What investigations are needed for hypercalcemia?

Diagnostic Approach to Hypercalcemia of 2.7 mmol/L

For hypercalcemia of 2.7 mmol/L, essential investigations include serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone-related protein (PTHrP), complete blood count, and biochemical profile including renal function, albumin, phosphorus, and magnesium. 1

Initial Assessment

Confirm Hypercalcemia

• Calculate albumin-corrected calcium using the formula:
  • Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Serum albumin (g/dL)] 1
• A level of 2.7 mmol/L (approximately 10.8 mg/dL) represents mild hypercalcemia

Classification by Severity

• Mild: <12 mg/dL (<3 mmol/L)
• Moderate: 12.0-13.5 mg/dL (3.0-3.375 mmol/L)
• Severe: ≥14 mg/dL (≥3.5 mmol/L) or ≥12 mg/dL with symptoms 1, 2

First-Line Investigations

Essential Laboratory Tests

1. Parathyroid Hormone (iPTH) - Most important initial test to distinguish PTH-dependent from PTH-independent causes 1, 2

   • Elevated/normal PTH: Suggests primary hyperparathyroidism
   • Suppressed PTH (<20 pg/mL): Suggests other causes (malignancy, granulomatous disease)

2. Vitamin D Metabolism

   • 25-hydroxyvitamin D (to assess vitamin D status)
   • 1,25-dihydroxyvitamin D (may be elevated in granulomatous disorders) 3, 1

3. Malignancy Workup

   • Parathyroid hormone-related protein (PTHrP)
   • Complete blood count (to assess for hematologic malignancies)
   • Serum and urine protein electrophoresis (for multiple myeloma) 1, 2

4. Basic Biochemical Profile

   • Renal function (BUN, creatinine)
   • Liver function tests
   • Serum phosphorus (typically low in hyperparathyroidism)
   • Serum magnesium
   • Urinalysis (to assess for hypercalciuria) 1

5. Thyroid Function

   • Thyroid-stimulating hormone (TSH) to rule out hyperthyroidism 1

Additional Investigations Based on Clinical Suspicion

For Suspected Granulomatous Disease

• Chest X-ray or CT scan (for sarcoidosis, tuberculosis)
• Angiotensin-converting enzyme (ACE) levels
• Tuberculin skin test or interferon-gamma release assay 3

For Suspected Malignancy

• Age-appropriate cancer screening
• Imaging studies based on symptoms (CT, MRI, PET scan)
• Tumor markers as appropriate 2

For Suspected Familial Hypocalciuric Hypercalcemia

• 24-hour urinary calcium excretion
• Calcium/creatinine clearance ratio 4

Diagnostic Algorithm

1. Step 1: Measure iPTH

   • If elevated/normal with hypercalcemia → Primary hyperparathyroidism (most common cause)
   • If suppressed → Proceed to step 2

2. Step 2: For suppressed iPTH, check:

   • PTHrP (for malignancy)
   • 1,25-dihydroxyvitamin D (for granulomatous disorders)
   • Medication review (thiazides, lithium, vitamin A, calcium supplements)
   • Thyroid function tests

3. Step 3: Based on initial results, consider:

   • Imaging studies (neck ultrasound for hyperparathyroidism, chest imaging for granulomatous disease or malignancy)
   • Bone turnover markers
   • Specialized tests based on suspected etiology

Common Pitfalls to Avoid

• Failing to correct calcium for albumin - This can lead to misdiagnosis of the severity of hypercalcemia 1
• Not measuring iPTH - The most critical test for differential diagnosis 2
• Overlooking medication causes - Always review current medications including supplements 1
• Missing familial hypocalciuric hypercalcemia - Can be mistaken for primary hyperparathyroidism but doesn't require surgery 4
• Focusing only on common causes - While primary hyperparathyroidism and malignancy account for 90% of cases, rare causes should be considered when appropriate 2

Special Considerations

• In sarcoidosis, abnormal calcium metabolism occurs in approximately 6% of patients, with potential progression to renal failure in 42% of untreated cases 3
• Patients with sarcoidosis often have low 25-OH vitamin D levels (84%) but may have elevated 1,25-(OH)₂ vitamin D (11%) 3
• For patients with hypercalcemia and cardiac disease, optimize heart failure management before any surgical intervention 1

The diagnostic approach should be systematic and thorough, as identifying the underlying cause is essential for appropriate management of hypercalcemia.