Initial Workup for Hypercalcemia
The initial workup for hypercalcemia must include measurement of intact parathyroid hormone (iPTH) to differentiate PTH-dependent from PTH-independent causes, along with serum calcium (total and ionized), albumin, phosphorus, creatinine, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and magnesium levels. 1
First-Line Laboratory Tests
The diagnostic approach begins with a focused panel of laboratory tests:
- Serum calcium: Measure both total and ionized calcium to confirm and quantify hypercalcemia severity 1, 2
- Albumin: Required to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 2
- Intact PTH (iPTH): This is the single most important initial test, as it distinguishes PTH-dependent from PTH-independent causes 1, 3
- Serum phosphorus: Typically low in primary hyperparathyroidism and high in vitamin D toxicity 1
- Renal function: Measure serum creatinine and blood urea nitrogen to assess kidney function 1
- Vitamin D metabolites: Obtain both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels 1, 2
- Magnesium: Should be measured as part of the initial panel 1
Severity Classification and Symptom Assessment
Before proceeding with further workup, classify the severity:
- Mild: >10 to <11 mg/dL (>5.0 to <5.5 mEq/L) 2
- Moderate: 11 to 12 mg/dL (5.5 to 6.0 mEq/L) 2
- Severe: >14.0 mg/dL (>6.0 mEq/L) 2, 3
Evaluate for symptoms including polyuria, polydipsia, nausea, vomiting, confusion, abdominal pain, myalgia, dehydration, and mental status changes 1, 2. Severe hypercalcemia can cause somnolence, coma, bradycardia, and hypotension 2, 3.
PTH-Based Diagnostic Algorithm
If PTH is Elevated or Normal (PTH-Dependent)
This pattern suggests primary hyperparathyroidism, which accounts for approximately 90% of outpatient hypercalcemia cases 1, 3:
- Obtain renal ultrasound to assess for nephrocalcinosis or nephrolithiasis 1
- Perform bone mineral density testing 1
- Measure urine calcium/creatinine ratio if hypercalciuria is suspected 1
If PTH is Suppressed (<20 pg/mL) (PTH-Independent)
This pattern indicates non-PTH mediated causes and requires additional testing 1:
- Measure PTHrP (parathyroid hormone-related protein) to evaluate for humoral hypercalcemia of malignancy 1, 2
- Obtain chest X-ray and perform age-appropriate cancer screening, as malignancy accounts for most inpatient hypercalcemia cases 1, 3
- Measure 1,25-dihydroxyvitamin D if granulomatous disease (sarcoidosis) is suspected 1
Critical Considerations
Malignancy-associated hypercalcemia requires expedited evaluation, as it indicates advanced disease with poor prognosis—median survival is approximately 1 month after discovery in lung cancer patients 1. This contrasts sharply with primary hyperparathyroidism, which typically presents with mild hypercalcemia (<12 mg/dL), longer duration (>6 months), and excellent prognosis 3, 4.
Common Pitfalls to Avoid
- Hyperalbuminemia can mask true calcium status: Always calculate corrected calcium or measure ionized calcium directly 2
- Don't overlook rare causes: Consider granulomatous diseases, thyroid disorders, adrenal insufficiency, medications (thiazide diuretics, vitamin D/A supplements), and newer associations with SGLT2 inhibitors, immune checkpoint inhibitors, and denosumab discontinuation 1, 3
- Primary hyperparathyroidism presents differently than malignancy: PHPT causes kidney calculi, hyperchloremic metabolic acidosis, and osteitis fibrosa cystica without anemia, while malignancy-associated hypercalcemia causes rapid onset, higher calcium levels, marked anemia, but never kidney calculi or metabolic acidosis 4