What is the workup for hypercalcemia?

Workup for Hypercalcemia

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

Initial Assessment

• Classify severity of hypercalcemia as mild (>5.0 to <5.5 mEq/L), moderate (5.5 to 6.0 mEq/L), or severe (>6.0 mEq/L or >14.0 mg/dL) 1
• Evaluate for symptoms based on severity and acuity of onset:
  • Mild/moderate: polyuria, polydipsia, nausea, constipation, fatigue, vomiting, abdominal pain, myalgia 1, 2
  • Severe: mental status changes, bradycardia, hypotension, dehydration, acute renal failure 1, 2

Diagnostic Algorithm

First-Line Laboratory Tests

• Serum calcium (total and ionized) 1
• Albumin (for corrected calcium calculation) 1
• Intact parathyroid hormone (iPTH) - most important initial test to distinguish PTH-dependent from PTH-independent causes 1, 2
• Serum creatinine and blood urea nitrogen 1
• Serum phosphorus and magnesium 1

Second-Line Laboratory Tests (Based on Initial Results)

• If PTH is elevated or inappropriately normal with hypercalcemia:

  • 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels 1
  • Urine calcium/creatinine ratio to evaluate for hypercalciuria 1
  • Consider familial hypocalciuric hypercalcemia if urine calcium is low 2

• If PTH is suppressed (<20 pg/mL):

  • Parathyroid hormone-related protein (PTHrP) 1
  • 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels 1
  • Consider malignancy workup (chest X-ray, mammogram, serum/urine protein electrophoresis) 2, 3
  • Consider medication review for calcium-raising drugs (thiazides, lithium, vitamin A, vitamin D supplements) 2

Additional Tests Based on Clinical Suspicion

• Renal ultrasonography if hypercalciuria is present to evaluate for nephrocalcinosis 1
• Serum angiotensin-converting enzyme (ACE) and chest imaging if granulomatous disease is suspected 3
• Thyroid function tests to rule out hyperthyroidism 2

Interpretation of Results

• Primary hyperparathyroidism: elevated or inappropriately normal PTH, mild hypercalcemia (<12 mg/dL), chronic course (>6 months), possible kidney stones, hyperchloremic metabolic acidosis 2, 3
• Malignancy: suppressed PTH, rapidly progressive hypercalcemia, higher calcium levels, anemia, no kidney stones or metabolic acidosis 3
• Vitamin D intoxication: suppressed PTH, elevated 25-hydroxyvitamin D 2
• Granulomatous disorders: suppressed PTH, elevated 1,25-dihydroxyvitamin D, normal 25-hydroxyvitamin D 2, 3

Common Pitfalls and Caveats

• Always correct calcium for albumin when using total calcium measurements 1, 2
• Mild hypercalcemia (serum calcium <12 mg/dL) is most commonly due to primary hyperparathyroidism, while severe hypercalcemia is more often associated with malignancy 2, 3
• Medications that can cause hypercalcemia include thiazide diuretics, lithium, vitamin A, vitamin D supplements, calcium supplements, and some newer agents like SGLT2 inhibitors 2
• Hypercalcemia of malignancy can occur even without bone metastases due to PTHrP production 4
• In patients with kidney disease, interpret PTH levels with caution as secondary hyperparathyroidism can coexist with other causes of hypercalcemia 5

Special Considerations

• In children with Williams syndrome, monitor calcium levels every 4-6 months until 2 years of age, then every 2 years thereafter 5
• For pediatric patients with hypercalcemia, check serum blood urea nitrogen, creatinine, vitamin D concentrations (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D), and intact parathyroid hormone 5
• In dialysis patients, consider dialysate calcium concentration adjustments based on PTH levels and bone disease status 5

By systematically following this diagnostic approach, the underlying cause of hypercalcemia can be identified, allowing for appropriate targeted treatment to reduce morbidity and mortality associated with this condition.