Diagnostic accuracy of free and total metanephrines in plasma and fractionated metanephrines in urine of patients with pheochromocytoma

Abstract

Background: Plasma free and urinary metanephrines are recognized biomarkers for the assessment of pheochromocytoma. Plasma total metanephrines with a long half-life may represent another useful biomarker. Objective: The aim of this study is to evaluate the diagnostic performances of plasma total metanephrines alone or combined with free metanephrines and fractionated 24-h urinary metanephrines. Methods: A retrospective, case-control diagnostic test study was conducted between 1999 and 2007 in two university hospitals in Switzerland and two institutions in France. The patients included 46 cases with histologically proven pheochromocytoma, and 181 controls suspected of tumor with negative investigations and 3-year follow-up. None had renal dysfunction. Sensitivity and specificity were compared after expressing each measurement result as a ratio over its upper reference limit, adding the ratios of normetanephrine and metanephrine, and defining cut-off values of 1 or 2 for this sum. Results: Applying a cut-off value of 1, plasma free and total metanephrines and urinary fractionated metanephrines had similar sensitivities of 96% (95% confidence interval, 86-99%), 95% (85-99%), and 95% (84-99%) along with similar specificities of 89% (83-94%), 91% (84-95%), and 86% (80-91%). A cut-off of 2 for the sum of ratios over reference limit improves the specificity, and it can be used for a confirmation test based on another biomarker taken among the three biomarkers. Conclusion: All three metanephrine-based tests perform equivalently for diagnosing pheochromocytoma in the absence of renal insufficiency, and can be conveniently associated two by two for confirming/excluding tumor.

Plasma free metanephrines in the diagnosis of pheochromocytoma: diagnostic accuracy and strategies for Japanese patients

“…chromocytoma, in addition to the use of clinical examinations, it is necessary to assess the secretory capacity of the tumor, including measuring catecholamine secretion based on the levels of direct secretory products of the adrenomedullary-sympathetic system in the plasma, urine or both. As this step is fraught with difficulties, measuring the levels of plasma free metanephrines (PFMs; fractionated measurement of both plasma free metanephrine and normetanephrine) is currently recognized to be the best biomarker for diagnosing pheochromocytoma in the United States and Europe especially due to its high sensitivity and fast and simple sample preparation [1][2][3][4][5][6][7]. However, these tests have not yet been evaluated in Japan due to the small amount of patients in each facility.…”

“…Currently, the available tests for a relatively accurate diagnosis in Japan include a combination of different tests: measurements of 24-hour urinary catecholamines, metanephrines and VMA in addition to measurement of the plasma concentrations of catecholamines. On the other hand, many previous studies, conducted outside of Japan, have reported the high performance and utility of measuring the levels of PFMs for the diagnosis of pheochromocytoma as an alternative to the standard methods [1][2][3][4][5][6].…”

Synthetic calibrators for the analysis of total metanephrines in urine: Revisiting the conditions of hydrolysis

“…Reactions were monitored by thin-layer chromatography (Merck silica gel 60F 254 plates). Detection was by UV light, or using KMnO 4 H assignments were confirmed by 2D-COSY spectra. Multiplicity reflects apparent patterns.…”

“…Forty microliters of eluate was injected into an isocratic HPLC model equipped with a dual piston pump and an autoinjector (model 542) coupled to a 5600A electrochemical Coularray system (ESA-Dionex, Sunnyvale, CA USA). The oven temperature for the column gasket was set to 30 °C and flow rate adjusted to 1 ml min − 1 .Thedetection was done with one cell module containing four electrochemical detector cells with cell potentials maintained at 240, 320, 340 and 360 mV, beginning with the first serially aligned sensor [4]. The inter-assay quality control was assessed by C1 value determination from RECIPE; coefficient of variation was 2.0% for normetanephrine (1400 nmol/l), 4.0% for metanephrine (715 nmol/l) and 4.0% for methoxytyramine (900 nmol/l).…”

“…The diagnosis of this rare disease relies on measures of the concentration of free metanephrines in plasma and total metanephrines in urine and plasma [4]. Sulfated metanephrines predominate over the unconjugated forms in human urine [5], 87± 1%, 56±6% and 66±4% of NMN, MN and MT, respectively, being recovered as sulfoconjugates [6].…”