Follow-Up Laboratory Testing for Hypercalcemia
For any patient with confirmed hypercalcemia, immediately measure serum intact parathyroid hormone (PTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, serum phosphorus, serum creatinine with eGFR, and albumin to calculate corrected calcium. 1 This initial panel distinguishes PTH-dependent from PTH-independent causes and guides all subsequent management decisions.
Initial Diagnostic Laboratory Panel
The cornerstone of hypercalcemia evaluation is the PTH level, which divides causes into two pathways 2, 3:
- Measure intact PTH simultaneously with calcium to determine if hypercalcemia is PTH-dependent (elevated or inappropriately normal PTH) or PTH-independent (suppressed PTH <20 pg/mL) 1, 2
- Obtain 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels together before any vitamin D supplementation, as their relationship provides critical diagnostic information 4, 1
- Check serum phosphorus, which is typically low-normal in primary hyperparathyroidism 1
- Measure serum creatinine and calculate eGFR to assess kidney function, as hypercalcemia can cause acute kidney injury 1
- Verify corrected calcium using albumin levels, or preferably measure ionized calcium (normal 4.65-5.28 mg/dL) for definitive assessment 1, 2
Critical PTH Measurement Considerations
Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C. 1 PTH assays vary significantly between laboratories—measurements can differ up to 47% between different assay generations—so always use assay-specific reference values 4, 1. The biological variation of PTH is substantial (20% in healthy individuals), meaning differences must exceed 54% to be clinically significant 1.
PTH-Dependent Hypercalcemia (Elevated or Normal PTH)
When PTH is elevated or inappropriately normal with hypercalcemia, primary hyperparathyroidism is the likely diagnosis 1, 2:
Additional Testing Required
- Measure 24-hour urine calcium or spot urine calcium/creatinine ratio to evaluate urinary calcium excretion and distinguish from familial hypocalciuric hypercalcemia 1
- Obtain renal ultrasonography to assess for nephrocalcinosis or kidney stones 1
- Order bone density scan (DEXA) if chronic hyperparathyroidism is suspected to evaluate for osteoporosis 1
- Ensure 25-hydroxyvitamin D level is >20 ng/mL to exclude vitamin D deficiency as a secondary cause of elevated PTH 1
Exclude Secondary Hyperparathyroidism
Vitamin D deficiency causes secondary hyperparathyroidism and must be excluded before diagnosing primary hyperparathyroidism. 1 PTH reference values are 20% lower in vitamin D-replete individuals compared to those with unknown vitamin D status 1. Secondary hyperparathyroidism presents with hypocalcemia or normal calcium, not hypercalcemia 1.
PTH-Independent Hypercalcemia (Suppressed PTH)
When PTH is suppressed (<20 pg/mL), measure additional markers to identify the cause 1, 2:
- PTHrP (parathyroid hormone-related peptide) if malignancy is suspected—elevated in humoral hypercalcemia of malignancy 1
- Both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to distinguish vitamin D intoxication from granulomatous disease 4, 1
Monitoring Frequency Based on Severity
Mild Hypercalcemia (10.2-12 mg/dL)
- Measure serum calcium every 3 months for patients with eGFR >30 mL/min/1.73 m² who are not surgical candidates 1
- Reassess renal function regularly (creatinine, eGFR) as hypercalcemia can worsen chronic kidney disease 1
Moderate to Severe Hypercalcemia (>12 mg/dL)
- Monitor serum calcium, phosphorus, and electrolytes closely during acute treatment 4, 2
- Check serum creatinine before each dose of bisphosphonates if treatment is initiated 5
During Vitamin D Supplementation
If vitamin D supplementation is initiated after calcium normalizes, monitor serum calcium and phosphorus at least every 3 months, and discontinue vitamin D immediately if calcium exceeds 10.2 mg/dL. 1 Do not supplement with vitamin D until hypercalcemia is resolved 1.
Special Populations
Chronic Kidney Disease (CKD Stage G3b or Higher)
- Measure calcium, phosphorus, and PTH as part of the evaluation for secondary or tertiary hyperparathyroidism 1
- Reduce or discontinue calcium-based phosphate binders if corrected calcium exceeds 10.2 mg/dL 1
- Avoid calcitriol or vitamin D analogues in CKD G3a-G5 not on dialysis, reserving them only for severe and progressive hyperparathyroidism in CKD G4-G5 1
Sarcoidosis or Granulomatous Disease
For patients with sarcoidosis who do not have symptoms or signs of hypercalcemia, obtain baseline serum calcium testing to screen for abnormal calcium metabolism. 4 If assessment of vitamin D metabolism is necessary, measure both 25- and 1,25-OH vitamin D levels before vitamin D replacement 4.
Common Pitfalls to Avoid
- Do not order parathyroid imaging before confirming biochemical diagnosis—imaging is for surgical planning, not diagnosis 1
- Do not use total calcium alone when albumin is abnormal—always calculate corrected calcium or measure ionized calcium 1, 2
- Do not assume normal PTH excludes primary hyperparathyroidism—inappropriately normal PTH in the setting of hypercalcemia is diagnostic 1
- Do not delay treatment waiting for laboratory confirmation if clinical suspicion for severe hypercalcemia is high based on symptoms 2
- Do not supplement vitamin D in patients with active hypercalcemia—this can worsen hypercalcemia by increasing intestinal calcium absorption 1
When to Refer
Refer to endocrinology and an experienced parathyroid surgeon for surgical evaluation if primary hyperparathyroidism is confirmed and the patient meets any of these criteria 1:
- Corrected calcium >1 mg/dL above upper limit of normal
- Age <50 years
- eGFR <60 mL/min/1.73 m²
- Osteoporosis (T-score ≤-2.5 at any site)
- History of nephrolithiasis or nephrocalcinosis
- 24-hour urine calcium >300 mg/24hr