What is the initial workup and treatment for hypercalcemia?

Workup for Hypercalcemia

Begin the diagnostic workup by measuring serum calcium (corrected for albumin or ionized calcium), intact parathyroid hormone (iPTH), parathyroid hormone-related protein (PTHrP), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, magnesium, albumin, creatinine, and blood urea nitrogen to determine the underlying etiology. 1, 2

Initial Laboratory Assessment

The cornerstone of hypercalcemia evaluation is the iPTH level, which distinguishes PTH-dependent from PTH-independent causes 3:

• Elevated or inappropriately normal iPTH (with hypercalcemia) indicates primary hyperparathyroidism 4, 3
• Suppressed iPTH (<20 pg/mL) points to malignancy, granulomatous disease, vitamin D disorders, or medications 3, 5

Calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4], or preferably measure ionized calcium directly, as total calcium can be inaccurate 2, 6

Severity Classification

Classify hypercalcemia severity to guide urgency of intervention 2:

• Mild: 10-11 mg/dL (2.5-2.75 mmol/L) - usually asymptomatic 3
• Moderate: 11-12 mg/dL (2.75-3.0 mmol/L) - polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain 1, 4
• Severe: >14 mg/dL (>3.5 mmol/L) - mental status changes, bradycardia, hypotension, dehydration, acute renal failure 1, 3

Etiology-Specific Testing

If iPTH is Elevated (Primary Hyperparathyroidism)

Primary hyperparathyroidism accounts for approximately 90% of hypercalcemia cases in outpatients 3, 5. Look for:

• Hypercalcemia with elevated or inappropriately normal iPTH 4
• Hypophosphatemia (phosphorus typically low) 1
• Hyperchloremic metabolic acidosis 5
• History of kidney stones 5
• Absence of anemia 5

If iPTH is Suppressed (Malignancy-Associated)

Malignancy causes the other ~45% of hypercalcemia cases and typically presents with 3, 5, 7:

• Rapid onset (days to weeks) with higher calcium levels (often >12 mg/dL) 5
• Elevated PTHrP in humoral hypercalcemia of malignancy (squamous cell lung cancer, renal cell carcinoma) 1, 4
• Low or normal 1,25-dihydroxyvitamin D (contrasts with primary hyperparathyroidism where it's elevated) 1
• Marked anemia present 5
• No kidney stones or metabolic acidosis 5

Vitamin D-Mediated Hypercalcemia

When iPTH is suppressed, measure vitamin D metabolites 1, 4:

• Elevated 1,25-dihydroxyvitamin D: granulomatous diseases (sarcoidosis), lymphomas 4, 3
• Elevated 25-hydroxyvitamin D: vitamin D intoxication from excessive supplementation 4

Additional Diagnostic Considerations

Assess renal function with serum creatinine and urinary calcium excretion, as hypercalcemia causes nephrocalcinosis and impaired calcium excretion 4, 8

Evaluate for symptoms based on severity: constitutional symptoms (fatigue, constipation) in mild cases occur in ~20% of patients, while severe hypercalcemia causes dehydration requiring urgent intervention 3

Consider medication history: thiazide diuretics, calcium/vitamin D supplements, lithium, and SGLT2 inhibitors can cause hypercalcemia 3, 6

Common Pitfalls to Avoid

• Do not rely solely on total calcium - hyperalbuminemia masks true calcium status; always calculate corrected calcium or measure ionized calcium 2, 6
• Distinguish primary hyperparathyroidism from malignancy - hyperparathyroidism has longer duration (>6 months), lower calcium levels (<12 mg/dL), kidney stones, and no anemia, while malignancy has rapid onset, higher calcium, severe symptoms, and anemia 5
• Avoid NSAIDs and IV contrast in patients with renal impairment to prevent worsening kidney function 1, 9

Treatment Approach

Immediate Management of Moderate to Severe Hypercalcemia

Initiate IV normal saline hydration immediately to correct hypovolemia and promote calciuresis, targeting urine output ≥100 mL/hour (3 mL/kg/hour in children <10 kg) 2, 9, 3

Administer IV bisphosphonates after starting hydration, with zoledronic acid preferred over pamidronate for initial treatment in malignancy-associated hypercalcemia 1, 2, 9, 3

Add calcitonin for immediate short-term management of severe symptomatic hypercalcemia while waiting for bisphosphonates to take effect (bisphosphonates require 3-6 days for full effect) 2, 3, 8, 5

Use loop diuretics (furosemide) only after volume repletion in patients with renal or cardiac insufficiency to prevent fluid overload 1, 5

Cause-Specific Treatment

Glucocorticoids are the primary treatment for vitamin D-mediated hypercalcemia (sarcoidosis, lymphomas, vitamin D intoxication, granulomatous disorders) 1, 4, 3, 8, 5

Denosumab (120 mg subcutaneously) is indicated for refractory hypercalcemia, especially in patients with renal impairment where bisphosphonates are contraindicated 2, 7

Dialysis is reserved for severe hypercalcemia complicated by kidney failure 9, 5, 7

Definitive Management

Parathyroidectomy is indicated for primary hyperparathyroidism in patients with: symptomatic disease, osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L above upper normal limit 4, 3

Treat the underlying malignancy when possible, as this is essential for long-term control of malignancy-associated hypercalcemia 9, 4

Monitoring

Monitor serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness 2, 9, 4

Watch for bisphosphonate complications: renal toxicity and osteonecrosis of the jaw with chronic use 1, 2

Avoid vitamin D supplements in patients with hypercalcemia, particularly in early childhood 2, 9, 4