Editorial: biochemical diagnosis of pheochromocytoma--is it time to switch to plasma-free metanephrines?

Current recommendations for biochemical diagnosis of pheochromocytoma remain more often based on institutional experience with certain methods than on evidence of carefully designed studies carried out to compare available tests. Experts from some centers emphasize measurements of plasma catecholamines, whereas others advocate urinary measurements. Emerging evidence now indicates that measurements of catecholamines, when carried out alone, are not sufficiently sensitive for reliable diagnosis. In particular, plasma and urinary catecholamines can be normal when testing is carried out between spells or when normotensive and asymptomatic patients with pheochromocytoma are screened for the tumor because of a hereditary predisposition or the incidental finding of an adrenal mass by imaging studies. Realization that pheochromocytomas may secrete catecholamines intermittently or in low amounts has led to recommendations that diagnosis should entail a combination of tests, and include measurements of metanephrines, the O-methylated metabolites of catecholamines (1, 2). Measurements of urinary metanephrines originally involved spectrophotometric methods where normetanephrine, the O-methylated metabolite of norepinephrine, and metanephrine, the O-methylated metabolite of epinephrine, are measured together in total as a single analyte—hence, the term “urinary total metanephrines. ” These methods have now been superseded by techniques involving liquid chromatography that allow separation of normetanephrine and metanephrine into fractionated components that can be measured individually—hence, the term “urinary fractionated metanephrines. ” Most of these latter methods also allow additional measurements of methoxytyramine, the O-methylated metabolite of dopamine. Measurements of the fractionated metabolites are superior to measurements of total metanephrines in that they allow better detection of tumors that produce predominantly or only one of the three O-methylated metabolites (3, 4). Tests involving measurements of total metanephrines are, therefore, best ignored by clinicians and abandoned by clinical laboratories in favor of modern liquid chromatographic methods. More recent developments in the biochemical diagnosis of pheochromocytoma include liquid chromatographic measurements of plasma-free metanephrines, the single largest source of which are adrenal chromaffin cells (5). In patients with pheochromocytoma the free metanephrines are produced within tumor cells from catecholamines leaking from storage vesicles continuously and independently of variations in exocytotic catecholamine release. The free metanephrines are either deaminated by monoamine oxidase or sulfate conjugated by a sulfotransferase isoenzyme located mainly in the digestive tract and important for metabolism of both dietary and locally produced monoamines. The sulfateconjugated metanephrines so produced represent the main form eliminated in the urine. Urinary metanephrines are usually measured after a deconjugation step and, therefore, represent different metabolites from the free metanephrines measured in plasma. In this issue of JCEM, Sawka et al. (6) report on the results of a study carried out at the Mayo Clinic in which the use of plasma-free metanephrines for diagnosis of pheochromocytoma was compared with that of 24-h urinary total metanephrines and catecholamines. This study follows on the heels of studies from the National Institutes of Health (NIH) (7–9), where the assay of plasma-free metanephrines was developed, and also from a group in Vienna, Austria, using a similar method (10). The importance of the present report is that it represents an independent study from a major reference laboratory, with extensive experience in urinary assays of total metanephrines and catecholamines, and where the assay of plasma-free metanephrines was established as a service offered on a commercial basis throughout the United States. The study from the Mayo Clinic confirms the high diagnostic sensitivity of plasma-free metanephrines reported independently by the two other centers (7–10). Only 1 of 33 patients with pheochromocytoma had normal levels of both normetanephrine and metanephrine, a patient with a dopamine-secreting paraganglioma. Such tumors are extremely rare, and presumably this tumor would have been picked up by the plasma test if measurements had included the O-methylated metabolite of dopamine, methoxytyramine. Inspection of the data in Fig. 2 of the Mayo Clinic report shows that compared with the 1 patient with pheochromocytoma who had normal levels of plasma-free metanephrines, there were 8 of 32 patients with normal urinary outputs of total metanephrines, indicating a sensitivity of only 75% compared with 97% for the test of plasma-free metanephrines. This is close to the sensitivity of 77% for the test of urinary total metanephrines reported in the most recent NIH study (9), supporting the view that tests of urinary total metanephrines are best abandoned in favor of newer tests involving fractionated measurements (3, 4). Further inspection of the data in Figs. 1 and 2 shows that there were 14 of 31 patients with pheochromocytoma who had normal levels of urinary norepinephrine, compared with 3 of 33 with normal plasma levels of normetanephrine. Moreover, the receiver-operating characteristic curves shown in Fig. 4 illustrate that a single measurement of plasma-free normetanephrine provides superior efficacy for diagnosis of 0013-7227/03/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 88(2):550–552 Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2002-021913