What are the primary causes of hypercalcemia?

Main Causes of Hypercalcemia

Primary hyperparathyroidism and malignancy are the two most common causes of hypercalcemia, accounting for approximately 90% of all cases. 1

PTH-Dependent Causes

1. Primary Hyperparathyroidism (PHPT)

   • Most common cause in outpatient settings
   • Due to parathyroid adenoma, hyperplasia, or rarely carcinoma
   • Characterized by elevated or inappropriately normal PTH levels with hypercalcemia 2
   • Often discovered incidentally in asymptomatic patients 3

2. Familial Hypocalciuric Hypercalcemia (FHH)

   • Genetic disorder with reduced urinary calcium excretion
   • Usually presents with mild, asymptomatic hypercalcemia
   • Distinguished by low urine calcium/creatinine ratio 3

Malignancy-Related Causes

1. Humoral Hypercalcemia of Malignancy

   • Mediated by parathyroid hormone-related protein (PTHrP)
   • Common in squamous cell carcinomas (lung, head and neck)
   • Also seen in renal cell carcinoma, ovarian cancer 4
   • Skeletal metastases may be minimal or absent 4

2. Local Osteolytic Hypercalcemia

   • Due to extensive bone invasion by tumor cells
   • Tumor-produced factors stimulate local bone resorption
   • Common in breast cancer and multiple myeloma 4
   • Associated with extensive osteolytic lesions 4

3. Common Malignancies Associated with Hypercalcemia

   • Non-small cell lung cancer
   • Breast cancer
   • Multiple myeloma
   • Kidney cancer
   • Head and neck cancers 4
   • Urologic malignancies 5

Medication-Induced Causes

1. Vitamin D Excess

   • Vitamin D supplements or metabolites
   • Increases intestinal calcium absorption 1

2. Other Medications

   • Thiazide diuretics (reduce urinary calcium excretion)
   • Lithium (increases PTH secretion)
   • Vitamin A supplements
   • Sodium-glucose cotransporter 2 (SGLT2) inhibitors 1
   • Denosumab discontinuation (rebound effect) 1

Endocrine Disorders

1. Thyroid Disorders

   • Hyperthyroidism can increase bone turnover 1

2. Adrenal Disorders

   • Adrenal insufficiency
   • Pheochromocytoma (rare)

Granulomatous Disorders

1. Sarcoidosis

   • Increased 1,25-dihydroxyvitamin D production by macrophages
   • Enhanced intestinal calcium absorption 1

2. Other Granulomatous Diseases

   • Tuberculosis
   • Histoplasmosis
   • Coccidioidomycosis
   • Berylliosis

Other Causes

1. Immobilization

   • Especially in patients with high bone turnover (e.g., adolescents)
   • Increased bone resorption due to lack of mechanical stress 1

2. Genetic Disorders

   • Williams syndrome (associated with hypercalcemia in infancy) 2
   • 22q11.2 deletion syndrome (can have hypercalcemia) 2

3. Miscellaneous

   • Milk-alkali syndrome (excessive calcium and absorbable alkali intake)
   • Rhabdomyolysis (acute phase)
   • Extreme exercise
   • Ketogenic diets
   • SARS-CoV-2 infection (rare) 1

Diagnostic Approach

The most important initial test in evaluating hypercalcemia is serum intact parathyroid hormone (PTH):

• Elevated or normal PTH with hypercalcemia suggests primary hyperparathyroidism
• Suppressed PTH (<20 pg/mL) indicates PTH-independent causes like malignancy 1

Additional tests should include:

• Serum calcium and albumin (for corrected calcium calculation)
• Vitamin D metabolites (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D)
• Parathyroid hormone-related protein (PTHrP) if malignancy suspected
• Magnesium and phosphorus levels
• Urine calcium/creatinine ratio 6

Management Considerations

Treatment depends on the severity of hypercalcemia and underlying cause:

1. Mild Asymptomatic Hypercalcemia

   • Often requires no acute intervention
   • Treat underlying cause when identified 1

2. Symptomatic or Severe Hypercalcemia

   • Aggressive IV normal saline hydration
   • Bisphosphonates (zoledronic acid or pamidronate) 6
   • Calcitonin for rapid but temporary effect
   • Denosumab for refractory cases or renal impairment 6
   • Glucocorticoids for vitamin D-mediated hypercalcemia 7

Remember that the prognosis varies significantly based on the underlying cause - excellent for asymptomatic PHPT but poor for malignancy-associated hypercalcemia 1.