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Plasma Metanephrines in the Diagnosis of Pheochromocytoma

Jacques W. M. Lenders; Harry R. Keiser; David S. Goldstein; Jacques J. Willemsen; Peter Friberg; Marie-Cecile Jacobs; Peter W. C. Kloppenborg; Theo Thien; and Graeme Eisenhofer
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From the National Institutes of Health, Bethesda, Maryland. St. Radboud University Hospital, Nijmegen, the Netherlands. The University of Goteborg, Goteborg, Sweden. Requests for Reprints: Jacques W.M. Lenders, MD, Division of General Internal Medicine, Department of Internal Medicine, St. Radboud University Hospital, Geert Grooteplein Zuid 8, 6525 GA, Nijmegen, the Netherlands. Acknowledgments: The authors thank Dr. Irwin J. Kopin for his support and critical review of the manuscript and Dr. Andre Verbeek for his assistance in the statistical analysis.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1995;123(2):101-109. doi:10.7326/0003-4819-123-2-199507150-00004
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Objective: To examine whether tests for plasma metanephrines, the o-methylated metabolites of catecholamines, offer advantages for diagnosis of a pheochromocytoma over standard tests for plasma catecholamines or urinary metanephrines.

Design: Cross-sectional study.

Setting: 3 clinical specialist centers.

Patients: 52 patients with a pheochromocytoma; 67 normotensive persons and 51 patients with essential hypertension who provided reference values; and 23 patients with secondary hypertension and 50 patients with either heart failure or angina pectoris who served as comparison groups.

Measurements: Plasma concentrations of catecholamines (norepinephrine and epinephrine) and metanephrines (normetanephrine and metanephrine) were measured in all patients. The 24-hour urinary excretion of metanephrines was measured in 46 patients with pheochromocytoma.

Results: Pheochromocytomas were associated with increases in plasma concentrations of metanephrines that were greater and more consistent than those in plasma catecholamine concentrations. No patient with a pheochromocytoma had normal plasma concentrations of both normetanephrine and metanephrine. The sensitivity of these tests was 100% (52 of 52 patients [95% CI, 94% to 100%]), and the negative predictive value of normal plasma concentrations of metanephrines was 100% (162 of 162 patients). Tests for plasma catecholamines yielded eight false-negative results and a sensitivity of 85% (44 of 52 patients [CI, 72% to 93%]). The negative predictive value of normal plasma concentrations of catecholamines was 95% (156 of 164 patients). Tests for urinary metanephrines yielded five false-negative results and a sensitivity of 89% (41 of 46 patients [CI, 76% to 96%]). Because no statistical difference was noted in the number of false-positive results between tests for plasma metanephrines (15%) and tests for plasma catecholamines (18%), the specificities of the two tests did not differ.

Conclusions: Normal plasma concentrations of metanephrines exclude the diagnosis of pheochromocytoma, whereas normal plasma concentrations of catecholamines and normal urinary excretion of metanephrines do not. Tests for plasma metanephrines are more sensi-tive than tests for plasma catecholamines or urinary metanephrines for the diagnosis of pheochromocytoma.


Grahic Jump Location
Figure 1.
The distributions for plasma concentrations of free normetanephrine (top) and metanephrine (bottom) are logarithmic transformations of the observed data.nnnnn

The upper reference limits, determined from the mean plus 2 standard deviations for the combined data from normotensive (NT) patients ( = 67) and those with essential hypertension (EHT) ( = 51) are shown by the dashed horizontal lines. CARD = patients with heart failure or angina pectoris ( = 50); PHEO = patients with pheochromocytoma ( = 52); SHT = patients with secondary hypertension ( = 23).

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Figure 2.
Relation between plasma concentrations of normetanephrine and norepinephrine (top) and between those of metanephrine and epinephrine (bottom) in individual patients with pheochromocytoma (○) and in patients without pheochromocytoma but with false-positive normetanephrine or norepinephrine test results (●).horizontal linesvertical lines

The dashed lines represent the upper reference limits for normetanephrine or metanephrine concentrations ( ) and norepinephrine or epinephrine concentrations ( ), and the gray square bounded by these lines represents the normal reference range for concentrations of metanephrines and catecholamines.

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Figure 3.
Differences among fold-increases in plasma concentrations of norepinephrine (NE), normetanephrine (NMN), and total normetanephrine (top) and differences among fold-increases in plasma epinephrine (EPI), metanephrine (MN), and total metanephrine (bottom) in patients with pheochromocytoma.P

Fold-increases were estimated from ratios of plasma concentrations of each compound in patients with pheochromocytoma to the respective median value for each compound in the reference group. Results represent mean ±SE values determined from logarithmically transformed values. * = significant difference ( < 0.05).

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Figure 4.
Receiver-operating characteristic curves (top) and the relation between pretest probability (that is, prevalence) and post-test probability (bottom).

Receiver-operating characteristic curves show the relative changes in rates of true-positive and false-positive results for the diagnosis of pheochromocytoma as a function of different upper reference limits for plasma metanephrines (○) and catecholamines (●). Curves were constructed from estimates of the true-positive (sensitivity) and false-positive (1 −specificity) rates obtained using upper reference limits determined from the mean plus 1, 1.5, 2.0, 2.5, 3.0, or 3.5 SDs. The different upper reference limits (nmol/L) for plasma catecholamines and metanephrines are tabulated below.

The relation between pretest probability (that is, prevalence) and post-test probability shows the effect of prevalence of pheochromocytoma on positive (upper curves) and negative (lower curves) predictive values for given test results of plasma metanephrines (○) and plasma catecholamines (●).

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