What are the symptoms and treatment of hypercalcemia?

Hypercalcemia: Symptoms and Treatment

Clinical Presentation

Moderate hypercalcemia (10-12 mg/dL) typically presents with polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia, fatigue, and constipation, while severe hypercalcemia (>14 mg/dL) manifests with mental status changes, bradycardia, hypotension, dehydration, confusion, somnolence, coma, and acute renal failure. 1, 2, 3

Symptom Severity Correlates with Calcium Level

• Mild hypercalcemia (<12 mg/dL) is usually asymptomatic but may cause constitutional symptoms like fatigue and constipation in approximately 20% of patients 3
• Moderate hypercalcemia (11-12 mg/dL) produces polyuria, polydipsia, nausea, confusion, vomiting, and abdominal pain 1, 2
• Severe hypercalcemia (>14 mg/dL) causes rapid deterioration with mental status changes, dehydration, somnolence, coma, and cardiovascular instability 1, 2, 3

Etiology-Specific Presentations

• Primary hyperparathyroidism tends to cause chronic, mild hypercalcemia with kidney stones, hyperchloremic metabolic acidosis, and bone disease (osteitis fibrosa cystica), but no anemia 4
• Malignancy-associated hypercalcemia presents with rapid onset, higher calcium levels, marked anemia, but never kidney stones or metabolic acidosis 4
• Williams syndrome in infants presents with extreme irritability, vomiting, constipation, and muscle cramps 1

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Treatment Algorithm

Step 1: Immediate Hydration (All Patients)

Initiate aggressive IV normal saline hydration immediately to correct hypovolemia and promote calciuresis, targeting urine output of 100-150 mL/hour (or 3 mL/kg/hour in children <10 kg). 1, 5, 2, 6

• Vigorous saline hydration is an integral part of hypercalcemia therapy and should be started promptly 6
• Avoid overhydration in patients with cardiac or renal insufficiency 5, 7
• Loop diuretics (furosemide) should only be used AFTER volume repletion in patients with renal or cardiac insufficiency to prevent fluid overload—never before correcting hypovolemia 1, 5, 2, 7

Step 2: Bisphosphonate Therapy (First-Line for Moderate-Severe Hypercalcemia)

Administer IV zoledronic acid 4 mg infused over no less than 15 minutes as the preferred bisphosphonate for moderate to severe hypercalcemia, especially malignancy-associated. 1, 5, 2, 6

• Zoledronic acid is superior to pamidronate in efficacy 5
• Dose adjustments for renal impairment: CrCl 50-60 mL/min: 3.5 mg; CrCl 40-49 mL/min: 3.3 mg; CrCl 30-39 mL/min: 3.0 mg 6
• Monitor serum creatinine before each dose and withhold if renal deterioration occurs (increase of 0.5 mg/dL in normal baseline or 1.0 mg/dL in abnormal baseline) 5, 6
• Bisphosphonates take 2-4 days to achieve full effect 8, 4
• Pamidronate IV is an alternative if zoledronic acid is unavailable 5

Step 3: Calcitonin (Bridge Therapy for Severe Symptomatic Cases)

Add calcitonin 4 IU/kg subcutaneously or intramuscularly every 12 hours for immediate short-term management of severe symptomatic hypercalcemia while waiting for bisphosphonates to take effect. 5, 2, 9, 4

• Calcitonin provides rapid onset within hours but has limited efficacy and duration 5, 9
• If response is unsatisfactory after 1-2 days, increase to 8 IU/kg every 12 hours; if still inadequate after 2 more days, increase to maximum 8 IU/kg every 6 hours 9
• Do not delay bisphosphonate therapy as calcitonin provides only short-term benefit (1-4 hours) 5

Step 4: Cause-Specific Treatment

For Vitamin D-Mediated Hypercalcemia (Sarcoidosis, Lymphomas, Vitamin D Intoxication, Granulomatous Disorders)

Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption. 1, 5, 2, 3, 10

• Glucocorticoids are effective when hypercalcemia is mediated by elevated 1,25-dihydroxyvitamin D 1, 4
• Avoid vitamin D supplements in all patients with hypercalcemia 1, 5, 2

For Refractory Hypercalcemia or Renal Impairment

Denosumab 120 mg subcutaneously is indicated for refractory hypercalcemia, especially when bisphosphonates are contraindicated due to renal impairment. 2

• Denosumab carries higher risk of hypocalcemia; correct hypocalcemia before initiating and monitor closely 5
• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during treatment 5

For Severe Hypercalcemia with Renal Failure

Dialysis with calcium-free or low-calcium dialysate is reserved for severe hypercalcemia complicated by kidney failure or oliguria. 5, 2, 4

• Hemodialysis effectively removes calcium through diffusive therapy 5

Step 5: Definitive Management

Primary Hyperparathyroidism

Parathyroidectomy is indicated for symptomatic patients and those with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L above upper normal limit. 1, 2

• In patients >50 years with calcium <1 mg/dL above upper limit and no skeletal or kidney disease, observation may be appropriate 3

Malignancy-Associated Hypercalcemia

Treat the underlying cancer when possible, as this is essential for long-term control; hypercalcemia of malignancy carries poor prognosis with median survival approximately 1 month. 1, 5, 2

• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 5
• Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 5

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Monitoring and Follow-Up

• Monitor serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness 1, 5, 2
• Assess for bisphosphonate complications: renal toxicity and osteonecrosis of the jaw with chronic use 2
• Retreatment with zoledronic acid 4 mg may be considered if calcium does not normalize; allow minimum 7 days between doses 6
• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 5

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Critical Pitfalls to Avoid

• Never use loop diuretics before volume repletion—this worsens hypovolemia and hypercalcemia 1, 5, 2, 7
• Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent further kidney deterioration 5
• Do not restrict calcium intake excessively without medical supervision, as this can worsen bone disease 5
• Avoid vitamin D supplements in all hypercalcemic patients, particularly children 1, 5, 2
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia; temporary measures provide only 1-4 hours of benefit 5