What is the initial workup and management for a patient presenting with hypercalcemia?

Hypercalcemia Workup

Initial Diagnostic Evaluation

The diagnostic workup for hypercalcemia should begin with measuring serum calcium (corrected for albumin), intact parathyroid hormone (iPTH), parathyroid hormone-related protein (PTHrP), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, serum phosphorus, magnesium, blood urea nitrogen, creatinine, and albumin. 1, 2

Calculate Corrected Calcium

• Use the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4.0 - Albumin (g/dL)] 2, 3
• Alternatively, measure ionized calcium directly if available 4

Classify Severity

• Mild hypercalcemia: Total calcium >10 to <11 mg/dL (>2.5 to <2.75 mmol/L) 2
• Moderate hypercalcemia: Total calcium 11 to 12 mg/dL (2.75 to 3.0 mmol/L) 2
• Severe hypercalcemia: Total calcium >14.0 mg/dL (>3.5 mmol/L) 1, 2, 4

Assess Clinical Symptoms by Severity

• Mild to moderate: Polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, myalgia, fatigue, constipation 1, 4
• Severe: Mental status changes, bradycardia, hypotension, dehydration, acute renal failure, somnolence, coma 1, 4

Determine Etiology Using PTH

PTH-Dependent Hypercalcemia (Elevated or Normal PTH)

• Primary hyperparathyroidism is the most likely diagnosis when iPTH is elevated or inappropriately normal in the setting of hypercalcemia 5, 4, 6
• This accounts for approximately 90% of outpatient hypercalcemia cases 4
• Typically presents with calcium <12 mg/dL, longer duration (>6 months), kidney stones, hyperchloremic metabolic acidosis, no anemia 6

PTH-Independent Hypercalcemia (Suppressed PTH <20 pg/mL)

• Malignancy-associated hypercalcemia: Check PTHrP levels, which are elevated in humoral hypercalcemia of malignancy (most common in squamous cell carcinomas and renal cell carcinoma) 1, 5
• Vitamin D-mediated: Elevated 1,25-dihydroxyvitamin D suggests granulomatous disease (sarcoidosis), lymphomas, or vitamin D intoxication 1, 5
• Osteolytic metastases: Consider in patients with known malignancy and suppressed PTH 1

Additional Diagnostic Considerations

• Obtain urine calcium/creatinine ratio to evaluate for familial hypocalciuric hypercalcemia (low urinary calcium excretion despite hypercalcemia) 1, 7
• Assess renal function carefully, as hypercalcemia causes nephrocalcinosis and impaired calcium excretion 8
• Review medications: thiazide diuretics, calcium supplements, vitamin D, vitamin A, lithium 4, 7

Initial Management Approach

Immediate Hydration

Aggressive IV normal saline rehydration is the cornerstone of initial management for moderate to severe hypercalcemia, targeting urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg). 2, 9, 3

• Restore extracellular volume before considering loop diuretics 3, 6
• Loop diuretics (furosemide) should only be used after adequate rehydration and in patients with renal or cardiac insufficiency to prevent fluid overload 1, 9, 6
• Avoid loop diuretics before volume repletion to prevent worsening hypocalcemia 3

Definitive Pharmacologic Treatment

For moderate to severe hypercalcemia, administer IV bisphosphonates after initiating hydration, with zoledronic acid 4 mg infused over at least 15 minutes as the preferred agent. 1, 9, 3

• Zoledronic acid is superior to pamidronate, achieving calcium normalization in 50% of patients by day 4 versus 33% with pamidronate 1
• Pamidronate 90 mg IV over 2 hours is an alternative if zoledronic acid is unavailable 1
• Bisphosphonates take 2-4 days to achieve maximum effect 6, 8

Adjunctive Rapid-Acting Therapy

• Calcitonin (100 IU subcutaneously or intramuscularly) provides rapid onset within hours but limited efficacy; use as a bridge until bisphosphonates take effect 2, 9, 6, 7
• Calcitonin is particularly useful for immediate short-term management of severe symptomatic hypercalcemia 6, 7

Cause-Specific Treatments

• Glucocorticoids are effective for vitamin D-mediated hypercalcemia (sarcoidosis, lymphomas, vitamin D intoxication, granulomatous diseases) 1, 4, 8
• Denosumab 120 mg subcutaneously for bisphosphonate-refractory hypercalcemia, especially in patients with renal impairment 1, 2
• Dialysis with calcium-free or low-calcium solution is reserved for severe hypercalcemia complicated by renal failure 9, 6

Monitoring and Follow-Up

• Monitor serum calcium, creatinine, phosphorus, magnesium, and electrolytes regularly 2, 9, 3
• Assess serum creatinine before each bisphosphonate dose; withhold treatment if creatinine increases by 0.5 mg/dL (normal baseline) or 1.0 mg/dL (abnormal baseline) 3
• Retreatment with zoledronic acid may be considered if calcium does not normalize, with minimum 7 days between doses 3
• For refractory cases, consider increasing zoledronic acid to 8 mg 1

Critical Pitfalls to Avoid

• Never administer bisphosphonates before adequate hydration, as this increases risk of renal toxicity 3
• Do not exceed 4 mg zoledronic acid for initial treatment or infuse faster than 15 minutes, as this significantly increases risk of renal failure 3
• Avoid NSAIDs and IV contrast in patients with renal impairment to prevent further renal deterioration 2, 9
• Do not restrict calcium intake without medical supervision in normocalcemic patients 1, 2
• Avoid vitamin D supplements in patients with hypercalcemia, particularly in early childhood 1, 9, 5
• Monitor for hypocalcemia after denosumab treatment, which carries higher risk than bisphosphonates; provide calcium and vitamin D supplementation 1, 9
• Assess for osteonecrosis of the jaw risk before initiating bisphosphonates; patients should have dental examination and maintain good oral hygiene 3

Long-Term Management Considerations

• Primary hyperparathyroidism: Consider parathyroidectomy for symptomatic patients, those with osteoporosis, impaired kidney function, kidney stones, age <50 years, or calcium >1 mg/dL above upper limit of normal 5, 4
• Patients >50 years with calcium <1 mg/dL above normal and no skeletal or kidney disease may be observed 4
• Malignancy-associated hypercalcemia: Treat underlying malignancy; prognosis is poor with median survival approximately 1 month after diagnosis 1, 4
• Bisphosphonates may be continued for up to 2 years in patients with multiple myeloma or bone metastases 1, 9