypercalcemia should include measurement of intact parathyroid hormone (iPTH), parathyroid hormone-related protein (PTHrP), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, and phosphorus levels to determine the underlying cause. 1

First-line Laboratory Tests

• Serum calcium (total and ionized) to confirm and quantify the severity of hypercalcemia 1
• Albumin level to correct for calcium binding 1
• Intact parathyroid hormone (iPTH) - the most important initial test to differentiate PTH-dependent from PTH-independent causes 1, 2
• Serum phosphorus level (typically low in primary hyperparathyroidism and high in vitamin D toxicity) 1
• Serum creatinine and blood urea nitrogen to assess renal function 1
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels 1
• Parathyroid hormone-related protein (PTHrP) if malignancy is suspected 1
• Magnesium level 1

Diagnostic Algorithm

Step 1: Confirm Hypercalcemia

• Repeat calcium measurement to confirm hypercalcemia 2
• Calculate corrected calcium if albumin is abnormal: Corrected Ca = Measured Ca + 0.8 × (4.0 - Albumin) 2

Step 2: Assess Severity and Symptoms

• Mild hypercalcemia: Total calcium <12 mg/dL or ionized calcium 5.6-8.0 mg/dL 2
• Moderate hypercalcemia: Total calcium 12-14 mg/dL 2
• Severe hypercalcemia: Total calcium ≥14 mg/dL or ionized calcium ≥10 mg/dL 2
• Evaluate for symptoms: polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, myalgia, dehydration, mental status changes 1

Step 3: Measure PTH Level

• Elevated or normal PTH with hypercalcemia suggests primary hyperparathyroidism 1, 2
• Suppressed PTH (<20 pg/mL) suggests non-PTH mediated causes (malignancy, vitamin D toxicity, granulomatous disease) 1, 2

Step 4: Additional Tests Based on Initial Results

If PTH is suppressed:

• PTHrP measurement to evaluate for humoral hypercalcemia of malignancy 1
• Chest X-ray and age-appropriate cancer screening 1
• Serum and urine protein electrophoresis to evaluate for multiple myeloma 2
• 1,25-dihydroxyvitamin D level if granulomatous disease is suspected 1

If PTH is elevated or normal:

• 24-hour urine calcium and creatinine to differentiate primary hyperparathyroidism from familial hypocalciuric hypercalcemia 2, 3
• Renal ultrasound to assess for nephrocalcinosis or nephrolithiasis 1
• Bone mineral density testing 1

Special Considerations

• Medication review is essential - check for thiazide diuretics, lithium, vitamin A, vitamin D supplements, and calcium supplements 2, 3
• For patients with malignancy, the diagnostic evaluation should be expedited as hypercalcemia may indicate advanced disease with poor prognosis (median survival approximately 1 month after discovery of hypercalcemia in lung cancer) 1
• In patients with severe hypercalcemia (>14 mg/dL), immediate treatment should be initiated concurrently with diagnostic workup 2, 4
• Urine calcium/creatinine ratio should be obtained if hypercalciuria is suspected 1

Common Pitfalls to Avoid

• Failing to correct calcium for albumin in hypoalbuminemic patients 2, 3
• Overlooking medication-induced causes of hypercalcemia 2, 3
• Assuming all hypercalcemia with elevated PTH is primary hyperparathyroidism without excluding familial hypocalciuric hypercalcemia 2, 3
• Delaying treatment in severely symptomatic patients while awaiting complete diagnostic workup 2, 4
• Not considering rare causes such as granulomatous diseases, thyroid disorders, or adrenal insufficiency 1

Remember that approximately 90% of hypercalcemia cases are due to primary hyperparathyroidism or malignancy, but a systematic approach is necessary to identify the specific cause and guide appropriate treatment 2, 3.