Context: The initial diagnosis of pheochromocytoma relies on plasma fractionated metanephrines levels. Normal levels exclude pheochromocytoma, but positive tests have a low positive predictive value, due to the disease's rarity.

Objectives: To evaluate three approaches to distinguish between true positive and false positive tests: (i) increased cutoff for plasma fractionated metanephrines, (ii) measurement of serum/plasma chromogranin A (CGA), and (iii) urine fractionated metanephrine testing

Design: We studied retrospectively all Mayo Clinic patients with positive plasma fractionated metanephrine tests over a 15 month period and determined their final diagnosis based on histology, imaging, additional biochemical tests, and more than 1 year follow-up. For a subgroup, urine fractionated metanephrine results were available. All original plasma samples were re-tested for CGA.

Results: Of 140 patients, 40 had a chromaffin tumor confirmed and 100 excluded, indicating a positive predictive value of plasma fractionated metanephrines of 28.6%. Increasing the threshold for a positive test improved specificity to 98%, but missed 8 cases (20%). Incorporation of urine fractionated metanephrine testing as follow-up test achieved 80% specificity and 91% sensitivity. The corresponding figures for CGA were 71% and 87% for all patients, and 89% and 87% when patients taking proton pump inhibitors were excluded.

Conclusions: Unless plasma fractionated metanephrines levels are elevated more than 4-fold above the upper limit of normal, patients with a positive plasma fractionated metanephrines test should be evaluated with urine fractionated metanephrines and serum/plasma CGA assays before being subjected to imaging or invasive diagnostic tests.