What is the step-by-step workup for hypercalcemia?

Step-by-Step Workup for Hypercalcemia

Initial Laboratory Evaluation

The diagnostic workup begins with a comprehensive metabolic panel and specific calcium-related tests to determine the underlying cause. 1, 2

First-Line Laboratory Tests (Order Immediately)

• Serum calcium (total and ionized) to confirm hypercalcemia and assess severity 1, 2
• Serum albumin to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 1, 2
• Intact parathyroid hormone (iPTH) - this is the single most important test to distinguish PTH-dependent from PTH-independent causes 2, 3
• Serum creatinine and blood urea nitrogen to assess renal function 1, 2
• Serum phosphorus - typically low in primary hyperparathyroidism, may be elevated in malignancy 1, 2
• Serum magnesium as part of the electrolyte assessment 1, 2

Severity Classification

• Mild hypercalcemia: >10 to <11 mg/dL (>5.0 to <5.5 mEq/L) 1
• Moderate hypercalcemia: 11 to 12 mg/dL (5.5 to 6.0 mEq/L) 1
• Severe hypercalcemia: >14.0 mg/dL (>6.0 mEq/L) 1

Algorithmic Approach Based on PTH Level

If PTH is Elevated or Inappropriately Normal

This pattern indicates PTH-dependent hypercalcemia (primary hyperparathyroidism or familial hypocalciuric hypercalcemia). 3, 4

• Measure 25-hydroxyvitamin D to assess vitamin D status 2
• Measure 1,25-dihydroxyvitamin D to evaluate for vitamin D-mediated causes 2
• Consider imaging studies (neck ultrasound or sestamibi scan) if primary hyperparathyroidism is confirmed and surgery is being considered 3

If PTH is Suppressed (<20 pg/mL)

This pattern indicates PTH-independent hypercalcemia and requires further workup. 3, 4

• Measure parathyroid hormone-related protein (PTHrP) - elevated in most cases of malignancy-associated hypercalcemia 1, 2
• Measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to evaluate for vitamin D intoxication or granulomatous disease 2
• Evaluate for malignancy with appropriate imaging (chest X-ray, CT scans) and laboratory tests (complete blood count, serum protein electrophoresis) 3, 4
• Consider checking thyroid function tests if hyperthyroidism is suspected 3

Clinical Assessment of Symptoms

Mild to Moderate Hypercalcemia Symptoms

• Polyuria and polydipsia (most common early symptoms) 1
• Nausea, constipation, and abdominal pain 1, 3
• Fatigue and myalgia 1
• Confusion or subtle cognitive changes 1

Severe Hypercalcemia Symptoms

• Marked mental status changes, somnolence, or coma 1, 3
• Severe dehydration 1
• Bradycardia and hypotension 1
• Acute renal failure 1
• Vomiting 1, 3

Special Diagnostic Considerations

Distinguishing Primary Hyperparathyroidism from Malignancy

• Primary hyperparathyroidism typically presents with calcium <12 mg/dL, duration >6 months, fewer symptoms, possible kidney stones, hyperchloremic metabolic acidosis, and no anemia 4
• Malignancy-associated hypercalcemia typically presents with rapid onset, calcium often >12 mg/dL, severe symptoms, marked anemia, but no kidney stones or metabolic acidosis 4

Dehydration-Related Considerations

• Check serum osmolality (>300 mOsm/kg indicates dehydration) if ionized calcium is only slightly elevated 2
• Dehydration can concentrate blood components and falsely elevate calcium levels 2
• Recheck calcium after adequate hydration if dehydration is suspected 2

Pediatric Considerations

• In children with suspected Williams syndrome, monitor calcium every 4-6 months until age 2 years, then every 2 years 2
• Check vitamin D concentrations (both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) in pediatric hypercalcemia 2

Common Diagnostic Pitfalls to Avoid

• Do not rely on total calcium alone - hyperalbuminemia can mask true calcium status; always calculate corrected calcium or measure ionized calcium 1
• Do not misinterpret "normal" PTH - in the setting of hypercalcemia, a PTH in the normal range is actually inappropriately elevated and suggests primary hyperparathyroidism 3, 4
• In patients with kidney disease, interpret PTH levels cautiously as secondary hyperparathyroidism can coexist with other causes of hypercalcemia 2
• Consider medication review - thiazide diuretics, calcium supplements, vitamin D supplements, vitamin A, lithium, and newer agents (SGLT2 inhibitors, immune checkpoint inhibitors) can cause hypercalcemia 3