What is the appropriate workup and treatment for a patient presenting with hypercalcemia?

Hypercalcemia Workup

Begin the workup by measuring serum calcium (corrected for albumin or ionized calcium directly), intact parathyroid hormone (iPTH), albumin, phosphorus, magnesium, creatinine, and BUN to distinguish PTH-dependent from PTH-independent causes. 1, 2

Initial Laboratory Assessment

The diagnostic approach hinges on the iPTH level, which immediately categorizes hypercalcemia into two pathways:

Core Initial Labs

• Corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)], or preferably measure ionized calcium directly to avoid pseudo-hypercalcemia 1, 2, 3
• Intact PTH - the single most important test that determines the entire diagnostic pathway 1, 2, 3
• Albumin - essential for calcium correction 1, 2
• Phosphorus - typically low in primary hyperparathyroidism, variable in malignancy 1, 2
• Magnesium - hypomagnesemia can suppress PTH secretion 1
• Creatinine and BUN - assess renal function and guide treatment decisions 1, 2

Diagnostic Algorithm Based on PTH

If PTH is Elevated or Inappropriately Normal (>20 pg/mL)

This indicates PTH-dependent hypercalcemia, most commonly primary hyperparathyroidism 2, 3, 4:

• Additional testing: 24-hour urine calcium and creatinine to calculate calcium-to-creatinine clearance ratio 5
• Distinguish PHPT from FHH: Urinary calcium excretion <100 mg/24 hours or calcium-to-creatinine clearance ratio <0.01 suggests familial hypocalciuric hypercalcemia rather than primary hyperparathyroidism 5
• Associated findings: Hypophosphatemia, hyperchloremic metabolic acidosis, and potential kidney stones support PHPT 2, 4
• Imaging: Consider parathyroid imaging (sestamibi scan or ultrasound) if surgery is being considered 3

If PTH is Suppressed (<20 pg/mL)

This indicates PTH-independent hypercalcemia, requiring further workup 2, 3:

Second-tier labs to order:

• PTHrP (parathyroid hormone-related protein) - elevated in humoral hypercalcemia of malignancy, particularly squamous cell carcinomas and renal cell carcinoma 1, 2, 6
• 25-hydroxyvitamin D - elevated in vitamin D intoxication from excessive supplementation 1, 2, 6
• 1,25-dihydroxyvitamin D - elevated in granulomatous diseases (sarcoidosis), lymphomas, and conditions with extrarenal 1-alpha-hydroxylase activity 1, 2, 6
• Measure BOTH vitamin D metabolites together for diagnostic accuracy, as measuring only one can lead to missed diagnoses 1

Malignancy evaluation if PTH suppressed:

• Review for known malignancy history, particularly multiple myeloma, breast cancer, lung cancer, or renal cell carcinoma 1, 6
• Consider serum and urine protein electrophoresis if multiple myeloma suspected 1
• Imaging studies (chest X-ray, CT scans) as clinically indicated based on symptoms and risk factors 1

Severity Classification

Classify hypercalcemia severity to guide urgency of intervention 2, 3:

• Mild: 10-11 mg/dL (2.5-2.75 mmol/L) - usually asymptomatic, may have fatigue or constipation in 20% 2, 3
• Moderate: 11-12 mg/dL (2.75-3.0 mmol/L) - polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain 2, 3
• Severe: >14 mg/dL (>3.5 mmol/L) - mental status changes, dehydration, acute renal failure, bradycardia, hypotension, coma 2, 6, 3

Medication and Supplement History

Critical medications and supplements to review that can cause or exacerbate hypercalcemia 1, 6:

• Thiazide diuretics 3
• Lithium 3
• Calcium supplements (>500 mg/day) 1, 6
• Vitamin D supplements (>400 IU/day) 1, 6
• Vitamin A 3
• Calcitriol or vitamin D analogues (paricalcitol) - cause hypercalcemia in 22.6-43.3% of patients 6
• Calcium-based phosphate binders in CKD patients 1, 6

Treatment Approach

Immediate Management for Moderate-to-Severe Hypercalcemia

Initiate aggressive IV normal saline hydration immediately to correct hypovolemia and promote calciuresis, targeting urine output ≥100 mL/hour (or 3 mL/kg/hour in children <10 kg) 1, 2, 7:

• Administer 250-500 mL boluses of normal saline every 15 minutes until rehydration achieved 1
• Target maintenance diuresis of 100-150 mL/hour or >2.5 L/day 1, 7
• Avoid loop diuretics (furosemide) until after complete volume repletion; only use in patients with renal or cardiac insufficiency to prevent fluid overload 1, 2, 7

Definitive Pharmacologic Treatment

Administer IV zoledronic acid 4 mg infused over no less than 15 minutes as the preferred bisphosphonate after starting hydration 1, 2, 7:

• Zoledronic acid is superior to pamidronate, normalizing calcium in 50% of patients by day 4 1, 3
• Dose adjustments for renal impairment: CrCl 50-60 mL/min use 3.5 mg; CrCl 40-49 mL/min use 3.3 mg; CrCl 30-39 mL/min use 3.0 mg 7
• Do not use in severe renal impairment (CrCl <30 mL/min) 7
• Check serum creatinine before each dose and withhold if renal deterioration occurs (increase of 0.5 mg/dL if normal baseline, or 1.0 mg/dL if abnormal baseline) 7
• Retreatment may be considered after minimum 7 days if calcium does not normalize 7

Add calcitonin 100 IU subcutaneously or intramuscularly for immediate short-term management of severe symptomatic hypercalcemia while waiting for bisphosphonates to take effect 1, 3, 4:

• Provides rapid onset within hours but limited efficacy and duration (1-4 hours) 1, 3
• Use as a bridge therapy only 1

Cause-Specific Treatment

For vitamin D-mediated hypercalcemia (sarcoidosis, granulomatous diseases, lymphomas, vitamin D intoxication):

• Glucocorticoids are the primary treatment: Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent 1, 3, 8, 4
• Allow 3-6 months to demonstrate responsiveness before escalation 1
• Target lowest effective dose ≤10 mg/day to minimize toxicity 1

For refractory hypercalcemia or bisphosphonate contraindication:

• Denosumab 120 mg subcutaneously lowers calcium in 64% of patients within 10 days, particularly useful in renal impairment 1
• Higher risk of hypocalcemia compared to bisphosphonates; correct hypocalcemia before initiating and monitor closely 1

For severe hypercalcemia with renal failure:

• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for severe cases complicated by renal insufficiency or oliguria 1, 2, 4

Definitive Management Based on Etiology

Primary hyperparathyroidism:

• Parathyroidectomy is indicated for symptomatic disease, osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L (>1 mg/dL) above upper normal limit 2, 3
• Observation may be appropriate for patients >50 years with calcium <1 mg/dL above upper limit and no skeletal or kidney disease 3

Malignancy-associated hypercalcemia:

• Treat the underlying cancer when possible, as this is essential for long-term control 1, 2, 6
• Prognosis is poor with median survival approximately 1 month 1

Monitoring and Follow-up

• Monitor serum calcium, renal function (creatinine), and electrolytes (potassium, magnesium, phosphorus) every 6-12 hours during acute phase 1, 2
• Coadminister oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia 1, 7
• Watch for bisphosphonate complications: renal toxicity and osteonecrosis of the jaw with chronic use 2

Critical Pitfalls to Avoid

• Never rely on corrected calcium alone; measure ionized calcium when possible to avoid pseudo-hypercalcemia from hemolysis or improper sampling 1
• Do not use loop diuretics before volume repletion, as this worsens hypovolemia 1, 2, 7
• Avoid NSAIDs and IV contrast in patients with renal impairment to prevent further kidney deterioration 1
• Do not delay bisphosphonate therapy in moderate-to-severe hypercalcemia, as temporary measures provide only 1-4 hours of benefit 1
• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy in PTH-independent hypercalcemia 1
• Stop all calcium supplements, vitamin D supplements, and calcium-based phosphate binders immediately in patients with hypercalcemia 1, 6