What are the symptoms and treatment of hypercalcemia?

Hypercalcemia: Symptoms and Treatment

Clinical Manifestations

Hypercalcemia presents with a spectrum of symptoms ranging from none in mild cases to life-threatening manifestations in severe cases, affecting multiple organ systems including neurologic, gastrointestinal, renal, cardiovascular, and musculoskeletal systems. 1, 2

Symptom Severity by Calcium Level

Mild Hypercalcemia (calcium <12 mg/dL or ionized calcium 5.6-8.0 mg/dL):

• Approximately 80% of patients are asymptomatic 2
• Constitutional symptoms occur in ~20% of cases, including fatigue and constipation 2
• May present with subtle symptoms that are easily overlooked 3

Moderate Hypercalcemia (calcium 11-12 mg/dL):

• Nausea and vomiting become prominent 1
• Abdominal pain is common 1
• Polyuria (excessive urination) and polydipsia (excessive thirst) develop 1

Severe Hypercalcemia (calcium ≥14 mg/dL or ionized calcium ≥10 mg/dL):

• Confusion and altered mental status 1, 2
• Dehydration from impaired renal calcium excretion 4
• Somnolence progressing to coma 2
• Cardiovascular manifestations including bradycardia and hypotension 1

System-Specific Symptoms

Neurologic:

• Confusion, mental status changes, and altered consciousness are hallmark features of severe hypercalcemia 1
• Extreme irritability, particularly in infantile hypercalcemia 5
• Emotional irritability and fatigue 5

Gastrointestinal:

• Vomiting and constipation are frequent complaints 5, 1, 2
• Muscle cramps and myalgia 5, 6

Renal:

• Polyuria leading to dehydration 6, 1
• Decreased glomerular filtration rate in severe cases 1
• Hypercalciuria and nephrocalcinosis with chronic hypercalcemia 5

Cardiovascular:

• QTc prolongation and cardiac arrhythmias 5
• Bradycardia and hypotension in severe cases 1

Skeletal:

• Bone pain and pathologic fractures with chronic hypercalcemia 1
• Predisposition to osteopenia/osteoporosis 5

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Treatment Algorithm

Initial Assessment and Stabilization

Measure serum calcium, albumin, intact parathyroid hormone (iPTH), parathyroid hormone-related protein (PTHrP), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, magnesium, phosphorus, and creatinine to determine the underlying cause. 6, 7

Classify severity:

• Mild: >5.0 to <5.5 mEq/L 7
• Moderate: 5.5 to 6.0 mEq/L 7
• Severe: >6.0 mEq/L or >14.0 mg/dL 7

Treatment Based on Severity

Mild Asymptomatic Hypercalcemia:

• Conservative management with saline hydration and loop diuretics may suffice 8
• Observation is appropriate for patients >50 years with calcium <1 mg above upper normal limit and no skeletal or kidney disease 2
• Discontinue any causative medications 9

Moderate to Severe Hypercalcemia:

Step 1: Aggressive Intravenous Hydration

• Administer IV normal saline to correct hypovolemia and promote calciuresis 6, 8
• Target urine output of at least 100 mL/hour (3 mL/kg/hour in children <10 kg) 6
• Avoid overhydration in patients with cardiac failure 8
• Loop diuretics may be necessary in patients with renal or cardiac insufficiency to prevent fluid overload 6
• Critical pitfall: Do not use diuretics before correcting hypovolemia 8

Step 2: Bisphosphonate Therapy (First-Line Definitive Treatment)

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate for moderate to severe hypercalcemia 6, 8, 2
• Zoledronic acid has superior efficacy compared to pamidronate 6
• Onset of action is delayed (3-6 days), so administer early 4
• Assess serum creatinine before each dose and withhold if renal deterioration occurs 6, 8

Dose adjustments for renal impairment (CrCl ≤60 mL/min): 8

• CrCl >60 mL/min: 4 mg
• CrCl 50-60 mL/min: 3.5 mg
• CrCl 40-49 mL/min: 3.3 mg
• CrCl 30-39 mL/min: 3 mg

Step 3: Adjunctive Rapid-Acting Agents

• Calcitonin 100 IU subcutaneously or intramuscularly provides rapid onset within hours but limited efficacy 6, 9
• Use as a bridge until bisphosphonates take effect 6
• Combining calcitonin with bisphosphonates enhances the rate of calcium decline 4

Cause-Specific Treatment

Hypercalcemia from Excessive Intestinal Calcium Absorption:

• Glucocorticoids are the primary treatment for vitamin D intoxication, granulomatous diseases (sarcoidosis), some lymphomas, and multiple myeloma 6, 2, 4

Malignancy-Associated Hypercalcemia:

• Hydration plus zoledronic acid 4 mg IV is the cornerstone of treatment 6
• Plasmapheresis for symptomatic hyperviscosity in multiple myeloma 6
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 6

Primary Hyperparathyroidism:

• Parathyroidectomy is indicated for patients meeting specific criteria 2, 9
• Many patients have a benign course and do not require surgery 9

Tertiary Hyperparathyroidism:

• Parathyroidectomy is considered for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy 6

Refractory or Severe Hypercalcemia with Renal Failure

Dialysis with calcium-free or low-calcium solution is reserved for patients with severe hypercalcemia complicated by renal insufficiency. 6, 3

Hemodialysis effectively removes calcium through diffusive therapy. 6

Retreatment Considerations

If serum calcium does not normalize after initial treatment with zoledronic acid, retreatment with 4 mg may be considered after a minimum of 7 days. 8

Renal function must be carefully monitored before retreatment. 8

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Supportive Care and Monitoring

Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia. 6

Correct hypocalcemia before initiating bisphosphonate therapy, especially with denosumab which carries higher risk. 6

Monitor serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness. 6

Only treat symptomatic hypocalcemia (tetany, seizures) following treatment; asymptomatic hypocalcemia does not require intervention. 6

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Critical Pitfalls to Avoid

• Do not restrict calcium intake without medical supervision in patients with normocalcemia 6
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment 6
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia 6
• Avoid vitamin D supplements in patients with hypercalcemia, particularly in early childhood 6
• Do not use diuretics before correcting hypovolemia 8
• Sedatives and narcotic analgesics can raise serum calcium by reducing activity and oral intake 4

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Special Populations

Williams Syndrome:

• Monitor calcium levels every 4-6 months until 2 years of age, then every 2 years thereafter 5, 7
• Educate parents regarding signs and symptoms of hypercalcemia 5
• Infants with hypercalcemia are treated with low-calcium diet and increased water intake under medical supervision 5

22q11.2 Deletion Syndrome:

• Hypocalcemia is more common than hypercalcemia in this population 5
• Monitor for hypercalcemia during biological stress (surgery, childbirth, infection) 5
• Caution regarding over-correction leading to iatrogenic hypercalcemia 5