What are the causes of hypercalcemia?

Causes of Hypercalcemia

The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy, which together account for approximately 90% of all cases. 1 Understanding the underlying etiology is crucial for appropriate management and treatment.

PTH-Dependent Causes

• Primary hyperparathyroidism: Most common cause overall, characterized by elevated or inappropriately normal PTH levels 2

  • Typically due to parathyroid adenoma, hyperplasia, or rarely carcinoma
  • Often presents as mild, asymptomatic hypercalcemia

• Tertiary hyperparathyroidism: Occurs in chronic kidney disease patients after prolonged secondary hyperparathyroidism 3

  • Results from autonomous parathyroid function after long-standing renal disease

• Familial hypocalciuric hypercalcemia: Genetic disorder with mutation in calcium-sensing receptor 4

  • Characterized by high calcium, normal/high PTH, and low urinary calcium excretion

• Lithium therapy: Causes hypercalcemia by reducing calcium-sensing receptor sensitivity in parathyroid glands 5

PTH-Independent Causes

Malignancy-Related

• Humoral hypercalcemia of malignancy: Mediated by PTHrP production 2

  • Common in squamous cell carcinomas of lung, head and neck, renal cell carcinoma, ovarian cancer
  • Often occurs with minimal or no bone metastases

• Local osteolytic hypercalcemia: Due to direct bone invasion 2

  • Common in breast cancer and multiple myeloma
  • Mediated by local cytokine production that stimulates osteoclasts

• 1,25-dihydroxyvitamin D production: Seen in some lymphomas 2, 4

Medication-Induced

• Thiazide diuretics: Reduce urinary calcium excretion 5
• Vitamin D toxicity: Excessive supplementation or treatment 2
• Vitamin A excess: Increases bone resorption 1
• Calcium supplements: Especially with milk-alkali syndrome 4
• Denosumab discontinuation: Rebound hypercalcemia after stopping therapy 1
• Sodium-glucose cotransporter 2 inhibitors: Rare cause 1
• Immune checkpoint inhibitors: Emerging cause in cancer immunotherapy 1

Other Causes

• Granulomatous disorders: Including sarcoidosis, tuberculosis 2

  • Increased 1,25-dihydroxyvitamin D production by activated macrophages
  • Requires measurement of both 25-OH and 1,25-OH2 vitamin D levels

• Endocrine disorders:

  • Thyrotoxicosis: Increases bone turnover 5
  • Adrenal insufficiency: Alters calcium homeostasis

• Immobilization: Particularly in patients with high bone turnover 1, 6

  • Common in young patients with paralysis or prolonged bed rest

• Williams syndrome: Idiopathic infantile hypercalcemia 3

  • Presents with irritability, vomiting, constipation, muscle cramps
  • Usually resolves during childhood but may persist

• Severe acute illness: Including SARS-CoV-2 infection (rare) 1

Diagnostic Approach

1. Initial laboratory evaluation: Complete blood count, renal function, albumin, phosphorus, magnesium 2

   • Calculate corrected calcium if albumin is abnormal:
   • Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Serum albumin (g/dL)] 3

2. Measure intact PTH level: Critical for differentiating causes 2, 1

   • Elevated/normal PTH → PTH-dependent causes (primarily hyperparathyroidism)
   • Suppressed PTH (<20 pg/mL) → PTH-independent causes (malignancy, vitamin D toxicity)

3. Additional testing based on clinical suspicion:

   • PTHrP for suspected malignancy
   • Vitamin D metabolites (25-OH and 1,25-OH2) for suspected granulomatous disease or vitamin D toxicity
   • Urinary calcium for familial hypocalciuric hypercalcemia
   • Serum protein electrophoresis for multiple myeloma

Clinical Pitfalls to Avoid

• Failing to correct calcium for albumin: Total calcium may not reflect true hypercalcemia in hypoalbuminemic states 3
• Overlooking medication causes: Always review medication list, including supplements 2
• Treating the laboratory value without addressing underlying cause: Essential to identify and treat the primary etiology 2
• Missing familial hypocalciuric hypercalcemia: Can be mistaken for primary hyperparathyroidism but does not require parathyroidectomy 4
• Delaying treatment of severe hypercalcemia: Life-threatening hypercalcemia requires prompt intervention regardless of diagnostic workup completion 7

Remember that while primary hyperparathyroidism often presents as mild, chronic hypercalcemia, malignancy-associated hypercalcemia typically develops more rapidly and may be more severe, requiring urgent intervention 1, 7.