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

Workup for Hypercalcemia

The initial workup for hypercalcemia should include serum calcium (corrected for albumin or ionized), intact parathyroid hormone (iPTH), parathyroid hormone-related protein (PTHrP), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, serum phosphorus, magnesium, blood urea nitrogen, creatinine, complete blood count, and urinalysis to determine the underlying cause and guide treatment. 1

Initial Laboratory Assessment

The diagnostic evaluation must begin with specific laboratory tests to differentiate the underlying etiology:

• Calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4.0 - Albumin (g/dL)] to accurately assess severity, or preferably measure ionized calcium directly 1, 2
• Measure intact PTH as the single most important test—elevated or inappropriately normal PTH indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) points to other causes 1, 3, 4
• Obtain PTHrP levels when PTH is suppressed, as this is elevated in humoral hypercalcemia of malignancy, particularly with squamous cell carcinomas and renal cell carcinoma 2, 3
• Check vitamin D metabolites (both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) to evaluate for vitamin D intoxication or granulomatous disease like sarcoidosis 5, 1, 3
• Assess renal function with BUN and creatinine, as hypercalcemia commonly causes renal impairment through dehydration and nephrocalcinosis 5, 1
• Measure serum phosphorus and magnesium as part of the complete metabolic evaluation 5, 1

Severity Classification

Classify the severity to determine urgency of intervention:

• Mild hypercalcemia: Total calcium 10-11 mg/dL (or >5.0 to <5.5 mEq/L)—usually asymptomatic but may cause fatigue and constipation in 20% of patients 1, 4
• Moderate hypercalcemia: Total calcium 11-12 mg/dL (or 5.5-6.0 mEq/L)—presents with polyuria, polydipsia, nausea, vomiting, abdominal pain 1, 3
• Severe hypercalcemia: Total calcium >14 mg/dL (or >6.0 mEq/L)—causes mental status changes, bradycardia, hypotension, dehydration, acute renal failure, confusion, somnolence, and coma 1, 3, 4

Additional Diagnostic Studies

• Obtain urine calcium/creatinine ratio from a random spot urine sample to assess for hypercalciuria, which may indicate nephrocalcinosis risk 5, 1
• Perform renal ultrasonography if hypercalciuria is present to evaluate for nephrocalcinosis 5
• Complete blood count and urinalysis should be included in the initial workup 5, 1
• Electrocardiogram and chest radiograph are recommended in the initial evaluation of patients presenting with significant symptoms 5

Etiology-Specific Considerations

Approximately 90% of hypercalcemia cases are due to primary hyperparathyroidism or malignancy 4, 6:

• Primary hyperparathyroidism typically presents with lower calcium levels (<12 mg/dL), longer duration (>6 months), kidney stones, hyperchloremic metabolic acidosis, and no anemia 3, 6
• Malignancy-associated hypercalcemia presents with rapid onset, higher calcium levels, severe symptoms, marked anemia, but no kidney stones or metabolic acidosis 2, 3, 6
• Granulomatous disorders (sarcoidosis) cause hypercalcemia through increased 1,25-dihydroxyvitamin D production 3
• Vitamin D intoxication results from excessive supplementation with elevated 25-hydroxyvitamin D levels 3

Management Approach Based on Workup Results

Immediate treatment for symptomatic or severe hypercalcemia:

• Administer IV normal saline to correct hypovolemia and promote calciuresis, targeting urine output ≥100 mL/hour 1, 2, 4
• Bisphosphonates (zoledronic acid 4 mg IV over 15 minutes preferred over pamidronate) should be given after initiating hydration for moderate to severe hypercalcemia, especially malignancy-associated 1, 2, 7
• Calcitonin provides rapid but short-term control while waiting for bisphosphonates to take effect 1, 4, 6
• Glucocorticoids are the primary treatment for vitamin D-mediated hypercalcemia (sarcoidosis, lymphomas, vitamin D intoxication) 1, 3, 4
• Denosumab 120 mg subcutaneously is reserved for bisphosphonate-refractory cases or patients with renal impairment 5, 1, 2

Common Pitfalls to Avoid

• Do not rely on total calcium alone in patients with abnormal albumin levels—always calculate corrected calcium or measure ionized calcium 1, 2
• Avoid restricting calcium intake without medical supervision in patients with normocalcemia 5, 1
• Do not use NSAIDs or IV contrast in patients with renal impairment as this worsens renal function 1
• Avoid vitamin D supplements in patients with confirmed hypercalcemia 5, 1, 3
• Monitor calcium levels closely post-denosumab due to significant risk of rebound hypocalcemia 5, 2
• Recognize that loop diuretics should not be used until after volume repletion is achieved 7

Monitoring and Follow-up

• Monitor serum calcium, renal function, and electrolytes regularly to assess treatment response 1, 3
• Referral to endocrinology or nephrology should be considered for persistent hypercalcemia, hypercalciuria, or nephrocalcinosis 5
• Treatment of the underlying cause (parathyroidectomy for primary hyperparathyroidism, cancer therapy for malignancy) is essential for long-term management 1, 2, 3