Initial Workup for Hypercalcemia
Measure serum intact parathyroid hormone (PTH) immediately alongside a repeat calcium level (corrected for albumin) to distinguish PTH-dependent from PTH-independent causes—this single test directs all subsequent evaluation. 1, 2
Essential First-Line Laboratory Tests
The initial workup must include:
- Serum intact PTH (use EDTA plasma for most stable results) 1, 3
- Corrected total calcium (or ionized calcium if albumin is abnormal) 1, 2
- Serum phosphate (typically low in hyperparathyroidism, variable in malignancy) 3
- Comprehensive metabolic panel including creatinine, BUN, and liver function tests 1
- Serum albumin to properly correct calcium levels 1
PTH-Based Diagnostic Algorithm
If PTH is Elevated or Inappropriately Normal (PTH-Dependent)
This pattern indicates primary hyperparathyroidism in >90% of cases 1, 2:
- Measure 25-hydroxyvitamin D to exclude vitamin D deficiency as a cause of secondary hyperparathyroidism (must be ruled out before confirming primary hyperparathyroidism) 1, 3
- 24-hour urine calcium or spot urine calcium/creatinine ratio to assess hypercalciuria and exclude familial hypocalciuric hypercalcemia 1, 3
- Renal ultrasound to evaluate for nephrocalcinosis or kidney stones 1
- Bone density scan if chronic hyperparathyroidism is suspected 1
Critical pitfall: Do NOT order parathyroid imaging (ultrasound or sestamibi scan) until biochemical diagnosis is confirmed—imaging is for surgical planning only, not diagnosis 1
If PTH is Suppressed (<20 pg/mL, PTH-Independent)
This pattern suggests malignancy or other non-PTH causes 2, 4:
- PTH-related peptide (PTHrP) if malignancy suspected (elevated in humoral hypercalcemia of malignancy) 1
- 1,25-dihydroxyvitamin D (elevated in granulomatous disease, lymphoma, or CYP24A1 mutations) 1, 5
- 25-hydroxyvitamin D (markedly elevated >150 ng/mL suggests vitamin D intoxication) 1, 5
- Chest imaging if not already done, to evaluate for malignancy or sarcoidosis 1
- Serum and urine protein electrophoresis if multiple myeloma suspected 4
Key diagnostic relationships: In PTH-independent hypercalcemia, the suppressed PTH leads to decreased 1,25-dihydroxyvitamin D production (except in granulomatous disease or lymphoma where ectopic CYP27B1 produces excess 1,25-dihydroxyvitamin D despite low PTH) 1, 5
Additional Considerations
- Medication review: Discontinue thiazide diuretics, calcium supplements, vitamin D supplements, and lithium if present 1, 2
- Assess severity: Mild hypercalcemia (<12 mg/dL) is often asymptomatic; severe hypercalcemia (≥14 mg/dL) requires urgent treatment 2
- Monitor frequency: Check calcium and PTH every 3 months initially if observation is chosen 1
Common Pitfalls to Avoid
- PTH assay variability: Different assays can vary by up to 47%; use assay-specific reference ranges and the same assay for serial measurements 1, 3
- Biotin interference: Stop biotin supplements 72 hours before PTH testing as they can falsely elevate or decrease results 3
- Timing matters: PTH has 20% biological variation in healthy individuals; differences must exceed 54% to be clinically significant 1
- Race and age factors: PTH is 20% higher in Black individuals and increases with age—interpret accordingly 3
When to Refer
Refer to endocrinology and an experienced parathyroid surgeon if primary hyperparathyroidism is confirmed and patient meets surgical criteria (age <50, calcium >1 mg/dL above upper limit, GFR <60 mL/min/1.73 m², nephrolithiasis, or osteoporosis) 1