What is the initial workup and treatment for a patient presenting with hypercalcemia?

Initial Workup and Treatment for Hypercalcemia

The initial workup for hypercalcemia should include serum intact parathyroid hormone (iPTH), parathyroid hormone-related protein (PTHrP), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, complete blood count, urinalysis, and serum concentrations of calcium, albumin, magnesium, and phosphorus, while treatment should begin with aggressive IV fluid resuscitation with normal saline for symptomatic or severe cases. 1

Diagnosis and Initial Assessment

Laboratory Evaluation

1. Essential initial tests:

   • Serum calcium (total and ionized if available)
   • Albumin (for corrected calcium calculation: cCa in mg/dL = Ca in mg/dL + 0.8 [4.0 g/dL - patient albumin (g/dL)]) 2
   • Intact parathyroid hormone (iPTH) - most important test to distinguish PTH-dependent from PTH-independent causes 3
   • Serum creatinine and BUN
   • Phosphorus
   • Magnesium
   • 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D
   • Urinalysis and urine calcium/creatinine ratio 4

2. Additional tests based on clinical suspicion:

   • Parathyroid hormone-related protein (PTHrP) if malignancy suspected
   • Thyroid-stimulating hormone (TSH)
   • Liver function tests
   • Complete blood count
   • Serum and urine protein electrophoresis (if multiple myeloma suspected)

Severity Classification

• Mild hypercalcemia: Total calcium <12 mg/dL (<3 mmol/L)
• Moderate hypercalcemia: Total calcium 12.0-13.5 mg/dL
• Severe hypercalcemia: Total calcium ≥14 mg/dL or ≥12 mg/dL with symptoms 1, 3

Treatment Algorithm

1. Mild Asymptomatic Hypercalcemia

• Usually does not require acute intervention 3
• Identify and address underlying cause
• Ensure adequate hydration
• Avoid medications that can worsen hypercalcemia (thiazide diuretics, calcium supplements, excessive vitamin D)
• Monitor serum calcium levels regularly

2. Symptomatic or Severe Hypercalcemia

• Step 1: Aggressive IV fluid resuscitation with normal saline

  • Cornerstone of initial management 1
  • Corrects hypercalcemia-associated hypovolemia
  • Enhances renal calcium excretion
  • Target urine output of approximately 2 L/day 2
  • Caution with overhydration in patients with cardiac failure 2

• Step 2: Pharmacologic therapy

  • Bisphosphonates (first-line pharmacologic treatment)

    • Zoledronic acid 4 mg IV over no less than 15 minutes 2
    • Assess renal function before administration 2
    • Response typically begins within 2-3 days, with maximum effect at 4-7 days 1
    • Retreatment may be considered if serum calcium does not normalize, with minimum 7 days between doses 2

  • Calcitonin

    • For immediate short-term management of severe symptomatic hypercalcemia 1
    • Rapid but modest effect
    • Can be combined with bisphosphonates for faster response

  • Denosumab

    • Alternative for patients with renal impairment or refractory hypercalcemia 1
    • Dosing: 120 mg subcutaneously every 4 weeks with additional doses on days 8 and 15 of the first month 1
    • Monitor for hypocalcemia, especially after treatment 1

  • Glucocorticoids

    • Effective for hypercalcemia due to vitamin D toxicity, granulomatous disorders, or some lymphomas 1, 3

  • Loop diuretics (e.g., furosemide)

    • Use only after adequate hydration to enhance calcium excretion 1, 5
    • Never use before correcting hypovolemia 1

• Step 3: Dialysis

  • Consider for severe refractory hypercalcemia, especially in patients with renal failure or heart failure limiting fluid administration 5

Monitoring and Follow-up

• Regular monitoring of serum calcium, phosphate, magnesium, and renal function 1
• Initially every 1-2 weeks, then monthly after stabilization 1
• Monitor for treatment complications:
  • Hypocalcemia (especially with denosumab)
  • Renal function deterioration
  • Electrolyte imbalances

Common Pitfalls to Avoid

1. Using diuretics before correcting hypovolemia 1
2. Failing to correct calcium for albumin 1
3. Inadequate hydration before bisphosphonate administration 1
4. Treating laboratory values without addressing the underlying cause 1
5. Delaying treatment of severe hypercalcemia 1
6. Administering bisphosphonates too rapidly 1
7. Failing to monitor for hypocalcemia after treatment, especially with denosumab 1

Special Considerations

• Primary hyperparathyroidism: Consider parathyroidectomy based on age, serum calcium level, and evidence of kidney or skeletal involvement 3
• Malignancy-associated hypercalcemia: Poor prognosis with median survival of about 1 month in lung cancer patients 1
• Chronic kidney disease: Hypercalcemia increases mortality risk and cardiovascular events 1
• Pediatric patients: May present with extreme irritability, vomiting, constipation, and muscle cramps 4

By following this systematic approach to diagnosis and treatment, clinicians can effectively manage hypercalcemia while addressing the underlying cause to improve patient outcomes.