What are the initial investigations for hypercalcemia?

Initial Investigations for Hypercalcemia

The initial diagnostic evaluation for hypercalcemia should include measuring serum concentrations of intact parathyroid hormone (iPTH), parathyroid hormone-related protein (PTHrP), vitamin D metabolites (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D), calcium, albumin, magnesium, and phosphorus. 1

Primary Laboratory Investigations

Essential First-line Tests

• Serum calcium (total and ionized)
• Serum albumin (for corrected calcium calculation)
• Intact parathyroid hormone (iPTH)
• Serum phosphorus
• Blood urea nitrogen and creatinine
• Vitamin D metabolites:
  • 25-hydroxyvitamin D
  • 1,25-dihydroxyvitamin D

Second-line Tests Based on Clinical Context

• Parathyroid hormone-related protein (PTHrP) - especially if cancer is suspected
• Urine calcium/creatinine ratio in a random spot urine 1
• Serum protein electrophoresis (if multiple myeloma is suspected)
• Thyroid function tests (to exclude hyperthyroidism)

Diagnostic Algorithm

1. Determine if PTH-dependent or PTH-independent hypercalcemia:

   • Elevated or inappropriately normal PTH → Primary hyperparathyroidism (most common cause)
   • Suppressed PTH (< 20 pg/mL) → Consider malignancy, granulomatous disease, medications 2

2. For PTH-independent hypercalcemia:

   • Measure PTHrP if malignancy is suspected
   • Check 1,25-dihydroxyvitamin D levels (elevated in granulomatous disorders)
   • Review medication list for calcium-raising drugs (thiazides, lithium, vitamin supplements)

3. Additional investigations based on suspected etiology:

   • If hypercalciuria is found → Renal ultrasonography to evaluate for nephrocalcinosis 1
   • If malignancy is suspected → Appropriate imaging based on symptoms and cancer type

Special Considerations

Severity Assessment

The urgency and extent of investigations depend on calcium levels:

• Mild hypercalcemia (< 12 mg/dL): Often asymptomatic, can proceed with outpatient workup
• Severe hypercalcemia (> 14 mg/dL): Requires urgent evaluation and treatment 2

Common Pitfalls to Avoid

• Failing to correct calcium for albumin levels
• Not considering medication-induced hypercalcemia
• Missing familial hypocalciuric hypercalcemia (check urine calcium/creatinine ratio)
• Overlooking vitamin D toxicity as a cause

In Specific Populations

• Children with Williams syndrome: Regular calcium monitoring is recommended (every 4-6 months until 2 years of age, every 2 years thereafter) 1
• Patients with lung cancer: Hypercalcemia occurs in 10-25% of cases, most commonly in squamous cell carcinoma 1
• Patients with hyperparathyroidism: Consider genetic testing for MEN syndromes if appropriate 1

Follow-up Investigations

If initial workup reveals hypercalcemia with hypercalciuria:

1. Assess hydration status
2. Measure serum calcium concentration
3. Assess dietary calcium intake
4. Perform renal ultrasonography 1

By systematically approaching the investigation of hypercalcemia with these laboratory and imaging studies, clinicians can efficiently determine the underlying cause and initiate appropriate treatment to reduce morbidity and mortality associated with this condition.