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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.

We quantified urinary excretion of total metanephrines (metanephrine plus normetanephrine) (UETM) in 261 patients with pheochromocytoma (PH) or secreting paraganglioma, before primary tumor resection. We then determined UETM 2 weeks after primary tumor resection and once per year thereafter. The tumor was considered benign in 242 patients and malignant in 19 patients. Patients with malignant tumors had higher UETM and tumor diameters, lower plasma epinephrine concentrations, and were more likely to have secreting paragangliomas than patients with benign tumors. In the 215 patients with a single-benign primary tumor, preoperative UETM and tumor diameter were significantly correlated. Thirty-six patients subsequently developed recurrences or new tumors, which were malignant in 18 cases. All recurrent or new tumors could be detected before the onset of symptoms, on the basis of an increase in metanephrine concentration. We followed one patient with von Hippel-Lindau disease and a new tumor for 50 months before reoperation and found that UETM and tumor diameter were significantly correlated. In patients with malignant tumors, the logarithm of UETM was significantly correlated with time, suggesting an exponential increase in tumor activity and, presumably, tumor burden. Urinary metanephrine excretion is a marker of tumor activity and a surrogate of tumor burden in patients with pheochromocytoma or secreting paraganglioma. UETM excretion could be used to assess treatment response in malignant cases.

Objective: Phaeochromocytoma crisis is a life-threatening emergency that may be undiagnosed because of its numerous, nonspecific manifestations. We analysed, retrospectively, the presentation, management and outcome of patients who were admitted to our institution with phaeochromocytoma crises over a 5-year period., Results: Five patients (two males, three females; mean age 34.6 years, range 19-51 years) who presented as emergencies requiring intensive care, with multiple non-specific manifestations and previously undiagnosed pheochromocytoma, were identified. The initial presentation included features of cardiomyopathy (n = 3), atypical pneumonia with myocarditis (n = 1) and acute abdomen (n = 1). Only one of the five cases had a raised blood pressure at the time of the acute presentation. Initiation of beta blockers in four patients was associated with further deterioration in haemodynamic status, labile blood pressure and cardiac arrhythmias, which led to the diagnosis of the underlying phaeochromocytoma. Following intensive supportive therapy and alpha blockade, all five patients recovered and underwent elective surgical removal of phaeochromocytoma, uneventfully., Conclusion: Unexplained cardiopulmonary dysfunction, particularly after the institution of beta blockers, should alert clinicians to the possibility of phaeochromocytoma. A high index of suspicion is essential to reduce morbidity and mortality in these patients through early diagnosis and aggressive management.

Pheochromocytoma may infrequently lead to dilated cardiomyopathy, which may reverse partially or completely after treatment. Progressive dyspnea, palpitations, and paroxysmal attacks of severe hypertension leading to cardiac failure had developed in a 25-yr-old woman. Chest radiography and echocardiography revealed a massive 4-chamber dilatation of the heart with an ejection fraction of 12%. Twenty-four-h urinary vanillylmandelic acid and metanephrine levels were elevated. Magnetic resonance imaging detected a large mass lesion in the right adrenal gland. Oral glucose tolerance testing revealed diabetes mellitus. Medical drug therapy with alpha-blocker, angiotensin converting enzyme inhibitor, beta-blocker, digoxin, and diuretic rapidly improved her cardiac condition. Repeat echocardiogram showed that the left ventricular function had improved substantially. The clinical condition of excess catecholaminemia (and thus, arterial hypertension and the abnormality of the glucose metabolism) subsided with complete resolution of the congestive heart failure following the surgical removal of the tumor. Evaluation for medullary thyroid carcinoma (MTC) revealed an elevated calcitonin level demonstrated by fine needle aspiration biopsy. There were no biochemical evidences for primary hyperparathyroidism. Multiple endocrine neoplasia 2 (MEN 2A) syndrome was diagnosed. An overwhelming secretion of catecholamine might cause severe cardiomyopathy and impair glucose metabolism, as evidenced by the improvement of both conditions following the medical treatment of catecholaminemia and surgical resection of the tumor.

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

We present a case report that the patient had symptoms suggesting pheochromocytoma, a large tumor (> 50 g) and a single minimally altered laboratorial test, exemplifying a diagnostic pitfall. A 31 y.o. male patient had two acute abdominal events, the last one accompanied by headache, arterial hypertension, facial flushing, perspiration and cutaneous pallor. In another admission, the patient had sustained arterial hypertension and cardiac arrhythmia. From laboratory analysis, the vanililmandelic acid was slightly modified. Scintigraphy disclosed a large adrenal mass suggesting pheochromocytoma. Histopathology confirmed this hypothesis. This report points out that patients with symptoms suggesting pheochromocytoma, even when plasma catecholamines and urinary metanephrines levels are normal, may harbor large tumors with a high catecholamines turnover or that had undergone hemorrhagic necrosis.

Objective: We have identified a large kindred with multiple endocrine neoplasia 2A (MEN 2A) due to a mutation at RET codon 609 that results in a cysteine to serine substitution, a mutation previously identified in only one case in the literature. We characterized the clinical phenotype of the kindred and the biochemical mechanism of this new mutation., Patients and Design: The index case, a 42-year-old woman, presented with pheochromocytoma. We screened 29 family members for the presence of the mutation. Of the 15 mutation-positive family members, 11 agreed to undergo further evaluation by physical examination, calcium and pentagastrin-stimulated calcitonin levels, measurement of urinary metanephrines, adrenal imaging and serum calcium levels. Biochemical characterization of the mutation was by transient transfection of human neuroblastoma cells and Western blot analysis., Results: This kindred demonstrated an inheritance pattern consistent with autosomal dominant pheochromocytoma. Strikingly, no clinically evident case of medullary thyroid cancer (MTC) was observed among mutation-positive family members. Thyroidectomy in six cases revealed C-cell hyperplasia in all and microscopic MTC in two cases. Transfection experiments using human neuroblastoma cells showed that the mutant RET, unlike the wild-type receptor, is constitutively phosphorylated in the absence of ligand, and thus resembles other previously characterized MEN 2A mutations., Conclusions: The identification of a new mutation causing a MEN 2A phenotype that features pheochromocytoma and the surprising absence of clinically apparent MTC has significant implications for carriers of this mutation and provides further insights into the genotype-phenotype correlation in MEN 2A.

Neuroblastoma of the adrenal gland is an extremely rare tumour in adulthood although it is one of the most common malignancies in childhood. In this report, we present a 52-year-old man who had a left adrenal mass on preoperative imaging. On laboratory, slightly elevated catecholamine metabolites were detected in the urine that was collected over 24 hours. He was operated and the mass was resected in en-block manner along with the regional lymph nodes. The histopathological examination of the specimen revealed the diagnosis of neuroblastoma. He had no metastatic disease at the time of diagnosis and received chemotherapy after the operation. However, the prognosis was poor and he died 10 months after the operation. Although neuroblastoma of adrenal gland is rare in adulthood, it should be considered in the differential diagnosis for patients with adrenal masses.

The discovery of novel mutations in genes encoding succinate dehydrogenase subunits has revealed that familial phaeochromocytomas are much more common than previously thought. Genetic screening should be offered to patients with apparently sporadic phaeochromocytomas and their first-degree relatives. An increasing proportion of phaeochromocytomas present preclinically on genetic testing or as "incidentalomas" on abdominal imaging, rather than with classic symptoms and signs. Clinical suspicion should prompt measurement of plasma levels of free metanephrine or 24-hour urinary catecholamine and metanephrine levels, followed, if positive, by tumour localisation studies. With appropriate perioperative care, surgical management of phaeochromocytomas is safe and effective. Most tumours can be removed laparoscopically.

Pheochromocytoma is a rare neuroendocrine tumor that secretes high levels of catecholamines and usually causes paroxysmal or sustained hypertension. Various forms of myocardial damage have also been reported, including cardiomyopathy, myocardial infarction, arrhythmias, and angina. When patients present with severe unexplained heart failure, exploring all causes for the source of cardiomyopathy is essential, especially if the cause is reversible. The authors describe the case of a young man who presented to the hospital with acute heart failure who was later diagnosed with a pheochromocytoma.

Background: Measurements of plasma free metanephrines (normetanephrine and metanephrine) provide a useful test for diagnosis of pheochromocytoma and may provide other information about the nature of these tumors., Methods: We examined relationships of tumor size, location, and catecholamine content with plasma and urinary metanephrines or catecholamines in 275 patients with pheochromocytoma. We then prospectively examined whether measurements of plasma free metanephrines could predict tumor size and location in an additional 16 patients., Results: Relative proportions of epinephrine and norepinephrine in tumor tissue were closely matched by relative increases of plasma or urinary metanephrine and normetanephrine, but not by epinephrine and norepinephrine. Tumor diameter showed strong positive relationships with summed plasma concentrations or urinary outputs of metanephrine and normetanephrine (r = 0.81 and 0.77; P <0.001), whereas relationships with plasma or urinary catecholamines were weaker (r = 0.41 and 0.44). All tumors in which increases in plasma metanephrine were >15% of the combined increases of normetanephrine and metanephrine either had adrenal locations or appeared to be recurrences of previously resected adrenal tumors. Measurements of plasma free metanephrines predicted tumor diameter to within a mean of 30% of actual diameter, and high plasma concentrations of free metanephrine relative to normetanephrine accurately predicted adrenal locations., Conclusions: Measurements of plasma free metanephrines not only provide information about the likely presence or absence of a pheochromocytoma, but when a tumor is present, can also help predict tumor size and location. This additional information may be useful for clinical decision-making during tumor localization procedures.

The term 'metanephrines' is used to indicate the two catechol 3-O-methylated metabolites of epinephrine (E) and norepinephrine (NE): metanephrine and normetanephrine (NMN). The corresponding 3-O-methylated metabolite of dopamine is usually referred to as 3-methoxytyramine rather than 3-methoxydopamine and is not generally considered a "metanephrine". O-Methylation occurs outside the sympathetic neuron and neuroeffector junction. Metanephrines are products of the enzyme catechol-O-methyltransferase (COMT). Subsequent conjugation with sulfate or deamination by monoamine oxidase (MAO) followed by reduction to vanilmandelic acid (VMA) facilitates urinary excretion. For the clinician, measurement of normetanephrine provides an index of norepinephrine released during sympathetic nervous system activity, whereas metanephrine concentration provides an indication of adrenal medullary metabolism of epinephrine prior to its discharge into the circulation. Plasma epinephrine concentration is the preferable index of adrenal medullary epinephrine discharge. Pheochromocytomas, with their protean clinical manifestations, may be diagnostic challenges, but assay of metanephrines, especially plasma metanephrine, can be particularly helpful in diagnosis. These COMT metabolites may also help in elucidation of still undiscovered genetic and acquired disorders of catecholamine metabolism.

A 26-year-old white woman had an ablated sino-atrial node and ventricular pacemaker as an unusual feature of a pheochromocytoma-compatible history. Her status quo included, on three occasions, elevated 24-hour urinary epinephrine and metanephrine excretion. She monitored her blood pressure (BP) and heart rate (HR) at 15- to 60-minute intervals over several days, with interruptions, before and after the institution of 10 mg phenoxybenzamine per os every 12 hours (between 7:30 and 8:00 and between 19:30 and 20:00), with continued monitoring over several months. Her data were summarized for consecutive 3-day intervals by sphygmochron. Circadian parameters and original data are compared with gender- and age-specified reference values, yielding also non-parametric endpoints, such as the percentage time elevation, the extent of excess, and the timing of excess, that all can be acceptable for some days but unacceptable for other days. In her broader time structure, or chronome, cosinor analyses revealed a prominent and statistically significant circadian rhythm in BP and HR before and during the 12-hourly therapy. The 12-hour component of BP was more prominent during therapy than prior to it. A statistically significant decreasing trend occurred before therapy, and recurred during treatment. Chronomically interpreted monitoring revealed: 1) the persistence of a statistically significant circadian rhythm during 12-hourly phenoxybenzamine treatment; 2) days-long changes in BP MESOR, the duration of which could not be previously determined based on spotchecks; 3) changes in the circadian amplitude of BP, which can be either very small or very large, compatible with the diagnosis of intermittent circadian hyper-amplitude-tension (CHAT); and 4) a very wide range of BP and HR values, so that occasional (casual) measurements fail to convey the dynamics that may underlie this infrequently found clinical condition of an elevated catecholamine excretion compatible with a pheochromocytoma. All findings support the need for long-term monitoring of BP and HR that may account for controversy in earlier publications.

Objectives: To assess the impact of [(131)I]meta-iodobenzylguanidine ((131)MIBG) scintigraphy on the management of phaeochromocytoma., Design and Patients: Between 1982 and 2002, 83 patients with histologically proven phaeochromocytoma or paraganglioma were investigated using (131)MIBG scintigraphy. Seventeen of these patients, with a hereditary form of the disease, presented with 23 phaeochromocytomas [three neurofibromatosis type 1 (NF1), five von Hippel-Lindau disease (VHL), eight multiple endocrine neoplasia type 2A (MEN2A) and one type 2B (MEN2B)]., Results: MIBG uptake was observed in 44/54 sporadic phaeochromocytomas (sensitivity 81.5%), 14/23 familial phaeochromocytomas (60.9%), 3/6 paragangliomas and 4/6 malignant phaeochromocytomas. No significant correlations were found between the degree of tracer uptake, tumour size and urinary metanephrine levels. No patients undergoing surgery for sporadic phaeochromocytoma had a second tumour located. Nine of 54 sporadic phaeochromocytomas had normal or mildly elevated urinary metanephrine levels (< 1.5 greater than normal). In eight of these patients, (131)MIBG was positive and confirmed the diagnosis of phaeochromocytoma. In malignant phaeochromocytomas (n = 6), MIBG demonstrated additional lesions not detected with computed tomography (CT) and/or magnetic resonance imaging (MRI) in three cases. The MIBG findings in the group with apparently sporadic paragangliomas (n = 6) were negative in four cases and failed to detect a cervical lesion in one multifocal paraganglioma., Conclusion: (131)MIBG was useful in confirming the diagnosis in phaeochromocytomas with low levels of catecholamine secretion. It contributed little to the management of patients when used as a means of screening for multifocality in sporadic phaeochromocytoma, or the management of patients with familial phaeochromocytoma. However, MIBG can be an informative method of investigation when dealing with malignant/ectopic forms, although the sensitivity of MIBG is lower in this group of patients.

Background: Adrenalectomy for pheochromocytoma is a life-threatening procedure. Few echocardiographic assessments have been reported in patients undergoing adrenalectomy for pheochromocytoma., Methods: Sixty-three consecutive patients undergoing adrenalectomy for pheochromocytoma underwent routine preoperative M-mode and two-dimensional echocardiography, and Doppler examination. Abnormal echocardiographic findings were defined as left ventricular dilatation or dysfunction (left ventricular percentage fractional shortening < 30%), and/or left ventricular wall motion abnormalities, and/or left ventricular hypertrophy (left ventricular mass index > 110 g m(-2) in women and >134 g m(-2) in men) and/or valvular abnormalities. Physical characteristics, daily urinary metanephrine and normetanephrine excretions, preoperative functional limitation, pre-existing congestive heart failure, type and duration of surgery, and haemodynamic instability in the intra and postoperative periods were compared in patients with normal and abnormal echocardiographic findings., Results: Twenty-four out of 63 patients were found to have abnormal preoperative echocardiography. There was no difference between patients with normal and abnormal preoperative echocardiography as regards to the investigated criteria, except for pre-existing self-reported functional limitation and chest pain suggesting coronary artery disease., Conclusions: The relevance of routine preoperative echocardiographic examination in patients scheduled for adrenalectomy for pheochromocytoma, who have no cardiac symptoms or clinical evidence of cardiac involvement, is questionable., (Copyright 2004 Acta Anaesthesiologica Scandinavica)

Objectives: To report one case of adrenal incidentaloma and to review the sensitivity and specificity of urine methanephrines in the diagnosis of pheochromocytoma., Methods: We report the case of a patient with high blood pressure and a left adrenal incidentaloma. Surgical excision of the mass was indicated after elevated urine methanephrine., Results: Pathologic study of the nodule established the diagnosis of cortical adenoma., Conclusions: The elevation of urine normethanephrine is a non-specific parameter for the diagnosis of pheochromocytoma.

Background: Some high-performance liquid chromatography techniques with electrochemical detection for urinary catecholamines and their metabolites can be subject to interference from drugs and their metabolites. Prime amongst these interferences are those due to paracetamol ingestion., Methods: The prevalence of paracetamol contamination was determined by measuring the drug in all patient specimens submitted for catecholamine analysis over a 2-month period. These findings were then related to the proportion of unreportable results at each range of specimen paracetamol concentration. The apparent results from a small representative sample of the paracetamol-positive specimens are illustrated., Results: Approximately one-third of urine specimens were found to contain paracetamol. Low-level contamination can produce apparent patterns of results which may easily be confused with those found in predominantly adrenaline-, or metadrenaline-secreting phaeochromocytomas., Conclusion: Despite the fact that significantly less than 5% of an oral dose of paracetamol is excreted as the free drug, its analysis provides a good surrogate marker for the likelihood of spurious results. It is useful to know prior to urinary free metadrenaline or catecholamine analysis which urine specimens are likely to contain potentially interfering paracetamol metabolites.

Pheochromocytoma is a rare, life-threatening condition. Using a modeling technique, we studied the economic implications of detection strategies for pheochromocytoma (third-party payer perspective). The diagnostic efficacy of biochemical tests was based on Mayo Clinic Rochester data. In all hypothetical algorithms, positive biochemical tests were followed by abdominal computerized tomography and, if negative, metaiodobenzylguanidine scintigraphy. In each hypothetical algorithm, imaging would be indicated after positive biochemical testing as follows: algorithm A, fractionated plasma metanephrine measurements above the laboratory reference range; or algorithm B, abnormal measurements of 24-h urinary total metanephrines or catecholamines. In algorithm C, subjects with fractions of plasma metanephrine at or above 0.5 nmol/liter or normetanephrine at or above 1.80 nmol/liter would undergo imaging, whereas those with values between the reference range and these cutoffs would undergo 24-h urinary measurements (total metanephrines and fractionated catecholamines) and be imaged if positive. We determined that, if 100,000 hypertensive patients (including 500 patients with pheochromocytoma) were tested, algorithm A (measurement of fractionated plasma metanephrines alone) would detect 489 pheochromocytoma patients at a cost of 56.6 million dollars, whereas B (24-h urinary measurements) would detect 457 pheochromocytoma patients for 39.5 million dollars, and C (combination of measurements of fractionated plasma metanephrines and urines) would detect 478 patients for 28.6 million dollars. None of the screening strategies for pheochromocytoma described are affordable if implemented on a routine basis in extremely low-risk patients. However, algorithm C may be the least costly, and at a reasonable level of sensitivity, for subjects in whom the suspicion of disease is moderate.

This Hypertension Grand Rounds shows how applying new clinical laboratory techniques helped to diagnose pheochromocytoma in a difficult case. In the setting of long-standing, sustained hypertension, the patient had a hypertensive paroxysm during anesthesia induction for surgery, leading to suspicion of a pheochromocytoma. Conventional testing, including CT scanning and fractionated urinary metanephrine test, was not diagnostic. The patient had another hypertensive paroxysm during subsequent anesthesia induction, requiring intensive care. Consistently elevated plasma levels of free normetanephrine provided the first and only biochemical evidence for a pheochromocytoma in this case. 6-[18F]Fluorodopamine positron emission tomography and 123I-metaiodobenzylguanidine scintigraphy subsequently agreed on the existence of a small left adrenal mass, which when removed surgically proved to be a pheochromocytoma. Postoperatively, plasma levels of normetanephrine normalized, and there were no further hypertensive paroxysms, although the patient remained hypertensive. This case illustrates the superiority of plasma levels of free (unconjugated) metanephrines, compared with other biochemical tests, to detect pheochromocytoma. It also confirms that functional imaging by 6-[18F]fluorodopamine or 123I-metaiodobenzylguanidine scanning can localize pheochromocytoma in difficult cases in which other imaging tests are not diagnostic.

Pheochromocytoma is a lethal tumor of chromaffin cells of the adrenal medulla that produces episodes of hypertension with the symptoms of palpitations, severe headaches, and sweating. The diagnosis of pheochromocytoma is a challenging one; autopsy series suggest that many pheochromocytomas are not clinically suspected, and the undiagnosed tumor can be associated with morbid consequences. The testing of catecholamines, metanephrines, and Vanillylymandelic acid commonly is used for screening of pheochromocytoma. The diagnostic value of various biochemical tests,as reported in recent Mayo and National Institutes of Health studies, have been compared and discussed in detail. The recent developments in the methodologies of metanephrines testing also are presented.

Adrenal incidentalomas are tumors that are serendipitously found by radiological examination. The incidence of adrenal incidentalomas in patients undergoing abdominal CT approaches 1 %. The evaluation of a patient with an adrenal incidentaloma requires, in addition to a clinical history and physical examination, a focused biochemical evaluation to investigate if there is excess secretion of catecholamines, glucocorticoids, or aldosterone. Some tumors have specific features on imaging that identify them as benign or malignant. The recommendations for management of adrenal incidentalomas include resection of all functioning tumors regardless of size, preferably by the laparoscopic approach. Large, non-functional tumors should also be removed. Biochemical and radiological surveillance is recommended for at least one year, if a tumor is left in place.

A 44-year-old woman presented with sudden onset of chest pain, headache and nausea. Physical examination was remarkable for mild hypotension and tachycardia. ECG demonstrated sinus tachycardia with poor R wave progression in precordial leads and T wave inversion in leads V1-3. Cardiac enzymes were raised. Echocardiographic examination revealed normal cavity diameters with basal and mid left ventricular hypokinesia and an ejection fraction of 45%. A diagnosis of non-ST elevation myocardial infarction was made. A few orthostatic hypotensive attacks occurred at follow-up. A coronary angiogram showed normal coronary arteries. Within a few days, the echocardiographic findings, ECG and all cardiac markers had returned to normal. Two months later she presented with headache, palpitation, fever, neck swelling, flushing and hypertensive attacks. Phaeochromocytoma was diagnosed on the basis of increased metanephrine on urinalysis and a left suprarenal mass on CT scan.

Adrenal cortical phaeochromocytomas (pseudo-phaeochromocytomas) are a very rare entity and a diagnostic challenge. Of the few cases previously reported, most have incomplete data or lack clinical and biochemical follow-up documenting the cure of the excess secretion of catecholamines after resection of the tumour. We report herein a 62-year-old patient with clinical and biochemical findings diagnostic of a phaeochromocytoma associated with a 2-cm adrenal mass on CT scan. Surgery revealed the presence of an adrenal cortical adenoma with positive staining for the neuroendocrine marker synaptophysin, but negative for chromogranin, as has been previously reported for these rare cortical phaeochromocytomas. After removal of the tumour the clinical symptoms resolved and biochemical markers normalized, demonstrating the causal relationship between the cortical tumour and the excess production of catecholamines.

We compared the diagnostic efficacy of fractionated plasma metanephrine measurements to measurements of 24-h urinary total metanephrines and catecholamines in outpatients tested for pheochromocytoma at Mayo Clinic Rochester from January 1, 1999, until November 27, 2000. Catecholaminesecreting tumors were histologically proven. The sensitivity of fractionated plasma metanephrines was 97% (30 of 31 patients), compared with a sensitivity of 90% (28 of 31) for urinary total metanephrines and catecholamines (P = 0.63). The specificity of fractionated plasma metanephrines was 85% (221 of 261), compared with 98% (257 of 261; P < 0.001) for urinary measurements. The likelihood ratios for positive tests were 6.3 (95% confidence interval, 4.7 to 8.5) for fractionated plasma metanephrines and 58.9 (95% confidence interval, 22.1 to 156.9) for urinary total metanephrines and catecholamines. An adrenal pheochromocytoma was missed by urinary testing in two patients with familial syndromes and one asymptomatic patient with an incidentally discovered adrenal mass. An extra-adrenal paraganglioma was missed by plasma testing in one patient. In conclusion, measurements of 24-h urinary total metanephrines and catecholamines yield fewer false-positive results, an attribute preferred for testing low-risk patients, but fractionated plasma metanephrine measurements may be preferred in high-risk patients with familial endocrine syndromes.

Objective: To present a case of multiple endocrine neoplasia type 2B (MEN2B) with a prolonged course., Methods: We describe the clinical, laboratory, and radiologic findings in a patient with MEN2B and review the various interventions during a period of approximately 3 decades., Results: In 1962, a 19-year-old man with a marfanoid body habitus presented with multiple thyroid nodules and neurofibromas of the tongue. Total thyroidectomy demonstrated multicentric medullary thyroid carcinoma with cervical lymph node metastatic involvement. At the time of the first description of the MEN2B syndrome, the patient was enrolled in a surveillance program. An increase in urinary metanephrines resulted in bilateral adrenalectomy for multinodular pheochromocytoma in 1972. Increased serum calcitonin levels and the appearance of cervical lymphadenopathy led to modified radical neck dissection 12 years after the initial diagnosis of medullary thyroid carcinoma. In 1975, angiography revealed extensive hepatic lesions metastatic from the medullary thyroid carcinoma; this finding was confirmed by open liver biopsy in 1988. The patient lived 16 years after the initial diagnosis of liver metastatic disease and died 29 years after the initial examination., Conclusion: The 3-decade course of this patient not only represents a classic case of MEN2B but also allows us to present the history of this disease from its discovery to the current era of genetic testing and exemplifies the possibility of long-term survival in a patient with liver metastatic involvement from medullary thyroid carcinoma.

Objective: Somatostatin receptors are present on human phaeochromocytomas. Catecholamine concentrations may decrease following short-term administration of somatostatin agonists to patients with phaeochromocytomas. We carried out a prospective study on 10 patients with malignant or recurrent phaeochromocytomas to examine the clinical and hormonal effects of three monthly intramuscular injections of 20 mg slow-release octreotide., Design and Measurements: Patients underwent somatostatin receptor scintigraphy using 111In-pentetreotide before slow-release octreotide was administered. The patients' symptoms, blood pressure, blood glucose concentrations, glycosylated haemoglobin concentra-tions, plasma insulin and noradrenaline concentrations, and the levels of two putative markers of tumour burden, urinary metanephrine excretion and plasma chromogranin A concentration, were recorded before the first injection and 28 days after the third injection., Results: Slow-release octreotide did not significantly alter symptoms, blood pressure, blood glucose concentrations, plasma catecholamine and chromogranin A concentrations or metanephrine excretion. Median glycosylated haemoglobin concentrations increased from 5.3% to 6.0% (P = 0.03). Patients whose tumours took up 111In- pentetreotide did not differ from those whose tumours did not after slow-release octreotide treatment in terms of symptoms, blood pressure, blood glucose, plasma catecholamine and chromogranin A concentrations or metanephrine excretion., Conclusion: Our data suggest that slow-release octreotide is of limited value for the long-term treatment of patients with malignant or recurrent benign phaeochromocytomas.

The psychobiologic status of cyclists after 4 days of training and the kinetics of recovery were assessed by measuring the sympatho-adrenal level, the central noradrenergic activity and the cortisol/testosterone status by non-invasive methods. For this purpose, urinary excretion of methoxyamines (metanephrine [MN], normetanephrine [NMN]), which are metabolites of circulating catecholamines, 3-methoxy-4-hydroxyphenyl glycol sulfate (MHPG-S), a metabolite of brain norepinephrine, and salivary output of cortisol and testosterone were measured in twelve national cyclists (aged 19.5 +/- 4.5 years), just before (T 1 ) and at the end of the training (T 2 ), and during the three following recovery days (R 1, R 2, R 3 ). Urinary and salivary samples were also collected during a period of relative rest, in order to get reference values (T 0 ). At T 0, T 1 and T 2, mood states, as measured by the Profile of Mood States, and rating of perceived muscle soreness were assessed. The overall mood and muscle soreness levels were not affected by the training. The load increased by 187 % as an average between the first and the fourth day of training. A significant increase in NMN levels and a decrease in T:F ratio were observed at T 2, while MHPG-S excretion remained unchanged. Persistent high urinary output of NMN and MN were observed during the post-training recovery period for 24 h (R 1 ) and 48 h (R 2 ), respectively. After 72 h of recovery (R 3 ), MN levels had returned to baseline while NMN output was lower than the control level. T:F values returned to their control levels within 48 h of recovery. The strenuous training seems to induce an alteration in peripheral neuro-endocrine parameters without modifications of central factors. The hormonal status remained altered for at least 1 day of post-training recovery and seemed to be achieved within 3 days.

Background: Normal urine catecholamine values in patients with phaeochromocytoma is an occasional finding and may lead to a missed diagnosis. Additional urinary free metadrenaline analysis may be of value in this situation., Methods: In addition to vanillylmandelic acid, homovanillic acid and the catecholamines, urinary free normetadrenaline (fNMA) and free metadrenaline (fMA) were measured. This report describes six confirmed cases of phaeochromocytoma showing normal urinary catecholamine output and compares fMA results and tumour size with other confirmed cases where the urine catecholamines were increased., Results: Urine catecholamines in these patients with, on average, smaller tumours, were all normal. Urinary fNMA and fMA were available on five patients, and were increased in three. The data suggest that, unlike the catecholamines, urinary fNMA and fMA could be a useful predictor of tumour size., Conclusion: The inclusion of fNMA and fMA in the test profile is likely to be of additional benefit in tumour detection, particularly when catecholamines or other metabolites are normal.

A method successfully coupling capillary electrophoretic separation to time-of-flight mass spectrometric (TOFMS) detection for the simultaneous analysis of catecholamines (dopamine, norepinephrine, and epinephrine) and their O-methoxylated metabolites (3-methoxytyramine, normetanephrine, and metanephrine) is described. The inner capillary wall was coated with polyvinyl alcohol in order to obtain baseline resolution of catecholamines and metanephrines and to ensure reproducibility without extensive restorative washing of the capillary. Using electrokinetic injection, detection limits of 0.3 microM for dopamine and norepinephrine, 0.2 microM for 3-methoxytyramine and normetanephrine, and 0.1 microM for epinephrine and metanephrine were achieved with standard solutions. The usefulness of this approach was demonstrated by applying the developed method to the analysis of a spot collection of human urine from a healthy volunteer. The catecholamines and metanephrines were removed from the urine samples and preconcentrated by simultaneous SPE on cation-exchange sorbents. The recoveries of all analytes, with the exception of epinephrine (75%), were over 80%. Catecholamines and metanephrines in the urine samples were quantitated using 3,4-dihydroxybenzylamine as an internal standard. Submicromolar concentrations, consistent with the catecholamine and metanephrine levels reported for normal human urine, were detected., (Copyright 2002 Elsevier Science B.V.)

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.

Pheochromocytomas, although a rare cause of hypertension, are dangerous tumors that require consideration among large numbers of patients. The subsequent low prevalence of the tumor among those tested and 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. Measurements of plasma concentrations of free metanephrines thereby promise more reliable and efficient diagnosis of pheochromocytoma than offered by conventional biochemical tests.

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

Background: The diagnosis of pheochromocytoma is based on laboratory tests that demonstrate an increase in urinary excretion of catecholamines or their metabolites. Chromogranin A (CgA) is a member of the granin family and is widely distributed in neuroendocrine cells and particularly in chromaffin adrenal cells. Consequently, serum CgA increases in patients affected by pheochromocytoma and other diseases of the chromaffin system., Aim: This study investigated the performance of serum CgA assay in the diagnosis of pheochromocytoma and compared serum CgA with 24-hour urinary epinephrine (E), norepinephrine (NE), vanillylmandelic acid (VMA) and metanephrines (MNs)., Methods: We enrolled 15 patients with histologically proven pheochromocytoma; 100 healthy blood donors and 148 patients with essential hypertension were enrolled as controls. Serum CgA was assayed by a specific immunoradiometric method (IRMA). Urinary tests were done with high performance liquid chromatography (HPLC)., Results: Circulating CgA showed a higher sensitivity (1.00), specificity (0.96) and accuracy (0.96) than all other tests. Serum levels of CgA clearly increased from blood donors and patients with essential hypertension to patients with pheochromocytoma (p<0.0001). Furthermore, a strong relationship between serum CgA and tumor mass was found (p<0.0001). In conclusion, our data suggest that the CgA assay might be used as a single test for the diagnosis of pheochromocytoma.

This report describes a rare case of ACTH-independent macronodular adrenal hyperplasia (AIMAH) arisen with symptomatic severe hypertension and hypokaliemia. A 55-year-old man was admitted to hospital with a clinical picture characterized by several episodes of transient ischemic attacks (TIA) and right hemiplegia, related to severe arterial hypertension. Laboratory tests showed urinary levels of catecholamines, metanephrines and vanillylmandelic acid (VMA) in normal range; high urinary free cortisol excretion, elevated serum cortisol with loss of the circadian rhythm and low ACTH plasma levels. ACTH failed to respond to CRH administration. Serum cortisol levels were not modified after high doses of dexamethasone. MRI showed bilateral macronodular hyperplasia of adrenal glands, whereas pituitary-MRI did not show tumoral lesions. Therefore, ACTH-independent macronodular hyperplasia was suspected. Though obese, the patient had no typical Cushing habit, and symptomatic hypertension with hypokaliemia was the only clinical evidence for this rare kind of Cushing's syndrome. After obtaining a satisfactory control of blood pressure, the patient was successfully submitted to laparoscopic bilateral adrenalectomy and underwent complete clinical remission. The histology showed adrenal macronodular hyperplasia. During the twenty-four month follow-up, the patient had no further transient ischemic attacks or need of glucocorticoid replacement therapy and withdrew the antihypertensive drugs.

Background: Metanephrines are biochemical markers for tumors of the adrenal medulla (e.g., pheochromocytoma) and other tumors derived from neural crest cells (e.g., paragangliomas and neuroblastomas). We describe a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the measurement of urinary conjugated metanephrines., Methods: We added 250 ng of d3-metanephrine (d3-MN) and 500 ng of d3-normetanephrine (d3-NMN) to 1 mL of urine samples as stable isotope internal standards. The samples were then acidified, hydrolyzed for 20 min in a 100 degree C water bath, neutralized, and prepared by solid-phase extraction. The methanol eluates were analyzed by LC-MS/MS in the selected-reaction-monitoring mode after separation on a reversed-phase amide C16 column., Results: Multiple calibration curves for the analysis of urine MN and NMN exhibited consistent linearity and reproducibility in the range of 10-5000 microg/L. Interassay CVs were 5.7-8.6% at mean concentrations of 90-4854 microg/L for MN and NMN. The detection limit was 10 microg/L. Recovery of MN and NMN (144-2300 microg/L) added to urine was 91-114%. The regression equation for the LC-MS/MS (x) and colorimetric (y) methods was: y = 0.81x - 0.006 (r = 0.822; n = 110). The equation for the HPLC (x) and LC-MS/MS (y) methods was: y = 1.09x + 0.05 (r = 0.998; n = 40)., Conclusions: The sensitivity and specificity of the MS/MS method for urinary conjugated metanephrines offer advantages over colorimetric, immunoassay, HPLC, and gas chromatography-mass spectrometry methods because of elimination of drug interferences, high throughput, and short chromatographic run time.

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

Objective: To describe a patient with the rare coexistence of acromegaly and pheochromocytoma., Methods: We report a case of a 57-year-old woman, who was initially examined because of polyarthritis, she was also diagnosed with type 2 diabetes mellitus and hypertension at age 56 years. Her history, clinical findings, laboratory results, and management are summarized, and etiologic hypotheses are discussed., Results: The patient had recurrent headaches and reported an increasing size of her shoes and gloves during the previous 4 years. Enlargement of her hands and feet and a bilateral temporal field defect were noted on examination. Laboratory studies revealed high levels of insulin-like growth factor I (IGF-I) and growth hormone (GH). Magnetic resonance imaging (MRI) showed a 3-cm sellar mass with impingement on the optic chiasm. The plasma level of growth hormone-releasing hormone (GHRH) was normal. She underwent transsphenoidal adenomectomy. Histologic examination confirmed a pituitary adenoma, immunoreactive for GH. Postoperatively, her headaches and arthritic pain diminished, and her levels of IGF-I and GH normalized; however, labile hypertension persisted. The urinary metanephrines and plasma catecholamines were increased. A 3-cm left adrenal mass, seen on abdominal MRI, was removed laparoscopically, after which urinary metanephrines normalized and both the diabetes and the hypertension resolved. Histopathologic analysis confirmed the diagnosis of pheochromocytoma. Immunohistochemical staining was negative for GHRH., Conclusion: The finding of a pheochromocytoma and acromegaly could be a fortuitous coexistence of two separate endocrine tumors; however, the probability of such an event is extremely low. A cause-and-effect relationship has been suggested because of previous reports of GHRH production by pheochromocytomas. Some investigators have also suggested that this coexistence might be a multiple endocrine neoplasia variant. Our patient had no evidence of GHRH production, nor did we document any familial autosomal dominant transmission pattern.

Pheochromocytomas cause the most dramatic, life-threatening crises in all of endocrinology. Pheochromocytoma is an explosive clinical syndrome characterized by severe hypertension associated with cardiac complications, hypotension, or even shock and sudden death. The key to diagnosing pheochromocytoma is to suspect it, then confirm it. The cases reported in this review illustrate how the diagnosis can be easily missed and definitive treatment delayed. An appreciation of the wide range of clinical manifestations, based on clear understanding of the mechanisms of catecholamine action and the pathophysiology of pheochromocytoma, and the availability of simple and accurate diagnostic tests should lead to earlier detection of these tumors. Advances in localization techniques and availability of various treatment modalities have made successful management more promising than ever before.

A method for the determination of metanephrine (MN; also known as metadrenaline), normetanephrine (NMN; also known as normetadrenaline) and 3-methoxytyramine (3-MT) in human urine using high-performance liquid chromatography followed by electrochemical detection (ECD) was validated primarily by comparing the results with those obtained by a gas chromatography mass spectrometry (GC-MS) reference method. Correlation coefficients of 0.93, 0.94 and 0.91 were obtained for MN, NMN and 3-MT, respectively, in a group of healthy controls consisting of 30 women and 30 men. A systematic difference was detected only for 3-MT (-16%). Further tests of accuracy (linearity and recovery) and precision demonstrated that the described method must be considered to be a reliable approach to assess urinary metanephrines in the diagnosis of phaeochromocytoma. At lower concentrations (MN, 248 nmol/L; NMN, 434 nmol/L; 3-MT, 402 nmol/L), within-assay coefficients of variation were close to 5% or less (5.3, 4.6 and 2.2%, respectively) and between-assay coefficients of variation were 8.9, 11.2 and 12.3%, respectively, for the same low levels. This raises the possibility that this method can also be applied to assess urinary free, unconjugated metanephrines. Sex differences were detected for MN and NMN excretion when expressed in nmol per 24h and nmol/mmol creatinine, respectively, by both ECD and GC-MS methods.

The only definitive therapy for patients with pheochromocytoma is surgical resection [1,2**]. Advances in preoperative medical management of hypertension/hypovolemia and improved intraoperative anesthetic care have reduced the operative mortality rate for pheochromocytoma to less than 5% in most series. In addition, accurate preoperative localization studies have eliminated the need for extensive exploratory laparotomy. Focused approach and laparoscopic resection have become the new "gold standard," with a reduced morbidity [4**]. Large or locally invasive pheochromocytomas may still require open resection.