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Ravinder J. Singh - One of the best experts on this subject based on the ideXlab platform.
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Plasma Chromogranin A or Urine Fractionated Metanephrines Follow-Up Testing Improves the Diagnostic Accuracy of Plasma Fractionated Metanephrines for Pheochromocytoma
The Journal of clinical endocrinology and metabolism, 2007Co-Authors: Alicia Algeciras-schimnich, Ravinder J. Singh, William F. Young, Carol M. Preissner, Stefan K.g. GrebeAbstract: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: The objective of the study was to evaluate three approaches to distinguish between true-positive and false-positive tests: 1) increased cutoff for plasma fractionated Metanephrines, 2) measurement of serum/plasma chromogranin A (CGA), and 3) 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 yr follow-up. For a subgroup, urine fractionated Metanephrine results were available. All original plasma samples were retested 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 eight 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.
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The diagnostic efficacy of urinary fractionated Metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma.
Clinical endocrinology, 2007Co-Authors: Colin Perry, Anna M. Sawka, Ravinder J. Singh, Lehana Thabane, J. Bajnarek, William F. YoungAbstract:Background There are limitations to currently available biochemical tests for pheochromocytoma. Our objective was to evaluate the diagnostic efficacy of a novel tandem mass spectrometry assay for the measurement of fractionated urinary Metanephrines in patients suspected to have a pheochromocytoma. We also developed clinically based cut-offs for positivity of this measurement. Methods We examined the medical records of 506 patients (including 102 patients with a catecholamine-producing tumour) who underwent measurement of 24-h urinary fractionated Metanephrines using tandem mass spectrometry as well as adrenal imaging at Mayo Clinic, Rochester. The cut-offs for positivity were defined as follows: total Metanephrines (sum of the Metanephrine fractions) 5163 nmol/day, norMetanephrine fraction 4001 nmol/day, Metanephrine fraction 1531 nmol/day. Receiver operating characteristic (ROC) curves were constructed. Results The diagnostic efficacy was as follows: norMetanephrine fraction sensitivity 87.3% [(95% confidence interval (CI) 79.4-92.4%], specificity 95.0% (92.5-96.8); Metanephrine fraction sensitivity 56.9% (47.2-66.1), specificity 95.0% (92.5-96.8); elevation of either norMetanephrine or Metanephrine fraction sensitivity 97.1% (91.7-99.0) and specificity 91.1% (87.9-93.5). Areas under the ROC curves (AUCs) were 0.972 (95% CI 0.955-0.990) for the norMetanephrine fraction, 0.800 (0.741-0.858) for the Metanephrine fraction, 0.991 (0.985-0.996) for total Metanephrines, and 0.991 (0.985-0.996) for a regression-derived ROC curve incorporating both the Metanephrine and norMetanephrine fractions. Conclusion Measurement of 24-h urinary fractionated Metanephrines by a tandem mass spectrometry assay appears to be an effective biochemical technique in the investigation of pheochromocytoma.
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Precisely Wrong? Urinary Fractionated Metanephrines and Peer-Based Laboratory Proficiency Testing
Clinical chemistry, 2005Co-Authors: Ravinder J. Singh, Stefan K.g. Grebe, Bingfang Yue, Alan L. Rockwood, John C. Cramer, Zoltan Gombos, Graeme EisenhoferAbstract:Measurements of urinary fractionated Metanephrines (norMetanephrine and Metanephrine), the O-methylated metabolites of norepinephrine and epinephrine, provide a sensitive test for diagnosis of pheochromocytoma. We present evidence suggesting inaccurate Metanephrine and norMetanephrine calibration by US laboratories. Metanephrines are present in urine mainly as sulfate- and glucuronide-conjugated metabolites produced from free Metanephrines by the actions of conjugating enzymes (1). An acid hydrolysis step is usually performed to liberate the free Metanephrines from the conjugated metabolites. This step minimizes requirements for high analytical sensitivity, simplifying subsequent measurement. Urinary fractionated Metanephrines are usually measured by HPLC with electrochemical detection (HPLC-EC). Gas chromatography with mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS/MS) are more recent alternatives offering high sample throughput and improved analytical specificity (2)(3). Clinical laboratories in the US participate in proficiency testing programs, primarily aimed at determining agreement in diagnostic test results among laboratories. Identical survey samples are distributed to participating laboratories, with results stratified according to testing methodologies. Laboratories that report results deviating by more than a certain amount from the mean of their peer groups fail the proficiency test. Until the spring of 2004, the only source of commercially available urine Metanephrine calibrators in the US was Bio-Rad. As with … aE-mail steve_binder{at}bio-rad.com
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measurement of plasma free Metanephrine and norMetanephrine by liquid chromatography tandem mass spectrometry for diagnosis of pheochromocytoma
Clinical Chemistry, 2004Co-Authors: Susan A Lagerstedt, Dennis J Okane, Ravinder J. SinghAbstract:Background: Quantification of plasma free Metanephrines is usually accomplished by HPLC with electrochemical detection, but sample preparation is labor-intensive and time-consuming, run times are long, and interfering substances sometimes obscure the relevant peaks. The aim of this study was to develop a sensitive and specific LC-MS/MS method for plasma free Metanephrines. Methods: After solid-phase extraction, chromatographic separation of norMetanephrine (NMN) and Metanephrine (MN) was accomplished by use of a cyano analytical column. NMN, MN, d3-NMN, and d3-MN positive ions were detected in the multiple-reaction monitoring mode using the specific transitions m/z 166→134, 180→148, 169→137, and 183→151, respectively, with an atmospheric pressure chemical ionization source. Results: Multiple calibration curves exhibited consistent linearity and reproducibility. Interassay imprecision values (CV; n = 20) for NMN at 0.64, 1.9, and 2.7 nmol/L were 6.6%, 7.8%, and 13%, respectively. Interassay CV for MN at 0.60, 1.2, and 2.1 nmol/L (n = 20) were 9.2%, 6.8%, and 9.8%, respectively. The mean recoveries of NMN and MN relative to the internal standard were 100% and 96%, respectively. The assays were linear between 0.20 and 10.0 nmol/L. Deming regression of HPLC and LC-MS/MS results yielded slopes of 0.93 (95% confidence interval, 0.89–0.98) and 0.89 (0.85–0.93) and y -intercepts of −0.16 and 0.03 nmol/L for NMN (n = 132) and MN (n = 92), respectively. Conclusions: This novel LC-MS/MS approach provides a precise, rapid, and specific alternative method to HPLC for the quantification of the low nanomolar concentrations of free Metanephrines in plasma.
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A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma Metanephrines compared with the combination of 24-hour urinary Metanephrines and catecholamines.
The Journal of clinical endocrinology and metabolism, 2003Co-Authors: Anna M. Sawka, Ravinder J. Singh, Roman Jaeschke, William F. YoungAbstract:We compared the diagnostic efficacy of fractionated plasma Metanephrine measurements to measurements of 24-h urinary total Metanephrines and catecholamines in outpatients tested for pheochromocytoma at Mayo Clinic Rochester from January 1, 1999, until November 27, 2000. Catecholaminesecreting tumors were histologically proven. The sensitivity of fractionated plasma Metanephrines was 97% (30 of 31 patients), compared with a sensitivity of 90% (28 of 31) for urinary total Metanephrines and catecholamines (P = 0.63). The specificity of fractionated plasma Metanephrines was 85% (221 of 261), compared with 98% (257 of 261; P < 0.001) for urinary measurements. The likelihood ratios for positive tests were 6.3 (95% confidence interval, 4.7 to 8.5) for fractionated plasma Metanephrines and 58.9 (95% confidence interval, 22.1 to 156.9) for urinary total Metanephrines and catecholamines. An adrenal pheochromocytoma was missed by urinary testing in two patients with familial syndromes and one asymptomatic patient wi...
Sihe Wang - One of the best experts on this subject based on the ideXlab platform.
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Quantitation of Free Metanephrines in Plasma by Liquid Chromatography-Tandem Mass Spectrometry.
Methods in molecular biology (Clifton N.J.), 2016Co-Authors: Courtney Heideloff, Drew Payto, Sihe WangAbstract:Plasma Metanephrines are measured to aid in the diagnosis of pheochromocytomas. In patients with pheochromocytomas there is excessive production of catecholamines and Metanephrines. Measurement of plasma free Metanephrines is one of the first-line clinical tests that are used for the diagnosis and follow-up of pheochromocytoma. We describe here a liquid chromatography-tandem mass spectrometry method to measure free Metanephrines in plasma. Free Metanephrine and norMetanephrine are extracted via solid-phase extraction. After extraction and evaporation, the reconstituted supernatant is analyzed by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The MS/MS is set to selective reaction monitoring mode (180.1 → 148.1 m/z for Metanephrine, 183.1 → 168.1 for d3-Metanephrine, 166.1 → 134.1 m/z for norMetanephrine, and 169.1 → 137.2 m/z for d3-norMetanephrine) with positive electrospray ionization. Quantitation is based on peak area ratio of the analyte to its respective deuterated internal standard. The assay is linear from 5.9 to 4090.0 pg/mL for Metanephrine and 22.0 to 4386.7 pg/mL for norMetanephrine with precision of
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quantification of Metanephrine and norMetanephrine in urine using liquid chromatography tandem mass spectrometry
Methods of Molecular Biology, 2016Co-Authors: Jessica Gabler, Sihe WangAbstract:Measuring urinary Metanephrines aides in the diagnosis of pheochromocytomas-catecholamine producing tumors. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows for greater sensitivity and simpler sample preparation as compared with other techniques. Here we describe a simple LC-MS/MS method for measuring Metanephrines in urine. Each urine sample was treated with diphenylboronic acid to create boronate complexes, and then applied to a Bond-Elut Plexa cartridge. After solid phase extraction, samples were concentrated and analyzed on an Atlantis T3 column with chromatographic run time totaling 8.5 min. MS/MS was set in positive electrospray ionization mode with multiple reaction monitoring for data collection. The assay was linear from 0.2 to 27.4 μmol/L and 0.3 to 14.6 μmol/L for Metanephrine and norMetanephrine, respectively. Intra-assay and total precision at three concentration levels over 10 days were <5 % for Metanephrine and <10 % for norMetanephrine.
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Quantification of Metanephrine and NorMetanephrine in Urine Using Liquid Chromatography-Tandem Mass Spectrometry.
Methods in molecular biology (Clifton N.J.), 2016Co-Authors: Jessica Gabler, Sihe WangAbstract:Measuring urinary Metanephrines aides in the diagnosis of pheochromocytomas-catecholamine producing tumors. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows for greater sensitivity and simpler sample preparation as compared with other techniques. Here we describe a simple LC-MS/MS method for measuring Metanephrines in urine. Each urine sample was treated with diphenylboronic acid to create boronate complexes, and then applied to a Bond-Elut Plexa cartridge. After solid phase extraction, samples were concentrated and analyzed on an Atlantis T3 column with chromatographic run time totaling 8.5 min. MS/MS was set in positive electrospray ionization mode with multiple reaction monitoring for data collection. The assay was linear from 0.2 to 27.4 μmol/L and 0.3 to 14.6 μmol/L for Metanephrine and norMetanephrine, respectively. Intra-assay and total precision at three concentration levels over 10 days were
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A Sensitive and Interference-Free Liquid Chromatography Tandem Mass Spectrometry Method for Measuring Metanephrines in Plasma
Journal of Chromatography & Separation Techniques, 2013Co-Authors: Jessica Gabler, Chao Yuan, Witold Woroniecki, Huafen Liu, Sihe WangAbstract:Background: Plasma Metanephrines are the primary biomarkers used to aid in diagnosing pheochromocytoma. However, the low physiological levels of Metanephrines, physicochemical properties, and potential interferences make it challenging to achieve high sensitivity and specificity. In this report, we developed and validated a sensitive and interference-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring plasma Metanephrines with simple sample preparation. Methods: Plasma samples were extracted using weak cation exchange solid-phase extraction cartridges, and analyzed by LC-MS/MS with an analytical cycle time less than six minutes. Results: Absolute ion suppression and matrix effect were observed, however, were completely compensated for by the internal standards. Epinephrine, an isobaric interferent of norMetanephrine, was chromatographically separated, and no interference was observed from other common interferents. The method was linear from 0.08 to 22.2 nmol/L for norMetanephrine and 0.03 to 8.2 nmol/L for Metanephrine with accuracy ranging from 81 to 107%. No carryover was observed up to 56.8 nmol/L for norMetanephrine and 8.7 nmol/L for Metanephrine. Intra-assay and total CVs were within 6.8% for norMetanephrine and 5.2% for Metanephrine for three levels tested. Based on Deming regression, comparison with a reference LC-MS/MS method using patient specimens (n=40) showed a slope of 0.973, intercept of 0.11 nmol/L and correlation coefficient of 0.9936 for norMetanephrine and a slope of 1.039, intercept of -0.014 nmol/L, and correlation coefficient of 0.9914 for Metanephrine. The mean difference was 3.5% and -1.6% for norMetanephrine and Metanephrine, respectively. Conclusion: This LC-MS/MS assay is sensitive and free of interference for quantitation of plasma Metanephrines
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A simple liquid chromatography-tandem mass spectrometry method for measuring Metanephrine and norMetanephrine in urine.
Clinical chemistry and laboratory medicine, 2011Co-Authors: Jessica Gabler, Abby Miller, Sihe WangAbstract:BACKGROUND Measuring urinary fractionated Metanephrines is one of the initial tests in the diagnosis of pheochromocytoma. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) represents the most specific and accurate technology for this purpose. The goal of this work was to develop a simple LC-MS/MS method for measuring Metanephrines in urine. METHODS Each urine sample was complexed with diphenylboronic acid, and purified on a Bond-Elute Plexa cartridge. The extract was concentrated and analyzed on a short Atlantis T3 column in 8.5 min. Metanephrines and their deuterated internal standards were monitored in positive electrospray ionization mode by multiple reaction monitoring. RESULTS Ion suppression was observed, but was compensated for by the respective internal standard. The analytical measurement range was 0.2-27.4 μmol/L and 0.3-14.6 μmol/L for Metanephrine and norMetanephrine, respectively. The intra-assay and total coefficient of variation throughout the linear ranges was 2.03%-2.11% and 2.20%-3.80% for Metanephrine, and 4.50%-8.09% and 9.00%-10.00% for norMetanephrine, respectively. Comparison with a commercial HPLC method using patient samples (n=65) by Passing-Bablok regression showed a slope of 1.000 and 1.014, y-intercept of -0.080 and -0.067, a correlation coefficient of 0.8830 and 0.9022, and a mean difference of 14.0% and -0.43% for Metanephrine and norMetanephrine, respectively. CONCLUSIONS This simple method for urine Metanephrines is suitable for clinical use.
Graeme Eisenhofer - One of the best experts on this subject based on the ideXlab platform.
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reference intervals for lc ms ms measurements of plasma free urinary free and urinary acid hydrolyzed deconjugated norMetanephrine Metanephrine and methoxytyramine
Clinica Chimica Acta, 2019Co-Authors: Graeme Eisenhofer, Mirko Peitzsch, Denise Kaden, Katharina Langton, Anastasios Mangelis, Christina Pamporaki, Jimmy Masjkur, Aikaterini Geroula, Max Kurlbaum, Timo DeutschbeinAbstract:Abstract Background Plasma or urinary Metanephrines are recommended for screening of pheochromocytomas and paragangliomas (PPGLs). Measurements of urinary free rather than deconjugated Metanephrines and additional measurements of methoxytyramine represent other developments. For all measurements there is need for reference intervals. Methods Plasma free, urinary free and urinary deconjugated O-methylated catecholamine metabolites were measured by LC-MS/MS in specimens from 590 hypertensives and normotensives. Reference intervals were optimized using data from 2,056 patients tested for PPGLs. Results Multivariate analyses, correcting for age and body surface area, indicated higher plasma and urinary Metanephrine in males than females and sex differences in urinary norMetanephrine and free methoxytyramine that largely reflected body size variation. There were positive associations of age with plasma metabolites, but negative relationships with urinary free Metanephrine and methoxytyramine. Plasma and urinary norMetanephrine were higher in hypertensives than normotensives, but differences were small. Optimization of reference intervals using the data from patients tested for PPGLs indicated that age was the most important consideration for plasma norMetanephrine and sex most practical for urinary metabolites. Conclusion This study clarifies impacts of demographic and anthropometric variables on catecholamine metabolites, verifies use of age-specific reference intervals for plasma norMetanephrine and establishes sex-specific reference intervals for urinary metabolites.
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Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free Metanephrines.
Clinical chemistry, 2005Co-Authors: Graeme Eisenhofer, Jacques W.m. Lenders, David S. Goldstein, Massimo Mannelli, Gyorgy Csako, Mcclellan M. Walther, Frederieke M. Brouwers, Karel PacakAbstract:Background: Measurements of plasma free Metanephrines (norMetanephrine and Metanephrine) provide a useful test for diagnosis of pheochromocytoma and may provide other information about the nature of these tumors. Methods: We examined relationships of tumor size, location, and catecholamine content with plasma and urinary Metanephrines or catecholamines in 275 patients with pheochromocytoma. We then prospectively examined whether measurements of plasma free Metanephrines could predict tumor size and location in an additional 16 patients. Results: Relative proportions of epinephrine and norepinephrine in tumor tissue were closely matched by relative increases of plasma or urinary Metanephrine and norMetanephrine, but not by epinephrine and norepinephrine. Tumor diameter showed strong positive relationships with summed plasma concentrations or urinary outputs of Metanephrine and norMetanephrine ( r = 0.81 and 0.77; P 15% of the combined increases of norMetanephrine and Metanephrine either had adrenal locations or appeared to be recurrences of previously resected adrenal tumors. Measurements of plasma free Metanephrines predicted tumor diameter to within a mean of 30% of actual diameter, and high plasma concentrations of free Metanephrine relative to norMetanephrine accurately predicted adrenal locations. Conclusions: Measurements of plasma free Metanephrines not only provide information about the likely presence or absence of a pheochromocytoma, but when a tumor is present, can also help predict tumor size and location. This additional information may be useful for clinical decision-making during tumor localization procedures.
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Precisely Wrong? Urinary Fractionated Metanephrines and Peer-Based Laboratory Proficiency Testing
Clinical chemistry, 2005Co-Authors: Ravinder J. Singh, Stefan K.g. Grebe, Bingfang Yue, Alan L. Rockwood, John C. Cramer, Zoltan Gombos, Graeme EisenhoferAbstract:Measurements of urinary fractionated Metanephrines (norMetanephrine and Metanephrine), the O-methylated metabolites of norepinephrine and epinephrine, provide a sensitive test for diagnosis of pheochromocytoma. We present evidence suggesting inaccurate Metanephrine and norMetanephrine calibration by US laboratories. Metanephrines are present in urine mainly as sulfate- and glucuronide-conjugated metabolites produced from free Metanephrines by the actions of conjugating enzymes (1). An acid hydrolysis step is usually performed to liberate the free Metanephrines from the conjugated metabolites. This step minimizes requirements for high analytical sensitivity, simplifying subsequent measurement. Urinary fractionated Metanephrines are usually measured by HPLC with electrochemical detection (HPLC-EC). Gas chromatography with mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS/MS) are more recent alternatives offering high sample throughput and improved analytical specificity (2)(3). Clinical laboratories in the US participate in proficiency testing programs, primarily aimed at determining agreement in diagnostic test results among laboratories. Identical survey samples are distributed to participating laboratories, with results stratified according to testing methodologies. Laboratories that report results deviating by more than a certain amount from the mean of their peer groups fail the proficiency test. Until the spring of 2004, the only source of commercially available urine Metanephrine calibrators in the US was Bio-Rad. As with … aE-mail steve_binder{at}bio-rad.com
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Plasma Metanephrines in renal failure
Kidney international, 2005Co-Authors: Graeme Eisenhofer, Karel Pacak, F.t.m. Huysmans, Macclellan M. Walther, Fred C.g.j. Sweep, Jacques W.m. LendersAbstract:Plasma Metanephrines in renal failure. Background Diagnosis of pheochromocytoma in renal failure poses a diagnostic dilemma due to lack of reliability of conventional urinary measurements of catecholamine excess. Measurements of the plasma Metanephrines, norMetanephrine and Metanephrine (the O-methylated metabolites of norepinephrine and epinephrine), provide an alternative diagnostic test. The Metanephrines may be measured as free metabolites or after a deconjugation step where measurements reflect mainly sulfate-conjugated metabolites. The influence of renal insufficiency states on these various measurements is unclear. Methods Plasma free and deconjugated Metanephrines and catecholamines in 17 patients on dialysis with end-stage renal disease and 19 patients with renal insufficiency (creatinine clearance, 5–78mL/min) were compared with levels in 89 hypertensives, 68 healthy normotensives, and 51 patients with von Hippel-Lindau syndrome. Results Patients with renal failure had up to two-fold higher plasma concentrations of catecholamines and free Metanephrines, and more than 12-fold higher plasma concentrations of deconjugated Metanephrines than comparison groups. Plasma free Metanephrines and catecholamines were, respectively, within the 95% confidence intervals of reference groups in 75% and 42% of the dialysis patients, and in 74% and 68% of patients with renal insufficiency. In contrast, no dialysis patient and only half the renal insufficiency patients had plasma levels of deconjugated Metanephrines within the reference intervals. Plasma levels of deconjugated Metanephrines, but not free Metanephrines, showed strong inverse relationships with creatinine clearance. Conclusion Plasma concentrations of free Metanephrines are relatively independent of renal function and are, therefore, more suitable for diagnosis of pheochromocytoma among patients with renal failure than measurements of deconjugated Metanephrines.
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NorMetanephrine and Metanephrine
Encyclopedia of Endocrine Diseases, 2004Co-Authors: Jacques W.m. Lenders, Graeme EisenhoferAbstract:The Metanephrines norMetanephrine and Metanephrine are O -methylated metabolites of the parent catecholamines norepinephrine and epinephrine. They are biologically inactive markers of extraneuronal and intra-adrenal metabolism of catecholamines and they can be measured in the free and conjugated forms in both plasma and urine. The main utility of measurement of Metanephrines is for the diagnosis of chromaffin cell tumors such as pheochromocytoma and paraganglioma. Due to their continuous production and secretion by tumoral tissue, measurements of Metanephrines offer the best test with the highest accuracy for the diagnosis of these tumors.
William F. Young - One of the best experts on this subject based on the ideXlab platform.
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Plasma Chromogranin A or Urine Fractionated Metanephrines Follow-Up Testing Improves the Diagnostic Accuracy of Plasma Fractionated Metanephrines for Pheochromocytoma
The Journal of clinical endocrinology and metabolism, 2007Co-Authors: Alicia Algeciras-schimnich, Ravinder J. Singh, William F. Young, Carol M. Preissner, Stefan K.g. GrebeAbstract: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: The objective of the study was to evaluate three approaches to distinguish between true-positive and false-positive tests: 1) increased cutoff for plasma fractionated Metanephrines, 2) measurement of serum/plasma chromogranin A (CGA), and 3) 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 yr follow-up. For a subgroup, urine fractionated Metanephrine results were available. All original plasma samples were retested 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 eight 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.
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The diagnostic efficacy of urinary fractionated Metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma.
Clinical endocrinology, 2007Co-Authors: Colin Perry, Anna M. Sawka, Ravinder J. Singh, Lehana Thabane, J. Bajnarek, William F. YoungAbstract:Background There are limitations to currently available biochemical tests for pheochromocytoma. Our objective was to evaluate the diagnostic efficacy of a novel tandem mass spectrometry assay for the measurement of fractionated urinary Metanephrines in patients suspected to have a pheochromocytoma. We also developed clinically based cut-offs for positivity of this measurement. Methods We examined the medical records of 506 patients (including 102 patients with a catecholamine-producing tumour) who underwent measurement of 24-h urinary fractionated Metanephrines using tandem mass spectrometry as well as adrenal imaging at Mayo Clinic, Rochester. The cut-offs for positivity were defined as follows: total Metanephrines (sum of the Metanephrine fractions) 5163 nmol/day, norMetanephrine fraction 4001 nmol/day, Metanephrine fraction 1531 nmol/day. Receiver operating characteristic (ROC) curves were constructed. Results The diagnostic efficacy was as follows: norMetanephrine fraction sensitivity 87.3% [(95% confidence interval (CI) 79.4-92.4%], specificity 95.0% (92.5-96.8); Metanephrine fraction sensitivity 56.9% (47.2-66.1), specificity 95.0% (92.5-96.8); elevation of either norMetanephrine or Metanephrine fraction sensitivity 97.1% (91.7-99.0) and specificity 91.1% (87.9-93.5). Areas under the ROC curves (AUCs) were 0.972 (95% CI 0.955-0.990) for the norMetanephrine fraction, 0.800 (0.741-0.858) for the Metanephrine fraction, 0.991 (0.985-0.996) for total Metanephrines, and 0.991 (0.985-0.996) for a regression-derived ROC curve incorporating both the Metanephrine and norMetanephrine fractions. Conclusion Measurement of 24-h urinary fractionated Metanephrines by a tandem mass spectrometry assay appears to be an effective biochemical technique in the investigation of pheochromocytoma.
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Measurement of fractionated plasma Metanephrines for exclusion of pheochromocytoma: Can specificity be improved by adjustment for age?
BMC Endocrine Disorders, 2005Co-Authors: Anna M. Sawka, Lehana Thabane, Amiram Gafni, Mitchell Levine, William F. YoungAbstract:Background Biochemical testing for pheochromocytoma by measurement of fractionated plasma Metanephrines is limited by false positive rates of up to 18% in people without known genetic predisposition to the disease. The plasma norMetanephrine fraction is responsible for most false positives and plasma norMetanephrine increases with age. The objective of this study was to determine if we could improve the specificity of fractionated plasma measurements, by statistically adjusting for age. Methods An age-adjusted Metanephrine score was derived using logistic regression from 343 subjects (including 33 people with pheochromocytoma) who underwent fractionated plasma Metanephrine measurements as part of investigations for suspected pheochromocytoma at Mayo Clinic Rochester (derivation set). The performance of the age-adjusted score was validated in a dataset of 158 subjects (including patients 23 with pheochromocytoma) that underwent measurements of fractionated plasma Metanephrines at Mayo Clinic the following year (validation dataset). None of the participants in the validation dataset had known genetic predisposition to pheochromocytoma. Results The sensitivity of the age-adjusted Metanephrine score was the same as that of traditional interpretation of fractionated plasma Metanephrine measurements, yielding a sensitivity of 100% (23/23, 95% confidence interval [CI] 85.7%, 100%). However, the false positive rate with traditional interpretation of fractionated plasma Metanephrine measurements was 16.3% (22/135, 95% CI, 11.0%, 23.4%) and that of the age-adjusted score was significantly lower at 3.0% (4/135, 95% CI, 1.2%, 7.4%) (p < 0.001 using McNemar's test). Conclusion An adjustment for age in the interpretation of results of fractionated plasma Metanephrines may significantly decrease false positives when using this test to exclude sporadic pheochromocytoma. Such improvements in false positive rate may result in savings of expenditures related to confirmatory imaging.
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A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma Metanephrines compared with the combination of 24-hour urinary Metanephrines and catecholamines.
The Journal of clinical endocrinology and metabolism, 2003Co-Authors: Anna M. Sawka, Ravinder J. Singh, Roman Jaeschke, William F. YoungAbstract:We compared the diagnostic efficacy of fractionated plasma Metanephrine measurements to measurements of 24-h urinary total Metanephrines and catecholamines in outpatients tested for pheochromocytoma at Mayo Clinic Rochester from January 1, 1999, until November 27, 2000. Catecholaminesecreting tumors were histologically proven. The sensitivity of fractionated plasma Metanephrines was 97% (30 of 31 patients), compared with a sensitivity of 90% (28 of 31) for urinary total Metanephrines and catecholamines (P = 0.63). The specificity of fractionated plasma Metanephrines was 85% (221 of 261), compared with 98% (257 of 261; P < 0.001) for urinary measurements. The likelihood ratios for positive tests were 6.3 (95% confidence interval, 4.7 to 8.5) for fractionated plasma Metanephrines and 58.9 (95% confidence interval, 22.1 to 156.9) for urinary total Metanephrines and catecholamines. An adrenal pheochromocytoma was missed by urinary testing in two patients with familial syndromes and one asymptomatic patient wi...
Shaw Callen - One of the best experts on this subject based on the ideXlab platform.
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Pilot quality assurance programme for plasma Metanephrines.
Annals of clinical biochemistry, 2010Co-Authors: Dilo Pillai, Shaw CallenAbstract:Up to 2007 there was no formal external quality assurance programme for plasma free Metanephrines. A pilot programme was conceived by the AACB (Australian Association of Clinical Biochemists) Working Party on biogenic amines. With support from the AACB and Royal College of Pathologists of Australasia Quality Assurance programmes, a pilot study was developed. Data from this study are presented for the first time. Twelve lyophilized plasma samples were distributed to 15 centres. Samples were spiked with Metanephrine (metadrenaline), norMetanephrine (normetadrenaline) and 3-methoxytyramine, all derived from human urine. Concentrations were arranged in a linear relationship. The analytes were present at six levels and samples were duplicated. High-pressure liquid chromatography and tandem mass spectrometry methods showed acceptable precision but in general enzyme immunoassay displayed a higher degree of imprecision as well as a negative bias. Differences in calibration and matrix effects are likely to have been responsible for the discrepancy between chromatographic and immunoassay methods. These differences need to be further examined although efforts at standardization between different methods have been hampered by the lack of a universal calibrator for plasma Metanephrines. Meanwhile, a laboratory's performance characteristics can be monitored and enhanced by participation in suitable external quality assurance programmes.
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Pilot quality assurance programme for plasma Metanephrines
Annals of Clinical Biochemistry, 2010Co-Authors: Dilo Pillai, Shaw CallenAbstract:BackgroundUp to 2007 there was no formal external quality assurance programme for plasma free Metanephrines. A pilot programme was conceived by the AACB (Australian Association of Clinical Biochemists) Working Party on biogenic amines. With support from the AACB and Royal College of Pathologists of Australasia Quality Assurance programmes, a pilot study was developed. Data from this study are presented for the first time.MethodsTwelve lyophilized plasma samples were distributed to 15 centres. Samples were spiked with Metanephrine (metadrenaline), norMetanephrine (normetadrenaline) and 3-methoxytyramine, all derived from human urine. Concentrations were arranged in a linear relationship. The analytes were present at six levels and samples were duplicated.ResultsHigh-pressure liquid chromatography and tandem mass spectrometry methods showed acceptable precision but in general enzyme immunoassay displayed a higher degree of imprecision as well as a negative bias.ConclusionsDifferences in calibration and matr...
