What is the workup to confirm primary hyperparathyroidism?

Workup to Confirm Primary Hyperparathyroidism

The definitive workup to confirm primary hyperparathyroidism (PHPT) requires measurement of serum calcium and intact parathyroid hormone (iPTH) levels, with hypercalcemia in the context of normal or elevated iPTH being diagnostic of PHPT. 1

Initial Laboratory Evaluation

• Serum calcium measurement: Albumin-adjusted serum calcium is the first step in evaluation

  • Hypercalcemia is the biochemical hallmark of PHPT
  • Persistent elevation is suggestive of PHPT

• Intact parathyroid hormone (iPTH) measurement: Must be measured simultaneously with calcium

  • Normal or elevated iPTH in the setting of hypercalcemia is diagnostic of PHPT 1
  • PTH should be measured using second or third-generation assays 1

• 25-hydroxyvitamin D level: Essential to exclude vitamin D deficiency

  • Low vitamin D can cause secondary elevation of PTH
  • Should be measured in all patients with suspected PHPT 1

Additional Testing to Confirm Diagnosis

• 24-hour urinary calcium excretion: Helps differentiate PHPT from familial hypocalciuric hypercalcemia (FHH)

  • PHPT typically shows normal or elevated urinary calcium (>2.5 mmol/24 hours) 2
  • Low urinary calcium suggests FHH

• Calcium to creatinine clearance ratio (CCCR): More specific for differentiating PHPT from FHH

  • CCCR >0.02 suggests PHPT (47% sensitivity, 93% specificity) 2
  • CCCR <0.01 strongly suggests FHH

• Serum phosphate: Often low in PHPT due to PTH's phosphaturic effect

• Renal function tests: To assess for kidney damage from hypercalcemia

Imaging Studies (After Biochemical Confirmation)

Imaging is not used for diagnosis but for localization after biochemical confirmation:

• Ultrasound and/or dual-phase 99mTc-sestamibi scintigraphy with SPECT/CT:
  • Combination of these tests is highly sensitive for localizing parathyroid adenomas 1
  • Used for preoperative planning, not for diagnosis

Potential Pitfalls and Special Considerations

1. Normocalcemic PHPT:

   • Characterized by normal serum calcium with elevated PTH
   • Requires exclusion of secondary causes of hyperparathyroidism

2. Assay variations:

   • Different PTH assays may give different results
   • Use assay-specific reference ranges 1
   • PTH fragments can vary from 20-90% in PHPT patients, affecting measurements 1

3. Vitamin D deficiency:

   • Can cause secondary hyperparathyroidism
   • Always check and correct vitamin D deficiency before confirming PHPT diagnosis

4. Familial Hypocalciuric Hypercalcemia (FHH):

   • Can mimic PHPT but requires different management
   • Genetic testing for calcium-sensing receptor (CASR) mutations may be needed if CCCR is low 3

5. Medication effects:

   • Biotin supplements can interfere with PTH assays 1
   • Lithium and thiazide diuretics can cause hypercalcemia

Diagnostic Algorithm

1. Measure serum calcium (albumin-adjusted) and iPTH simultaneously
2. If calcium is elevated and iPTH is normal or elevated → suspect PHPT
3. Check 25-hydroxyvitamin D level to exclude vitamin D deficiency
4. Measure 24-hour urinary calcium and calculate CCCR
5. If CCCR >0.02 and urinary calcium >2.5 mmol/24h → confirms PHPT
6. If CCCR <0.01 → consider FHH and genetic testing
7. After biochemical confirmation, proceed with localization studies for surgical planning

Remember that the diagnosis of PHPT is primarily biochemical, not radiological. Imaging studies should only be performed after biochemical confirmation to localize abnormal parathyroid tissue for surgical planning.