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At least 19 recordsLinked to original sources
PubMed2003

A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines.

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 with an incidentally discovered adrenal mass. An extra-adrenal paraganglioma was missed by plasma testing in one patient. In conclusion, measurements of 24-h urinary total metanephrines and catecholamines yield fewer false-positive results, an attribute preferred for testing low-risk patients, but fractionated plasma metanephrine measurements may be preferred in high-risk patients with familial endocrine syndromes.

Adolescent↗
PubMed1995

Plasma metanephrines in the diagnosis of pheochromocytoma.

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 sensitive than tests for plasma catecholamines or urinary metanephrines for the diagnosis of pheochromocytoma.

Adolescent↗
PubMed2005

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, 5-78 mL/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.

Adrenal Gland Neoplasms↗
PubMed1996

The urinary metanephrine-to-creatinine ratio for the diagnosis of pheochromocytoma.

OBJECTIVE: To compare the operating characteristics of two tests for diagnosing pheochromocytoma: 1) measurement of the ratio between urinary metanephrine and creatinine levels and 2) measurement of urinary metanephrine levels alone. A second objective was to ascertain the reasons for false-positive test results. DESIGN: Cross-sectional study. SETTING: Hypertension referral center. PATIENTS: 1013 patients referred for hypertension and tested for pheochromocytoma. MEASUREMENTS: 24-hour urinary levels of metanephrine (measured using liquid chromatography) and creatinine. The presence of pheochromocytoma was confirmed at surgery. In patients with positive test results, the absence of pheochromocytoma was documented by negative results of retests and imaging procedures. RESULTS: Of 58 patients with increased metanephrine levels or increased metanephrine-to-creatinine ratios, 20 had pheochromocytoma and 38 did not. Of the 38 patients without pheochromocytoma, 15 had high metanephrine levels but normal metanephrine-to-creatinine ratios. The respective operating characteristics of measurement of urinary metanephrine levels and measurement of the metanephrine-to-creatinine ratio were as follows: sensitivity, 95% and 100%; specificity, 98% and 98%; positive predictive value, 46% and 47%; and negative predictive value, 100% and 100%. In 13 of the 23 patients who had a high metanephrine-to-creatinine ratio, various acute events may have caused hypersecretion of catecholamines. CONCLUSIONS: Measurement of the metanephrine-to-creatinine ratio is a sensitive and specific test for pheochromocytoma. However, acute events may increase urinary metanephrine excretion to the level that occurs with tumors.

Adolescent↗
PubMed2005

Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines.

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 <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. 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.

Adrenal Gland Neoplasms↗
PubMed1998

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.

Adult↗
PubMed2000

Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma.

BACKGROUND: Recently, measurement of plasma metanephrines was suggested to improve the detection of pheochromocytoma compared with the other common biochemical tests. OBJECTIVE: To examine the diagnostic precision of measurements of plasma metanephrines, plasma catecholamines, and urinary catecholamines and to assess their variability. METHODS: Plasma metanephrine as well as plasma and urinary catecholamine concentrations were measured by high-performance liquid chromatography with electrochemical detection. Before surgery, responses of plasma metanephrines and catecholamines to change of posture were determined. Intraoperatively, metanephrines and catecholamines were measured before skin incision, during maximal mechanical tumor manipulation, and repetitively after the tumor was separated from the circulation. Patients were reexamined 1 and 3 months after surgery. Patients with pheochromocytoma (n = 17) and with histologically proved other adrenal tumors (n = 14) were studied before, during, and after surgery. RESULTS: Measurement of plasma metanephrines and plasma and urinary catecholamines provided 100% and 82% sensitivity, respectively, for the detection of pheochromocytoma (P<.001). Levels of plasma catecholamines but not metanephrines increased in response to change of posture (norepinephrine, P =.03; epinephrine, P =.07) and intraoperative stress (norepinephrine, P =.002; epinephrine, P =.009). CONCLUSIONS: Plasma metanephrines offer improved efficacy for the diagnosis of pheochromocytoma. Less variability in response to external factors may favor plasma metanephrines in the screening for this disease. Arch Intern Med. 2000;160:2957-2963

Adrenal Gland Neoplasms↗
PubMed2002

Rapid analysis of metanephrine and normetanephrine in urine by gas chromatography-mass spectrometry.

BACKGROUND: Widely used HPLC methods for quantification of metanephrine and normetanephrine in urine often have long analysis times and are frequently plagued by drug interferences. We describe a gas chromatography-mass spectrometry method designed to overcome these limitations. METHODS: Metanephrine and normetanephrine conjugates were converted to unconjugated metanephrine and normetanephrine by acid hydrolysis. To avoid the rapid decomposition of the deuterated internal standards (metanephrine-d(3) and normetanephrine-d(3)) under hydrolysis conditions, the internal standards were added after hydrolysis. Solid-phase extraction was used to isolate the hydrolyzed metanephrines from urine. Samples were concentrated by evaporation, then derivatized simultaneously with N-methyl-N-(trimethylsilyl)trifluoroacetamide and N-methyl-bis-heptafluoro-butryamide at room temperature. RESULTS: The assay was linear from 25 to 7000 microg/L. The intraassay CVs were < 5 % and the interassay CVs < 12%. Comparison with a routine HPLC method (n = 192) by Deming regression yielded a slope of 1.00 +/- 0.02 microg/L, an intercept of -5.8 +/- 7.8 micro/L, and S(y/x) = 50.6 microg/L for metanephrine and a slope of 0.94 +/- 0.03, intercept of 19 +/- 11 microg/L, and S(y/x) = 60 microg/L for normetanephrine. The correlation coefficients (r) were calculated after log transformation of the data and gave r = 0.97 for metanephrine and r = 0.97 for normetanephrine. Interference from common medications or drug metabolites was seen in <1% of samples. The time between sequential injections was < 7 min. CONCLUSIONS: This new gas chromatography-mass spectrometry assay for total fractionated metanephrines is rapid, compares well with a standard HPLC assay, and avoids most drug interferences that commonly affect HPLC assays for urine metanephrines.

Biomarkers, Tumor↗
PubMed2005

The use of plasma metanephrine to normetanephrine ratio to determine epinephrine poisoning.

BACKGROUND: Intravenous epinephrine (EPI) is used as a pharmacologic agent to acutely treat patients in cardiac arrest. Unfortunately, there have been several homicide cases where hospitalized patients died due to a purposeful overdose of epinephrine. We measured plasma epinephrine metabolites (metanephrine, MET, and normetanephrine, NMET) to determine if exogenous epinephrine can be distinguished from endogenous epinephrine concentrations in a controlled animal study. METHODS: Rabbits were subjected to three different protocols. In the physiologic stress group (n=8), rabbits were immobilized for 30 min in a restraining tube. In the sub-lethal dose (n=9), 0.01 mg/kg of epinephrine was injected into anesthetized rabbits. In the lethal dose group (n=8), 1.0 mg/kg of epinephrine was administered into anesthetized rabbits. Blood was collected at regular intervals for up to 480 min. The plasma metanephrine and normetanephrine concentrations were measured by liquid chromatography/mass spectrometry and the serum cortisol concentrations by immunoassay. RESULTS: Serum cortisol and plasma metanephrine and normetanephrine concentrations increased in the stressed animals during immobilization demonstrating the endogenous stress model. Following a sub-therapeutic epinephrine dose, plasma metanephrine increased while plasma normetanephrine decreased. The peak plasma metanephrine concentrations were similar to the concentrations observed in the stressed animals; however, the ratio of plasma metanephrine to normetanephrine was significantly different. In the lethal epinephrine dose, both the plasma metanephrine concentrations and ratio of metabolites were significantly greater than those observed in the endogenously stressed animals. CONCLUSIONS: The ratio of plasma metanephrine to normetanephrine is the best marker to determine the presence of exogenous therapeutic and lethal epinephrine administration. However, there were limitations to the study design that could alter these conclusions.

Animals↗
PubMed2001

Disappearance rate of catecholamines, total metanephrines, and neuropeptide Y from the plasma of patients after resection of pheochromocytoma.

BACKGROUND: Plasma free metanephrines are a more reliable analyte to measure than catecholamines for the biochemical diagnosis of pheochromocytomas. We hypothesized that the long persistence of total (sulfate-conjugated plus free) metanephrines in the blood might have a significant diagnostic value. METHODS: We measured plasma concentrations of catecholamines and total metanephrines (sulfate-conjugated plus free forms) by HPLC with amperometric detection, and neuropeptide Y (NPY) by an amplified ELISA in seven patients before and after removal of their pheochromocytomas. The results for catecholamine, total metanephrines, and NPY in each patient were analyzed for up to 120 min, starting from the time of tumor vessel clamping. The persistence of analytes was quantified as the area under the concentration-time curve over 120 min. RESULTS: On the basis of the upper reference limit for each variable, plasma free norepinephrine (NE) and epinephrine (E) concentrations were increased preoperatively in at least one sample in seven and six patients, respectively. Total normetanephrine (NMN) and metanephrine (MN) were increased in all samples in seven and six patients, respectively. NPY was increased 2- to 465-fold. After removal of the tumor, MN and NMN showed a higher average relative increase above the upper limit of the reference interval than NE and E (P = 0.05), whereas NPY was intermediate. The persistence of increased values was significantly shorter for catecholamines than for metanephrines. The half-life estimated by nonlinear regression was 12.3 +/- 7.8 min for NPY. Significant correlations were observed among NE, E, NMN, MN, and NPY concentrations, but parent markers (E and MN or NE and NMN) did not appear significantly intercorrelated. CONCLUSIONS: A larger increase and a longer persistence of total metanephrines (reflecting predominantly sulfo-conjugated metanephrines) than catecholamines and NPY in plasma may contribute to their greater diagnostic accuracy in pheochromocytoma.

Catecholamines↗
PubMed1986

Radioimmunoassay of metanephrine and normetanephrine for diagnosis of pheochromocytoma.

Sensitive and specific radioimmunoassays of metanephrine and normetanephrine were developed by use of 125I-labeled synephrine and specific metanephrine antibody, and 125I-labeled octopamine and specific normetanephrine antibody. Specific antibody for both metanephrine and normetanephrine was raised in rabbits by immunization with bovine serum albumin conjugated with the corresponding hapten, prepared by the method of Grota and Brown (Endocrinology 1976;98:615). The detection limits of the metanephrine and the normetanephrine radioimmunoassays were 2 and 6 pg/tube, respectively. Mean plasma metanephrine and normetanephrine values for 24 normal subjects were 62 (SD 14) and 100 (SD 40) ng/L, respectively. Mean urinary metanephrine and normetanephrine values for 22 normal subjects were 154 (SD 74) and 217 (SD 109) micrograms/day. For 14 pheochromocytoma patients, plasma metanephrine and normetanephrine values ranged from 29 to 683 and from 28 to 7850 ng/L, and urinary metanephrine and normetanephrine values were 606 to 6630 and 296 to 4800 micrograms/day, respectively. The present methods are simple and suitable for routine tests or for mass screening for pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1981

Urinary metanephrine radioimmunoassay: comparison with the colorimetric assay.

A radioimmunoassay involving an 125I ligand has been developed and applied to the measurement of urinary metanephrine. To validate the clinical usefulness of this assay, we compared measurement of metanephrine by radioimmunoassay and of total urinary metanephrines by the Pisano colorimetric method. The radioimmunoassay is specific for metanephrine, whereas the colorimetric method measures both metanephrine and normetanephrine. We used both methods to determine urinary metanephrine or total metanephrines in subjects with essential hypertension, pheochromocytoma, the syndrome of multiple endocrine adenomatosis type 2, and normotensive volunteers. The mean and upper limit of normal (3 SD) for metanephrine by radioimmunoassay in our normotensive volunteers was 94.2 microgram/24 h and 229 microgram/24 h, respectively, which compares well with reported values of 87.6 microgram/24 h and 319 microgram/24 h by non-radioimmunoassay methods. Both radioimmunoassay and colorimetry accurately identified five patients with known pheochromocytoma. Good correlation (r = 0.993) was demonstrated between the two assays in a comparison of patients with essential hypertension and pheochromocytoma. We conclude that the radioimmunoassay is at least equivalent to the colorimetric methods in distinguishing pathological and normal catecholamine secretion, and is faster, more precise, and 1000-fold more sensitive.

Adrenal Gland Neoplasms↗
PubMed2005

Measurement of fractionated plasma metanephrines for exclusion of pheochromocytoma: Can specificity be improved by adjustment for age?

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.

Journal Article↗