What are the causes of hypercalcemia?

Causes of Elevated Calcium Level

The two most common causes of hypercalcemia are primary hyperparathyroidism and malignancy, which together account for over 90% of all cases. 1

Primary Causes of Hypercalcemia

Primary Hyperparathyroidism (PHPT)

• Most common cause of hypercalcemia in ambulatory patients 2
• Typically presents with mild hypercalcemia (< 12 mg/dL) 3
• Usually caused by:
  • Single parathyroid adenoma (80%)
  • Multiple adenomas or parathyroid hyperplasia (15-20%)
  • Parathyroid carcinoma (< 1%) 4
• Laboratory findings:
  • Elevated or inappropriately normal parathyroid hormone (PTH) levels
  • Hypercalcemia
  • Often low phosphorus levels
• More common in women, with increasing prevalence with age 4

Malignancy-Related Hypercalcemia

• Most common cause of hypercalcemia in hospitalized patients 2
• Occurs in 10-25% of patients with cancer, especially squamous cell lung cancer 4
• Mechanisms include:
  • Parathyroid hormone-related protein (PTHrP) production
  • Increased calcitriol (1,25-dihydroxyvitamin D)
  • Localized osteolytic hypercalcemia 4
• Laboratory findings:
  • Suppressed PTH levels
  • Low or normal calcitriol levels (in PTHrP-mediated cases)
  • Often rapid onset with higher calcium levels (>12 mg/dL) 3
• Poor prognosis - median survival approximately 1 month after discovery 4

Other Important Causes

Granulomatous Disorders

• Sarcoidosis is the most common granulomatous cause 4
• Mechanism: Increased 1α-hydroxylase production by granulomatous macrophages, converting 25-(OH) vitamin D to 1,25-(OH)₂ vitamin D 4
• Laboratory findings:
  • Elevated 1,25-(OH)₂ vitamin D levels
  • Suppressed PTH levels
  • Normal or low 25-(OH) vitamin D levels 4

Medication-Induced Hypercalcemia

• Thiazide diuretics (reduce urinary calcium excretion)
• Excessive calcium or vitamin D supplementation
• Vitamin A excess
• Lithium (increases PTH secretion)
• Newer agents:
  • Sodium-glucose cotransporter 2 protein inhibitors
  • Immune checkpoint inhibitors
  • Denosumab discontinuation 1

Endocrine Disorders

• Thyrotoxicosis (increased bone turnover)
• Adrenal insufficiency
• Multiple endocrine neoplasia syndromes (MEN 1, MEN 2A) 4

Other Causes

• Chronic kidney disease with tertiary hyperparathyroidism 4
• Familial hypocalciuric hypercalcemia
• Immobilization (especially in patients with high bone turnover)
• Milk-alkali syndrome
• Extreme exercise
• Ketogenic diets 1

Diagnostic Approach

1. Confirm hypercalcemia with repeat testing and calculate corrected calcium if albumin is abnormal
2. Measure intact PTH level - the most important initial test 1
   • Elevated/normal PTH → PHPT
   • Suppressed PTH (< 20 pg/mL) → non-PTH dependent causes
3. Additional testing based on clinical suspicion:
   • 25-OH and 1,25-(OH)₂ vitamin D levels
   • PTHrP for suspected malignancy
   • Serum and urine protein electrophoresis for multiple myeloma
   • Thyroid function tests
   • Chest imaging for granulomatous disease or malignancy

Clinical Pearls and Pitfalls

• Mild hypercalcemia (< 12 mg/dL) is often asymptomatic but may cause fatigue, constipation, and other constitutional symptoms in approximately 20% of patients 1
• Severe hypercalcemia (≥ 14 mg/dL) can cause life-threatening complications including dehydration, confusion, somnolence, and coma 1
• Always correct total calcium for albumin levels when hypoalbuminemia is present
• The duration of hypercalcemia can help distinguish causes - PHPT typically has a longer duration (> 6 months) compared to malignancy 3
• Patients with PHPT may develop kidney stones and metabolic bone disease, while those with malignancy-related hypercalcemia often have marked anemia but rarely develop kidney stones 3
• In patients with chronic kidney disease, phosphate retention can provoke secondary hyperparathyroidism, which may eventually lead to hypercalcemia 4