What investigation is preferred to confirm biochemical primary hyperparathyroidism?

Biochemical Diagnosis of Primary Hyperparathyroidism

The preferred investigation to confirm biochemical primary hyperparathyroidism is simultaneous measurement of serum calcium and parathyroid hormone (PTH), combined with assessment of urinary calcium excretion or fractional excretion of calcium (FeCa). 1, 2

Core Diagnostic Tests

The diagnosis is fundamentally biochemical and requires three key measurements:

1. Serum Calcium and PTH (Mandatory)

• Measure both simultaneously - this is the cornerstone of diagnosis
• The typical pattern shows hypercalcemia with elevated or inappropriately normal PTH
• PTH should be "inappropriate" to the calcium level - meaning it fails to suppress despite elevated calcium 1, 2

2. Urinary Calcium Assessment (Mandatory)

You must measure urinary calcium to complete the diagnosis and exclude familial hypocalciuric hypercalcemia (FHH):

• 24-hour urinary calcium is the gold standard
• Alternatively, calculate fractional excretion of calcium (FeCa) using the formula: (urinary calcium × plasma creatinine)/(urinary creatinine × plasma calcium)
• FeCa >2% supports primary hyperparathyroidism
• FeCa ≤2% suggests FHH and requires genetic screening 1, 2

3. Additional Essential Tests

• Serum phosphorus - typically low or low-normal
• 25(OH) vitamin D - must be measured and corrected if deficient, as vitamin D deficiency can cause secondary hyperparathyroidism that mimics primary disease 1, 2
• Serum creatinine - to assess renal function

Typical Biochemical Pattern

The classic presentation combines:

• Hypercalcemia (usually <1 mg/dL above normal)
• Elevated PTH (or inappropriately normal for the calcium level)
• Increased urinary calcium or FeCa >2% 1, 2

Atypical Forms Requiring Additional Testing

When Calcium is Normal but PTH is Elevated (Normocalcemic PHPT)

Before accepting this diagnosis, you must:

1. Maintain normal vitamin D levels for >6 months and recheck
2. Rule out all causes of secondary hyperparathyroidism (renal disease, malabsorption, medications)
3. Consider oral calcium loading test - shows hypercalcemia after loading with failure of PTH suppression 1, 2

When Calcium is High but PTH is Normal

• Measure ionized calcium to confirm true hypercalcemia
• Calculate Pro-FHH score to distinguish from FHH
• Consider oral calcium loading test 1, 2

Common Pitfalls to Avoid

1. Don't diagnose normocalcemic PHPT without correcting vitamin D first - vitamin D deficiency is the most common mimic and must be excluded over at least 6 months 1

2. Don't rely on total calcium alone - measure ionized calcium in borderline cases, especially when albumin is abnormal 1

3. Don't forget urinary calcium - this is essential to exclude FHH, which requires completely different management (no surgery) 2

4. Don't accept a single elevated PTH - the diagnosis requires demonstration that PTH is inappropriate relative to the calcium level, not just elevated in isolation 1

Diagnostic Algorithm

Based on the 2025 French consensus 2:

Step 1: Measure serum calcium + PTH simultaneously

• If both elevated → proceed to Step 2
• If calcium elevated, PTH normal → measure ionized calcium, consider FHH
• If calcium normal, PTH elevated → check vitamin D, rule out secondary causes

Step 2: Measure urinary calcium (24-hour or FeCa)

• FeCa >2% → confirms primary hyperparathyroidism
• FeCa ≤2% → suspect FHH, calculate Pro-FHH score, consider genetic testing

Step 3: Measure vitamin D, phosphorus, creatinine

• Correct vitamin D deficiency before finalizing diagnosis in normocalcemic cases

Step 4: In atypical cases, consider oral calcium loading test

This algorithmic approach ensures accurate diagnosis while avoiding the most common diagnostic errors, particularly confusion with FHH and secondary hyperparathyroidism.