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Background: Up to 2007 there was no formal external quality assurance programme for plasma free metanephrines. A pilot programme was conceived by the AACB (Australian Association of Clinical Biochemists) Working Party on biogenic amines. With support from the AACB and Royal College of Pathologists of Australasia Quality Assurance programmes, a pilot study was developed. Data from this study are presented for the first time., Methods: Twelve lyophilized plasma samples were distributed to 15 centres. Samples were spiked with metanephrine (metadrenaline), normetanephrine (normetadrenaline) and 3-methoxytyramine, all derived from human urine. Concentrations were arranged in a linear relationship. The analytes were present at six levels and samples were duplicated., Results: High-pressure liquid chromatography and tandem mass spectrometry methods showed acceptable precision but in general enzyme immunoassay displayed a higher degree of imprecision as well as a negative bias., Conclusions: Differences in calibration and matrix effects are likely to have been responsible for the discrepancy between chromatographic and immunoassay methods. These differences need to be further examined although efforts at standardization between different methods have been hampered by the lack of a universal calibrator for plasma metanephrines. Meanwhile, a laboratory's performance characteristics can be monitored and enhanced by participation in suitable external quality assurance programmes.

Urinary adrenaline (epinephrine), noradrenaline, dopamine, metadrenaline (metanephrine) and normetadrenaline to creatinine ratios were measured from spot samples of seven client-owned dogs with a histologically confirmed phaeochromocytoma. Urine was collected on day 0 in the hospital in six dogs, and additionally on days 2, 6 and 7 after discharge in two of these dogs. In one dog, urine was sampled on day 7 only. Samples were also collected from 10 healthy control dogs on days 0, 1 and 7. In dogs with phaeochromocytomas, normetadrenaline:creatinine ratios at all time points ranged from 103 to 6430 nmol/mmol. From day 0, ratios of samples taken at the hospital (range 157 to 925 nmol/mmol) were significantly higher (P<0.0012) compared with control samples (range 14 to 91 nmol/mmol). The highest normetadrenaline:creatinine ratios were found in two dogs with bilateral phaeochromocytomas. Adrenaline:creatinine and noradrenaline:creatinine ratios were also significantly increased (P<0.016) in dogs with a phaeochromocytoma at day 0 compared with controls, although the difference was less pronounced than that between controls and dogs with a phaeochromocytoma for the normetadrenaline:creatinine ratio. Urine normetadrenaline:creatinine ratios may be useful in the diagnosis of canine phaeochromocytomas.

To investigate clinical characteristics, metabolic parameters and follow-up findings of subjects with incidentally discovered adrenal tumors. 376 consecutive subjects who have been evaluated since 2002 were included. Initial radiological examination was CT. Hormonal evaluation included 8.00 a.m. cortisol, DHEA-S, ACTH and in hypertensive subjects, plasma renin activity, and serum aldosterone. Urinary free cortisol (UFC), urinary normetanephrine, and metanephrine were measured. Overnight 1 mg dexamethasone suppression test was performed. Radiological evaluation was performed at 6th and 12th months and annually in subsequent visits. Hormonal evaluation was performed 6 months after the initial visit and annually in subsequent visits. Additionally, patients were evaluated for the development of Type 2 diabetes mellitus, hypertension, hyperlipidemia, and metabolic syndrome in 6-month intervals. Mean age of the participants was 54.7 ± 13.1. Female subjects were more commonly affected (70%). CT was the most frequent radiological intervention that discovered adrenal masses (57%). The vast majority of the participants (85.6%) had benign adrenal adenomas. Primary adrenocortical malignancy was detected in 4 subjects (1.1%). Subjects with adrenal adenomas had significantly smaller tumor diameters (P ≤ 0.001 vs. other tumors). Sensitivity and specificity of 40 mm as a cut-off value in the differentiation of adrenal gland malignancies from benign tumors was 73.3 and 54.8%, respectively. Most of the adrenal adenomas were non-functioning (73.5%). Subclinical Cushing syndrome (sCS) was detected in 12.5%. The overall prevalence of Type 2 diabetes mellitus, hypertension, hyperlipidemia, and metabolic syndrome was 18.4, 54.9, 59.6, and 48.1%, respectively. They were significantly more common in middle-aged and elderly subjects. During 24 months follow-up 10.2% of adenomas featured increase in tumor diameter and 2.06% developed sCS. Young subjects featured more stable tumor diameter and hormonal status. Most of the incidentally discovered adrenal tumors were non-functioning adrenal adenomas. Clinically overt hormone hypersecretion syndromes were mainly shown in young subjects, while adrenal gland malignancies and sCS were more common in older ages. Mass enlargement and development of subclinical cortisol secretion were not rare and observed especially in middle-aged and elderly subjects. Metabolic derangements were common; however, a possible independent association between adrenal adenoma and metabolic problems need to be elucidated with prospective studies.

Background: The goal of our study was to test the relative stability of urine, unconjugated, free catecholamines and the methyl derivatives. We measured the change in concentrations in commercially available urines after storage at various pH values, temperatures and time, from days up to 10 weeks., Methods: Samples of commercial control urines were adjusted to pH 2.0, 4.0, 6.0 and 8.0 and aliquots stored at ambient temperature (20-26 degrees C), 4 degrees C and -18(o)C. The free catecholamines (cats) and the free methyl derivatives (mets) were measured after 1, 2, 3 and 6 days and 1, 2, 3 and 10 weeks using the automated sample trace enrichment dialysis (ASTED) procedure with reversed phase ion pair high performance liquid chromatography (HPLC) and coulometric detection., Results: Free catecholamines were relatively stable, with <15% loss of concentration, when stored at pH 6.0 or less for at least 4 days and up to 10 weeks at pH 2.0 at either 4(o)C or -18(o)C. At pH 8.0, the concentration fell to <60% after 48 h and at a pH of 6.0 or 8.0, up to 90% was lost within the first week at 4(o)C and 25(o)C. More than 40% of free normetadrenaline and metadrenaline were lost after 1-2 weeks when stored at 20-25(o)C and pH 8.0. After 10 weeks at pH 4.0, 6.0 and 8.0, up to 90% loss was observed at 25(o)C. Free cats were stable at pH 2.0 and 4.0 at -18(o)C and the free mets were stable at -18(o)C over the entire time period studied and at all pHs., Conclusions: In the analysis of free catecholamine and the free methyl derivatives, urine samples should be acidified to a pH range 2.0-3.0 to ensure stability and hence the correct analysis.

Objective: The influence of obesity on cancer development has been proven for numerous tumours. In contrast, the association between obesity and non-secreting adrenal incidentaloma has never been proven. Therefore, the aim of this study was to investigate this relationship in a large sample of patients., Methods: 143 patients with benign non-secreting adrenal incidentalomas treated in the Department of Endocrinology at the Poznan University of Medical Sciences between the years 2000-2007 were examined. To rule out subclinical hyperfunctioning lesions, serum dehydroepiandrosterone sulphate, cortisol (8 am, 6 pm, and after 1 mg dexamethasone suppression), sodium and potassium, along with concentrations of sodium, potassium, vanillylmandelic acid, metanephrine and normetanephrine in 24-hour urine collection were determined. Radiological evaluation included computed tomography and/or magnetic resonance imaging. Only non-secreting lesions and those of benign radiologic appearance were considered. The patients body mass index was compared to that of the general population of Poland and the Western Poland Region of Wielkopolska., Results: The average body mass index of our patients was 28.77 kg/m2 (SD=4.71), with a 40% prevalence of obesity in the study group. One-proportion z-test showed a statistically significantly higher prevalence of obesity as compared to the general population of Poland and Wielkopolska (40% vs 12.5%, p<0.005); the results were similar for the whole cohort, and for each gender separately., Conclusions: This clinical research study demonstrates a strong association between obesity and incidentally discovered non-functioning adrenal tumours.

Background: Because of the increased use of imaging interventions, more subjects have been diagnosed with adrenal incidentaloma in recent years., Aim: To evaluate the risk of mass enlargement, hormone hypersecretion and development of adrenal carcinomas during short-term followup., Subjects and Methods: There were 317 subjects with incidentally discovered adrenal tumors in the registry. Forty subjects were excluded because of clinically overt hormone secretion at diagnosis and subjects with complete data were included in radiological (no.=150) and hormonal (no.=150) follow- up. Radiological evaluation was performed with computed tomography (CT) and/or magnetic resonance imaging (MRI). There were 143 subjects with adrenal adenomas and 7 subjects with other tumor types (cyst or myelolipoma). Median follow-up duration was 24 months., Results: Increase in tumor size was detected in 25 subjects (17.4%) with adenomas and 1 subject with adrenal myelolipoma (14.3%). Decrease in tumor size was found in 7 subjects (4.8%) with adrenal adenomas. One patient was diagnosed with adrenocortical carcinoma during follow-up. In subjects with non-functioning adrenal adenoma (NFA, no.=120) or subclinical Cushing syndrome (sCS) (no.=30), no subject developed clinically overt hormone hypersecretion, while 8 (6%) subjects in the NFA group developed sCS. Tumor diameter and follow-up duration were significantly higher in subjects who developed sCS., Conclusion: In conclusion, we demonstrated that, despite being infrequent, adrenal tumors may increase in size, develop overt or subclinical hormone secretion or feature malignant transformation. Therefore, radiological and hormonal follow-up should be recommended to the patients. More investigations are needed for the establishment of long-term follow-up protocols.

An undiagnosed pheochromocytoma may result in life-threatening consequences. The diagnosis of pheochromocytoma is based on the overproduction of catecholamines. Highly sensitive biochemical assays are essential to avoid false-negative results. Determinations of 24-h urinary epinephrine and norepinephrine levels are established diagnostic tools. However, they may be falsely negative in patients with a biochemically-silent or periodically-secreting pheochromocytoma. Metanephrines, which are metabolites of catecholamines, have been suggested as an alternative diagnostic tool. Urinary metanephrines are determined by high-pressure liquid chromatography (HPLC) in an increasing number of laboratories, whereas plasma metanephrines measured by HPLC are available in specialised centres only. The different HPLC methods may be cost- and time-intensive. Immunoassays such as radio- or enzyme-immunoassays may be alternative procedures. Measurement of metanephrines instead of catecholamines by either technique improved the diagnostic accuracy for the diagnosis of pheochromocytomas. Determination of plasma free metanephrines demonstrated a higher accuracy than their urinary counterparts. The use of immunoassays may be an alternative to the laborious HPLC, although the method needs to be evaluated in more detail.

Context: Measurements of the 3-O-methylated metabolites of catecholamines [metanephrines (MNs)] in plasma or urine are recommended for diagnosis of pheochromocytoma. It is unclear whether these tests are susceptible to dietary influences., Objective: The aim of the study was to determine the short-term influence of a catecholamine-rich diet on plasma and urinary fractionated MNs., Design, Setting, and Participants: We conducted a crossover study in a specialist medical center involving 26 healthy adults., Interventions: Subjects consumed catecholamine-rich nuts and fruits at fixed times on one day (about 35 mumol dopamine and 1 mumol norepinephrine) and catecholamine-poor products on another day. Blood and urine samples were collected at timed intervals before, during, and after experimental and control interventions., Main Outcome Measures: Isotope-dilution mass spectrometry-based measurements of plasma and urinary concentrations of free and deconjugated 3-methoxytyramine (3-MT), normetanephrine (NMN), and MN were made., Results: The catecholamine-rich diet had substantial effects (up to 3-fold increases) on plasma concentrations and urinary outputs of free and deconjugated 3-MT. Dietary catecholamines had negligible influences on free NMN in plasma and urine, but substantial effects (up to 2-fold increases) on deconjugated NMN in plasma and urine. Concentrations of free and deconjugated MN in plasma and urine remained unaffected., Conclusions: Dietary restrictions should be considered to minimize false-positive results for urinary and plasma deconjugated MNs during diagnosis of pheochromocytoma. Similar considerations appear warranted for plasma and urinary free 3-MT, but not for free NMN or MN, indicating advantages of measurements of the free compared to deconjugated metabolites.

A 53-year-old woman presented with labile and difficult to control hypertension on 3 different anti-hypertensive medications. Abdominal computed tomography and ultrasonography of the thyroid gland showed a 1.8 cm thyroid nodule. Fine needle aspiration biopsy of the thyroid nodule revealed papillary thyroid carcinoma. Serum thyroid stimulating hormone and free thyroxine, calcitonin, carcinoembryonic antigen, intact parathyroid hormone, and calcium levels were within normal limits. A 24-hour urine metanephrine showed significant elevation in urine metanephrine of approximately 3 times the upper limit of normal, and the result of 131I-metaiodobenzyleguanjdjne (131I-MIBG) scintigraphy confirmed that the adrenal mass was pheochromocytoma. Right adrenalectomy and total thyroidectomy were performed. The final pathology was pheochromocytoma and papillary thyroid carcinoma. An analysis of c-ret porto-oncogene mutation yielded a negative result. This unusual association of 2 tumors represents a new entity.

Introduction: Pheochromocytoma is rare tumor with a highly variable clinical presentation. This report provides clinical picture, efficiency of diagnostics and treatment of pheochromocytoma in 8-years in the endocrinological center in Wroclaw., Material and Methods: The records of 37 patients with pheochromocytoma were identified, who were treated in 2000-2007 in the Department of Endocrinology, Diabetology and Isotope Treatment in Wroclaw. There were 23 women (age 23-75 year) and 14 men (age 17-74). We studied frequency of clinical signs, usefulness of diagnostic methods and efficacy of treatment., Results: The duration of the clinical history ranged from 2 months to 16 years. The most frequent symptoms were: hypertension paroxysmal and constant, palpitations, headache, sweating and anxiety. The most sensitive diagnostic method was increased concentration of urinary metanephrine in 24-hour urine. Computed tomography was the most widely used method for tumor localization. Adrenal pheochromocytoma was detecting by CT in all patients, predominated in right adrenal, in 1 case in urinary bladder. Surgery caused remission of hypertension in 59%, improvement in 26.8%, and no changes in 13.9% of patients. Malignancy was reported in 2 cases, 1 woman died after surgery. MEN 2A occur in 21.6%., Conclusions: The diagnosis of pheochromocytma is usually made after long duration of the disease. The study confirms that clinical presentation of pheochromocytoma is variable and nonspecific, this finding makes the diagnosis very difficult. The most typical symptom is paroxysmal hypertension, which is present only in 40%, other symptoms are nonspecific. The measurement of 24-hour urinary metanephrines was the best indicator. CT was almost always successful in localizing the tumor. Patients with pheochromocytoma should be consider for other endocrine diseases especially medullary carcinoma, primary hyperparathyroidism and other component of MEN 2A.

Objective: To examine what tests are ordered by physicians for pheochromocytoma diagnosis and how those tests perform in modern clinical practice., Methods: In this case series, electronic medical records of patients seen between January 2000 and July 2008 at a large academic hospital in Los Angeles, California, were queried, and patients older than 15 years who underwent any 1 of 5 tests for pheochromocytoma (measurement of plasma catecholamines, plasma fractionated metanephrines, urinary catecholamines, urinary metanephrines, or urinary vanillylmandelic acid) were identified. Because testing was performed in various reference laboratories, test results were classified into 1 of 3 categories: (a) markedly elevated, (b) moderately elevated, or (c) normal. Patient demographics, clinical history, test results, imaging study findings, and pathology records were reviewed., Results: A total of 3980 tests were ordered for 1898 patients. Pretest probability was 2.2% (based on 681 patients in whom pheochromocytoma was confirmed or excluded), and hypertension was the most common indication for testing. The number of patients tested and the number of tests ordered increased over the years. The ordering pattern stabilized since 2006 when urinary metanephrines, urinary catecholamines, and plasma metanephrines were ordered more frequently. Sensitivity was highest for urinary metanephrines and vanillylmandelic acid, specificity was highest for vanillylmandelic acid and urinary catecholamines, and positive likelihood ratio was highest for vanillylmandelic acid. Positive predictive value for markedly elevated test results was 39% to 83%, while that for moderately elevated test results was only 2% to 14%., Conclusions: Ordering pattern and test performance differ significantly from those recommended and reported by large centers. The best testing strategy should incorporate local experience. Categorizing test results as markedly elevated, moderately elevated, and normal is important for result interpretation.

Objective: To establish reference intervals for urinary excretion of biogenic amines from birth to adulthood., Design and Methods: 865 outpatients were categorized into nine groups ranging from birthday to 25 years. Free catecholamines, total metanephrines, vanillylmandelic and homovanillic acids were determined in urine samples by HPLC with amperometric detection., Results: The ratio of each analyte-to-creatinine declined gradually from birth to 15-18 years reaching adults values. No difference was observed by sex except a lower excretion of epinephrine and metanephrine in girls than in boys below 1 year., Conclusion: Our data provide age-appropriate reference ranges for the diagnosis of tumors from neural crest in children.

Background: The measurement of catecholamines and metanephrines in urine is an important diagnostic test in biochemical screening for phaeochromocytoma. Tandem mass spectrometry (MSMS) has the potential to be used in a profiling method for simultaneous assay of these analytes., Methods: Optimal conditions were established for the MSMS detection of catecholamines (noradrenalin, adrenalin and dopamine) and metanephrines (normetanephrine and metanephrine), including commercially available isotopically labelled compounds for use as internal standards. Chromatographic separation of all five polar biogenic amines was achieved under solvent conditions that were compatible with MSMS and multiple reaction monitoring. Several types of solid-phase extraction cartridge were used to investigate clean-up conditions for urine, and acid-hydrolysates of urine, prior to LC-MSMS., Results: Total catecholamines and metanephrines from acid-hydrolysed urines, or free catecholamines and free metanephrines from native urines, were complexed with diphenyl-boronate and recovered in high yield from polymer cartridges after elution with formic acid. Direct injection of eluates into the LC-MSMS system allowed quantitation of catecholamines and metanephrines with a run time of 6 min per sample. Biogenic amine concentrations for patient urines and quality assurance programme samples, and assay imprecision, were similar to values obtained with high-performance liquid chromatography methods, which used electrochemical detection. In normal urines, the ratio of free to total catecholamines was around three-fold higher than the ratio of free to total metanephrines., Conclusion: The assay of urinary catecholamines and metanephrines can be achieved simultaneously using one LC-MSMS method, which is rapid and reduces labour and consumable costs for routine application.

We report a patient who presented with two episodes of severe hypertension after intramuscular injection of betamethasone. The first attack was associated with pulmonary edema, while the second attack was associated with high anion gap metabolic acidosis, renal failure, hyperglycemia, and hypokalemia. The attacks led to the diagnosis of pheochromocytoma, which was confirmed by appropriate diagnostic tests. The tumor was excised successfully and the patient is presently asymptomatic.We believe that these episodes were initiated by glucocorticoid injection, an event reported in a few cases. We briefly review potential mechanisms resulted in hypertensive crisis in such patients.

Adrenal tumors diagnosed after work-up of an incidentaloma can be responsible for excessive secretion of steroids or catecholamines. On the other hand, an infiltrative process (metastases, infection...) involving both adrenals can cause adrenal insufficiency. Clinical and biological work-up is performed to detect hormonal imbalances requiring treatment, and further characterize the nature of the lesion. Screening for pheochromocytoma should be systematic with metanephrine assays on urine or plasma. Screening for cortisol secreting tumors, often responsible for Cushing's syndrome of moderate severity (pre-clinical) in patients with incidentaloma, will be performed using the overnight dexamethasone suppression test (1 mg). Depending on results from the imaging and clinical work-up, excessive secretion of aldosterone, androgens or steroid precursors may sometimes be investigated. In patients with bilateral incidentalomas, the normal synacthen test and ACTH assay are also performed to exclude adrenal insufficiency.

Background/aims: Congenital adrenal hyperplasia (CAH) is characterized by adrenal insufficiency with or without salt wasting. It is also accompanied by adrenomedullary hypofunction. The aim of the present study was to investigate adrenomedullary function in patients with CAH due to 21-hydroxylase and 11beta-hydroxylase deficiencies and in age-matched normal subjects., Methods: We measured plasma catecholamines (epinephrine and norepinephrine) and urine metanephrine in 44 patients with CAH, 32 due to 21-hydroxylase deficiency (17 patients with the salt-wasting form and 15 patients with the simple virilizing form), and 12 due to 11beta-hydroxylase deficiency, and in 25 healthy controls., Results: Plasma epinephrine and urine metanephrine levels were significantly higher in the controls than in patients with CAH (p = 0.02 and p < 0.001, respectively). Plasma norepinephrine levels were significantly lower in the controls than in patients with CAH (p < 0.001). Interestingly, patients with the salt-wasting form had lower norepinephrine levels in comparison to the other subgroups of CAH., Conclusion: Despite the fact that CAH patients have insufficient epinephrine secretion, these patients have the ability to increase compensatory norepinephrine. However, this increase is much lower in patients with the salt-wasting form. These findings need to be confirmed by other studies.

Context: Patients with adrenal and extra-adrenal abdominal paraganglioma (PGL) almost invariably have increased plasma and urine concentrations of metanephrines, the O-methylated metabolites of catecholamines. We report four cases of biochemically silent abdominal PGL, in which metanephrines were normal despite extensive disease., Objective: Our objective was to identify the mechanism underlying the lack of catecholamine hypersecretion and metabolism to metanephrines in biochemically silent PGL., Design: This is a descriptive study., Setting: The study was performed at a referral center., Patients: One index case and three additional patients with large abdominal PGL and metastases but with the lack of evidence of catecholamine production, six patients with metastatic catecholamine-producing PGL and a mutation of the succinate dehydrogenase subunit B (SDHB) gene, and 136 random patients with catecholamine-producing PGL were included in the study., Main Outcome Measures: Plasma, urine, and tumor tissue concentrations of catecholamines and metabolites were calculated with electron microscopy and tyrosine hydroxylase immunohistochemistry., Results: All four patients with biochemically silent PGL had an underlying SDHB mutation. In the index case, the tumor tissue concentration of catecholamines (1.8 nmol/g) was less than 0.01% that of the median (20,410 nmol/g) for the 136 patients with catecholamine-producing tumors. Electron microscopy showed the presence of normal secretory granules in all four biochemically silent PGLs. Tyrosine hydroxylase immunoreactivity was negligible in the four biochemically silent PGLs but abundant in catecholamine-producing PGLs., Conclusions: Patients with SDHB mutations may present with biochemically silent abdominal PGLs due to defective catecholamine synthesis resulting from the absence of tyrosine hydroxylase. Screening for tumors in patients with SDHB mutations should not be limited to biochemical tests of catecholamine excess.

Pheochromocytoma is a rare tumor responsible for paroxysmal hypertension which is difficult to control. Diagnosis is important because it represents a curable form of hypertension. Few cases of pheochromocytoma patients with end-stage renal failure were reported in the literature. These cases are specially responsible for diagnosis and therapeutic problems. We report here a case of an end-stage renal failure patient who has pheochromocytoma, he was treated by automated peritoneal dialysis. The patient is a 47-year-old man who has an IgA glomerulonephritis. On peritoneal dialysis, his blood pressure level remains high despite four antihypertensive drugs association and adequate dialysis. Furthermore, the patient suffered from headaches, sweats and palpitations. This leads to suspect pheochromocytoma. Thus, urinary excretion rates of metanephrines and normetanephrines were high. Radiographic diagnosis tests were negative but MIBG scintigraphy was able to localise the tumor in the left suprarenal gland. He had coelioscopic left adrenalectomy without complications, microscopic studies showed an hyperplasia of the adrenal medulla. Soon after surgery his blood pressure was well controlled by one antihypertensive drug. We conclude that refractory hypertension, as a possible diagnosis, is uncommon in peritoneal dialysis patients. Pheochromocytoma must be eliminated by careful evaluation.

Introduction: We report the results of a laboratory evaluation of the BioRad Urinary Metanephrines Reagent Kit. The test was designed for the quantitative measurement of normetanephrine and metanephrine in urine by high performance liquid chromatography. The kit was evaluated in view of improving assay reliability and specificity as compared to the manual method based on cation exchange chromatography and spectrophotometry., Methods: Performance was evaluated for precision, linearity, accuracy, sensitivity and detection limit based on National Committee on Clinical Laboratory Standards (NCCLS) protocols. Analytical precision was evaluated using commercial controls and patient sample. Accuracy was evaluated by assessing recovery. Linearity was determined using aqueous standards., Results: The within-run coefficient of variation (CV) for metanephrine and normetanephrine were 1.9 percent and 2.4 percent (low control); 4.2 percent and 3.5 percent (high control); 3.8 percent and 3.3 percent (patient sample), respectively. The between-day precisions were 3.8 percent and 4.3 percent (low control); and 5.5 percent and 3.7 percent (high control) for metanephrine and normetanephrine, respectively. The linearity curve showed metanephrine and normetanephrine to be linear with concentrations, to at least 1,600 microgramme per litre and 2,000 microgramme per litre, respectively. Analytical recovery averaged 102 percent for metanephrine and 95 percent for normetanephrine. Levels as low as 23 microgramme per litre normetanephrine and 10 microgramme per litre metanephrine were measured with this method. The detection limit was 3.3 microgramme per litre for metanephrine., Conclusion: The performance characteristics of automated sample preparation and auto-injection facilitate handling of larger number of samples as well as improve assay reliability.

Findings from five independent studies - with close to 350 patients with pheochromocytoma and more than 2,500 in whom the tumor was excluded - indicate that measurements of plasma free metanephrines provide an overall diagnostic sensitivity of 98% and specificity of 92%. The recommendation that initial testing for the tumor should always include measurements of either plasma or urinary fractionated metanephrines results from recognition of the high diagnostic sensitivity of measurements of plasma metanephrines. The few patients with pheochromocytoma in whom the test may not yield a positive result include those with very small tumors or microscopic disease and others with tumors that do not produce norepinephrine and epinephrine. Such patients are typically normotensive and do not exhibit symptoms of catecholamine excess. Additional measurements of methoxytyramine can be useful for detecting those tumors that produce only dopamine. Suboptimal diagnostic specificity and difficulties in distinguishing true- from false-positive elevations of plasma metanephrines remain challenges for diagnosis. Improvements in analytical technology (e.g., liquid chromatography with tandem mass spectrometry) and new strategies for follow-up testing provide possible solutions to these problems. The single most important remaining clinical care challenge is the development of effective cures for patients with malignant disease. Current treatments, none of which are truly satisfactory, include chemotherapy and radiopharmaceutical therapy with (131)I-labelled M-iodobenzylguanidine or radioactive somatostatin analogues. Improvements in treatment may in the future come from several fronts, but proof of efficacy ideally will require well-coordinated multicenter prospective trials in larger numbers of patients than in previous studies.

A 41-year-old lady presented with classical symptoms of a phaeochromocytoma and markedly elevated urinary adrenaline concentration. Urinary fractionated metanephrine and normetanephrine concentrations were within the normal reference range. Computed tomography of the abdomen/pelvis and I(123) meta-iodobenzylguanidine scans were negative. Factitious adrenaline use was established as the diagnosis.

Background: A 46-year-old man presented with headaches, paroxysmal palpitations, anxiety and hypertension. The patient had undergone surgery for a retroperitoneal tumor at the age of 31 years, when histological examination revealed an extra-adrenal pheochromocytoma. The patient's 68-year-old mother had a history of a carotid body tumor, which had been resected when she was 34 years old. She was diagnosed with a meningioma at 54 years of age and a jugular paraganglioma at 68 years of age., Investigations: A 24h urine catecholamine assay was performed. CT imaging of the abdomen and (123)I-labeled metaiodobenzylguanidine scintigraphy revealed a right pheochromocytoma and left adrenal incidentaloma. An inherited neoplasia syndrome was suspected and molecular genetic analyses were performed., Diagnosis: Right adrenal pheochromocytoma and left adrenal nonfunctioning incidentaloma, as part of a familial pheochromocytoma-paraganglioma syndrome associated with a germline mutation in SDHC (gene encoding succinate dehydrogenase complex, subunit C, integral membrane protein, 15 kDa)., Management: Predictive testing, with genetic counseling. Management included surgical resection of the existing pheochromocytoma. The patient continues to be monitored with MRI scans of the neck, thorax, abdomen and pelvis every 1-2 years and an annual 24h urine collection for the measurement of metanephrines and catecholamines.

Phaeochromocytomas are rare tumours that require consideration among large numbers of patients with hypertension. If not diagnosed, the excessive secretion of catecholamines by these tumours can cause considerable morbidity and mortality. With a wide clinical variability in presentation, diagnosis can be difficult and invariably requires the biochemical confirmation of excessive catecholamine production by the tumour. At the First International Symposium on Phaeochromocytoma in October 2005, a panel of experts recommended that initial biochemical testing for phaeochromocytoma should include measurements of plasma and urinary metadrenalines. The accumulated evidence clearly indicates that measurement of fractionated metadrenalines in urine or plasma provides superior diagnostic sensitivity over plasma or urine measurements of catecholamines and metabolites. The low prevalence of phaeochromocytoma and paraganglioma (PGL) emphasizes the need to use biochemical tests of the highest sensitivity. To achieve this, it is recommended that the initial biochemical testing for phaeochromocytoma and secreting PGL should always include the measurements of metadrenalines in plasma or urine or both.

Context: The initial diagnosis of pheochromocytoma relies on plasma fractionated metanephrines levels. Normal levels exclude pheochromocytoma, but positive tests have a low positive predictive value due to the disease's rarity., Objectives: The objective of the study was to evaluate three approaches to distinguish between true-positive and false-positive tests: 1) increased cutoff for plasma fractionated metanephrines, 2) measurement of serum/plasma chromogranin A (CGA), and 3) urine fractionated metanephrine testing., Design: We studied retrospectively all Mayo Clinic patients with positive plasma fractionated metanephrine tests over a 15-month period and determined their final diagnosis based on histology, imaging, additional biochemical tests, and more than 1 yr follow-up. For a subgroup, urine fractionated metanephrine results were available. All original plasma samples were retested for CGA., Results: Of 140 patients, 40 had a chromaffin tumor confirmed and 100 excluded, indicating a positive predictive value of plasma fractionated metanephrines of 28.6%. Increasing the threshold for a positive test improved specificity to 98% but missed eight cases (20%). Incorporation of urine fractionated metanephrine testing as follow-up test achieved 80% specificity and 91% sensitivity. The corresponding figures for CGA were 71 and 87% for all patients and 89 and 87% when patients taking proton pump inhibitors were excluded., Conclusions: Unless plasma fractionated metanephrines levels are elevated more than 4-fold above the upper limit of normal, patients with a positive plasma fractionated metanephrines test should be evaluated with urine fractionated metanephrines and serum/plasma CGA assays before being subjected to imaging or invasive diagnostic tests.

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

Ectopic ACTH secretion represents 8-18% of the cases of endogenous hypercortisolism. Pheochromocytomas correspond to 2-25% of the cases and surgery is the indicated treatment. We describe a case of ACTH-secreting pheochromocytoma treated with percutaneous ethanol injection (PEI) guided by computed tomography (CT). A 71-yr-old man presented with diabetes, severe hypokalemia, weight loss, muscle weakness, and hypertension. Hormonal evaluation revealed elevated levels of urinary cortisol, ACTH, catecholamines, and urinary metanephrines. There was no cortisol or ACTH response to desmopressin stimulation test. Magnetic resonance revealed bilateral adrenal nodules, larger on the left side. The suspected diagnosis was ectopic ACTH syndrome caused by pheochromocytoma. Ketoconazole treatment resulted in reduction of urinary cortisol levels but was followed by severe cholestasis and hepatic dysfunction, preventing surgery; it was substituted by octreotide with reduction of ACTH and cortisol levels, but without improvement of cholestasis. The patient presented cachexia and developed multiple pulmonary abscesses that also prevented surgical treatment, thus he was treated with percutaneous ethanol injection guided by CT of the left adrenal tumor. During the procedure, the patient had an increase in blood pressure controlled by the infusion of sodium nitroprusside followed by hypotension that required infusion of dopamine and volume expansion. Afterwards, he presented hormonal normalization, normal catecholamines levels, and clinical improvement. Histological tissue analysis confirmed pheochromocytoma. We concluded that CT-guided PEI represents an efficient alternative therapy to ectopic ACTH-secreting pheochromocytomas in patients without clinical conditions for surgery.

Introduction: The paraganglioma is a rare tumour that can sometimes develop near to the pancreatic gland and can occasionally mimic an intra pancreatic mass. Invasive investigations with puncture or primary surgical resection must be avoided because of the risk of vital complications., Exegesis: We report on the case of a 41 years old woman presenting with a mass apparently affecting the pancreatic gland. She also presented with malaises. Paraganglioma was suspected because of the malaises and the blood pressure crises. The diagnosis was permitted by the findings of high urinary metanephrine levels. So the tumour was resected without previous fine needle aspiration and with specific anaesthetic measures. No complication was observed., Conclusion: When a patient presents with a pancreatic mass, physician must carefully take into account the possibility of a paraganglioma particularly when malaises are present.

Objective: To assess the risk of pheochromocytoma in patients with borderline-elevated urine or plasma metanephrine levels., Design: Retrospective review., Setting: University tertiary care center., Patients: Forty-two consecutive patients with adrenal incidentalomas (defined as adrenal tumors identified during routine imaging for another condition) who were treated at the UCSF (University of California, San Francisco) Medical Center between January 1, 1995, and July 31, 2005. Patients with genetic syndromes were excluded., Intervention: Laparoscopic adrenalectomy for adrenal incidentaloma based on size criteria and preoperative hormonal test results., Main Outcomes Measures: Urine or plasma metanephrine and catecholamine levels, tumor size, and presence of pheochromocytoma., Results: Of 42 patients, 14 (33%) had a pheochromocytoma (11 of whom had clear-cut elevations in urine or plasma metanephrine levels defined as greater than 2 times the upper limit of normal) and 28 did not. Ten of the 42 patients (24%) had borderline elevations in urine or plasma metanephrine levels (defined as 1-2 times the upper limit of normal), 3 of whom had a pheochromocytoma (30%). Of patients with borderline elevations, mean +/- SD tumor size was 5.4 +/- 3.1 and 4.8 +/- 1.9 cm for patients with and without pheochromocytoma, respectively (P = .37). In these 10 patients, no clinical factors (age, sex, hypertension, presence of symptoms, number of antihypertensive medications, preoperative hemodynamics, or size of tumor on computed tomographic scan) allowed differentiation between those with and without pheochromocytoma., Conclusions: Thirty percent of patients with adrenal incidentaloma and borderline-elevated urine or plasma metanephrine levels had a pheochromocytoma. Clinical factors cannot distinguish between those with and without pheochromocytoma. In this group of patients, we advocate either routine alpha-blockade preoperatively or further diagnostic tests to better characterize the tumor.

Background: L-dopa is an important antiparkinsonian drug. It is a precursor of dopamine and the other catecholamines. Potentially, administration of L-dopa could lead to increased urinary excretion of catecholamines and their metabolites to abnormal amounts. The current study aimed to determine these excretions in patients with Parkinson's disease (PD) receiving L-dopa compared with suitable controls. This is the first assessment of the effect of exogenous administration of L-dopa on urinary free metadrenalines., Methods: Using one-way analysis of variance (ANOVA), urine catecholamines and metabolites, expressed as mmol per mole creatinine, were compared in: patients with PD who were receiving L-dopa; patients with PD but not receiving L-dopa; and patients without PD who were being investigated for the presence of phaechromocytoma but were found not to have the disease., Results: Significantly higher values for urinary dopamine, homovanillic acid, free normetadrenaline and free metadrenaline were found in patients with PD receiving L-dopa compared with the other two control groups. In all the patients with PD, these four analytes were significantly correlated with daily dose of L-dopa., Conclusion: L-dopa therapy can result in production of false positives for urinary excretion of dopamine, homovanillic acid, free normetadrenaline or free metadrenaline and thereby decrease the diagnostic value of these measurements in identifying phaeochromocytoma and related tumours.

Unlabelled: A diagnosis of bilateral pheochromocytoma warrants exclusion of hereditary pheochromocytoma., Objective: To describe the first case of a bilateral pheochromocytoma associated with V804M mutation in the RET proto-oncogene., Patients: The index case was a 54-year-old man with bilateral adrenal masses discovered during a CT scan performed for other reasons., Measurements: Genetic analysis included exons 8-11 and 13-17 in the RET proto-oncogene, all four exons and flanking intronic regions in the SDHD gene, all eight exons and flanking intronic regions in the SDHB, and all three exons in the VHL gene., Results: Investigations revealed elevated urinary metanephrines (32.3 micromol/day), and laparoscopic bilateral adrenalectomy confirmed bilateral pheochromocytomas. A heterozygous V804M mutation in exon 14 of the RET was found in the index case and in four relatives. Total thyroidectomy, performed in four of five affected members in this kindred, disclosed a medullary thyroid carcinoma in the index case and in a 50-year-old woman, and nodular C-cell hyperplasia in the other two subjects., Conclusions: This clinical case suggests that individuals carrying the germline V804M mutation should be screened annually for the presence of pheochromocytoma.

Pheochromocytoma is a rare tumor of chromaffin tissues most commonly arising from the adrenal medulla. We retrospectively reviewed the records of 38 patients with pheochromocytoma who underwent surgical treatment between 1977 and 2004 at our Yokohama City University Medical Center and Yokohama City University Hospital. Twenty two patients (57.9%) were females and 16 (42.1%) were males. The most frequent symptoms were headache (58%). One patient had bilateral adrenal tumors and pathological examination revealed malignant pheochromocytoma. Six patients had an extra-adrenal tumor and in 2 patients the tumor occurred in the urinary bladder. Twelve patients (31.6%) had sustained hypertension, 21 patients (55.3%) had paroxysmal hypertension and 5 patients (13.1%) remained normotensive. The 24-h urinary total metanephrines and vanillylmandelic acid (VMA) were the most sensitive biochemical tests for the diagnosis of pheochromocytoma. The sensitivity of urinary total metanephrines was 92.0% for all the patients and was 92.3% for the patients without paroxysmal hypertension. Fifteen patients had intraoperative hypertensive reactions in the surgical manipulation or hypotension after tumor resection. This group had more urinary excretion of VMA before surgery, compared with that with stable intraoperative blood pressure (p < 0.005).

Objectives: We aimed to evaluate the interictal cardiovascular autonomic functions in pediatric patients with idiopathic epilepsy, both partial and generalized., Materials and Methods: The study included 25 patients with idiopathic epilepsy and 50 control subjects. Patients underwent five standardized clinical cardiovascular reflex autonomic tests [resting heart rate (HR), HR response to deep breathing and to Valsalva maneuver, the 30:15 ratio of HR response to standing, and blood pressure response to standing], as well as a 12 lead surface electrocardiogram. Heart rate variability (HRV) was tested via 24-h Holter monitoring and the time domain parameters (SDNN, PNN50, rMSDD) were assessed. Excretion of vanillyl mandelic acid and metanephrine was measured in 24-h urine collection., Results: Clinical reflex autonomic tests showed mild dysfunction in 8%, moderate dysfunction in 44% and severe dysfunction in 4% of patients. The HRV parameter, SDNN, was reduced in all age groups, while rMSDD and PNN50 were reduced only in the older age group. Metanephrine levels were significantly reduced in the patients group. Patients with uncontrolled epilepsy had a significantly higher frequency of autonomic dysfunction as assessed by clinical scoring., Conclusion: Cardiac autonomic dysfunction is not uncommon in pediatric patients with epilepsy. Altered cardiovascular regulation seems to be related to the epilepsy itself rather than to the characteristics of the disorder.

Background: Measurement of high concentrations of urine catecholamines and metanephrines is useful in diagnosing pheochromocytoma in humans. Stress increases catecholamine excretion in urine., Hypothesis: Stress of a hospital visit increases urinary catecholamine and metanephrine excretion in dogs., Animals: Fourteen clinically normal dogs, 2 dogs with pheochromocytoma., Methods: Voided urine samples were collected by the owners 7 days before (t-7), during the hospital visit immediately after diagnostic procedures (t0), as well as 1 (t1) and 7 days (t7) after the hospital visit. Urine catecholamine and metanephrine concentrations were measured using high-pressure liquid chromatography and expressed as ratios to urine creatinine concentration., Results: In client-owned dogs epinephrine and norepinephrine ratios at t0 were significantly higher compared with ratios at t7. Metanephrine and normetanephrine ratios at t-7, t0, and t1 did not differ significantly from each other; however, at t7 they were significantly lower compared to values at t-7. In staff-owned dogs no significant differences were detected among the different collecting time points for any variable. Metanephrine and normetanephrine ratios were significantly higher in client-owned dogs compared to staff-owned dogs at t-7, t0, and t1 but not at t7., Conclusions and Clinical Importance: Stress associated with a hospital visit and with the sampling procedure causes increases in urine catecholamine and metanephrine excretion. Urine collection for the diagnosis of pheochromocytoma probably should take place at home after adaptation to the sampling procedure.

Background: There are limitations to currently available biochemical tests for pheochromocytoma. Our objective was to evaluate the diagnostic efficacy of a novel tandem mass spectrometry assay for the measurement of fractionated urinary metanephrines in patients suspected to have a pheochromocytoma. We also developed clinically based cut-offs for positivity of this measurement., Methods: We examined the medical records of 506 patients (including 102 patients with a catecholamine-producing tumour) who underwent measurement of 24-h urinary fractionated metanephrines using tandem mass spectrometry as well as adrenal imaging at Mayo Clinic, Rochester. The cut-offs for positivity were defined as follows: total metanephrines (sum of the metanephrine fractions) 5163 nmol/day, normetanephrine fraction 4001 nmol/day, metanephrine fraction 1531 nmol/day. Receiver operating characteristic (ROC) curves were constructed., Results: The diagnostic efficacy was as follows: normetanephrine fraction sensitivity 87.3% [(95% confidence interval (CI) 79.4-92.4%], specificity 95.0% (92.5-96.8); metanephrine fraction sensitivity 56.9% (47.2-66.1), specificity 95.0% (92.5-96.8); elevation of either normetanephrine or metanephrine fraction sensitivity 97.1% (91.7-99.0) and specificity 91.1% (87.9-93.5). Areas under the ROC curves (AUCs) were 0.972 (95% CI 0.955-0.990) for the normetanephrine fraction, 0.800 (0.741-0.858) for the metanephrine fraction, 0.991 (0.985-0.996) for total metanephrines, and 0.991 (0.985-0.996) for a regression-derived ROC curve incorporating both the metanephrine and normetanephrine fractions., Conclusion: Measurement of 24-h urinary fractionated metanephrines by a tandem mass spectrometry assay appears to be an effective biochemical technique in the investigation of pheochromocytoma.

The patient is a 44-year-old man with a 4-year history of intermittently elevated blood pressure (BP) controlled by diet and exercise. Three months before evaluation he described daily "spikes" of BP with sharp unilateral headaches. He was seen in the emergency department with a BP of 212/106 mm Hg and was started on hydrochlorothiazide 25 mg daily. He denied palpitations, diaphoretic episodes, pallor, and tremor. The patient did not want to take medication and specifically requested an evaluation to rule out pheochromocytoma. Results from 24-hour urine tests for total metanephrines was 812 mg/24 h (normal, 130-520 mg/24 h), for total catecholamines was 53 mg/24 h (normal, 0-135 mg/24 h), and for vanillylmandelic acid was 4.7 mg/24 h (normal, <7 mg/24 h). Thyroid-stimulating hormone was 0.87 (normal, 0.4-4.0 IU/mL). Physical examination revealed normal optic fundi, negative cardiac examination results, and presence of peripheral pulses without bruits. His BP was now 136/74 mm Hg, with a heart rate of 76 beats per minute.

Background: Measurements of 24-h fractionated urinary metanephrines and catecholamines are used for the diagnosis of pheochromocytoma, but adequate information is needed regarding collection, storage, and shipment conditions., Methods: Spot urine samples were collected from 8 healthy volunteers. Aliquots were immediately frozen at -20 degrees C, or acidified to pH 4 and then frozen either directly or after 24 h at room temperature. The remaining urine was left at room temperature for 24 h and then split into one portion that was acidified and one portion that was not. Aliquots were either frozen or allowed to stand at room temperature for an additional 24, 48, 72, 96, and 168 h before freezing. We also tested the efficacy of adding Na(2)EDTA and Na(2)S(2)O(5), as an alternative to acidification for preservation of the catecholamines., Results: No clinically relevant degradation (<5%) was observed for the fractionated metanephrines under any of the storage conditions. In contrast, in approximately 50% of the untreated samples catecholamines were partially degraded during the first 24 h at room temperature. Immediate acidification, however, prevented degradation, whereas acidification after 24 h prevented further decay. Addition of Na(2)EDTA and Na(2)S(2)O(5) fully prevented degradation of catecholamines during the first 24 h in 4 of 5 cases. In the remaining case, degradation did not exceed 10%., Conclusion: Preservation of samples for measurements of urinary fractionated metanephrines is not necessary if samples are assayed or frozen within 1 week, which is an important advantage if transport of samples is necessary. In contrast, urinary catecholamines require preservation measures during collection.

This study aimed to investigate the effect of acute mental stress on erythrocyte deformability (ED) in women during different phases of the menstrual cycle and to compare the results with men. For this purpose, healthy males (n=10) and females (n=10) (during follicular and luteal phases) underwent Stroop color-word interference and cold pressor tests. Hemoglobin, hematocrit and leukocyte counts before and after this stress test revealed no difference in either group; erythrocyte sedimentation rate was significantly lower in the post-test samples in all. In all groups erythrocyte filtration time was significantly higher and thus ED was significantly lower after the stress test (mean+/-SEM, PRE-TEST: follicular: 3.08+/-0.05; luteal: 2.07+/-0.05; men: 2.9+/-0.05) (POST-TEST: follicular: 4.5+/-0.07; luteal: 4.1+/-0.07; men: 4.39+/-0.1). ED was appreciably influenced by gender and menstrual cycle. Women at the luteal phase had better ED compared to both women at the follicular phase and men, the effect being especially pronounced in the pre-test samples. Our results suggest that stress may induce cardiovascular diseases by lowering ED in both genders. The effect of stress on ED varies with gender and during different phases of the menstrual cycle, which may be explained by variations in the sex hormones.

Aim: The aim of the study was to assess the effects of valsartan, a new generation angiotensin II receptor antagonist, on portal and systemic hemodynamics and on renal function in cirrhosis., Methods: Eighty patients with cirrhosis and portal hypertension were divided in two groups as follows: group I - 40 patients who received valsartan (Diovan) 80 mg /day for 7 days and group II - 40 patients who received placebo. All the patients had hemodynamic, endocrine and renal parameters measured on day 0 and 7. The following were assessed: creatinine clearance, lithium clearance, plasma renin activity, concentration of plasma aldosteron and sodium homeostasis. Hemodynamic effects were assessed sonographically by portal flow volume and velocity evaluation, and mean arterial blood pressure., Results: Valsartan increased the portal blood flow and the portal velocity (p < 0.01). These changes occurred without any significant changes in blood pressure and renal function or the glomerular filtration rate, compared with controls (p > 0.05). Valsartan also reduced the concentration of plasma aldosteron (p < 0.01) and increased the urinary sodium excretion (p < 0.001)., Conclusion: A one week treatment with valsartan in cirrhotic patients with portal hypertension determines an increase in natriuresis, which could be regarded as beneficial and changes in the portal hemodynamics which might be speculated to represent a reduction of portal resistance.

Background: Despite the rarity of pheochromocytoma, diagnosis is important because of the dangers of uncontrolled severe hypertension and the availability of very effective surgical treatment. Urinary or plasma catecholamines or catecholamine derivatives are commonly used to screen for pheochromocytomas before imaging, but data from 24-h urinary metanephrine results, patient age, and sex may better predict tumors in populations with a low pretest probability., Methods: We retrospectively studied outcomes of an unselected population (1819 patients) referred to a tertiary hospital laboratory for urinary metanephrine testing and investigated the usefulness of some simple derivative measures for detecting pheochromocytoma. We normalized values for urinary 24-h excretion of metanephrine, normetanephrine, and 3-methoxytyramine by dividing by an age- and sex-specific reference range. We then compared pheochromocytoma prediction by the use of products of these normalized measures with the gold standard of biopsy-confirmed tumor., Results: The product of the excretion of normalized metanephrine (nMAD) and normalized normetanephrine (nNMT) (nMAD.nNMT) was a highly sensitive (100%) and specific (99.1%) measure, yielding a positive predictive value of 82%. ROC curves were not improved by including the normalized 3-methoxytyramine concentrations in the product. The test for nMAD.nNMT gave higher sensitivity and specificity than the tests for either substance alone., Conclusion: The test for nMAD.nNMT is a useful measure for identifying pheochromocytoma in a population with a low pretest probability.

Objective: To report a case of epinephrine-induced factitious pheochromocytoma in a young woman with a past medical history of Conn's syndrome., Methods: We present a case report with clinical and laboratory details, review related reports in the literature, and demonstrate the usefulness of plasma free metanephrine levels in facilitating the diagnosis of factitious pheochromocytoma., Results: A 34-year-old woman was admitted to our hospital for confirmation and localization of an occult pheochromocytoma. After thorough investigation, we discovered that the patient was surreptitiously injecting epinephrine in order to induce symptoms and signs consistent with a pheochromocytoma. Analysis of the patient's biochemical profile during and between her catecholaminergic crises revealed plasma epinephrine and free metanephrine levels that would be highly unusual for a patient with a pheochromocytoma., Conclusion: This case illustrates the utility of implementing the ratio of plasma epinephrine to free metanephrine levels in distinguishing factitious from organic pheochromocytoma.

Context: Several authors have reported the unsuspected finding of low cortisol levels (urinary, salivary, and serum) in patients with posttraumatic stress disorder (PTSD)., Objective: Our objective was to assess concentrations of cortisol and its predominant metabolites, cortisol production rate (CPR), and glucocorticoid receptor (GR) binding characteristics in PTSD compared with normal subjects., Design: Matched PTSD patients and control subjects had CPR determined by a stable isotope dilution technique after infusion of deuterated cortisol. Serum cortisol, urinary cortisol, and its metabolites were measured by gas chromatography/mass spectrometry. GR binding capacity (R(o)) and ligand binding affinity (K(d)) were measured in mononuclear leukocytes., Setting: All subjects were tested during a 40-h admission in an inpatient clinical research center., Patients and Participants: Ten patients with PTSD were matched by age and gender with 10 controls., Outcome Measures: Statistical comparison was conducted for various measures of cortisol in PTSD patients and normal subjects., Results: No statistical difference was found in mean level or circadian pattern of cortisol secretion using serum or salivary immunoassay detection methods. Although in the normal range, urinary cortisol by immunoassay showed statistically lower values over a 24-h period in PTSD patients compared with controls. This finding was not confirmed by gas chromatography/mass spectrometry determination of cortisol or its metabolites. CPR was not statistically different between these groups. GR also showed no alteration in R(o) or K(d) between the groups., Conclusion: The data indicate that PTSD in the chronic and unprovoked state is not characterized by an acute biological stress response.

Objective: To present a case that demonstrates the evolution of a pheochromocytoma over a several-year period and to emphasize the importance of a thorough work-up for pheochromocytoma in patients with neurofibromatosis type 1 (NF1) and hypertension., Methods: We review the long-term clinical, biochemical, and imaging findings in a man with a complex medical history of hypertension, NF1, and cardiomyopathy., Results: A 44-year-old man, with a well-documented history of headaches, hypertension, and NF1, was referred for evaluation of a right adrenal enlargement. He had developed cardiomyopathy and undergone an evaluation for cardiac transplantation. Initial computed tomography revealed subtle asymmetry in the upper right adrenal gland. Biochemical studies for pheochromocytoma yielded equivocal findings, with a 1.5-fold elevation in the urinary norepinephrine and near-normal urinary metanephrine level. Because 131I-metaiodobenzylguanidine imaging showed no tracer uptake in the area of the right adrenal gland, the patient was thought not to have a pheochromocytoma. The patient eventually underwent cardiac transplantation and did well. On reassessment 3 1/2 years later, he was found to have a larger right adrenal mass. The second endocrine evaluation demonstrated substantial elevation in the urinary metanephrine level, and the patient underwent laparoscopic right adrenalectomy to remove the tumor (3.5 by 3.0 by 2.5 cm), which proved to be a pheochromocytoma., Conclusion: This case shows that a pheochromocytoma can be difficult to diagnose and can evolve to become a large, biochemically active tumor. It is imperative that patients with an adrenal tumor undergo periodic reevaluation to ensure that the tumor remains stable in size. If the tumor enlarges, further biochemical testing is warranted.

Objective: Chromogranin A (CgA) is the most accurate general marker of neuroendocrine tumours. Supranormal CgA concentrations have been recorded in patients with tumours of neuroectodermal origin such as phaeochromocytoma and paraganglioma., Design: The present study was performed to assess the role of CgA determination in the management of patients with phaeochromocytoma, in comparison with urinary catecholamines and their metabolites., Patients: The patients studied included 22 cases with phaeochromocytoma at initial presentation or at relapse some years after surgical cure or during follow-up of a malignant phaeochromocytoma. Seventeen patients were evaluated before and after surgical removal of phaeochromocytoma. To assess the specificity of the hormonal parameters, 20 subjects were enrolled as controls; they were from a group of patients referred to our observation for possible phaeochromocytoma and who were subsequently proven not to have the disease., Results: Urinary epinephrine and norepinephrine were supranormal in 82% and 77% of patients, respectively. Urinary metanephrines and normetanephrines were supranormal in 84% and 89% of patients, respectively. The combination of urinary metanephrine and normetanephrine had a sensitivity of 100% in identifying a phaeochromocytoma. CgA was supranormal in 91% of patients. Combining the results of CgA and urinary catecholamines (epinephrine and norepinephrine), the sensitivity for diagnosis of phaeochromocytoma was 100%. Urinary catecholamines, metabolites (metanephrine and normetanephrine) and CgA levels in patients with malignant phaeochromocytoma did not differ significantly from those of patients with benign lesions. In most cases, CgA normalized after surgery., Conclusions: Our results indicate that CgA is a good marker of phaeochromocytoma; measurement of CgA could have a role in the follow-up of patients operated on for phaeochromocytoma.