What is the workup for hypercalcemia?

Workup for Hypercalcemia

The initial workup for hypercalcemia should include corrected calcium calculation, intact parathyroid hormone (iPTH), phosphorus, magnesium, renal function tests, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels, and urinary calcium/creatinine ratio to differentiate PTH-dependent from PTH-independent causes. 1

Initial Assessment

1. Calculate corrected calcium level:

   • Formula: Corrected calcium = Total calcium + 0.8 × (4.0 - serum albumin) 1
   • Alternatively, measure ionized calcium directly if available

2. Assess severity:

   • Mild: Total calcium <12 mg/dL (<3 mmol/L)
   • Severe: Total calcium ≥14 mg/dL (≥3.5 mmol/L) 2

3. Evaluate symptoms:

   • Neurological: Confusion, irritability, altered mental status
   • Gastrointestinal: Nausea, vomiting, constipation
   • Renal: Polyuria, polydipsia, renal injury
   • Cardiovascular: Arrhythmias, QT interval shortening
   • Musculoskeletal: Weakness, fatigue 1

Diagnostic Algorithm

Step 1: First-line Laboratory Tests

• Serum intact parathyroid hormone (iPTH) - most critical initial test 1, 2
• Phosphorus
• Magnesium
• BUN/Creatinine (renal function)
• 25-hydroxyvitamin D
• 1,25-dihydroxyvitamin D
• Urinary calcium/creatinine ratio 1

Step 2: Differential Diagnosis Based on iPTH Results

If iPTH is elevated or inappropriately normal:

• PTH-dependent hypercalcemia:
  • Primary hyperparathyroidism (most common)
  • Consider familial hypocalciuric hypercalcemia (FHH) - check urinary calcium/creatinine ratio 1, 2
  • Tertiary hyperparathyroidism

If iPTH is suppressed (<20 pg/mL):

• PTH-independent hypercalcemia:
  • Malignancy (check PTH-related peptide)
  • Granulomatous disorders (check 1,25-dihydroxyvitamin D)
  • Vitamin D toxicity (check 25-hydroxyvitamin D)
  • Medications (review medication list for thiazides, lithium, etc.)
  • Endocrinopathies (check thyroid function tests) 1, 2, 3

Additional Workup Based on Initial Results

For Suspected Primary Hyperparathyroidism:

• Bone density scan
• Renal ultrasound (to assess for nephrolithiasis)
• 24-hour urine calcium and creatinine 1, 2

For Suspected Malignancy:

• Complete blood count (anemia often present)
• PTH-related peptide (PTHrP)
• Age-appropriate cancer screening
• Consider CT chest/abdomen/pelvis 1, 2, 4

For Suspected Granulomatous Disease:

• Chest X-ray or CT
• Angiotensin-converting enzyme (ACE) levels
• Consider tuberculosis testing 1

Common Pitfalls to Avoid

1. Failing to correct calcium for albumin - can miss true hypercalcemia in hypoalbuminemic patients 1

2. Not distinguishing between PTH-dependent and PTH-independent causes - iPTH is essential for this differentiation 1, 2, 3

3. Overlooking familial hypocalciuric hypercalcemia - check urinary calcium/creatinine ratio to avoid unnecessary parathyroidectomy 1

4. Missing vitamin D toxicity - measure both 25(OH)D and 1,25(OH)₂D levels 1

5. Treating laboratory values without addressing underlying cause - identify and treat the primary etiology 1

Special Considerations

• Remember that primary hyperparathyroidism and malignancy account for approximately 90% of hypercalcemia cases 1, 2

• In patients with malignancy-associated hypercalcemia, distinguish between humoral hypercalcemia (PTHrP-mediated) and direct bone involvement 4, 5

• Consider medication review, as drugs like thiazide diuretics, lithium, and excessive vitamin A or D supplementation can cause hypercalcemia 2

• For patients with primary hyperparathyroidism who are >50 years with serum calcium <1 mg/dL above upper limit and no evidence of skeletal or kidney disease, observation with monitoring may be appropriate 1, 2