Hypercalcemia Workup Algorithm
Initial Laboratory Panel
The first step in evaluating hypercalcemia is to measure intact parathyroid hormone (iPTH), which is the single most important test to distinguish PTH-dependent from PTH-independent causes. 1, 2, 3
Obtain the following tests simultaneously:
- Serum calcium (total and ionized) to confirm hypercalcemia and assess severity 1, 2
- Albumin level to calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] 2
- Intact PTH (most critical test) 1, 2, 3
- Serum phosphorus (typically low in primary hyperparathyroidism, high in vitamin D toxicity) 1
- Serum creatinine and BUN to assess renal function 1, 2
- 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D 1, 2
- Magnesium level 1
Severity Classification
Classify hypercalcemia severity to guide urgency of intervention 2:
- Mild: 10-11 mg/dL (usually asymptomatic) 2, 3
- Moderate: 11-12 mg/dL (symptomatic) 2
- Severe: >14 mg/dL (life-threatening) 2, 3
Symptom Assessment
Evaluate for the following clinical manifestations 1, 2:
- Polyuria, polydipsia
- Nausea, vomiting, abdominal pain
- Confusion, altered mental status
- Dehydration
- Myalgia
- In severe cases: somnolence, coma 3
PTH-Based Diagnostic Algorithm
If PTH is Elevated or Inappropriately Normal (>20 pg/mL)
This indicates primary hyperparathyroidism. 2, 3, 4
Proceed with:
- Renal ultrasound to assess for nephrocalcinosis or nephrolithiasis 1
- Bone mineral density testing 1
- Urine calcium/creatinine ratio to exclude familial hypocalciuric hypercalcemia 1
- Review medication history for lithium (can cause PTH-mediated hypercalcemia) 2
If PTH is Suppressed (<20 pg/mL)
This indicates non-PTH mediated causes. 1, 2, 3
Proceed with additional testing based on clinical suspicion:
For Malignancy Evaluation:
- PTHrP measurement (elevated in humoral hypercalcemia of malignancy) 1, 2
- Chest X-ray and age-appropriate cancer screening 1
- Note: Hypercalcemia of malignancy carries poor prognosis with median survival approximately 1 month after discovery in lung cancer 1
For Vitamin D-Related Causes:
- 1,25-dihydroxyvitamin D level (elevated in granulomatous diseases like sarcoidosis, lymphoma) 1, 2
- 25-hydroxyvitamin D level (elevated in vitamin D intoxication) 2
For Granulomatous Disease:
- Consider chest imaging if sarcoidosis suspected 2
- Measure 1,25-dihydroxyvitamin D (will be elevated) 1, 2
Critical Medication and Supplement History
Document use of the following hypercalcemia-inducing agents 2:
- Thiazide diuretics 3, 4
- Lithium 2, 3
- Calcium supplements (>500 mg/day) 2
- Vitamin D supplements (>400 IU/day) 2
- Vitamin A 3
- Calcitriol or vitamin D analogs (paricalcitol, doxercalciferol) 5
Common Pitfalls to Avoid
- Do not rely on corrected calcium alone—measure ionized calcium when possible to avoid pseudo-hypercalcemia from hemolysis or improper sampling 2
- Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy, as they provide different information 2
- Do not delay workup in malignancy-associated hypercalcemia—this requires expedited evaluation due to poor prognosis 1
- PTH assays vary between laboratories due to lack of standardization; trend monitoring is more reliable than absolute values 2
Special Population Considerations
Chronic Kidney Disease Patients:
- Distinguish between secondary hyperparathyroidism (appropriate PTH elevation with hypocalcemia) and tertiary hyperparathyroidism (autonomous PTH secretion with hypercalcemia) 5
- Calculate corrected calcium carefully as albumin levels may be abnormal 2
- Consider dialysate calcium concentration as a contributing factor 5