VMA Level in Pheochromocytoma
VMA (vanillylmandelic acid) testing is NOT recommended as a first-line diagnostic test for pheochromocytoma due to poor sensitivity and should be replaced by plasma free metanephrines or urinary fractionated metanephrines, which have superior diagnostic accuracy. 1, 2
Current Guideline Recommendations
Plasma free metanephrines are the preferred first-line biochemical test for diagnosing pheochromocytoma, with the highest sensitivity (96-100%) and specificity (89-98%) 1, 2. The European Society of Endocrinology specifically recommends plasma-free metanephrines as first-line testing, providing 99% sensitivity and the highest negative predictive value 1.
Alternative Testing Options
- Urinary fractionated metanephrines are an acceptable alternative with high sensitivity (86-97%) and specificity (86-95%), and may be preferred for pediatric patients or those unable to undergo proper plasma collection 1, 2
- 24-hour urine catecholamines and metanephrines should be used as confirmatory testing when plasma results are equivocal (less than fourfold elevation) 3, 1, 2
Why VMA Testing is Inadequate
Poor Diagnostic Performance
Research evidence demonstrates significant limitations of VMA testing:
- Variable and poor sensitivity (28-90%) despite high specificity (85-100%) in some studies 4
- One institutional study found VMA had only 8% positive predictive value and 79% specificity, contrasting sharply with international data 5
- VMA can be normal even in confirmed pheochromocytoma cases, with documented cases showing elevated metanephrines as the only biochemical finding 6
Comparative Studies
A comparative analysis found that while urinary VMA had 100% sensitivity, it had only 31% specificity, whereas urinary total metanephrines achieved both 100% sensitivity and 100% specificity when using appropriate cutoff values 4.
Clinical Algorithm for Biochemical Testing
Initial Testing
- Measure plasma free metanephrines (preferred) OR urinary fractionated metanephrines 1, 2
- For plasma testing, collect from indwelling venous catheter after 30 minutes supine to minimize false positives 1, 2
Interpretation Based on Results
- ≥4 times upper limit of normal: Proceed immediately to imaging for tumor localization 1, 2
- 2-4 times upper limit of normal: Repeat testing in 2 months and consider genetic testing 1, 2
- 1-2 times upper limit of normal: Repeat in 6 months and consider clonidine suppression test (100% specificity, 96% sensitivity) 1, 2
Equivocal Results Management
If plasma testing shows less than fourfold elevation with strong clinical suspicion, perform 24-hour urine collection for catecholamines and metanephrines 3, 1, 2. Consider clonidine suppression testing for definitive diagnosis 1, 2.
Additional Biomarkers
Plasma methoxytyramine measurement should be obtained when available, as elevated levels indicate higher malignancy risk and help assess likelihood of metastatic disease 3, 1, 2.
Common Pitfalls to Avoid
- Never rely on VMA alone for diagnosis, as it has documented cases of false negatives in confirmed pheochromocytoma 6, 4, 5
- Ensure proper patient preparation before testing—avoid interfering medications and foods 1
- Never perform fine needle biopsy of suspected pheochromocytoma before biochemical exclusion, as this can precipitate fatal hypertensive crisis 3, 1, 2
- Do not proceed to imaging without biochemical confirmation first 1, 2
Historical Context
While VMA testing was historically used (with studies from 1980 showing utility in random 1-hour urine samples 7), modern guidelines have moved away from this test due to superior alternatives. The 2003 literature described 24-hour urine VMA as a "favored confirmatory test" 8, but current 2025 guidelines from multiple societies no longer recommend VMA as first-line or even alternative testing 1, 2.