Plasma Free Metanephrines Research Articles

Peripartum Hypertension from Pheochromocytoma: A Rare and Challenging Entity

Pheochromocytoma, a rare and usually curable cause of hypertension, is characterized by symptoms and signs related to increased catecholamine secretion. Pregnancy can elicit clinical manifestations of otherwise unrecognized pheochromocytoma. Four women, ranging in age from 27 to 37 years, were referred to the hypertension clinic with the following presentations: 1) a 35-year-old woman, diagnosed with gestational hypertension and headaches during the third trimester of her pregnancy and 5 months after delivery, was hospitalized with pulmonary edema. Echocardiography revealed severe dilated left ventricular (LV) dysfunction. Cardiac function was normalized after surgical resection of a pheochromocytoma from her left adrenal; 2) a 37-year-old woman suffered from preeclampsia, persistent hypertension and orthostatic hypotension after a cesarean section. A diagnostic work-up revealed a catecholamine-secreting paraganglioma in the retroperitoneum. The patient underwent a laparosopic resection of the tumor; 3) a 27-year-old woman suffered from hypertension and episodes of palpitations, sweating, and dyspnea in the first trimester of her pregnancy. An ultrasound revealed a 5-cm mass in the left adrenal. She underwent a left adrenalectomy at the 17th week of pregnancy, which confirmed the diagnosis of pheochromocytoma; 4) a 34-year-old woman, at the 26th week of pregnancy, presented with an acute loss of vision and blood pressure of 230/140 mm Hg. Fundoscopy showed papilledema with soft exudates in both eyes. Chemical studies were positive and imaging revealed a left adrenal pheochromocytoma. Despite aggressive medical treatment, fetal distress mandated a laparotomy at the end of the 28th week of pregnancy. A healthy newborn was delivered and resection of the adrenal tumor confirmed the diagnosis of pheochromocytoma. Although rare, pheochromocytoma can cause severe peripartum hypertension. Screening for pheochromocytoma, ideally with plasma-free metanephrines, should be considered in cases of peripartum hypertension.

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.

Adrenal incidentaloma diagnosed as pheochromocytoma by serum chromogranin A and plasma metanephrines

A 61 year old woman underwent an abdominal ultrasound for heartburn and mild renal insufficiency. A mass of the left adrenal gland was detected. CT and MRT confirmed a left adrenal mass of 2.5×1.7cm size. The patient suffered from stable hypertension without hypertensive attacks or other symptoms suggestive of pheochromocytoma. Under treatment with ramipril, hydrochlorothiazide and prazosin blood pressure was less than 140/90mm Hg. Timolol eye drops were administered for chronic glaucoma. In addition, the patient had diabetes mellitus type 2 with nephropathy and a hiatal hernia. She reported increasing hair-growth at chin and upper lip for about half a year. Except for obesity (height 164cm, weight 111kg), physical examination was otherwise unremarkable. Serum creatinine was 122µmol/l (normal: 45–84), DHEAS 5.32µmol/l (high), FSH 102 U/l (high), E2 29 pmol/l (low), electrolytes were normal. The low-dose (2mg) dexamethasone suppression test, plasma aldosterone/renin ratio, and initial 24h-urinary catecholamine and metanephrine levels were in the normal range. Serum chromogranin A was 517µg/l (normal: <110). A second determination of 24h-urinary catecholamines and metanephrines showed a less than 2-fold increase of metanephrines. Using HPLC, levels of free plasma metanephrine were 3-fold and of normetanephrine 2-fold elevated. An MIBG scan showed increased uptake only in the left adrenal region. Pheochromocytoma was suspected. Left-sided adrenalectomy was performed and pheochromocytoma histologically confirmed. Postoperatively, hypertension and diabetes mellitus improved. This case underscores the superiority of measuring free plasma metanephrines by HPLC for the diagnosis of pheochromocytoma during evaluation of an adrenal incidentaloma. In addition, it demonstrates that measuring serum chromogranin A in combination with urinary fractionated metanephrines can also be useful in this setting, especially in hospitals where HPLC-measured free plasma metanephrines cannot be determined.

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.

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, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour

Approximately 50% of patients with multiple endocrine neoplasia (MEN) 2A or 2B develop pheochromocytoma. These tumours are almost exclusively benign and localized in the adrenal glands. About one-third are bilateral at initial diagnosis. Amongst patients with pheochromocytoma, those with MEN 2A have subtler symptoms compared to those with sporadic disease. Since pheochromocytomas in patients with MEN 2 often secrete catecholamines episodically (but metabolize them continuously to metanephrines), the first choice for biochemical diagnosis is the measurement of free metanephrines in plasma, with urinary fractionated metanephrines being the second choice. In patients with pheochromocytomas that produce exclusively normetanephrine, MEN 2 can be excluded. In patients with biochemically proven MEN 2-related pheochromocytoma, anatomical imaging of the adrenals (with either computerized tomography or magnetic resonance) should be obtained next. Functional imaging with specific ligands (e.g. scintigraphy with [(123)I]-metaiodobenzylguanidine or, if available, positron emission tomography with [(18)F]-fluorodopamine, [(18)F]-dihydroxyphenylalanine, [(11)C]-adrenaline or [(11)C]-hydroxyephedrine) may then be particularly useful in patients with distorted anatomy from previous surgery, in cases of equivocal biochemical data despite high clinical suspicion for a tumour, to rule out multifocal disease, or where there is suspicion of metastatic disease (e.g. tumours larger than 5 cm). Laparoscopic surgery is the treatment of choice and subtotal (cortical-sparing) adrenalectomy is the procedure of choice in bilateral pheochromocytomas.

Pheochromocytoma: current perspectives in the pathogenesis, diagnosis, and management

Pheochromocytomas (pheo) cause the most dramatic, life-threatening crises in all of endocrinology. A proper screening for pheo must be performed in any patient who has: 1) episodic headaches, tachycardia, and diaphoresis; 2) family history of pheo or multiple endocrine neoplasia; 3) incidental suprarenal mass; 4) paroxysms of tachyarrhythmias or hypertension; 5) adverse cardiovascular responses to anesthetic agents, histamine, phenothiazine, tricyclic antidepressants, etc); and 6) spells occurring during exercise, straining, etc. The key to diagnosing pheo is to suspect it, then to confirm it. Early recognition of its presence is critical to avoiding significant morbidity and mortality. Once suspected, the diagnosis can be confirmed with biochemical testing in virtually all patients. The combination of resting plasma catecholamines > or =2000 pg/mL and urinary metanephrines > or =1.8 mg/24 h has a diagnostic accuracy of 98% in both sporadic and hereditary pheos. When available, measurement of plasma free metanephrines should be performed especially in hereditary pheos. Provocative (glucagon) and suppression tests (clonidine) may be necessary when baseline measurements are inconclusive. CT and MRI are equally sensitive for localization (98% and 100%, respectively), but have lower specificities (70% and 67%). MIBG is 100% specific, but less sensitive (78%). The availability of various medical (selective alpha-1- and beta-adrenergic receptor antagonists, calcium channel blockers) and surgical modalities have made successful management more promising than ever before.

Plasma Metanephrines: the Optimal Diagnostic Tool for Pheochromocytoma?

Diagnosis of pheochromocytoma depends on biochemical evidence of catecholamine production by the tumor, but the best test for establishing the diagnosis remains unsettled. The objective of this study was to determine which biochemical test or combination of tests provides the optimal method for diagnosis of pheochromocytoma.; Tests of plasma catecholamines, plasma free metanephrines, and urinary catecholamines, total and fractionated metanephrines and vanillylmandelic acid (VMA) were compared in 858 patients tested for pheochromocytoma on clinical suspicion of the tumor. Pheochromocytoma was confirmed in 214 patients and excluded in 644 patients according to independent standard criteria (surgical pathology, imaging studies, follow-up).; Sensitivities of plasma free metanephrines (99%) and urinary fractionated metanephrines (97%) were higher than those for plasma catecholamines (84%), urinary catecholamines (86%), urinary total metanephrines (77%) or VMA (64%). Specificity was highest for urinary VMA (95%) and urinary total metanephrines (93%), intermediate for plasma free metanephrines (89%), urinary catecholamines (88%) and plasma catecholamines (81%) and lowest for urinary fractionated metanephrines (69%). As shown by receiver-operating characteristic curves, aggregate sensitivity and specificity values at different upper reference limits were highest for plasma free metanephrines. Combining different tests did not improve the diagnostic yield significantly beyond that of a single test of plasma free metanephrines.; Measurements of plasma free metanephrines or urinary fractionated metanephrines are equally effective in excluding pheochromocytoma. However, due to the higher specificity of plasma than urinary fractionated metanephrines, plasma free metanephrines should be the test of first choice in the diagnostic work-up of a patient with suspected pheochromocytoma.

What's new in general surgery: endocrine surgery.

t t c n a t t c C p d C c o drenal n 1911, Dr Harvey Cushing said, “I would like to see he day when somebody would be appointed surgeon omewhere who had no hands, for the operative part is he least part of the work.” In no area of endocrine urgery is this more true than in the diagnostic workup nd surgical planning of patients with adrenal patholgy. The past year saw the publication of a consensus onference on diagnosis and treatment of Cushing’s synrome. Although only 20% of Cushing’s syndrome paients have ACTH-independent Cushing’s resulting rom an adrenal source, the article provides an excellent onsensus statement on the diagnostic criteria needed in he workup of these complex and often challenging atients. Another important area for the endocrine surgeon is he laboratory diagnosis of pheochromocytomas. Auhors from the Mayo Clinic compared their experience efore the use of fractionated, plasma-free metanephrine 1978 to 1996) with current data obtained after the ntroduction of such testing. Plasma metanephrines ad a sensitivity of 96%, yet a specificity of only 85%. heir experience demonstrated that biochemical testing or pheochromocytomas should be directed by the deree of clinical suspicion. Fractionated, plasma-free etanephrines were ideal in patients with a high pretest robability of the disease, such as familial patients MEN IIa, IIb, von Hippel-Lindau [VHL], neurofibroatosis type 1, or familial paraganglion syndrome) or atients in whom urinary collection is problematic (peiatric population). In the more common scenarios, hose with incidentalomas, or patients with poorly con-

A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma.

BackgroundFractionated plasma metanephrine measurements are commonly used in biochemical testing in search of pheochromocytoma.MethodsWe aimed to critically appraise the diagnostic efficacy of fractionated plasma free metanephrine measurements in detecting pheochromocytoma. Nine electronic databases, meeting abstracts, and the Science Citation Index were searched and supplemented with previously unpublished data. Methodologic and reporting quality was independently assessed by two endocrinologists using a checklist developed by the Standards for Reporting of Diagnostic Studies Accuracy Group and data were independently abstracted.ResultsLimitations in methodologic quality were noted in all studies. In all subjects (including those with genetic predisposition): the sensitivities for detection of pheochromocytoma were 96%–100% (95% CI ranged from 82% to 100%), whereas the specificities were 85%–100% (95% CI ranged from 78% to 100%). Statistical heterogeneity was noted upon pooling positive likelihood ratios when those with predisposition to disease were included (p < 0.001). However, upon pooling the positive or negative likelihood ratios for patients with sporadic pheochromocytoma (n = 191) or those at risk for sporadic pheochromocytoma (n = 718), no statistical heterogeneity was noted (p = 0.4). For sporadic subjects, the pooled positive likelihood ratio was 5.77 (95% CI = 4.90, 6.81) and the pooled negative likelihood ratio was 0.02 (95% CI = 0.01, 0.07).ConclusionNegative plasma fractionated free metanephrine measurements are effective in ruling out pheochromocytoma. However, a positive test result only moderately increases suspicion of disease, particularly when screening for sporadic pheochromocytoma.

Development of enantioselective immunoassays for free plasma metanephrines.

The development of an enantioselective radioimmunoassay (RIA) and enzyme immunoassay (EIA) for L-normetanephrine (NM) and L-metanephrine (M) were studied. Prior to the immunoassay, the protein matrix of the ethylenediaminetetraacetic acid (EDTA) plasma samples was removed by acid precipitation, followed by derivatization of the L-metanephrines to N-acyl-L-metanephrines. For the EIA, N-acyl-L-NM and N-acyl-L-M were bound to the surface of microtiter plates. Acylated L-metanephrines from the sample and solid-phase-bound N-acyl-L-NM or N-acyl-L-M competed for a fixed number of rabbit anti-N-acyl-NM or anti-N-acyl-M antibody binding sites. When the system was in equilibrium, free antigens and free antigen-antibody complexes were removed by washing. The antibodies bound to the respective solid-phase N-acyl-L-NM or N-acyl-L-M were detected by a goat anti-rabbit IgG-peroxidase conjugate using tetramethyl benzidine (TMB) as a substrate. The RIAs were conventional double antibody tests using the above rabbit antisera and specific (125)I-N-acyl-L-metanephrine tracers. Chiral recognition of the L-enantiomers was observed not only for the native molecules but for all N-acyl derivatives tested. The cross-reactivity to the corresponding D-enantiomers was always <1%. The detection limits were found to be approximately 0.04 nmol/L (7.5 pg/mL) for M and 0.08 nmol/L (15 pg/mL) for NM in RIA and EIA.

Symptomatic pheochromocytoma with normal urinary catecholamine metabolites

A 61-year old female presented with paroxysmal hypertension and a 4.5cm left adrenal mass on CT scan. Repeated measurements of 24-hour urinary fractionated metanephrines, total catecholamines and vanillylmandelic acid (VMA) were within normal range. A further scintigraphic study with (131)I -metaiodobenzylguanidine ((131)I-MIBG) revealed selective concentration of the radiotracer, corresponding to the CT mass. After adequate preoperative treatment, successful surgical excision of the tumor was performed and the pathological examination confirmed the diagnosis of a cystic pheochromocytoma with a 2cm solid tumor. On reevaluation three months later using (131)I-MIBG, no evidence of remaining or recurrent disease was found. The patient, off any antihypertensive medication, reported mild recurrent hypertension and panic attacks that were adequately controlled with antidepressants. This is a rare case of a symptomatic pheochromocytoma without elevated urine catecholamines and metanephrines. According to the literature, plasma free metanephrines would be the ideal test for biochemical detection of the tumor. However, in the event that they are not available and there is a high clinical suspicion for the presence of pheochromocytoma, as in our patient, we suggest performance of a functional nuclear medicine study, such as (131)I-MIBG, to confirm the clinical diagnosis.

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.

Stability of plasma free metanephrines during collection and storage as assessed by an optimized HPLC method with electrochemical detection.

There is substantial evidence that plasma concentrations of the free (unconjugated) metanephrines metanephrine (MN) and normetanephrine (NMN) are better than other indices of catecholamine excess for detecting pheochromocytomas (1)(2)(3). However, it currently is unknown how stable these compounds are after blood collection and after separation of plasma as well as during storage. To investigate this, we modified the original method by Lenders et al. (4), which consists of HPLC with electrochemical detection, preceded by a prepurification step on cation-exchange columns, to increase the procedural recovery and thereby sensitivity. The principal adjustments were as follows: Before plasma was passed through the cation-exchange column, 1 mL of Aqua Dest and 135 μL of a solution of 0.2 mol/L ammonium acetate (pH 6.0) were added to 1 mL of plasma. The 135 μL of ammonium acetate solution included 100 μL of internal standard solution [108.7 nmol/L 3-ethoxy-4-hydroxyphenylethanolamine oxalate (EHPEA)] and 35 μL of ammonium acetate containing, only for addition experiments, MN and NMN. The calibrator mixture consisted of 19.5 nmol/L MN, 18.1 nmol/L NMN, and 108.7 nmol/L EHPEA in the aforementioned ammonium acetate solution, of which 140 μL was injected directly. After column elution, dried residues were dissolved in 150 μL of the ammonium acetate solution, of which 140 μL was injected. In all plasma samples assayed, MN and NMN peaks were completely separated from surrounding peaks by virtue of a slight increase in polarity of the mobile phase. Within-assay SDs, estimated from duplicate measurements of various samples (n = 11) containing 98–351 pmol/L MN and 129–350 pmol/L NMN, were 12.3 pmol/L for MN and 11.6 pmol/L for NMN (mean CVs, 7.0% and 4.5%, respectively). Single measurements of a control sample in 15 separate runs gave mean (SD) values of 207 (22.9) pmol/L (CV, 11%) for MN and 277 …

Clinical review 164: The laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience.

P a catecholamine-producing tumor arising in the adrenal medulla, has an estimated incidence of two to eight cases per million persons annually (1, 2). Its clinical hallmark is sustained or intermittent hypertension often associated with paroxysmal symptoms (3). Pheochromocytoma should also be considered if a patient has labile hypertension, hypertension resistant to antihypertensive therapy, or paroxysmal symptoms (“spells”) (3, 4). Correct diagnosis is important because resection of the tumor dramatically reverses the clinical symptoms and may cure the hypertension (5). A missed or delayed diagnosis may cause considerable morbidity and mortality (5, 6). Clinically significant pheochromocytoma was first recognized in 1926 when Cesar Roux in Switzerland and Charles H. Mayo in the United States successfully removed pheochromocytomas to cure the catecholamine-associated symptom complex (7, 8). A biochemical assessment of catecholamine hypersecretion was not possible in 1926. Since then, the diagnostic approach has progressed from clinical impressions and exploratory laparotomies to histamine stimulation and phentolamine suppression tests in the 1940s, crude catecholamine measurements and iv urograms in the 1950s and 1960s, and refined measurements of catecholamine levels and computerized imaging in the 1970s and 1980s. Most laboratories now measure catecholamines by HPLC with electrochemical detection or gas chromatography and mass spectrometry. Catecholamines and their metabolites can be measured in the blood or urine. There are major regional, institutional, and international differences in the approach to the biochemical diagnosis of pheochromocytoma. For example, at Mayo Clinic, physicians have relied on the 24-h urinary excretion of catecholamines and total metanephrines for more than 2 decades (9, 10). If the baseline 24-h urinary studies are normal, the study is repeated when the patient is symptomatic (e.g. with a spell). From 1976–1993, Mayo Clinic clinicians performed histamine and glucagon stimulation tests (with measurement of blood pressure and plasma fractionated catecholamines) in 542 patients in whom pheochromocytoma was highly suspected despite normal 24-h urinary catecholamine or total metanephrine excretion; none of these patients had a positive stimulation test in this setting (11). Thus, we did not find the addition of histamine and glucagon stimulation tests helpful after 24-h urinary testing. The most recent addition to the biochemical testing armamentarium is fractionated plasma free metanephrines, a test proposed to be the superior to urinary testing by some investigators (12, 13). Herein, we focus on the biochemical tests used to diagnose sporadic adrenal pheochromocytoma. To provide perspective, two datasets from Mayo Clinic are summarized: 1) historical data before the use of fractionated free plasma metanephrines (1978–1996), and 2) current data obtained after the introduction of fractionated free plasma metanephrines (after 1998).

Pheochromocytoma.

Pheochromocytoma is a rare tumor, but it represents a potentially curable form of hypertension. In patients with inherited pheochromocytoma, benign and bilateral tumors are more common. The diagnosis of pheochromocytoma rests in biochemical confirmation of catecholamine excess. Plasma-free metanephrine levels are arguably the most sensitive and specific test for the biochemical diagnosis of pheochromocytoma in high-risk patient populations. A timed 24-hour urine collection for total catecholamines and metabolic products (eg, vanillylmandelic acid and metanephrines) is the favored confirmatory test. Localization is most commonly accomplished with high-resolution computed tomography imaging, but magnetic resonance imaging can also be used. If both of these imaging modalities are nonlocalizing or equivocal, then radiolabeled meta-iodobenzylguanidine or somatostatin can be used to identify an adrenal or extra-adrenal tumor (paraganglioma). These imaging modalities can be used in the evaluation of patients with suspected or confirmed recurrent or metastatic disease. Systemic therapies for the treatment of patients with recurrent or metastatic disease have been disappointing. Radiation therapy is best applied for palliative relief of pain associated with bony metastases. In the absence of radiographic evidence for local tumor invasion, laparoscopic resection of small- to medium-sized (< 6 cm) pheochromocytomas is indicated. Abundant evidence indicates that this approach is safe and well tolerated and results in more rapid recovery and less long-term wound morbidity compared to open anterior or posterior adrenalectomy. Open anterior adrenalectomy is appropriate for patients with large or recurrent tumors, suspected or documented locoregional invasion, or for those patients in whom a laparoscopic approach is technically contraindicated. For selected patients with pheochromocytoma in the von Hipple-Lindau syndrome or multiple endocrine neoplasia type 2 setting in which the cumulative incidence of clinical bilateral tumors is high, a cortical-sparing approach may minimize the risk of Addisonian complications.

Management of the clinically inapparent adrenal mass ("incidentaloma").

The National Institutes of Health Consensus Development Program convened surgeons, endocrinologists, pathologists, biostatisticians, radiologists, oncologists, and other health care professionals, as well as members of the general public, to address the causes, prevalence, and natural history of clinically inapparent adrenal masses, or "incidentalomas"; the appropriate evaluation and treatment of such masses; and directions for future research. Improvements in abdominal imaging techniques have increased detection of adrenal incidentalomas, and because the prevalence of these masses increases with age, appropriate management of adrenal tumors will be a growing challenge in our aging society. To address six predetermined questions, the 12-member nonfederal, nonadvocate state-of-the-science panel heard presentations from 21 experts in adrenal incidentalomas and consulted a systematic review of medical literature on the topic provided by the Agency for Healthcare Research and Quality and an extensive bibliography developed by the National Library of Medicine. The panel recommended a 1-mg dexamethasone suppression test and measurement of plasma-free metanephrines for all patients with an adrenal incidentaloma; additional measurement of serum potassium and plasma aldosterone concentration-plasma renin activity ratio for patients with hypertension; and surgery for patients with biochemical evidence of pheochromocytoma, patients with tumors greater than 6 cm, and patients with tumors greater than 4 cm who also meet other criteria. The panel also advocated a multidisciplinary approach to managing adrenal incidentalomas. The statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the federal government.

Biochemical diagnosis of pheochromocytoma.

higher than those for plasma catecholamines (84% [95% CI, 78%-89%]), urinary catecholamines (86% [95% CI, 80%-91%]), urinary total metanephrines (77% [95% CI, 68%-85%]), and urinary vanillylmandelic acid (64% [95% CI, 55%-71%]). Specificity was highest for urinary vanillylmandelic acid (95% [95% CI, 93%-97%]) and urinary total metanephrines (93% [95% CI, 89%-97%]); intermediate for plasma free metanephrines (89% [95% CI, 87%-92%]), urinary catecholamines (88% [95% CI, 85%91%]), and plasma catecholamines (81% [95% CI, 78%-84%]); and lowest for urinary fractionated metanephrines (69% [95% CI, 64%-72%]). Sensitivity and specificity values at different upper reference limits were highest for plasma free metanephrines using receiver operating characteristic curves. Combining different tests did not improve the diagnostic yield beyond that of a single test of plasma free metanephrines. Conclusion Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.

Pheochromocytoma: Rediscovery as a catecholamine-metabolizing tumor

Catecholamine-producing tumors are rare neoplasms derived mainly from chromaffin cells of the adrenal medulla (pheochromocytomas) or, in about 10% of cases, from paraganglia (paragangliomas). Diagnosis of these tumors relies heavily on measurements of urinary or plasma catecholamines or catecholamine metabolites. The metabolites are usually thought to be produced after release of catecholamines into the bloodstream. This, however, ignores observations of over 40 yr ago that catecholamines are metabolized within pheochromocytoma tumor cells. Development of improved methods for measurement of catecholamine metabolites, in particular, plasma concentrations of free normetanephrine and metanephrine, has reestablished the importance of intratumoral catecholamine metabolism. In patients with pheochromocytoma, over 90% of the elevations in plasma free normetanephrine and metanephrine result from metabolism of catecholamines within pheochromocytoma tumor cells. This process occurs continuously and independently of variations in catecholamine release. As a consequence, measurements of plasma concentrations and urinary outputs of normetanephrine and metanephrine provide more reliable methods for diagnosis of pheochromocytoma than measurements of the parent amines. Rediscovery of the importance of intratumoral catecholamine metabolism is leading to a reevaluation of the procedures used to diagnose pheochromocytoma. This review provides an update on the diagnosis of pheochromocytoma, with emphasis on identifying and correcting relevant misconceptions about catecholamine metabolism.

New advances in the biochemical diagnosis of pheochromocytoma: moving beyond catecholamines.

Pheochromocytomas are dangerous tumors that, although a rare cause of hypertension, require consideration among large numbers of patients. The resulting low prevalence of the tumor among tested populations and the inadequacies of commonly used biochemical tests make excluding or confirming the tumor an often difficult and time-consuming task. Recognition that catecholamines are metabolized to free metanephrines within pheochromocytoma tumor cells, and that this process is independent of catecholamine release, provides a rationale for use of these metabolites in the biochemical diagnosis of pheochromocytoma. Here we briefly review the history of biochemical diagnosis of pheochromocytoma in relation to recent data about the diagnostic utility of plasma free metanephrines for detection of these tumors. Measurements of urinary or plasma catecholamines have reasonable sensitivity for detection of most pheochromocytomas, particularly those in patients with sustained hypertension. False-negative test results can, however, occur in asymptomatic patients tested because of an adrenal incidentaloma or a familial predisposition for pheochromocytoma, or when sampling is carried out between episodes of paroxysmal hypertension. Measurements of urinary total metanephrines or vanillylmandelic acid are less reliable and are of little value as initial screening tests. In contrast, measurements of plasma concentrations or free metanephrines or 24-hour urinary outputs of fractionated normetanephrine and metanephrine almost always reveal the tumor. Although, both tests have similarly high sensitivity, the relatively low specificity of urinary fractionated metanephrines means that pheochromocytomas can be more efficiently excluded or confirmed using measurements of plasma free metanephrines.