What is the workup for hypercalcemia with normal electrolytes?

Workup for Hypercalcemia with Normal Electrolytes

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

Initial Laboratory Assessment

• Calculate corrected calcium: Total calcium + 0.8 × (4.0 - serum albumin) if ionized calcium is not available 1
• Essential first-line tests:
  • Intact parathyroid hormone (iPTH) - most important initial test
  • Phosphorus
  • Magnesium
  • Renal function tests (BUN, creatinine)
  • 25-hydroxyvitamin D
  • 1,25-dihydroxyvitamin D
  • Urinary calcium/creatinine ratio

Diagnostic Algorithm Based on PTH Results

If PTH is elevated or inappropriately normal:

• Primary hyperparathyroidism is likely (accounts for ~90% of hypercalcemia cases along with malignancy) 2
• Additional testing:
  • 24-hour urinary calcium (to rule out familial hypocalciuric hypercalcemia)
  • Renal ultrasound (to check for nephrolithiasis)
  • Bone density scan (to assess for bone involvement)

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

• PTH-independent hypercalcemia - consider:

  1. Malignancy workup:

     • Complete blood count
     • Serum and urine protein electrophoresis
     • PTH-related protein (PTHrP)
     • Chest X-ray
     • Age-appropriate cancer screening

  2. Vitamin D disorders:

     • Already included in initial panel
     • Assess for granulomatous diseases if 1,25-dihydroxyvitamin D is elevated

  3. Medication review:

     • Thiazide diuretics
     • Lithium
     • Vitamin A, D supplements
     • Calcium supplements

  4. Other causes:

     • Thyroid function tests (hyperthyroidism)
     • Cortisol levels (adrenal insufficiency)
     • Serum ACE levels (sarcoidosis)

Special Considerations

• Mild hypercalcemia (total calcium <12 mg/dL) is often asymptomatic but may cause fatigue and constipation in approximately 20% of patients 2
• Severe hypercalcemia (≥14 mg/dL) requires more urgent evaluation and treatment
• Hypercalcemia of malignancy typically has a rapid onset with higher calcium levels and more severe symptoms compared to primary hyperparathyroidism 3
• Primary hyperparathyroidism tends to cause kidney calculi and hyperchloremic metabolic acidosis, while hypercalcemia of malignancy typically presents with anemia 3

Common Pitfalls to Avoid

• Failing to correct calcium for albumin levels 1
• Not distinguishing between PTH-dependent and PTH-independent causes
• Overlooking medication-induced hypercalcemia (especially thiazides, which can cause severe hypercalcemia up to 19.8 mg/dL) 4
• Focusing only on common causes and missing rare etiologies
• Treating laboratory values without addressing the underlying cause 1

Follow-up Testing

For patients with mild hypercalcemia due to primary hyperparathyroidism:

• Monitor serum calcium and phosphorus at least every 3 months 1
• Avoid excessive calcium intake (total elemental calcium should not exceed 2,000 mg/day) 1
• Consider parathyroidectomy based on age, serum calcium level, and evidence of kidney or skeletal involvement 2

By systematically following this diagnostic approach, you can efficiently determine the underlying cause of hypercalcemia even when other electrolytes are normal, allowing for appropriate management of the condition.