For a patient suspected of having pheochromocytoma, which is better for diagnosis, serum (blood) free metanephrines or 24-hour urine fractionated metanephrines?

Plasma Free Metanephrines Are Superior to 24-Hour Urine Testing

Plasma free metanephrines should be your first-line test for diagnosing pheochromocytoma, as they provide the highest sensitivity (96-100%) and specificity (89-98%) compared to 24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%). 1, 2

Why Plasma Free Metanephrines Win

The American Heart Association, American College of Cardiology, and European Society of Endocrinology all recommend plasma free metanephrines as the first-line diagnostic test because they provide the highest sensitivity (99%) and negative predictive value, reliably excluding pheochromocytoma when normal 1, 2. The landmark 2002 JAMA study definitively demonstrated that plasma free metanephrines outperform all other biochemical tests, including urinary fractionated metanephrines, with superior receiver operating characteristic curves 3.

When 24-Hour Urine Testing Is Acceptable

• 24-hour urinary fractionated metanephrines remain an acceptable alternative for testing low-risk patients or pediatric patients who are not yet continent of urine 1
• Urine testing is particularly useful as a confirmatory test when plasma results are equivocal (less than fourfold elevation), as recommended by the American Society of Clinical Oncology 1, 2
• Urinary free metanephrines demonstrated 100% sensitivity in one study, though with lower specificity (94%) compared to plasma testing 4

Critical Collection Requirements for Plasma Testing

For plasma free metanephrines, ideally collect from an indwelling venous catheter after the patient has been lying supine for 30 minutes to limit false positive results 1, 2. This is especially important for:

• Initial screening in high-risk populations with hereditary syndromes 1
• Follow-up testing for marginally elevated results 1
• Any situation where you want to minimize false positives 1

However, clinicians may elect to bypass the ideal collection approach, but marginally elevated results should prompt repetition of testing under ideal conditions 1.

Interpretation Algorithm Based on Results

• If levels are ≥4 times upper limit of normal: Proceed directly to imaging to localize the lesion—this degree of elevation is consistent with pheochromocytoma regardless of collection method 1, 2, 5
• If levels are 2-4 times upper limit of normal: Repeat testing in 2 months, ideally using an indwelling catheter with proper positioning 1
• If marginally elevated (1-2 times upper limit): Repeat testing in 6 months using an indwelling catheter after 30 minutes supine rest, or consider clonidine suppression test 1

Common Pitfalls to Avoid

• False positive elevations are usually <4 times the upper limit of normal and can occur with obesity, obstructive sleep apnea, or tricyclic antidepressant use 1
• Confirm that interfering agents were avoided prior to testing, including tricyclic antidepressants, sympathomimetics, and decongestants 1, 2
• Common antihypertensive medications do not affect plasma free metanephrine measurements when using LC-MS/MS analysis, according to the American College of Cardiology 1
• Never proceed to imaging without biochemical confirmation first, as unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures 1

The Bottom Line on Test Selection

While both tests have excellent diagnostic performance, plasma free metanephrines provide superior sensitivity and are more convenient for patients (single blood draw vs. 24-hour collection) 3. The 24-hour urine test serves best as a confirmatory test when plasma results are equivocal or when plasma collection under ideal conditions is not feasible 1, 2.