What is the appropriate diagnostic workup for suspected hyperparathyroidism?

Diagnostic Workup for Suspected Hyperparathyroidism

The diagnosis of primary hyperparathyroidism requires simultaneous measurement of serum calcium (corrected for albumin) and intact parathyroid hormone (PTH), with the hallmark finding being hypercalcemia or high-normal calcium alongside elevated or inappropriately normal PTH levels. 1, 2

Essential Initial Laboratory Panel

Obtain the following tests simultaneously in the fasting state:

• Serum calcium (total, corrected for albumin) – The cornerstone diagnostic test; hypercalcemia threshold is >10.2 mg/dL (normal range 8.6-10.3 mg/dL) 1
• Intact parathyroid hormone (PTH) – Must be measured at the same time as calcium; elevated or inappropriately normal PTH (failing to suppress) in the setting of hypercalcemia confirms primary hyperparathyroidism 1, 2, 3
• Ionized calcium – More sensitive than total calcium and may detect disease when total calcium is borderline; normal range is 4.65-5.28 mg/dL 1, 4
• 25-hydroxyvitamin D – Critical to exclude vitamin D deficiency as a cause of secondary hyperparathyroidism; levels should be >20 ng/mL (>50 nmol/L) before diagnosing primary hyperparathyroidism 1, 2
• Serum phosphorus – Typically low or low-normal in primary hyperparathyroidism 1, 2
• Serum creatinine and eGFR – Essential to assess kidney function and rule out chronic kidney disease-related secondary hyperparathyroidism; eGFR should be ≥60 mL/min/1.73 m² for primary hyperparathyroidism diagnosis 1, 2

Critical Technical Considerations for PTH Measurement

Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma stored at 4°C. 1, 2 PTH assays vary dramatically between laboratories—differences of up to 47% have been reported between different assay generations—so always use assay-specific reference ranges when interpreting results. 1, 2 Biotin supplements can interfere with PTH assays and should be discontinued at least 72 hours before testing. 2

Exclude Secondary Causes Before Confirming Primary Hyperparathyroidism

You must systematically rule out secondary hyperparathyroidism:

• Vitamin D deficiency – The most common cause of elevated PTH; ensure 25-hydroxyvitamin D is >20 ng/mL 1, 2
• Inadequate dietary calcium intake – Confirm the patient consumes 1,000-1,200 mg of elemental calcium daily 1, 2
• Chronic kidney disease – Verify eGFR ≥60 mL/min/1.73 m² 1, 2
• Medications – Review for thiazide diuretics, lithium, or excessive vitamin D supplementation 1, 3

PTH reference values are 20% lower in vitamin D-replete individuals compared to those with unknown vitamin D status, making vitamin D assessment mandatory before interpreting PTH levels. 1

Confirmatory and Complication Assessment Tests

Once biochemical diagnosis is established, obtain:

• 24-hour urine calcium (or spot urine calcium/creatinine ratio) – Most primary hyperparathyroidism patients demonstrate hypercalciuria (>250-300 mg/day); levels >400 mg/day indicate increased risk for kidney stones and bone complications and constitute a surgical indication 1, 2, 5
• 1,25-dihydroxyvitamin D – Typically elevated in primary hyperparathyroidism due to PTH-stimulated conversion; helps differentiate from other causes of hypercalcemia 1, 3
• Serum chloride – May be elevated in primary hyperparathyroidism 2, 3
• Bone density scan (DEXA) – Assess for osteoporosis (T-score ≤-2.5), which is a surgical indication 1, 2
• Renal ultrasound – Evaluate for nephrolithiasis or nephrocalcinosis 1, 2

Diagnostic Algorithm Based on PTH and Calcium Levels

Elevated or Inappropriately Normal PTH with Hypercalcemia

This confirms primary hyperparathyroidism after excluding secondary causes. 1, 2, 3 However, if the 24-hour urine calcium/creatinine clearance ratio is <0.01, consider familial hypocalciuric hypercalcemia instead. 3, 6

Elevated PTH with Normal or Low Calcium

This suggests secondary hyperparathyroidism from vitamin D deficiency, chronic kidney disease, or inadequate calcium intake. 2, 5, 6

Suppressed PTH (<20 pg/mL) with Hypercalcemia

This indicates PTH-independent hypercalcemia; immediately measure PTHrP to evaluate for malignancy-associated hypercalcemia (median survival approximately 1 month if positive). 1 Also measure both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to distinguish vitamin D intoxication (markedly elevated 25-OH vitamin D) from granulomatous disease such as sarcoidosis (low 25-OH vitamin D but elevated 1,25-dihydroxyvitamin D). 1

Normocalcemic Primary Hyperparathyroidism

Persistently elevated PTH with consistently normal albumin-corrected serum calcium defines normocalcemic primary hyperparathyroidism, but only after rigorous exclusion of all secondary causes. 1, 2 This requires:

• 25-hydroxyvitamin D >20 ng/mL 1
• Adequate dietary calcium intake (1,000-1,200 mg/day) 1
• eGFR ≥60 mL/min/1.73 m² 1

Normocalcemic primary hyperparathyroidism is not benign and carries a risk profile comparable to hypercalcemic disease. 1

Common Pitfalls to Avoid

• Never order parathyroid imaging (ultrasound or sestamibi scan) before confirming the biochemical diagnosis—imaging is for surgical planning only, not diagnosis 1
• Do not interpret PTH levels without simultaneously assessing vitamin D status—vitamin D deficiency is the most frequent cause of secondary hyperparathyroidism and will lead to misdiagnosis 1, 2
• Avoid using total calcium alone when albumin is abnormal—always calculate corrected calcium or measure ionized calcium directly 1, 4
• Do not assume a single elevated PTH confirms primary hyperparathyroidism—biological variation of PTH is substantial (20% in healthy individuals), so differences must exceed 54% to be clinically significant; confirm with repeat testing 1
• Recognize that PTH increases with age, BMI, and varies by race—higher levels are found in Black individuals and those with elevated BMI 1, 2

When to Refer to Endocrinology and Surgery

All patients with confirmed primary hyperparathyroidism should be referred to both an endocrinologist for medical management and a high-volume parathyroid surgeon for surgical evaluation. 1 Surgical indications include:

• Corrected calcium >1 mg/dL above upper limit of normal 1, 2
• Age <50 years 1, 5
• eGFR <60 mL/min/1.73 m² 1, 5
• Osteoporosis (T-score ≤-2.5 at any site) 1, 5
• History of nephrolithiasis or nephrocalcinosis 1, 5
• 24-hour urine calcium >400 mg/day 1, 5
• Symptomatic disease 1, 2
• Patient preference for definitive treatment 1