What is hypercalcemia?

Elevated Calcium Levels: Understanding Hypercalcemia

Hypercalcemia is defined as an abnormally high level of calcium in the blood, affecting approximately 1% of the global population, with primary hyperparathyroidism and malignancy accounting for 90% of cases. 1, 2

Definition and Classification

Hypercalcemia is typically classified by severity:

• Mild hypercalcemia: Total calcium <12 mg/dL (<3 mmol/L) or ionized calcium 5.6-8.0 mg/dL (1.4-2 mmol/L)
• Severe hypercalcemia: Total calcium ≥14 mg/dL (>3.5 mmol/L) or ionized calcium ≥10 mg/dL (≥2.5 mmol/L) 2

When interpreting calcium levels, it's important to calculate corrected calcium if ionized calcium is unavailable, using the formula: Corrected calcium = Total calcium + 0.8 × (4.0 - serum albumin) 1

Common Causes

1. Primary hyperparathyroidism (most common cause)
2. Malignancy-associated hypercalcemia:
   • Humoral hypercalcemia (mediated by PTH-related protein)
   • Direct bone invasion by tumor cells 3, 2
3. Other causes:
   • Granulomatous diseases (e.g., sarcoidosis)
   • Medications (thiazide diuretics, calcium/vitamin D supplements)
   • Endocrinopathies (thyroid disorders)
   • Familial hypocalciuric hypercalcemia
   • Immobilization 1, 2

Clinical Manifestations

Hypercalcemia affects multiple body systems:

• Neurological: Fatigue, confusion, somnolence, coma (in severe cases)
• Gastrointestinal: Nausea, vomiting, constipation, anorexia
• Renal: Polyuria, dehydration, nephrocalcinosis, kidney stones
• Cardiovascular: Hypertension, QT interval shortening, arrhythmias
• Musculoskeletal: Muscle weakness, bone pain 1, 2

The classic mnemonic for hypercalcemia symptoms is "stones, bones, abdominal groans, and psychic moans."

Diagnostic Approach

1. Initial laboratory evaluation:

   • Serum calcium (corrected for albumin)
   • Intact parathyroid hormone (iPTH) - critical for determining cause
   • Phosphorus, magnesium, renal function tests
   • 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D
   • Urinary calcium/creatinine ratio 1, 4

2. Interpretation of results:

   • Elevated or inappropriately normal PTH with hypercalcemia suggests primary hyperparathyroidism
   • Suppressed PTH (<20 pg/mL) suggests non-PTH mediated causes like malignancy 1, 2

3. Additional testing based on clinical suspicion:

   • PTH-related protein (PTHrP) for suspected malignancy
   • Chest radiography to evaluate for malignancy
   • Ultrasound for renal function and nephrolithiasis 1

Management

Treatment approach depends on severity, cause, and symptoms:

Mild Asymptomatic Hypercalcemia

• Often requires only monitoring, especially in primary hyperparathyroidism
• Address underlying cause when identified
• Avoid dehydration and medications that can worsen hypercalcemia 2

Symptomatic or Severe Hypercalcemia

1. Aggressive IV fluid resuscitation with normal saline:

   • Cornerstone of initial management
   • Corrects dehydration and promotes calciuresis
   • Avoid calcium-containing solutions 1

2. Pharmacological interventions:

   • Bisphosphonates: First-line treatment (e.g., zoledronic acid 4 mg IV)
   • Denosumab: For hypercalcemia refractory to bisphosphonates or in severe renal impairment
   • Calcitonin: For immediate short-term management of severe symptomatic hypercalcemia
   • Glucocorticoids: For vitamin D toxicity, granulomatous disorders, or some lymphomas
   • Loop diuretics: Only after adequate hydration to enhance calcium excretion 1, 3

3. Treatment of underlying cause:

   • Parathyroidectomy for appropriate cases of primary hyperparathyroidism
   • Anti-tumor therapy for malignancy-associated hypercalcemia 1, 2

Special Considerations

• Hypercalcemia in Williams syndrome: May contribute to irritability, vomiting, constipation, and muscle cramps in infants. Usually resolves during childhood but may require low-calcium diet and increased water intake under medical supervision 4

• Monitoring: Regular assessment of serum calcium, phosphate, magnesium, and renal function is essential during treatment 1

• 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 underlying cause
  • Delaying treatment of severe hypercalcemia 1

Hypercalcemia, especially when severe or rapidly developing, requires prompt recognition and treatment to prevent serious complications including dehydration, renal failure, and neurological deterioration.