Plasma Normetanephrine Research Articles

Comparison of free plasma metanephrines enzyme immunoassay with 131I-MIBG scan in diagnosis of pheochromocytoma

Measurement of free plasma metanephrines (metanephrine and normetanephrine), usually performed by high-performance liquid chromatography with electrochemical detection (HPLC-ECD), has been recommended as the single biochemical test of choice for the diagnosis of pheochromocytoma. Alternatively, a widely available, simple means to measure these biomarkers with enzyme immunoassay (EIA) needs to be studied. The aim of this study was to investigate the diagnostic efficacy of such a method in comparison with (131)I-metaiodobenzylguanidine (MIBG) whole body scan (WBS) in patients with pheochromocytoma. We enrolled patients undergoing (131)I-MIBG WBS due to clinical findings suggestive of pheochromocytoma (n = 45), and patients with primary hypertension (n = 36). All subjects had blood tests for free plasma metanephrine (MN) and normetanephrine (NM) with a commercially available EIA kit. WBS was positive in 30 pheochromocytoma patients and negative in 15 refuted ones, with 100% accuracy. The sensitivity, specificity and accuracy of MN and NM in combination (either or both positive) were 96.7%, 86.3% and 90.1%, showing comparable diagnostic performance both to (131)I-MIBG WBS (all p > 0.1), and also to the same markers measured with HPLC-ECD reported in the literature. These results showed that the EIA method may be eligible as an alternative to HPLC-ECD for plasma metanephrine determination in the identification of pheochromocytoma.

Plasma catecholamine and nephrine responses to brief intermittent maximal intensity exercise

Catecholamines (noradrenaline, NA; adrenaline, AD; dopamine, DA) influence the metabolic and cardiovascular responses to exercise. However, changes in catecholamine metabolism during exercise are unclear. Plasma normetanephrine (NMET), metanephrine (MET) and catecholamine responses to a laboratory-based model of games-type exercise were examined. Twelve healthy men completed a resting control trial and a trial consisting of ten 6 s cycle ergometer sprints interspersed with 30 s recovery, in randomised order. Resting and post-sprint venous blood samples were taken. Plasma NA and AD increased after each sprint but DA was unaltered. Plasma nephrines increased significantly from sprint 4 onwards with peak NMET increasing 60% to 0.76 +/- 0.19 nmol l(-1) and MET 230% to 0.37 +/- 0.16 nmol l(-1) from resting values (P < 0.05). The results demonstrate increased catecholamine metabolism via elevated catechol-O-methyl transferase activity during intermittent sprinting. The results may aid regulation of the metabolic and cardiovascular responses to exercise by maintaining tissue adrenoceptor sensitivity to circulating catecholamines.

Plasma Free Metanephrine Measurement Using Automated Online Solid-Phase Extraction HPLC–Tandem Mass Spectrometry

Quantification of plasma free metanephrine (MN) and normetanephrine (NMN) is considered to be the most accurate test for the clinical chemical diagnosis of pheochromocytoma and follow-up of pheochromocytoma patients. Current methods involve laborious, time-consuming, offline sample preparation, coupled with relatively nonspecific detection. Our aim was to develop a rapid, sensitive, and highly selective automated method for plasma free MNs in the nanomole per liter range. We used online solid-phase extraction coupled with HPLC-tandem mass spectrometric detection (XLC-MS/MS). Fifty microliters plasma equivalent was prepurified by automated online solid-phase extraction, using weak cation exchange cartridges. Chromatographic separation of the analytes and deuterated analogs was achieved by hydrophilic interaction chromatography. Mass spectrometric detection was performed in the multiple reaction monitoring mode using a quadrupole tandem mass spectrometer in positive electrospray ionization mode. Total run-time including sample cleanup was 8 min. Intra- and interassay analytical variation (CV) varied from 2.0% to 4.7% and 1.6% to 13.5%, respectively, whereas biological intra- and interday variation ranged from 9.4% to 45.0% and 8.4% to 23.2%. Linearity in the 0 to 20 nmol/L calibration range was excellent (R(2) > 0.99). For all compounds, recoveries ranged from 74.5% to 99.6%, and detection limits were <0.10 nmol/L. Reference intervals for 120 healthy adults were 0.07 to 0.33 nmol/L (MN), 0.23 to 1.07 nmol/L (NMN), and <0.17 nmol/L (3-methoxytyramine). This automated high-throughput XLC-MS/MS method for the measurement of plasma free MNs is precise and linear, with short analysis time and low variable costs. The method is attractive for routine diagnosis of pheochromocytoma because of its high analytical sensitivity, the analytical power of MS/MS, and the high diagnostic accuracy of free MNs.

Free plasma metanephrines as a screening test for pheochromocytoma in low-risk patients

Detection of free plasma metanephrines seems to be the most exact method for biochemical diagnosis of pheochromocytoma, but their diagnostic efficacy in the common low-risk clinical settings is debated. A cross-sectional multicentre study including 1260 subjects assessed the diagnostic efficacy of free plasma metanephrine and normetanephrine in low-risk patients screened for resistant or markedly accelerated hypertension, paroxysmal hypertension, 'flushes' and, in a small proportion, for adrenal incidentaloma or genetic predisposition to pheochromocytoma. Pheochromocytoma was identified and verified by histology in 25 subjects (2%), with the diagnosis not confirmed by long-term follow-up or use of imaging techniques in the remaining 1235 individuals. The combined assay of free plasma metanephrines was a highly sensitive (100%) and specific (96.7%) measure, yielding a negative predictive value of 100%. The satisfactory diagnostic efficacy of free plasma metanephrines allows their use as a single screening test in cases of suspected pheochromocytoma in the population with a low pretest probability.

Possible New Causes For False-Positive Diagnosis of Pheochromocytoma

Sir: Pheochromocytomas are rare neuroendocrine tumors diagnosed by elevated plasma and/or urine catecholamines or their metabolites.1,2 Medications reported to cause false-positive serum or urine studies include acetaminophen, phenoxybenzamine, amitriptyline, labetolol, haloperidol, levodopa, tamsulosin, venlafaxine, hydrochlorothiazide, and buspirone.2,3 We report a case in which lamotrigine, aripiprazole, or both caused symptoms and biochemical evidence suggesting pheochromo-cytoma that resolved when the drugs were discontinued. There are no previous reports of lamotrigine or aripiprazole associated with false-positive biochemical testing for pheochromocytoma. Case report. Mr. A, a 60-year-old white man, presented in May 2005 with anxiety, palpitations, and panic attacks starting 3 months prior to evaluation, immediately after he underwent cardiac bypass surgery. He had no medical complications peri-operatively and initially attributed his symptoms to the stress of surgery. He was seen by Psychiatry and diagnosed with depression, attention-deficit/hyperactivity disorder, and bipolar disorder and placed on treatment with aripiprazole, lamotrigine, and venlafaxine. Mr. A's attacks became more frequent, and he felt incapacitated. On examination, he appeared anxious. His blood pressure was 141/96 mm Hg, and his pulse was 97 bpm. The remainder of his examination was unremarkable. Additional medical history of the patient included hypothyroidism, hypertension, and obstructive sleep apnea. At initial presentation to the Division of Diabetes, Endocrinology and Metabolism, 3 months after his first evaluation by Psychiatry, his medications were lamotrigine, venlafaxine, and aripiprazole in addition to tamsulosin, aspirin, levothyroxine, amlodipine, benazepril, and rosuvastatin. He was taken off tamsulosin and venlafaxine to undergo biochemical testing for pheochromocytoma. Laboratory tests showed elevated urine and plasma normetanephrines (Table 1). Abdominal computed tomography scan and metaiodobenzyl-guanidine (MIBG) scan findings were normal. Table 1. Biochemical Workup for Pheochromocytoma We discontinued lamotrigine and aripiprazole treatment and repeated plasma and urine studies 3 weeks later, at which time results of Mr. A's plasma and urine studies had normalized, and his symptoms had resolved (Table 1). Lamotrigine is an antiseizure medication, and aripiprazole is a new atypical antipsychotic; both are used in the treatment of bipolar disorder. Lamotrigine prolongs the refractory phase of voltage-gated sodium channels.4 Aripiprazole is a partial D2 agonist and acts differently from the existing atypical antipsy-chotics.5 Neither drug has an obvious mechanism for raising catecholamines or its metabolites. Given the severity of our patient's symptoms, both drugs were stopped simultaneously. His laboratory values returned to normal, and his symptoms resolved completely. He is unwilling to reintroduce each medication separately to determine if the effect observed was an individual drug effect or a synergistic occurrence. Additional reports are needed to evaluate this further. Given this case, we recommend considering lamotrigine and aripiprazole as 2 additional medications that could cause a false-positive biochemical result when evaluating for pheochromocytoma. Dr. Goldner has received honoraria from Abbott and Takeda and has been a member of the speakers/advisory board for Takeda.

Diagnostic value of various biochemical parameters for the diagnosis of pheochromocytoma in patients with adrenal mass

Pheochromocytomas are neoplasms generally characterized by the autonomous production of catecholamines. This study compared various biochemical parameters for the diagnosis of adrenal pheochromocytoma in patients with adrenal mass. One hundred and fifty subjects were studied, including 24 histologically proven pheochromocytomas, 17 aldosterone-secreting and 21 cortisol-secreting adrenal adenomas and 30 nonfunctioning adrenal masses, 16 patients with essential hypertension and 42 healthy normotensive volunteers. Spontaneous blood samples and 24-h urine samples were collected prospectively. Plasma and urinary epinephrine and norepinephrine levels were measured by high performance liquid chromatography, whereas plasma and urinary metanephrine and normetanephrine levels were determined by radioimmunoassay (RIA). Putative ratio thresholds were calculated by receiver operating characteristic (ROC) analysis to balance between sensitivity and specificity. Plasma normetanephrine was found to be the best single parameter with the highest sensitivity (91.7%) and specificity (95.6%) using a threshold of 126 pg/ml. In combination, plasma normetanephrine and metanephrine had a higher sensitivity of 95.8% with lower specificity (79.4%). All other combinations of plasma and/or urinary parameters demonstrated a lower accuracy. Plasma metanephrines measured by RIA are reliable screening parameters for the diagnosis of pheochromocytoma.

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.

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

BackgroundBiochemical 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.MethodsAn 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.ResultsThe 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).ConclusionAn 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.

Plasma metanephrines in renal failure

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. 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. 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. 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.

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.

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.

Nonparametric Determination of Reference Intervals for Plasma Metanephrine and Normetanephrine

Measurement of plasma metanephrine and normetanephrine concentrations has recently been acknowledged as one of the leading tests for the diagnosis of the neuroendocrine tumor, pheochromocytoma (1). The occurrence of the tumor is rare, and it is often difficult to diagnose. The wide spectrum of signs and symptoms includes hypertension, headaches, and diaphoresis. Located primarily in the adrenal gland, these tumors produce excess catecholamines and their metabolites. Assays have been developed to measure catecholamines and metanephrines in both plasma and urine. Although tests for all of these compounds can be diagnostically useful, measurement of metanephrine and normetanephrine in plasma has been reported as a particularly sensitive and specific indicator of the disease. The utility of the test is limited by uncertainty of the predictive value of measured concentrations. This is attributable in part to ambiguity in published reference intervals for these analytes. Lenders et al. (1) reported upper reference limits of 0.3 nmol/L for plasma metanephrine and 0.6 nmol/L for normetanephrine, whereas a reference laboratory (2) reported values <0.5 nmol/L for metanephrine and <0.9 nmol/L for normetanephrine as within the reference interval. In this study, we established a reference interval by measuring metanephrine and normetanephrine concentrations in plasma collected from 120 volunteers after obtaining informed consent. Reference individuals (53 females and 67 males; age range, 20–73 years) fasted for 12 h before sampling. Interviews were conducted to excuse individuals taking medications, particularly for hypertension. All participants were sitting upright as their blood was collected by needlestick. The whole blood, in EDTA, was stored at 2–8 °C until it was centrifuged within a few hours after collection. Plasma was separated and stored at −70 °C until …

Measurement of plasma free metanephrine and normetanephrine by liquid chromatography-tandem mass spectrometry for diagnosis of pheochromocytoma.

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. After solid-phase extraction, chromatographic separation of normetanephrine (NMN) and metanephrine (MN) was accomplished by use of a cyano analytical column. NMN, MN, d(3)-NMN, and d(3)-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. 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. 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.

Laparoscopic Management of Extra-Adrenal Pheochromocytoma

Laparoscopic management of extra-adrenal pheochromocytoma presents a unique surgical challenge due to variable anatomical presentation and potential catecholamine surge during operative manipulation. We report our experience with laparoscopic removal of extra-adrenal pheochromocytomas. Between 1999 and 2002, 5 patients presented with retroperitoneal extra-adrenal pheochromocytomas. Of the patients 2 had a history of von Hippel-Lindau disease, and the remaining 3 patients were diagnosed with sporadic extra-adrenal pheochromocytoma during hypertension evaluation. Although 4 patients had a history of hypertension, only 2 reported symptoms (episodic flushing, headaches, blurred vision) associated with excess catecholamine production. All patients had markedly increased preoperative urinary and plasma normetanephrine and/or norepinephrine levels, and 3 had positive I131 metaiodobenzylguanidine scan. In each case tumor was accurately identified on computerized tomography before surgery. Laparoscopic resection of extra-adrenal pheochromocytoma was successful in 4 patients. Open conversion was required in 1 patient, who also had von Hippel-Lindau related bilateral adrenal pheochromocytomas due to significant adhesion of the extra-adrenal tumor to the aorta and renal hilum, and a concern for possible local invasion. Mean laparoscopic operative time and blood loss were 273 minutes (range 240 to 350) and 119 cc (range 75 to 200), respectively. Three 10 mm ports in a standard triangular fashion were used for the left side tumors, in which the tumors were found lateral to the aorta. For the right side tumors located either in the inter-aortacaval or para-caval region, a fourth port (10 mm) was inserted for liver retraction as needed. Laparoscopic ultrasound was used to localize the tumor and to assess the retroperitoneum for possible metastasis (none detected) in 3 cases. None of the patients had a hypertensive crisis intraoperatively, and all had unremarkable postoperative recovery with an average hospital stay of 3.8 days (range 3 to 4). Plasma and/or urinary norepinephrine and normetanephrine levels returned to normal range postoperatively in all cases. One patient was noted to have left lower extremity lymphedema and gluteal hematoma due to a positional injury related to prolonged pressure from the operating table and was treated conservatively. There has been no tumor recurrence at a median followup of 14 months (range 9 to 36). With careful surgical planning and appropriate preoperative pharmacological blockade, laparoscopic surgery can be safely performed in patients with extra-adrenal pheochromocytomas with minimal morbidity. Laparoscopic ultrasound may be helpful in precise localization and evaluation of tumor extension.

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.

Pheochromocytoma in a Patient With End-Stage Renal Disease

Pheochromocytoma is a rare tumor. To our knowledge only 15 cases have been reported in patients with end-stage renal disease (ESRD). We describe a 46-year-old woman with ESRD and a history of paroxysmal and difficult-to-control hypertension. During anesthesia for a surgical procedure, the patient experienced blood pressure lability with systolic blood pressures ranging from 76 to 360 mm Hg. Serum catecholamine concentrations were 2,698 pg/ mL (reference value, <750 pg/mL) for norepinephrine, 33 pg/mL (<110 pg/mL) for epinephrine, and 55 pg/mL (<30 pg/mL) for dopamine. The concentrations of plasma metanephrines were 6.84 nmol/L (<0.50 nmol/L) for metanephrine and 14.64 nmol/L (<0.90 nmol/L) for normetanephrine. Abdominal computed tomography showed a right-sided, 4-cm mass posterior to the infrahepatic inferior vena cava. Following blood pressure control with alpha- and beta-adrenergic blockade, the mass was removed. Pathologic examination demonstrated the mass was a pheochromocytoma. The maximum postoperative systolic blood pressure was 160 mm Hg. Postoperative plasma normetanephrine concentration was 2.80 nmol/L, and metanephrine was obscured by interfering substances. This case report and literature review emphasizes the difficulty in diagnosing pheochromocytomas in patients with ESRD despite the myriad of available diagnostic tests.

Quantification of Unconjugated Metanephrines in Human Plasma without Interference by Acetaminophen

Pheochromocytoma is a rare cause of hypertension resulting from increased catecholamine secretion. We aimed to develop a method to measure unconjugated plasma normetanephrine (NMN) and metanephrine (MN) without interference from acetaminophen, a widely prescribed drug for headaches. Plasma samples were obtained from 48 subjects (23 males, 25 females; mean age, 49 +/- 14 years; hypertension, n = 37) under resting conditions. Following extraction on solid-phase cation-exchange columns, unconjugated metanephrines were analyzed by HPLC with electrochemical detection and with 4-hydroxy-3-methoxybenzylamine as an internal standard. Catecholamines were measured by HPLC. The assays were linear up to 2000 pg for NMN and for MN. Intraassay imprecisions (CVs) were 4.7% for NMN and 7.0% for MN, and the interassay CV was 12% for both NMN and MN. The limit of detection was 11 fmol for NMN and 17 fmol for MN. Ingestion of acetaminophen or its addition to plasma did not interfere with the MN peaks. Plasma NMN and MN were positively correlated (r = 0.52 and 0.49, respectively; P <0.01 for both) with the respective catecholamines. Plasma NMN (r = 0.27; P = 0.02) but not MN positively correlated with age, whereas only plasma catecholamines (and not metanephrines) were positively correlated (P <0.05) with diastolic blood pressure. This sensitive MN assay is not affected by simultaneous acetaminophen medication, and reveals a correlation of metanephrines with plasma and urinary catecholamines and age but not with blood pressure.

Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2.

The detection of pheochromocytomas in patients at risk for these tumors, such as patients with von Hippel-Lindau disease or multiple endocrine neoplasia type 2 (MEN-2), is hindered by the inadequate sensitivity of commonly available biochemical tests. In this study we evaluated measurements of plasma normetanephrine and metanephrine for detecting pheochromocytomas in patients with von Hippel-Lindau disease or MEN-2. We studied 26 patients with von Hippel-Lindau disease and 9 patients with MEN-2 who had histologically verified pheochromocytomas and 50 patients with von Hippel-Lindau disease or MEN-2 who had no radiologic evidence of pheochromocytoma. Von Hippel-Lindau disease and MEN-2 were diagnosed on the basis of germ-line mutations of the appropriate genes. The plasma concentrations of normetanephrine and metanephrine were compared with the plasma concentrations of catecholamines (norepinephrine and epinephrine) and urinary excretion of catecholamines, metanephrines, and vanillylmandelic acid. The sensitivity of measurements of plasma normetanephrine and metanephrine for the detection of tumors was 97 percent, whereas the other biochemical tests had a sensitivity of only 47 to 74 percent. All patients with MEN-2 had high plasma concentrations of metanephrine, whereas the patients with von Hippel-Lindau disease had almost exclusively high plasma concentrations of only normetanephrine. One patient with von Hippel-Lindau disease had a normal plasma normetanephrine concentration; this patient had a very small adrenal tumor (<1 cm). The high sensitivity of measurements of plasma normetanephrine and metanephrine was accompanied by a high level of specificity (96 percent). Measurements of plasma normetanephrine and metanephrine are useful in screening for pheochromocytomas in patients with a familial predisposition to these tumors.

Genetic Deficiencies of Monoamine Oxidase Enzymes: A Key to Understanding the Function of the Enzymes in Humans

Monoamine oxidase (MAO) plays a pivotal role in the noxidative deamination of catecholamines, serotonin, and the trace amines, phenylethylamine and tyramine. Pharmacological inhibition of MAO in animals and humans has profound neurophysiological effects by modulating neurotransmitter function. Consequently, it has been assumed that genetically determined variations of MAO activity might be associated with behavioral and mood disorders. Although the different substrate and inhibitor specificities of the two isoenzymes, MAO-A and MAO-B, are well documented, their relative roles for the metabolism of catecholamines in vivo are less established. The metabolism of catecholamines by MAO in vivo in humans can be examined in several ways. First, it is possible to block MAO pharmacologically by specific inhibitors. A second approach is to examine the metabolic fate of radiolabeled catecholamines and their metabolites. Third is to examine the catecholamines and their metabolites in subjects who have a genetically determined absence of one or both MAO isoenzymes. Knowledge of the specific patterns of metabolites associated with deficiency of a specific (iso-) enzyme offer diagnostic possibilities for detection of patients with genetic disorders of biogenic amine metabolism associated with psychiatric disturbances. Studies in rats have also shown that inhibition of MAO resulted in larger elevations of plasma normetanephrine (NMN) than of plasma metanephrine (MN). The contribution of the adrenal glands to the plasma concentration of NMN is much less than their contribution to the plasma concentration of metanephrine (MN) (40% versus. 90%), indicating that deamination does not play an important role in the degradation of catecholamines within the adrenal glands of MAO-A and MAO-B and a combined deficiency of MAO-A and MAO-B. This chapter on comparison of the selective deficiencies of MAO-A and MAO-B and the combined deficiency of MAO-AB provides insight into the metabolic roles of the MAO isoenzymes in humans.