What are fractionated metanephrines?

What Are Fractionated Metanephrines?

Fractionated metanephrines are the O-methylated metabolites of catecholamines—specifically metanephrine (derived from epinephrine) and normetanephrine (derived from norepinephrine)—that serve as the most sensitive and specific biochemical markers for diagnosing pheochromocytoma and paraganglioma. 1, 2

Biochemical Origin and Clinical Significance

• Metanephrines are produced when the enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamines (epinephrine and norepinephrine) into their methylated forms 2
• The term "fractionated" refers to measuring metanephrine and normetanephrine separately (as distinct fractions), rather than as a combined total, which provides superior diagnostic information 3, 4
• These metabolites are continuously produced by catecholamine-secreting tumors, making them more reliable markers than measuring catecholamines directly, which are released episodically 1

Measurement Methods and Specimen Types

Plasma Free Metanephrines

• Plasma free metanephrines represent the gold standard screening test, with the highest sensitivity (96-100%) and specificity (89-98%) for pheochromocytoma diagnosis 1, 4
• The American College of Cardiology recommends collecting plasma samples from an indwelling venous catheter after 30 minutes of supine rest to minimize false positives 1, 5
• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the preferred analytical method due to superior accuracy and lack of interference from common antihypertensive medications 1, 2

Urinary Fractionated Metanephrines

• 24-hour urinary fractionated metanephrines provide high sensitivity (86-97%) and specificity (86-95%) as an acceptable alternative to plasma testing 1, 3
• Urinary testing may be preferred for low-risk patients or pediatric patients who are not yet continent, as it yields fewer false positives than plasma testing 1, 4
• The normetanephrine fraction has higher diagnostic sensitivity (87.3%) than the metanephrine fraction (56.9%) when measured individually 3
• Spot urinary fractionated metanephrines adjusted by creatinine can provide diagnostic accuracy similar to 24-hour collections, offering a more convenient screening option 6

Clinical Interpretation Algorithm

Levels ≥4 Times Upper Limit of Normal

• This degree of elevation is diagnostic for pheochromocytoma/paraganglioma and warrants immediate imaging to localize the tumor 1, 5
• No additional confirmatory testing is needed at this threshold 1

Levels 2-4 Times Upper Limit of Normal

• Repeat testing in 2 months and consider genetic testing for hereditary syndromes, particularly in younger patients 1, 5
• These elevations require careful follow-up but are not immediately diagnostic 1

Levels 1-2 Times Upper Limit of Normal (Marginally Elevated)

• Repeat testing in 6 months using optimal collection conditions (indwelling catheter, 30 minutes supine rest for plasma) 1, 5
• Consider clonidine suppression testing if clinical suspicion remains high, which has 100% specificity and 96% sensitivity 1
• False positive elevations in this range are common in hypertensive patients, especially with obesity, obstructive sleep apnea, or tricyclic antidepressant use 1, 7

Additional Biomarkers

• Plasma methoxytyramine (the O-methylated metabolite of dopamine) should be measured when available, as elevated levels indicate higher malignancy risk and are particularly relevant for head/neck paragangliomas 1
• Up to 30% of head/neck paragangliomas produce dopamine, indicated by increases in plasma methoxytyramine 1
• Urinary methoxytyramine is not clinically useful as it derives from renal DOPA decarboxylation rather than tumor production 1

Critical Clinical Pitfalls

• Never proceed to imaging, biopsy, or surgical intervention without biochemical confirmation first, as unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures 1, 5
• Fine needle biopsy of suspected pheochromocytoma is absolutely contraindicated and can precipitate fatal hypertensive crisis 1, 5
• Ensure proper collection technique, as improper positioning or stress during blood draw commonly causes false elevations 5, 7
• Common antihypertensive medications do not interfere with LC-MS/MS measurements, but tricyclic antidepressants and certain other medications can cause false positives 1, 7