In a patient with persistent hypercalcemia for two years, what further workup is recommended to evaluate for primary hyperparathyroidism?

Workup for Persistent Hypercalcemia to Evaluate Primary Hyperparathyroidism

Measure serum intact parathyroid hormone (PTH) immediately—this single test distinguishes primary hyperparathyroidism from all other causes and directs your entire diagnostic pathway. 1, 2

Initial Laboratory Panel (Order Simultaneously)

Obtain these tests together, ideally fasting, to establish the diagnosis:

• Serum intact PTH (use EDTA plasma, not serum, for most stable measurement) 1
• Ionized calcium (definitive assessment; normal 4.65-5.28 mg/dL) alongside corrected total calcium 1
• 25-hydroxyvitamin D (must be >20 ng/mL to exclude secondary hyperparathyroidism from vitamin D deficiency) 1
• Serum creatinine and eGFR (impaired kidney function with eGFR <60 mL/min/1.73 m² is itself a surgical indication) 1
• Serum phosphorus (typically low-normal in primary hyperparathyroidism) 1
• 24-hour urine calcium or spot urine calcium/creatinine ratio (to assess for hypercalciuria and nephrolithiasis risk) 1

Critical timing note: Ensure fasting samples, as calcium supplements or dietary calcium can cause transient elevations lasting several hours and lead to unnecessary further testing 3. Prolonged venous stasis during blood draw also artificially elevates calcium 3.

Interpretation Algorithm

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

This confirms primary hyperparathyroidism when hypercalcemia is present 1, 2. The parathyroid glands autonomously secrete PTH despite elevated calcium—the hallmark of this disease 1. Even PTH in the "normal range" is inappropriate when calcium is elevated, as PTH should be suppressed below 20 pg/mL in response to hypercalcemia 2, 4.

Before finalizing the diagnosis, exclude secondary causes:

• Vitamin D deficiency: If 25-hydroxyvitamin D is <20 ng/mL, this can cause secondary hyperparathyroidism with elevated PTH but typically normal or low calcium 1. Supplement first, then recheck calcium and PTH after vitamin D normalizes 1
• Inadequate dietary calcium: Confirm intake of 1000-1200 mg/day; low intake mimics secondary hyperparathyroidism 1
• Chronic kidney disease: eGFR <60 mL/min/1.73 m² can cause secondary hyperparathyroidism, though this typically presents with normal or low calcium, not hypercalcemia 1

Important assay consideration: PTH assays vary by up to 47% between different generations; always use assay-specific reference values 1. PTH is most stable in EDTA plasma at 4°C 1.

If PTH is Suppressed (<20 pg/mL)

This excludes primary hyperparathyroidism and indicates PTH-independent hypercalcemia 1, 2. Measure:

• PTHrP (parathyroid hormone-related peptide): Elevated in humoral hypercalcemia of malignancy, which carries a median survival of approximately 1 month 1
• 1,25-dihydroxyvitamin D: Elevated in granulomatous diseases (sarcoidosis, lymphoma) despite low 25-hydroxyvitamin D 1
• 25-hydroxyvitamin D: Markedly elevated in vitamin D intoxication 1

If PTHrP is elevated, initiate urgent malignancy workup immediately with chest CT, abdominal/pelvic CT or MRI, and PET-CT if available, as the most common sources are squamous cell lung cancer, head-and-neck cancer, renal cell carcinoma, and breast cancer 1. Do not delay imaging while treating hypercalcemia 1.

Additional Baseline Studies

Once primary hyperparathyroidism is biochemically confirmed:

• Renal ultrasonography to assess for nephrocalcinosis or kidney stones 1
• Bone density scan (DEXA) to evaluate for osteoporosis (T-score ≤-2.5 at any site is a surgical indication) 1

Surgical Referral Criteria

Refer to both endocrinology and an experienced high-volume parathyroid surgeon if any of the following are present 1:

• Corrected calcium >1 mg/dL above upper limit of normal (>11.3 mg/dL if upper limit is 10.3 mg/dL) 1
• Age <50 years 1
• eGFR <60 mL/min/1.73 m² 1
• Osteoporosis (T-score ≤-2.5 at any site) 1
• History of nephrolithiasis or nephrocalcinosis 1
• 24-hour urine calcium >300 mg/24hr 1
• Patient preference for definitive treatment 1

Do not order parathyroid imaging (ultrasound or sestamibi scan) before confirming the biochemical diagnosis—imaging is for surgical planning, not diagnosis 1.

Common Pitfalls to Avoid

• Do not supplement vitamin D until hypercalcemia resolves if calcium is >10.2 mg/dL, as vitamin D increases intestinal calcium absorption and can worsen hypercalcemia 1
• Avoid calcium-based supplements or phosphate binders during the workup 1
• Recognize normocalcemic primary hyperparathyroidism: Persistently elevated PTH with consistently normal calcium (after excluding all secondary causes) still represents primary hyperparathyroidism and carries comparable risk to hypercalcemic disease 1
• Do not dismiss "normal" PTH in the setting of hypercalcemia—any detectable PTH when calcium is elevated is inappropriate and diagnostic of primary hyperparathyroidism 2, 4
• Ensure fasting samples to avoid false elevations from recent calcium intake 3

If Observation Rather Than Surgery

For patients >50 years with calcium <1 mg/dL above upper limit and no end-organ damage who decline surgery 2:

• Monitor serum calcium every 3 months 1
• Maintain 25-hydroxyvitamin D >20 ng/mL with cautious supplementation 1
• Ensure dietary calcium intake of 1000-1200 mg/day (not exceeding 2000 mg/day total) 1
• Avoid thiazide diuretics 2
• Reassess annually for development of surgical indications 1