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

Hypercalcemia Workup

The initial workup for hypercalcemia requires measuring serum calcium (corrected for albumin or ionized), intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, magnesium, creatinine, and albumin to determine the underlying cause, with PTH being the single most critical test to distinguish PTH-dependent from PTH-independent etiologies. 1, 2

Initial Laboratory Assessment

The diagnostic algorithm begins with these specific tests:

• Measure ionized calcium directly rather than relying solely on corrected calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 1
• If using total calcium, calculate corrected calcium: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 2, 3
• Intact PTH is the most important initial test - it distinguishes PTH-dependent (elevated or inappropriately normal PTH) from PTH-independent causes (suppressed PTH <20 pg/mL) 1, 4
• Measure both 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy 1
• Check serum phosphorus, magnesium, BUN, and creatinine to assess renal function and identify patterns (hyperparathyroidism causes low phosphorus; malignancy may show elevated phosphorus) 1, 2

Severity Classification

Classify hypercalcemia severity to guide urgency of intervention:

• Mild: 10-11 mg/dL (2.5-2.75 mmol/L) - usually asymptomatic but may have fatigue and constipation in 20% 2, 4
• Moderate: 11-12 mg/dL or 12-13.5 mg/dL (2.75-3.4 mmol/L) 2, 3
• Severe: >14 mg/dL (>3.5 mmol/L) or ionized calcium ≥10 mg/dL (≥2.5 mmol/L) - causes nausea, vomiting, dehydration, confusion, somnolence, coma 2, 4

Symptom Assessment

Evaluate for specific symptoms based on severity:

• Mild/moderate: polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, myalgia 1, 2
• Severe: mental status changes, bradycardia, hypotension, dehydration, acute renal failure 2
• ECG changes: assess for QT interval prolongation in severe cases 1

Etiology-Specific Workup

If PTH is Elevated or Normal (PTH-dependent)

• Primary hyperparathyroidism is the diagnosis - accounts for ~90% of hypercalcemia cases along with malignancy 4, 5
• Characterized by: calcium <12 mg/dL, duration >6 months, fewer symptoms, possible kidney stones, hyperchloremic metabolic acidosis, no anemia 5

If PTH is Suppressed (PTH-independent)

• Measure PTHrP - elevated in humoral hypercalcemia of malignancy 1, 2
• Check malignancy markers and assess for underlying cancer 1
• Malignancy-associated hypercalcemia shows: rapid onset, calcium often >12 mg/dL, severe symptoms, marked anemia, no kidney stones or metabolic acidosis 5
• Elevated 1,25-dihydroxyvitamin D suggests granulomatous disease (sarcoidosis), lymphoma, or vitamin D intoxication 1, 4

Medication and Supplement History

Obtain detailed history of:

• Thiazide diuretics (cause hypercalcemia) 1
• Lithium (causes hypercalcemia) 1
• Calcium supplements >500 mg/day 1
• Vitamin D supplements >400 IU/day 1
• Vitamin A intake 1
• Recent denosumab discontinuation, immune checkpoint inhibitors, SGLT2 inhibitors 4

Critical Pitfalls to Avoid

• Do not rely on corrected calcium alone - measure ionized calcium when possible for accuracy 1
• Hyperalbuminemia can mask true calcium status - always verify with ionized calcium or proper correction 2
• Do not check only one vitamin D metabolite - measure both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together 1
• Primary hyperparathyroidism and malignancy account for >90% of cases - if neither is present, consider granulomatous disease, endocrinopathies, immobilization, genetic disorders 4, 5

Immediate Management Considerations

While completing workup:

• Initiate IV normal saline immediately for moderate-to-severe or symptomatic hypercalcemia to correct hypovolemia and promote calciuresis, targeting urine output ≥100 mL/hour 1, 2, 3
• Avoid overhydration in patients with cardiac or renal insufficiency; use loop diuretics after volume repletion 1
• Administer zoledronic acid 4 mg IV over 15 minutes for moderate-to-severe hypercalcemia after initiating hydration (preferred over pamidronate) 1, 2, 3
• Consider calcitonin for immediate short-term management of severe symptomatic cases while waiting for bisphosphonates to take effect 2, 4, 5
• Use glucocorticoids (prednisone 1 mg/kg/day) when hypercalcemia is due to vitamin D-mediated causes (sarcoidosis, lymphoma, vitamin D intoxication, granulomatous disease) 1, 2, 4