Test For Diagnosis Of Pheochromocytoma Research Articles

Accuracy of recommended sampling and assay methods for the determination of plasma-free and urinary fractionated metanephrines in the diagnosis of pheochromocytoma and paraganglioma: a systematic review.

To determine the accuracy of biochemical tests for the diagnosis of pheochromocytoma and paraganglioma. A search of the PubMed database was conducted for English-language articles published between October 1958 and December 2016 on the biochemical diagnosis of pheochromocytoma and paraganglioma using immunoassay methods or high-performance liquid chromatography with coulometric/electrochemical or tandem mass spectrometric detection for measurement of fractionated metanephrines in 24-h urine collections or plasma-free metanephrines obtained under seated or supine blood sampling conditions. Application of the Standards for Reporting of Diagnostic Studies Accuracy Group criteria yielded 23 suitable articles. Summary receiver operating characteristic analysis revealed sensitivities/specificities of 94/93% and 91/93% for measurement of plasma-free metanephrines and urinary fractionated metanephrines using high-performance liquid chromatography or immunoassay methods, respectively. Partial areas under the curve were 0.947 vs. 0.911. Irrespective of the analytical method, sensitivity was significantly higher for supine compared with seated sampling, 95 vs. 89% (p < 0.02), while specificity was significantly higher for supine sampling compared with 24-h urine, 95 vs. 90% (p < 0.03). Partial areas under the curve were 0.942, 0.913, and 0.932 for supine sampling, seated sampling, and urine. Test accuracy increased linearly from 90 to 93% for 24-h urine at prevalence rates of 0.0-1.0, decreased linearly from 94 to 89% for seated sampling and was constant at 95% for supine conditions. Current tests for the biochemical diagnosis of pheochromocytoma and paraganglioma show excellent diagnostic accuracy. Supine sampling conditions and measurement of plasma-free metanephrines using high-performance liquid chromatography with coulometric/electrochemical or tandem mass spectrometric detection provides the highest accuracy at all prevalence rates.

Plasma fractionated total metanephrines for biochemical diagnosis of neuroblastoma.

9571 Background: Urine catecholamines and their metabolites are used for diagnosis and follow-up of patients with neuroblastoma. O-methylated metabolites of catecholamines (plasma free or total metanephrines) are the most sensitive tests for diagnosis of pheochromocytoma. We postulate that neuroblastoma transforms catecholamines into metanephrines which may be more sensitive and specific than urine catecholamines for diagnosis and follow-up of the disease. The aim of the study was to establish reference values for plasma fractionated metanephrines in children and provide preliminary results on their diagnostic values. Methods: We included into the study 191 healthy children aged 0-17 years needing a venous puncture. 2 ml of heparinized blood were drawn to measure plasma total metanephrines. Additionally, we included ten patients with neuroblastoma to evaluate the diagnostic utility of the test. Results: Upper reference limit of total plasma normetanephrine (NMN), metanephrine (MN) and methoxytyramine (MT) were: 9.67 nmol/l (95% CI: 8.32-10.1) for NMN, 4.95 nmol/l (95% IC: 4.19-6.05) for MN, 5.8 nmol/l (95% IC: 4.85-7.37) for MT. There was no significant difference between boys and girls. A linear trend gradually decreasing from birth to 17 years was observed for NMN and MT which was statistically significant for both. Plasma concentration of MN showed a non-linear relationship to age. In patients with neuroblastoma, plasma total MT and NMN measurements were highly sensitive and specific at diagnosis. The highest sensitivity and specificity (100% and 99.48%, respectively) were achieved for plasma total NMN with a cutoff at 19.64 nmol/l (odds ratio 1.18, CI 1.06-1.31) and for plasma total MT (sensitivity 100% and specificity 98.95%) with a cutoff at 9.43 nmol/l (odds ratio 1.8, CI 1.32-2.46). Conclusions: These preliminary results provide pediatric reference limits for total plasma metanephrines and suggest a promising role in diagnosis and follow-up of neuroblastoma patients. Further data are necessary to confirm its validity. No significant financial relationships to disclose.

Comparison of Diagnostic Accuracy of Urinary Free Metanephrines, Vanillyl Mandelic Acid, and Catecholamines and Plasma Catecholamines for Diagnosis of Pheochromocytoma

Recent evidence suggests that plasma-free metanephrines provide a highly sensitive test in patients requiring exclusion of pheochromocytoma. The diagnostic efficacy of urinary free metanephrines, however, has not been evaluated. OBJECTIVE, DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: We compared retrospectively the diagnostic efficacy of 24-h urinary free metanephrines with our currently available measurements of 24-h urinary vanillyl mandelic acid (VMA), urinary catecholamines, and plasma catecholamines in 159 outpatients tested in a tertiary referral center for pheochromocytoma over a 4-yr period. The sensitivity of urinary free metanephrines was 100% [25 of 25 patients; 95% confidence interval (CI) 86-100%)] compared with the sensitivity of 84% (21 of 25; 95% CI 64-95%) for urinary catecholamines; 72% (18 of 25; 95% CI 51-88%) for urinary VMA; and 76% (16 of 21; 95% CI 53-92%) for plasma catecholamines. The specificity of urinary free metanephrines was 94% (116 of 123; 95% CI 89-98%), compared with the specificity of 99% (127 of 129; 95% CI 96-100%) for urinary catecholamines; 96% (130 of 134; 95% CI 91-98%) for urinary VMA; and 88% (66 of 75; 95% CI 78-94%) for plasma catecholamines. Receiver operating characteristic curves for all test groups were generated. Pairwise comparisons of the area under the receiver operating characteristic curve for urinary free metanephrines with that of each of the other three test groups individually were: 0.993 (95% CI 0.962-0.999) vs. 0.919 (95% CI 0.862-0.957, P = 0.032) for urine catecholamines; 0.993 (95% CI 0.962-0.999) vs. 0.846 (95% CI 0.778-0.900, P = 0.002) for urine VMA; and 0.992 (95% CI 0.945-0.998) vs. 0.852 (95% CI 0.762-0.918, P = 0.009) for plasma catecholamines. Testing with urinary free metanephrines failed to misidentify a single case of pheochromocytoma, compared with four missed cases for urinary catecholamines, seven missed cases for urinary VMA, and five missed cases for plasma catecholamines. Urinary free metanephrines were superior to urinary VMA, urinary catecholamines, and plasma catecholamines and can provide a valuable test for diagnosis of pheochromocytoma in adults.

Pheochromocytoma Catecholamine Phenotypes and Prediction of Tumor Size and Location by Use of Plasma Free Metanephrines

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. 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. 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 <0.001), whereas relationships with plasma or urinary catecholamines were weaker (r = 0.41 and 0.44). All tumors in which increases in plasma metanephrine were >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. 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.

Precisely Wrong? Urinary Fractionated Metanephrines and Peer-Based Laboratory Proficiency Testing

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

Biochemical and Clinical Manifestations of Dopamine-Producing Paragangliomas: Utility of Plasma Methoxytyramine

Measurements of plasma-free normetanephrine and metanephrine provide a sensitive test for diagnosis of pheochromocytoma but may fail to detect tumors that produce predominantly dopamine. Such tumors are extremely rare, usually found as extraadrenal paragangliomas. This report describes measurements of plasma concentrations of free methoxytyramine, the O-methylated metabolite of dopamine, in 120 patients with catecholamine-producing tumors, including nine with extraadrenal paragangliomas secreting predominantly dopamine. In seven of these nine patients, tumors were found incidentally or secondary to the space-occupying complications of the lesions. Plasma concentrations of free methoxytyramine and dopamine were increased in all nine patients, including two with normal plasma and urinary normetanephrine and metanephrine and normal urinary outputs of dopamine. Relative increases above normal for plasma methoxytyramine (104-fold) and dopamine (56-fold) were much greater (P < 0.001) than those for urinary dopamine (3-fold). Insensitivity of the latter for identification of dopamine-secreting tumors was due to dependence of the urinary amine on renal extraction and decarboxylation of circulating 3,4-dihydroxyphenylalanine. Measurements of plasma-free methoxytyramine, in addition to normetanephrine and metanephrine, are unlikely to improve diagnosis of pheochromocytomas in hypertensive patients with symptoms of catecholamine excess but may be useful in selected patients for identification of tumors that produce predominantly dopamine.

Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results.

Measurements of plasma normetanephrine and metanephrine provide a highly sensitive test for diagnosis of pheochromocytoma, but false-positive results remain a problem. We therefore assessed medication-associated false-positive results and use of supplementary tests, including plasma normetanephrine responses to clonidine, to distinguish true- from false-positive results. The study included 208 patients with pheochromocytoma and 648 patients in whom pheochromocytoma was excluded. Clonidine-suppression tests were carried out in 48 patients with and 49 patients without the tumor. Tricyclic antidepressants and phenoxybenzamine accounted for 41% of false-positive elevations of plasma normetanephrine and 44-45% those of plasma and urinary norepinephrine. High plasma normetanephrine to norepinephrine or metanephrine to epinephrine ratios were strongly predictive of pheochromocytoma. Lack of decrease and elevated plasma levels of norepinephrine or normetanephrine after clonidine also confirmed pheochromocytoma with high specificity. However, 16 of 48 patients with pheochromocytoma had normal levels or decreases of norepinephrine after clonidine. In contrast, plasma normetanephrine remained elevated in all but 2 patients, indicating more reliable diagnosis using normetanephrine than norepinephrine responses to clonidine. Thus, in patients with suspected pheochromocytoma and positive biochemical results, false-positive elevations due to medications should first be eliminated. Patterns of biochemical test results and responses of plasma normetanephrine to clonidine can then help distinguish true- from false-positive results.

Utility of plasma free metanephrines for detecting childhood pheochromocytoma.

Measurements of plasma free metanephrines, normetanephrine (NMN) and metanephrine (MN), provide a sensitive test for diagnosis of pheochromocytoma in adults but have not been evaluated in children. We therefore established reference ranges for plasma and urinary metanephrines and the catecholamines, norepinephrine (NE) and epinephrine (E), in 86 healthy children (age 5-17). A group of 158 healthy adults (age 18-72) served as a comparison group. Pediatric reference ranges were applied to examine the diagnostic utility of the various tests in 45 children evaluated for pheochromocytoma (age 8-17; 38 with von Hippel-Lindau syndrome), with tumors found on 12 occasions. Upper reference limits for E and MN were higher and those for NE and NMN lower in children than in adults. Boys had higher plasma levels of E and MN and higher urinary excretion of all four amines than girls. Plasma free metanephrines provided a diagnostic test with values for sensitivity (100%) and specificity (94%) that were equal to or higher than those of other tests. In two children screened for pheochromocytoma on multiple occasions, use of pediatric reference ranges for plasma free metanephrines indicated the tumor a year earlier than indicated using adult reference ranges. The findings indicate that plasma free metanephrines provide a sensitive tool for detection of pheochromocytoma in children. Age appropriate reference ranges should be used and gender differences should be considered.

Free or Total Metanephrines for Diagnosis of Pheochromocytoma: What Is the Difference?

Pheochromocytomas, although a rare cause of hypertension, are dangerous tumors that require consideration in large numbers of patients. The resulting low prevalence of these tumors among the tested population and the inadequate sensitivity and specificity of commonly used biochemical tests make diagnosis of pheochromocytoma difficult and time-consuming. As outlined in two articles in this issue of the Journal (1)(2), measurements of plasma concentrations of metanephrines provide a promising, new, highly sensitive test for diagnosis of pheochromocytoma. A negative test result for plasma metanephrines means that a pheochromocytoma is highly unlikely so that no other tests are necessary (3)(4). Thus, measurements of plasma metanephrines provide a particularly good initial diagnostic test for exclusion of pheochromocytoma. The diagnostic superiority of plasma metanephrines over plasma or urinary catecholamines and urinary vanillylmandelic acid is clear (3)(4)(5)(6). What remains unclear, as illustrated in the two articles in this issue of the Journal (1)(2), is whether measurements of plasma free (unconjugated) metanephrines or total metanephrines provide the better diagnostic test, and how these tests differ. Also unclear is how these tests differ from measurements of urinary metanephrines. Part of the confusion about tests of urinary total or fractionated metanephrines and plasma free, unconjugated, or total metanephrines stems from the unfortunate and confusing terminology used to distinguish these analytes. The term “metanephrines” describes two catecholamine metabolites: …

Plasma metanephrines: a novel and cost-effective test for pheochromocytoma.

Pheochromocytomas are rare chromaffin cell tumors that nevertheless must be excluded in large numbers of patients who develop sustained or episodic hypertension as well as in many others with suggestive symptoms or with a familial history of pheochromocytoma. Diagnosis of pheochromocytoma depends importantly on biochemical evidence of excess catecholamine production by a tumor. Imperfect sensitivity and specificity of commonly available biochemical tests and the low incidence of the tumor among the tested population mean that considerable time and effort can be expended in confirming or ruling out pheochromocytoma in patients where the tumor is suspected. Measurements of plasma free metanephrines provide a superior test compared to other available tests for diagnosis of pheochromocytoma. In particular, the high sensitivity of plasma free metanephrines means that a normal test result reliably excludes all but the smallest of pheochromocytomas so that no other tests are necessary. Measurements of plasma free metanephrines, when systematically combined with other diagnostic procedures outlined in this review, provide a more efficient, reliable and cost-effective approach for diagnosis of pheochromocytoma than offered by previously available approaches.

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

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.