What are the causes and management of hypercalcemia?

Causes and Management of Hypercalcemia

Hypercalcemia is primarily caused by primary hyperparathyroidism and malignancy (accounting for approximately 90% of cases), with several other etiologies including granulomatous diseases, medications, and endocrinopathies requiring consideration for proper diagnosis and management. 1

Common Causes of Hypercalcemia

Primary Hyperparathyroidism

• Characterized by elevated or inappropriately normal parathyroid hormone (PTH) levels with hypercalcemia 2
• Laboratory findings include elevated intact PTH and calcitriol levels 2
• Most common cause of hypercalcemia in outpatient settings 1

Malignancy-Associated Hypercalcemia

• Occurs in 10-25% of patients with lung cancer, most commonly in squamous cell carcinoma 2
• Three main mechanisms:
  • Parathyroid hormone-related protein (PTHrP) production (humoral hypercalcemia) - most common in squamous cell cancers of lung, head and neck, renal cell carcinoma, and ovarian cancer 2, 3
  • Increased active vitamin D (calcitriol) production 2
  • Localized osteolytic hypercalcemia from bone metastases - common in breast cancer and multiple myeloma 3
• PTHrP-mediated hypercalcemia shows suppressed intact PTH and low/normal calcitriol levels 2
• Poor prognosis - median survival after discovery in lung cancer is approximately 1 month 2

Medication-Induced Hypercalcemia

• Medications that can cause hypercalcemia include:
  • Thiazide diuretics 1
  • Calcium supplements 1
  • Vitamin D supplements 1
  • Vitamin A supplements 1
  • Lithium 2

Other Causes

• Granulomatous diseases (e.g., sarcoidosis) 1
• Endocrine disorders (e.g., thyroid disease) 1
• Immobilization 1
• Genetic disorders 1
• Familial hypocalciuric hypercalcemia 4

Clinical Presentation

Symptoms Based on Severity

• Mild hypercalcemia (<12 mg/dL):

  • Often asymptomatic 1
  • Constitutional symptoms like fatigue and constipation in ~20% of patients 1

• Moderate hypercalcemia:

  • Polyuria, polydipsia 2
  • Nausea, vomiting, abdominal pain 2
  • Myalgia, confusion 2

• Severe hypercalcemia (>14 mg/dL):

  • Mental status changes 2
  • Bradycardia and hypotension 2
  • Severe dehydration and acute renal failure 2
  • Somnolence and coma 1

Diagnostic Evaluation

Initial Workup

• Measure serum intact parathyroid hormone (iPTH) - most important initial test 1

  • Elevated/normal iPTH suggests primary hyperparathyroidism 1
  • Suppressed iPTH (<20 pg/mL) suggests other causes, particularly malignancy 1

• Additional laboratory tests:

  • PTHrP 2
  • 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D 2
  • Albumin (for corrected calcium calculation) 2
  • Magnesium and phosphorus 2

Management Approach

Mild Asymptomatic Hypercalcemia

• Usually does not require acute intervention 1
• For primary hyperparathyroidism:
  • Consider parathyroidectomy based on age, calcium level, and organ involvement 1
  • Observation may be appropriate for patients >50 years with calcium <1 mg/dL above upper limit and no skeletal/kidney disease 1

Moderate to Severe Hypercalcemia

• Hydration is the cornerstone of initial management:

  • IV crystalloid fluids not containing calcium 2
  • Correction of intravascular volume 2
  • Loop diuretics (e.g., furosemide) after volume restoration 2

• Bisphosphonates:

  • First-line pharmacologic therapy for moderate to severe hypercalcemia 3, 1
  • Options include zoledronic acid, pamidronate, and clodronate 2
  • Inhibit osteoclastic activity and induce osteoclast apoptosis 3

• Additional therapeutic options:

  • Calcitonin - more rapid but modest effect, often combined with bisphosphonates 5
  • Glucocorticoids - effective for vitamin D-mediated hypercalcemia (sarcoidosis, lymphomas) 2, 5
  • Denosumab - particularly useful in patients with renal failure 1
  • Hemodialysis - for patients with advanced kidney disease and refractory hypercalcemia 6

Hypercalcemia of Malignancy

• Treat the underlying malignancy when possible 6
• Early involvement of oncology and palliative care specialists 6
• Aggressive hydration and bisphosphonates are mainstays of treatment 3, 6

Important Clinical Considerations

• Pseudo-hypercalcemia should be ruled out - can occur from improper blood sampling 2
• Corrected calcium calculation should be used when albumin is abnormal 3
• Patients with malignancy-associated hypercalcemia have poor prognosis, with median survival of approximately 1 month in lung cancer 2
• Mobilization (standing/walking) can help reduce bone resorption in hypercalcemic patients 5
• Avoid medications that can worsen hypercalcemia, such as thiazide diuretics and calcium supplements 1