What is the appropriate workup for a patient with hypercalcemia and an elevated parathyroid hormone level?

Parathyroid Workup for Hypercalcemia with Elevated PTH

In a patient with hypercalcemia and elevated PTH, immediately confirm the diagnosis of primary hyperparathyroidism by measuring serum calcium, intact PTH, 25-hydroxyvitamin D, serum phosphate, serum creatinine with eGFR, and 24-hour urine calcium—then refer to endocrinology and an experienced parathyroid surgeon for evaluation. 1

Immediate Diagnostic Laboratory Panel

The biochemical confirmation requires simultaneous measurement of specific markers to distinguish primary hyperparathyroidism from secondary causes:

• Repeat serum calcium (corrected for albumin) to confirm persistent hypercalcemia, as the diagnosis requires demonstration of sustained elevation, not a single value 1
• Intact PTH (iPTH) measured in EDTA plasma rather than serum, as PTH is most stable in EDTA plasma at 4°C 1, 2
• 25-hydroxyvitamin D level to exclude vitamin D deficiency, which is the most common cause of secondary hyperparathyroidism and can complicate PTH interpretation 1, 2
• Serum phosphate, which is typically low or low-normal in primary hyperparathyroidism 1, 2
• Serum creatinine and eGFR to assess kidney function and surgical candidacy 1
• 24-hour urine calcium or spot urine calcium-to-creatinine ratio to exclude familial hypocalciuric hypercalcemia (FHH), which presents with a ratio <0.01 2, 3

Understanding the Biochemical Pattern

The key diagnostic feature is that PTH fails to suppress appropriately:

• In normal physiology, elevated calcium should suppress PTH to very low levels (<20 pg/mL) 1
• In primary hyperparathyroidism, the parathyroid glands autonomously secrete PTH despite hypercalcemia, resulting in elevated or "inappropriately normal" PTH levels (typically >65 pg/mL when calcium is elevated) 1, 3
• A PTH level of 90 pg/mL in the context of hypercalcemia confirms autonomous parathyroid function and establishes the diagnosis 1

Critical Measurement Considerations

• PTH assays differ markedly between generations—variations of up to 47% have been reported—so always use assay-specific reference values 1, 2
• Biological variation of PTH is substantial (20% in healthy individuals), so differences must exceed 54% to be clinically significant 2
• Several biological factors including race, age, BMI, and vitamin D status can influence PTH concentration 2

Exclude Secondary Causes Before Confirming Primary Hyperparathyroidism

Vitamin D Status

• Measure 25-hydroxyvitamin D and aim for levels >20 ng/mL (>50 nmol/L) before confirming the diagnosis, as vitamin D deficiency is the most frequent cause of secondary hyperparathyroidism 1, 2
• Vitamin D deficiency causes secondary hyperparathyroidism and must be excluded before diagnosing primary hyperparathyroidism 2
• PTH reference values are 20% lower in vitamin D-replete individuals compared to those with unknown vitamin D status 2

Rule Out Familial Hypocalciuric Hypercalcemia

• Calculate the calcium-to-creatinine clearance ratio from 24-hour urine collection 2, 3
• A ratio <0.01 suggests FHH rather than primary hyperparathyroidism, even with elevated PTH 2, 3
• In the absence of thiazide intake or severe vitamin D deficiency, a low urinary calcium-to-creatinine ratio should redirect diagnosis toward benign familial hypercalcemic hypocalciuria 3

Medication Review

• Discontinue thiazide diuretics if currently prescribed, as they can cause hypercalcemia 1
• Discontinue all vitamin D supplements until hypercalcemia resolves, as they increase intestinal calcium absorption and can exacerbate hypercalcemia 1, 2
• Review for lithium use, which can cause hypercalcemia 3

Assess Surgical Indications

Once primary hyperparathyroidism is confirmed, evaluate for criteria that mandate surgical referral:

Absolute Surgical Indications

• Calcium >1 mg/dL above the upper limit of normal (e.g., calcium 11.2 mg/dL when upper limit is 10.3 mg/dL) 1
• Age <50 years 1
• eGFR <60 mL/min/1.73 m² 1, 2
• Osteoporosis on DEXA scan (T-score ≤-2.5 at any site) 1
• History of kidney stones or nephrocalcinosis 1
• 24-hour urine calcium >300 mg 1

Additional Considerations

• Even asymptomatic patients meeting any of the above criteria should be referred for surgical evaluation 1
• Neurocognitive symptoms (depression, emotional lability, impaired cognition, "brain fog," memory loss) are recognized target-organ manifestations that justify surgical intervention 2

Pre-Operative Localization Imaging

Do not order parathyroid imaging before confirming the biochemical diagnosis—imaging is for surgical planning, not diagnosis. 2

Once surgery is planned:

• Neck ultrasound is the initial localization study 1
• Dual-phase 99mTc-sestamibi scintigraphy with SPECT/CT is recommended as second-line imaging 1
• Combination of ultrasound plus sestamibi offers the highest sensitivity for localization 1

Immediate Medical Management Pending Surgery

While awaiting surgical evaluation:

• Ensure adequate hydration to prevent worsening hypercalcemia 1
• Maintain normal calcium intake (1000-1200 mg/day) and avoid both high and low calcium diets 1
• Total elemental calcium intake should not exceed 2000 mg/day 1
• Monitor serum calcium and ionized calcium every 1-2 weeks until stable 1
• Check PTH levels every 3 months 1
• Monitor serum creatinine to assess kidney function 1

Referral Pathway

• Refer to endocrinology for confirmation of diagnosis, exclusion of secondary causes, and determination of surgical candidacy 2
• Refer to an experienced, high-volume parathyroid surgeon for all patients meeting surgical criteria, as outcomes are significantly better with specialized expertise 2

Common Pitfalls to Avoid

• Never order parathyroid imaging before biochemical confirmation, as imaging cannot diagnose primary hyperparathyroidism 2
• Do not assume normal PTH excludes primary hyperparathyroidism—"inappropriately normal" PTH (failure to suppress below 20 pg/mL) in the setting of hypercalcemia confirms the diagnosis 1, 3
• Do not supplement with vitamin D until hypercalcemia resolves, as this will worsen calcium levels 1, 2
• Do not use calcitriol or active vitamin D analogs in primary hyperparathyroidism, as they increase intestinal calcium absorption and exacerbate hypercalcemia 2
• Always measure 25-hydroxyvitamin D before confirming primary hyperparathyroidism, as vitamin D deficiency can mimic or coexist with the condition 1, 2