What is the most common cause of hypercalcemic crisis?

The Most Common Cause of Hypercalcemic Crisis is Malignancy

The most common cause of hypercalcemic crisis is malignancy (option d), accounting for over 90% of cases in hospitalized patients. 1 Malignancy-associated hypercalcemia is the most frequent cause of hypercalcemia in hospitalized patients, with an incidence of approximately 15 cases per 100,000 person-years, affecting nearly 10% of patients with advanced cancer. 2

Pathophysiology of Malignancy-Associated Hypercalcemia

Malignancy causes hypercalcemia through several mechanisms:

1. Parathyroid hormone-related protein (PTHrP) production - The most common mechanism, seen in approximately 80% of cases 2
2. Increased active metabolite of vitamin D (calcitriol)
3. Localized osteolytic hypercalcemia from bone metastases 3

PTHrP-mediated hypercalcemia is characterized by:

• Suppressed intact parathyroid hormone (iPTH) level
• Low or normal calcitriol level

This contrasts with primary hyperparathyroidism, which shows elevated iPTH and calcitriol levels. 3

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 3, 1

Severe hypercalcemia (>14.0 mg/dL) often leads to mental status changes, bradycardia, and hypotension. The rapidity of onset often determines symptom severity. 3

Differential Diagnosis

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

1. Primary hyperparathyroidism - Most common cause of hypercalcemia in ambulatory patients, but less common in hypercalcemic crisis 4
2. Sarcoidosis - Can cause hypercalcemia through increased vitamin D metabolism
3. Secondary hyperparathyroidism - Rarely causes severe hypercalcemia
4. Renal failure - Usually associated with secondary hyperparathyroidism but rarely causes crisis-level hypercalcemia

Diagnostic Approach

When hypercalcemic crisis is suspected, diagnostic evaluation should include:

• Serum calcium (total and ionized)
• Albumin (for calcium correction)
• iPTH, PTHrP
• 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D
• Phosphorus, magnesium 3

Management

Treatment of hypercalcemic crisis 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) - First-line pharmacologic therapy
3. Loop diuretics (furosemide) after volume restoration
4. Calcitonin for rapid but short-term calcium reduction
5. Denosumab for bisphosphonate-refractory cases 3, 1

The American College of Chest Physicians guidelines note that the median survival after discovery of hypercalcemia of malignancy in patients with lung cancer is about 1 month, highlighting the poor prognosis associated with this condition. 3

Prognosis

The prognosis of hypercalcemic crisis depends on the underlying cause. While patients with primary hyperparathyroidism may have a 3-year survival rate of 80%, those with malignancy-associated hypercalcemia have a much poorer prognosis, with malignancy-associated hypercalcemia often representing end-stage disease. 1