What is the preferred method for testing metanephrines (metanephrine), blood or urine, for diagnosing pheochromocytoma and paraganglioma?

Plasma Free Metanephrines vs. Urine Metanephrines for Diagnosing Pheochromocytoma and Paraganglioma

Plasma free metanephrines are the preferred first-line test for diagnosing pheochromocytoma and paraganglioma due to their superior sensitivity (96-100%) compared to urinary fractionated metanephrines (86-97%). 1

Diagnostic Performance Comparison

Plasma Free Metanephrines

• Highest sensitivity (96-100%) and specificity (89-98%) for diagnosing pheochromocytoma and paraganglioma 1
• Recommended as the most sensitive and specific single test by multiple clinical guidelines 2
• Provides the lowest risk of missing a diagnosis, which is critical given the potentially lethal nature of these tumors 3
• Particularly valuable for testing high-risk patients with familial endocrine syndromes 4
• Can help predict tumor size, location (adrenal vs. extra-adrenal), presence of metastases, and underlying genetic mutations 3

Urine Fractionated Metanephrines

• High but slightly lower sensitivity (86-97%) and specificity (86-95%) 1
• Considered an acceptable alternative to plasma testing 5
• May have fewer false-positive results, making it potentially preferable for testing low-risk patients 4
• More practical option for pediatric patients who are not yet continent of urine 5
• May be preferred in centers without specialized collection protocols for plasma metanephrines 3

Collection and Testing Considerations

For Plasma Testing

• To limit false positive results, plasma free metanephrines should ideally be collected:
  • From an indwelling venous catheter 5
  • After patient has been lying supine for 30 minutes 5, 3
  • After an overnight fast 3
• LC-MS/MS is the preferred analytical method, especially when measurements include methoxytyramine 3
• Serum samples may be a suitable alternative to plasma with comparable results and better stability 6

For Urine Testing

• 24-hour urine collection is required 7
• More practical for mainstream use when proper plasma collection protocols cannot be implemented 3
• Particularly useful for pediatric patients once they are continent of urine 5

Interpretation of Results

Plasma Metanephrines

• Results >4× upper limit of normal: consistent with disease, proceed with imaging 5, 1
• Results 2-4× upper limit of normal: repeat testing in 2 months 5, 1
• Marginally elevated results: repeat testing in 6 months or consider clonidine suppression test 5, 1

Potential False Positives

• Several medications and foods can interfere with metanephrine analysis 5, 1
• False positive elevations are usually <4 times the upper limit of normal 1
• Common causes of false positives include obesity, obstructive sleep apnea, and tricyclic antidepressants 1

Special Considerations

• If plasma testing is equivocal (less than fourfold elevation), follow-up with 24-hour urine collection for fractionated metanephrines 8, 2
• For patients with confirmed pheochromocytoma, long-term follow-up should include annual surveillance with plasma metanephrines 8
• In pediatric patients with suspected hereditary syndromes, surveillance should begin at age 2 years for von Hippel-Lindau syndrome 5, 1
• Fine needle biopsy of suspected pheochromocytoma is contraindicated due to risk of hypertensive crisis 8

Clinical Algorithm for Testing

1. First-line test: Plasma free metanephrines (when proper collection protocols can be implemented) 1, 2
2. Alternative first-line test: 24-hour urinary fractionated metanephrines (when proper plasma collection is not feasible or for pediatric patients) 5, 3
3. For equivocal plasma results: Follow up with 24-hour urine collection 8, 2
4. For borderline elevations: Consider clonidine suppression test (100% specificity, 96% sensitivity) 1
5. After positive biochemical testing: Proceed to imaging (CT or MRI) for tumor localization 8, 2