What is the workup for hypercalcemia?

Workup for Hypercalcemia

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

Initial Assessment

Step 1: Confirm Hypercalcemia

• Measure total serum calcium and albumin to calculate corrected calcium
• Ideally, measure ionized calcium (more accurate than total calcium) 2
• Hypercalcemia is defined as:
  • Mild: Total calcium <12 mg/dL (<3 mmol/L)
  • Moderate: Total calcium 12-14 mg/dL (3-3.5 mmol/L)
  • Severe: Total calcium ≥14 mg/dL (≥3.5 mmol/L) 3

Step 2: Assess for Symptoms and Severity

• Mild hypercalcemia: Often asymptomatic or with constitutional symptoms like fatigue and constipation
• Severe hypercalcemia: Nausea, vomiting, dehydration, confusion, somnolence, polyuria, polydipsia, abdominal pain, myalgia 1, 3

Diagnostic Algorithm

Step 3: Measure Intact PTH

This is the most critical initial test to distinguish between PTH-dependent and PTH-independent causes:

• Elevated/normal PTH: Consistent with primary hyperparathyroidism
• Suppressed PTH (<20 pg/mL): Indicates non-PTH mediated cause (e.g., malignancy) 3

Step 4: Additional Laboratory Tests Based on PTH Results

If PTH is Elevated or Normal:

• 24-hour urinary calcium excretion and creatinine clearance
  • Low urinary calcium (<100 mg/24h): Consider familial hypocalciuric hypercalcemia
  • High urinary calcium (>300 mg/24h): Typical of primary hyperparathyroidism
• Serum creatinine to assess kidney function
• 25-hydroxyvitamin D to rule out vitamin D deficiency
• Assess for medications that may cause hypercalcemia (thiazides, lithium, calcium supplements)

If PTH is Suppressed:

• PTHrP measurement (elevated in humoral hypercalcemia of malignancy)
• 1,25-dihydroxyvitamin D (elevated in granulomatous diseases, lymphomas)
• 25-hydroxyvitamin D (elevated in vitamin D intoxication)
• Serum and urine protein electrophoresis (to detect multiple myeloma)
• Complete blood count with differential
• Thyroid function tests (hyperthyroidism can cause hypercalcemia)
• Consider chest X-ray or CT scan to evaluate for malignancy or granulomatous disease 1

Common Etiologies to Consider

1. Primary Hyperparathyroidism (PHPT): Most common cause of outpatient hypercalcemia (~90% of cases along with malignancy) 3

   • Characterized by elevated or inappropriately normal PTH
   • Often discovered incidentally on routine blood tests

2. Malignancy-Associated Hypercalcemia: Most common cause of inpatient hypercalcemia 4

   • Mechanisms include:
     • PTHrP production (suppressed iPTH, low/normal calcitriol)
     • Increased calcitriol production
     • Localized osteolytic hypercalcemia
   • Most common in squamous cell lung cancer 1

3. Other Causes:

   • Granulomatous diseases (sarcoidosis, tuberculosis)
   • Medications (thiazides, lithium, vitamin A or D supplements)
   • Endocrine disorders (thyrotoxicosis, adrenal insufficiency)
   • Chronic kidney disease with tertiary hyperparathyroidism 2

Special Considerations

Chronic Kidney Disease

• In CKD patients, maintain corrected total calcium within the normal range (8.4-9.5 mg/dL) 1
• If calcium exceeds 10.2 mg/dL in CKD patients:
  • Reduce or discontinue calcium-based phosphate binders
  • Reduce or discontinue vitamin D sterols
  • Consider low calcium dialysate if hypercalcemia persists 1

Pitfalls to Avoid

• Relying solely on total calcium without correcting for albumin
• Failing to measure PTH as the initial diagnostic test
• Not considering medication-induced causes
• Overlooking familial hypocalciuric hypercalcemia (which typically doesn't require treatment)
• Delaying treatment for severe symptomatic hypercalcemia while completing diagnostic workup 3, 5

Treatment Considerations

While not the focus of the diagnostic workup, it's worth noting that treatment depends on severity:

• Mild asymptomatic hypercalcemia: May not need acute intervention
• Symptomatic or severe hypercalcemia: Requires hydration and IV bisphosphonates
• For hypercalcemia of malignancy: Treat underlying cancer
• For PHPT: Consider parathyroidectomy based on age, calcium level, and end-organ involvement 3

Remember that identifying and treating the underlying cause is essential for long-term management of hypercalcemia.