What is the most common cause of hypercalcemic crisis?

Most Common Cause of Hypercalcemic Crisis

Malignancy is the most common cause of hypercalcemic crisis, accounting for over 90% of cases in hospitalized patients. 1

Pathophysiology of Hypercalcemic Crisis

Hypercalcemic crisis occurs through several mechanisms in malignancy:

• Malignancy-related mechanisms:

  • Localized osteolytic hypercalcemia from bone metastases
  • PTHrP-mediated hypercalcemia (humoral hypercalcemia of malignancy)
  • Direct tumor invasion of bone

• Pathophysiologic cascade:

  • Excessive bone resorption releases calcium into bloodstream
  • Results in polyuria and gastrointestinal disturbances
  • Leads to progressive dehydration and decreased glomerular filtration rate
  • Causes increased renal resorption of calcium
  • Creates cycle of worsening systemic hypercalcemia 1, 2

Common Malignancies Associated with Hypercalcemia

• Humoral hypercalcemia (PTHrP-mediated):

  • Squamous cell carcinomas of lung or head/neck
  • Genitourinary tumors (renal cell carcinoma, ovarian cancer)
  • Often with minimal or absent skeletal metastases 2

• Local osteolytic hypercalcemia:

  • Breast cancer
  • Multiple myeloma 2

Clinical Presentation

Hypercalcemic crisis presents with:

• Neurological symptoms: confusion, lethargy, altered mental status, coma
• Gastrointestinal symptoms: nausea, vomiting, constipation, abdominal pain
• Renal manifestations: polyuria, polydipsia, dehydration, acute renal failure
• Cardiovascular effects: bradycardia, hypotension, cardiac arrest in severe cases 1

Diagnostic Approach

When hypercalcemic crisis is suspected, evaluation should include:

• Serum calcium (total and ionized)
• Albumin (for calcium correction)
• Intact parathyroid hormone (iPTH)
• PTHrP
• Vitamin D metabolites
• Phosphorus and magnesium 1

Treatment

Treatment requires urgent intervention:

1. Aggressive IV fluid rehydration with isotonic saline (0.9% NaCl) to correct volume depletion and enhance renal calcium excretion

2. Bisphosphonates (pamidronate, zoledronic acid) as first-line pharmacologic therapy:

   • Inhibit osteoclastic activity and induce osteoclast apoptosis
   • Block osteoclastic resorption of mineralized bone 2, 3

3. Loop diuretics (furosemide) after volume restoration

4. Calcitonin for rapid but short-term calcium reduction

5. Denosumab for bisphosphonate-refractory cases 1

Prognosis

The prognosis for hypercalcemic crisis due to malignancy is generally poor, with median survival after discovery of hypercalcemia in patients with lung cancer being approximately 1 month 1.

Differential Diagnosis of Hypercalcemic Crisis

While malignancy is the most common cause of hypercalcemic crisis, other causes include:

• Primary hyperparathyroidism (second most common cause)
• Granulomatous diseases (e.g., sarcoidosis)
• Medication-induced hypercalcemia
• Vitamin D intoxication 4, 5

The answer to the question is (d) malignancy.