Metanephrines, Fractionated, Free, LC/MS/MS, Plasma

Both plasma metanephrines and plasma catecholamines have been used for the diagnosis of pheochromocytoma. If plasma metanephrines and/or catecholamines are not available, then the next best test is urinary fractionated metanephrines and/or catecholamines.

The 24-hour urine tests for metanephrines and catecholamines remain useful screening tests for pheochromocytoma, based on data from some research groups showing good diagnostic specificity of urine testing.¹ The urine specimen requires a complete 24-hour collection and an acid preservative must be added to the collection container. 

Urinary VMA is no longer used as a diagnostic test for pheochromocytoma. However, urinary VMA can be used in conjunction with urinary HVA for the diagosis of neuroblastoma.

There are considerable data showing that the plasma metanephrines test is more sensitive than urinary metanephrines and/or catecholamines, likely because even small pheochromocytomas may continually leak metanephrines even if they are not actively secreting catecholamines. Another consideration is practicality, in that a 24-hour urinary collection can be difficult for some patients. A potential disadvantage of the plasma metanephrines test is that it requires additional patient preparation (at least 20 minutes of rest prior to blood draw, preferably in a reclining or seated position with a butterfly or indwelling blood drawing catheter in place). Also, because plasma metanephrine levels are affected by acute stress, patients in whom blood drawing generates great anxiety (e.g., children) may be more likely to have mildly elevated levels from stress alone. A normal result for plasma metanephrines is strong evidence against the diagnosis except in early pre-clinical disease.

Sensitivity for plasma metanephrines is 96% to 99% and the specificity is 79% to 89%.¹

Plasma metanephrine and/or normetanephrine levels ≥4-fold over the upper limits of the reference ranges are strongly suggestive of a pheochromocytoma.² Levels between 1 and 4-fold elevated are considered borderline and are significant, but not diagnostic, and may be due to other factors such as medications (see Question 6 below) or stress.

The standard protocol to minimize stress during sample collection stipulates that the patient should be reclining for 20 minutes with an IV inserted before withdrawing the specimen from the IV. Patient should also refrain from alcohol and tobacco for 12 hours prior to testing.

24-hour urine for metanephrines should be ordered. Chromogranin A levels are elevated in most patients with pheochromocytoma; however, the test is not specific and is seen in other disorders such as carcinoid.

Drugs that may cause false-positive elevations of plasma metanephrine and/or normetanephrine include: tricyclic antidepressants, alpha-blockers, beta-blockers, monoamine oxidase inhibitors, sympathomimetics, and stimulants. It is important that patients abstain from these medications preferably for 1-2 weeks prior to sample collection.

If clinical suspicion remains high, and especially if symptoms are episodic, plasma metanephrines should be measured due to their high diagnostic sensitivity. The 24-hour urine tests are not always successful in detecting intermittently secreting tumors.