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

Etiology of Hypercalcemic Crisis

Hypercalcemic crisis is a life-threatening emergency defined as severe hypercalcemia (total calcium >14.0 mg/dL or >3.5 mmol/L) with accompanying severe symptoms. The major causes include:

1. Malignancy (>90% of cases) 1, 2

   • Occurs through several mechanisms:
     • Localized osteolytic hypercalcemia from bone metastases
     • PTHrP-mediated hypercalcemia (characterized by suppressed iPTH and low/normal calcitriol)
   • Affects nearly 10% of patients with advanced cancer
   • Incidence: approximately 15 cases per 100,000 person-years

2. Primary hyperparathyroidism

   • Second most common cause overall 3
   • Characterized by elevated or normal PTH levels
   • Better prognosis compared to malignancy-associated hypercalcemia (80% 3-year survival rate) 2

3. Other less common causes:

   • Granulomatous diseases (e.g., sarcoidosis)
   • Medication-induced hypercalcemia
   • Endocrinopathies
   • Immobilization

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

The severity of symptoms often correlates with both the calcium level and the rapidity of onset.

Diagnostic Approach

When hypercalcemic crisis is suspected, diagnostic evaluation should include:

• Serum calcium (total and ionized)
• Albumin (for calcium correction)
• Intact parathyroid hormone (iPTH)
• PTHrP
• Vitamin D metabolites (1,25-dihydroxyvitamin D and 25-hydroxyvitamin D)
• Phosphorus and magnesium 1

The most important initial test is serum intact PTH, which distinguishes PTH-dependent from PTH-independent causes 3.

Treatment

Urgent intervention is required:

1. Aggressive IV fluid rehydration with isotonic saline (0.9% NaCl)
2. Bisphosphonates (pamidronate, zoledronic acid) as 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 1

Prognosis

The prognosis depends heavily on the underlying cause:

• Malignancy-associated hypercalcemia: Poor prognosis with median survival of about 1 month in patients with lung cancer 1
• Primary hyperparathyroidism: Much better prognosis with 80% 3-year survival rate 2

Common Pitfalls to Avoid

• Delaying treatment while waiting for complete diagnostic workup
• Administering loop diuretics before adequate volume repletion
• Failing to identify and treat the underlying cause
• Missing the diagnosis due to attributing non-specific symptoms to the underlying cancer or other conditions

In summary, while primary hyperparathyroidism is the most common cause of hypercalcemia in the general population, malignancy is overwhelmingly the most common cause of hypercalcemic crisis, especially in hospitalized patients.