Hypercalcemia: Symptoms and Treatment
Clinical Presentation
Symptoms of hypercalcemia vary by severity and acuity of onset, ranging from subtle constitutional complaints in mild cases to life-threatening neurologic and cardiovascular manifestations in severe cases. 1
Mild to Moderate Hypercalcemia (10-12 mg/dL or <3 mmol/L)
- Polyuria and polydipsia due to nephrogenic diabetes insipidus 1
- Gastrointestinal symptoms: nausea, vomiting, abdominal pain, constipation 1
- Neurologic symptoms: confusion, difficulty concentrating, fatigue 1, 2
- Musculoskeletal complaints: myalgia, muscle weakness 1
- Approximately 20% of patients with mild hypercalcemia remain asymptomatic 2
Severe Hypercalcemia (>14 mg/dL or >3.5 mmol/L)
- Mental status changes: somnolence, confusion, coma 1, 2
- Cardiovascular manifestations: bradycardia, hypotension 1
- Severe dehydration and acute renal failure 1
- This represents a hypercalcemic crisis requiring immediate intervention 3, 4
Special Populations
In infants with Williams syndrome, hypercalcemia presents with extreme irritability, vomiting, constipation, and muscle cramps 1
Diagnostic Evaluation
Measure serum calcium (corrected for albumin), intact parathyroid hormone (iPTH), PTH-related protein (PTHrP), vitamin D metabolites (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D), phosphorus, magnesium, and renal function to determine the underlying cause. 1, 5
Key Diagnostic Steps
- Calculate corrected calcium: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 5
- PTH level distinguishes causes: Elevated or normal PTH suggests primary hyperparathyroidism; suppressed PTH (<20 pg/mL) indicates malignancy or other non-PTH-mediated causes 2, 6
- Assess severity: Mild (10-11 mg/dL), moderate (11-12 mg/dL), severe (>14 mg/dL) 5
- In malignancy-associated hypercalcemia, median survival is approximately 1 month after diagnosis 1
Treatment Algorithm
Step 1: Immediate Stabilization (All Patients with Moderate-Severe Hypercalcemia)
Administer IV normal saline to correct hypovolemia and promote calciuresis as the first-line intervention, targeting urine output of at least 100 mL/hour (3 mL/kg/hour in children <10 kg). 5, 7
- Vigorous hydration is an integral part of therapy and should be initiated promptly 8
- Avoid overhydration in patients with cardiac or renal failure 1, 8
- Loop diuretics (furosemide) should only be used after correcting hypovolemia, not before 1, 3
Step 2: Pharmacologic Therapy to Reduce Calcium
For Moderate to Severe Hypercalcemia (Especially Malignancy-Associated)
Bisphosphonates are first-line therapy after initiating hydration, with zoledronic acid preferred over pamidronate for initial treatment. 5, 7, 2
- Zoledronic acid 4 mg IV is the preferred bisphosphonate 7, 2
- Pamidronate is an alternative option 8, 2
- Onset of action is 2-3 days; calcium nadir occurs at 4-7 days 2, 3
- Do not delay bisphosphonate therapy while waiting for diagnostic workup in severe cases 7
For Immediate Short-Term Management
Calcitonin (4-8 International Units/kg subcutaneously or intramuscularly every 6-12 hours) provides rapid but temporary calcium reduction while awaiting bisphosphonate effect. 5, 9, 6
- Onset of action within hours, but tachyphylaxis develops after 48 hours 10, 6
- Combine calcitonin with bisphosphonates to enhance rate of calcium decline 10
- Standard dosing: 100 IU subcutaneously or intramuscularly 7
For Vitamin D-Mediated Hypercalcemia
Glucocorticoids are the primary treatment for hypercalcemia due to granulomatous diseases (sarcoidosis), lymphomas, or vitamin D intoxication. 5, 11, 2
- Effective by blocking vitamin D metabolism and reducing intestinal calcium absorption 10, 4
- Not effective for PTH-mediated or most malignancy-associated hypercalcemia 6
Step 3: Refractory Cases
For patients with renal impairment or refractory hypercalcemia, denosumab 120 mg subcutaneously may be used. 5
- Dialysis with calcium-free dialysate is reserved for severe hypercalcemia complicated by renal failure 7, 3, 6
- Hemodialysis can effectively remove calcium through diffusive therapy 7
Cause-Specific Long-Term Management
Treatment of the underlying cause is essential for definitive management. 11, 2
Primary Hyperparathyroidism
- Parathyroidectomy is indicated for symptomatic patients or those with osteoporosis, impaired kidney function, kidney stones, age ≥50 years, or calcium >0.25 mmol/L above upper limit of normal 11
- Observation may be appropriate for patients >50 years with calcium <1 mg/dL above normal and no skeletal or renal disease 2
Malignancy-Associated Hypercalcemia
- Treat the underlying cancer when possible 7, 11
- Continue bisphosphonates for up to 2 years in patients with multiple myeloma or bone metastases 7
- Prognosis is poor, with median survival of 1 month 1
Williams Syndrome (Pediatric)
- Low-calcium diet and increased water intake under medical supervision 1, 11
- Monitor serum calcium every 4-6 months until age 2, then every 2 years 1
Critical Pitfalls to Avoid
- Never use loop diuretics before correcting hypovolemia—this worsens dehydration and hypercalcemia 1, 8
- Avoid NSAIDs and IV contrast in patients with renal impairment 7
- Do not restrict calcium intake without medical supervision in normocalcemic patients (e.g., Williams syndrome) 1, 7
- Avoid vitamin D supplements in patients with hypercalcemia, particularly in early childhood 1, 7, 11
- Do not delay treatment for diagnostic workup in severe symptomatic hypercalcemia 3, 4
- Remember that hyperalbuminemia can mask true calcium status—always calculate corrected calcium or measure ionized calcium 5
Monitoring
Monitor serum calcium, renal function (creatinine, BUN), and electrolytes (potassium, magnesium, phosphorus) regularly to assess treatment effectiveness. 5, 7, 11