What causes hypercalcemia?

Causes of Hypercalcemia

Primary hyperparathyroidism and malignancy account for approximately 90% of hypercalcemia cases, with the remaining 10% attributed to various other conditions including granulomatous diseases, medications, endocrinopathies, and genetic disorders. 1

Major Causes of Hypercalcemia

1. Primary Hyperparathyroidism (PHPT)

• Most common cause in outpatient settings
• Characterized by elevated or inappropriately normal PTH levels despite hypercalcemia
• May be asymptomatic or present with constitutional symptoms like fatigue and constipation 1
• Surgical management (parathyroidectomy) is indicated based on age, serum calcium level, and evidence of kidney or skeletal involvement

2. Malignancy-Associated Hypercalcemia

• Most common cause in hospitalized patients
• Two primary mechanisms:
  • Humoral hypercalcemia of malignancy: Mediated by PTHrP, commonly seen in squamous cell cancers of lung/head/neck, renal cell carcinoma, and ovarian cancer 2
  • Direct bone invasion: Local tumor products stimulate osteoclastic bone resorption, common in breast cancer and multiple myeloma 2
• Associated with poor prognosis (median survival ~1 month in lung cancer) 3

3. Medication-Induced Hypercalcemia

• Thiazide diuretics: Reduce urinary calcium excretion
• Lithium: Increases PTH secretion
• Vitamin A/D supplements: Excessive intake or toxicity
• Calcium supplements: Excessive intake (milk-alkali syndrome)
• Newer medications: Sodium-glucose cotransporter 2 inhibitors, immune checkpoint inhibitors, denosumab discontinuation 1

4. Granulomatous Disorders

• Sarcoidosis, tuberculosis, histoplasmosis
• Increased 1,25-dihydroxyvitamin D production by activated macrophages 3
• Responsive to glucocorticoid therapy

5. Endocrine Disorders

• Hyperthyroidism
• Adrenal insufficiency
• Williams syndrome (idiopathic infantile hypercalcemia) 4

6. Other Causes

• Chronic kidney disease with tertiary hyperparathyroidism 4
• Immobilization (especially in patients with high bone turnover)
• Familial hypocalciuric hypercalcemia (genetic disorder)
• Vitamin D intoxication
• Extreme exercise
• Ketogenic diets 1

Clinical Presentation

Hypercalcemia may present with:

• Gastrointestinal symptoms: Nausea, vomiting, constipation, abdominal pain, reduced appetite
• Renal manifestations: Polyuria, dehydration, hypercalciuria, nephrocalcinosis
• Neurological symptoms: Confusion, lethargy, impaired cognitive function, somnolence, coma (in severe cases)
• Musculoskeletal symptoms: Muscle cramps, muscle pain, bone pain, weakness 3

In infants and children with Williams syndrome, hypercalcemia may manifest as extreme irritability, vomiting, constipation, and muscle cramps 4

Diagnostic Approach

1. Initial laboratory evaluation:

   • Serum calcium (total and ionized)
   • Albumin (for corrected calcium calculation)
   • Intact parathyroid hormone (iPTH) - most important initial test
   • Phosphorus, magnesium
   • Renal function tests

2. Based on PTH results:

   • Elevated/normal PTH → Primary hyperparathyroidism
   • Suppressed PTH (<20 pg/mL) → Consider malignancy, vitamin D disorders, granulomatous disease

3. Additional testing based on clinical suspicion:

   • PTHrP for suspected malignancy
   • 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D
   • Thyroid function tests
   • Urinary calcium/creatinine ratio
   • Renal ultrasonography if hypercalciuria present 4, 3

Management Considerations

Severe or Symptomatic Hypercalcemia

1. Aggressive IV fluid resuscitation with normal saline to correct dehydration and promote calciuresis
2. Bisphosphonates (e.g., zoledronic acid 4 mg IV) for cancer-related hypercalcemia
3. Denosumab for patients with renal impairment or refractory cases
4. Glucocorticoids for granulomatous disorders, vitamin D toxicity, or some lymphomas
5. Calcitonin for immediate short-term management
6. Loop diuretics only after adequate hydration 3

Mild Asymptomatic Hypercalcemia

• Often requires no acute intervention
• Treatment of underlying cause
• Avoid dehydration and prolonged immobilization
• Avoid medications that can worsen hypercalcemia (e.g., thiazides)

Common 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
• Failing to monitor for hypocalcemia after treatment, especially with denosumab 3

Remember that while mild hypercalcemia may be asymptomatic, severe hypercalcemia is a medical emergency requiring prompt intervention to prevent complications and reduce mortality.