What are the signs and symptoms of hypercalcemia?

Signs and Symptoms of Hypercalcemia

Hypercalcemia presents with a spectrum of symptoms affecting multiple organ systems, with severity depending on both calcium levels and rate of onset, ranging from fatigue and constipation in mild cases to confusion, somnolence, and coma in severe cases. 1

Classification and Presentation

Hypercalcemia can be categorized based on 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)

  • Often asymptomatic
  • Constitutional symptoms in ~20% of patients 2

• Severe hypercalcemia: Total calcium ≥14 mg/dL (>3.5 mmol/L) or ionized calcium ≥10 mg/dL (≥2.5 mmol/L)

  • More pronounced symptoms
  • Medical emergency requiring prompt treatment 1

Organ-Specific Manifestations

Neurological/Muscular

• Altered mental status (confusion, irritability, coma) 3
• Fatigue and weakness 3
• Seizures (particularly with rapid calcium elevation) 1
• Movement disorders (tremors, abnormal involuntary movements) 1
• Lethargy and somnolence 2

Gastrointestinal

• Nausea and vomiting 3
• Constipation 3
• Abdominal pain 4
• Anorexia 5

Renal

• Polyuria (excessive urination) 3
• Polydipsia (excessive thirst) 3, 4
• Dehydration 2
• Risk of kidney stones 2
• Decreasing glomerular filtration rate 6
• Renal injury 3

Cardiovascular

• QT interval shortening 1
• Heart blocks 1
• Potentially life-threatening dysrhythmias 1
• Cardiomyopathy (in rare cases of prolonged severe hypercalcemia) 1

Skeletal

• Osteopenia/osteoporosis with prolonged hypercalcemia 1
• Increased risk of fractures 1

Other

• Electrolyte imbalances (hypokalemia, hypomagnesemia) 1
• Excessive thirst 4

Pathophysiology

The underlying mechanism of hypercalcemia involves:

• Excessive bone resorption releasing calcium into the bloodstream 6, 7
• Progressive dehydration due to polyuria 6
• Decreasing glomerular filtration rate 6
• Increased renal resorption of calcium, creating a cycle of worsening hypercalcemia 6

Common Causes

1. Primary hyperparathyroidism and malignancy (account for 90% of cases) 1, 2
2. Vitamin D toxicity (particularly when 25(OH)D levels exceed 150 ng/mL) 3, 1
3. Granulomatous disorders (sarcoidosis, tuberculosis, some lymphomas) 1
4. Medications:
   • Thiazide diuretics 2, 4
   • Excessive vitamin D supplementation (>4,000 IU daily considered potentially unsafe) 3, 1
   • Calcium supplements 1

Clinical Pearls and Pitfalls

• Important pitfall: Total serum calcium may not reflect severity due to common hypoalbuminemia; corrected calcium or ionized calcium should be used 1, 6, 7
• Calculation: Corrected calcium = Total calcium + 0.8 × (4.0 - serum albumin) 1
• Common error: Treating laboratory values without addressing the underlying cause 1
• Risk factor: Patients with granulomatous disorders are at increased risk even with normal vitamin D levels 1
• Monitoring: Regular assessment of serum calcium, phosphate, magnesium, and renal function is essential 1

Diagnostic Approach

Initial laboratory tests should include:

• Corrected calcium calculation
• Intact parathyroid hormone (iPTH)
• Phosphorus, magnesium, renal function tests
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels
• Urinary calcium/creatinine ratio 1

Treatment Considerations

For severe symptomatic hypercalcemia:

1. Aggressive IV fluid resuscitation with normal saline (first-line) 1
2. Bisphosphonates (zoledronic acid 4 mg IV over 15 minutes preferred due to superior efficacy and longer duration) 1, 6
3. Denosumab for refractory cases or severe renal impairment 1
4. Glucocorticoids for vitamin D toxicity, granulomatous disorders, or lymphomas 1

By recognizing these signs and symptoms early, clinicians can initiate appropriate treatment and prevent potentially life-threatening complications of hypercalcemia.