What causes severe hypercalcemia with a calcium level greater than 14?

Causes of Severe Hypercalcemia (Calcium > 14 mg/dL)

Severe hypercalcemia with calcium levels greater than 14 mg/dL is most commonly caused by malignancy, followed by primary hyperparathyroidism, with these two conditions accounting for over 90% of all cases. 1

Primary Causes of Severe Hypercalcemia

1. Malignancy-Associated Hypercalcemia

• Most common cause of severe hypercalcemia (calcium >14 mg/dL)
• Typically develops rapidly (days to weeks)
• Mechanisms:
  • Humoral hypercalcemia: Tumor production of PTH-related protein (PTHrP)
    • Common in squamous cell cancers of lung/head/neck
    • Renal cell carcinoma and ovarian cancer
  • Direct bone invasion by tumor cells
    • Common in breast cancer and multiple myeloma
  • Laboratory findings: Suppressed PTH levels (<20 pg/mL) 1, 2

2. Primary Hyperparathyroidism

• Usually causes mild-moderate hypercalcemia (<12 mg/dL)
• Can occasionally cause severe hypercalcemia
• Atypical parathyroid adenomas or parathyroid carcinomas may cause extremely high calcium levels (documented case with calcium of 23.2 mg/dL) 3
• Laboratory findings: Elevated or inappropriately normal PTH levels 1, 2

Less Common Causes of Severe Hypercalcemia

• Granulomatous disorders: Sarcoidosis, tuberculosis
• Endocrine disorders: Thyrotoxicosis, adrenal insufficiency
• Medication-induced:
  • Vitamin D intoxication
  • Vitamin A excess
  • Thiazide diuretics
  • Lithium
• Immobilization: Especially in patients with high bone turnover
• Familial hypocalciuric hypercalcemia: Rare genetic disorder 4, 1

Clinical Presentation of Severe Hypercalcemia

Patients with calcium >14 mg/dL typically present with:

• Polyuria and polydipsia
• Gastrointestinal disturbances (nausea, vomiting)
• Dehydration
• Neurological symptoms (confusion, somnolence, coma)
• Decreased glomerular filtration rate
• Progressive renal dysfunction 4, 5, 1

Diagnostic Approach

1. Essential laboratory tests:

   • Intact parathyroid hormone (iPTH) - most important initial test
   • Albumin-corrected calcium calculation
   • Parathyroid hormone-related protein (PTHrP)
   • 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D
   • Complete blood count
   • Renal function tests
   • Phosphorus, magnesium levels 4

2. Differential diagnosis based on PTH levels:

   • Elevated/normal PTH → Primary hyperparathyroidism
   • Suppressed PTH → Malignancy or other non-PTH mediated causes 1, 2

Treatment Considerations

Severe hypercalcemia (>14 mg/dL) requires urgent treatment:

1. Aggressive IV fluid resuscitation with normal saline (200-300 mL/hour initially)
2. Bisphosphonates: Zoledronic acid 4 mg IV over 15 minutes (first-line)
3. Denosumab: For refractory cases or severe renal impairment
4. Calcitonin: For immediate short-term management
5. Loop diuretics: After adequate hydration
6. Glucocorticoids: For vitamin D toxicity, granulomatous disorders, or lymphomas 4, 1, 2

Important Pitfalls to Avoid

• Using diuretics before correcting hypovolemia
• Failing to correct calcium for albumin
• Inadequate hydration before bisphosphonate administration
• Treating laboratory values without addressing the underlying cause
• Delaying treatment of severe hypercalcemia
• Administering bisphosphonates too rapidly 4

Severe hypercalcemia is a medical emergency that requires prompt diagnosis and treatment to prevent life-threatening complications. The underlying cause must be identified and addressed for long-term management.