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Plasma Metanephrines Are Markers of Pheochromocytoma Produced by Catechol-O-Methyltransferase Within Tumors

Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke (G.E., E.M., T.-T.H., B.H., T.E., S.D.) and Hypertension Endocrine Branch, National Heart Lung and Blood Institute (H.K.), National Institutes of Health, Bethesda, Maryland 20892-1424; Department of Clinical Physiology, University of Göteborg, Göteborg, Sweden (P.F.); and Departments of Rheumatology (A.E.) and Internal Medicine (J.W.M.L.), St. Radboud University Hospital, Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Graeme Eisenhofer, Building 10, Room 4D20, National Institutes of Health 10 Center Drive, Bethesda, Maryland 20892-1424. E-mail: ge{at}box-g.nih.gov

This study examined whether the high sensitivity of plasma free metanephrines for diagnosis of pheochromocytoma may result from production of free metanephrines within tumors. Presence in pheochromocytomas of catechol-O-methyltransferase (COMT), the enzyme responsible for conversion of catecholamines to metanephrines, was confirmed by Western blot analysis, enzyme assay, and immunohistochemistry. Western blot analysis and enzyme assay indicated that membrane-bound and not soluble COMT was the predominant form of the enzyme in pheochromocytoma. Immunohistochemistry revealed colocalization of COMT in the same chromaffin cells where catecholamines are translocated into storage vesicles by the vesicular monoamine transporter. Levels of free metanephrines in pheochromocytoma over 10,000 times higher than plasma concentrations in the same patients before removal of tumors indicated production of metanephrines within tumors. Comparisons of the production of metanephrines in patients with pheochromocytoma with production from catecholamines released or infused into the circulation indicated that more than 93% of the consistently elevated levels of circulating free metanephrines in patients with pheochromocytoma are derived from metabolism before and not after release of catecholamines into the circulation. The data indicate that the elevated plasma levels of free metanephrines in patients with pheochromocytoma are derived from catecholamines produced and metabolized within tumors. Some tumors do not secrete catecholamines, but all appear to metabolize catecholamines to free metanephrines, thus explaining the better sensitivity of plasma free metanephrines over other tests for diagnosis of pheochromocytoma.

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