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Introduction Methods Results Conclusion Pheochromocytoma is a unique tumour with a variety of clinical presentations. Coined as ‘the great masquerader’, it can present with the classical triad of headache, sweating and tachycardia and sometimes in an acute hypertensive crisis. This paper describes the evolutionary history of the diagnosis of this condition.A literature review was conducted using Medline Database from 1900 to 2023 outlining the methods of diagnosis for pheochromocytoma.There have been diagnostic dilemmas and localization challenges of pheochromocytoma over the last century. From the first description of pheochromocytoma in 1886 to the first successful resection in 1926, there was poor recognition of its atypical symptoms and lack of reliable diagnostic tests. Over the next few decades, there were significant advances in screening and biochemical tests. Further understanding of catecholamine release and metabolic pathways led to the development of tests to identify end products of catecholamine metabolism in plasma and urine. Computed imaging however heralded significant improvement in surgical planning and management. The evolution of histopathological diagnosis with the use of immunostains and genetic testing has further contributed to the identification of malignant pheochromocytomas and an understanding of their behaviours.Significant advances in the biochemical and imaging have shaped our understanding of pathophysiology and management. These diagnostic advances have enabled early and accurate detection and localization of pheochromocytomas to enable prompt surgical management. [ABSTRACT FROM AUTHOR]

Noncardiogenic pulmonary edema (NCPE) in hunting dogs is an uncommon and poorly described condition for which no preventive treatment is available. Two dogs were presented for recurrent respiratory distress strictly associated with hunting activities. Diagnosis was based on bilateral, symmetrical, interstitial‐to‐alveolar pattern in the caudodorsal lung fields on thoracic radiographs, exclusion of other causes, and spontaneous clinical and radiographic improvement. Considering that the pathogenesis of exercise‐induced NCPE likely involves α‐ and β‐adrenergic overstimulation, treatment with sympathetic blockers was used in both dogs. The first dog no longer showed respiratory signs during hunting activities. However, treatment failed to prevent respiratory distress in the other dog. Based on the large number of red blood cells in the bronchoalveolar lavage fluid of the second dog, exercise‐induced pulmonary hemorrhage was suspected, as described in racing horses. The loop diuretic furosemide successfully prevented further hunting‐associated respiratory distress episodes in this dog. [ABSTRACT FROM AUTHOR]

Background: Measurement of free metanephrines is recommended for screening of pheochromocytoma (PCC) but requires appropriate reference intervals (RIs). Hypothesis/Objectives: To report RIs for plasma, urinary and salivary concentrations of free metanephrines and to determine the diagnostic performance of plasma free normetanephrine (pNMN) and metanephrine (pMN) concentrations in dogs with PCC, hypercortisolism (HC), and nonadrenal illness (NAI). Animals: Eighty healthy dogs, 11 PCC dogs, 25 HC dogs, 6 NAI dogs. Methods: Plasma, urine, and saliva were collected prospectively from healthy dogs, and free metanephrine concentrations were determined by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). In addition, medical records of dogs that had plasma free metanephrine concentrations measured by LC‐MS/MS between 2018‐2021 were studied retrospectively. Results: The RIs for free metanephrines in plasma, urine and saliva are reported. Dogs with PCC had significantly higher pNMN than dogs with HC (P <.001) and NAI (P =.002). The PCC dogs had significantly higher pMN than HC dogs (P <.001), but not higher than NAI dogs (P =.29). Using the upper reference limit, pNMN (>3.56 nmol/L) showed high sensitivity (100%, 95% confidence interval [CI]: 72‐100) and specificity (94%, 95% CI: 79‐99) for diagnosis of PCC, whereas pMN (>2.49 nmol/L) showed moderate sensitivity (73%, 95% CI: 39‐94) and high specificity (94%, 95% CI: 79‐99). Conclusions and Clinical Importance: With establishment of these RIs, biochemical testing for PCC in dogs can be substantially improved. Measurement of pNMN is superior to pMN in dogs with PCC. [ABSTRACT FROM AUTHOR]

Objective: In clinical practice, false‐positive results in biochemical testing for suspected pheochromocytoma/paraganglioma (PPGL) are not infrequent and may lead to unnecessary examinations. We aimed to evaluate the role of the clonidine suppression test (CST) in the era of analyses of plasma‐free metanephrines for the diagnosis or exclusion of PPGL in patients with adrenal tumours and/or arterial hypertension. Design and Methods: This single‐centre, prospective trial investigated the use of CST in 60 patients with suspected PPGL associated with out‐patient elevations of plasma normetanephrine (NMN) and/or metanephrine (MN), in most cases accompanied with hypertension or an adrenal mass. Measurements of plasma catecholamines and free metanephrines were performed by liquid chromatography with electrochemical detection and tandem mass spectrometry, respectively. Results: Forty‐six patients entered final analysis (n = 20 with PPGL and n = 26 with a nonfunctional adrenal mass and/or hypertension). CST reliably excluded false‐positive baseline NMN results with a specificity of 100%. The sensitivity of CST improved from 85% to 94% when tumours with isolated MN increase (n = 3) were not considered. In patients with elevated baseline NMN (n = 24), CST correctly identified all patients without PPGL. Patients with falsely elevated baseline NMN results (n = 7, 26.9%) exhibited increases of baseline NMN up to 1.7‐fold above the upper reference limit. Conclusion: CST qualifies as a useful diagnostic tool for differential diagnosis of borderline elevated plasma‐free NMN in patients with suspected PPGL. In this context, CST helps to correctly identify all false‐positive NMN screening results. [ABSTRACT FROM AUTHOR]

Objective: A 24‐hour urine nor/metanephrine (urine NM‐MN) measurements are a recommended first step in pheochromocytoma diagnosis. We hypothesized the presence of renal impairment (CKD) significantly confounds the results obtained in a urine NM‐MN collection, giving artificially lower measurements. Design: Retrospective review of a comprehensive laboratory database with all urine NM‐MN results from Southern Alberta from 2010 to 2018 (n = 15 505). After excluding high probability pheochromocytoma cases, results from patients with three levels of CKD (n = 796) were compared to those without CKD to determine the potential CKD effect. Patients: All patients having urine NM‐MN collection during the time period, irrespective of ordering physician or test indication. Measurements: Urine NM‐MN was measured by liquid chromatography‐tandem mass spectrometry and glomerular filtration rate determined within a median of 1.9 days, as estimated by CKD‐EPI equation. Results: In subjects with mild‐to‐moderate renal impairment, there was no continuous gradient between subnormal renal function and urine NM‐MN measures. When the estimated GFR was < 15 mL/min/m2, the hypothesized effect on lowered urine NM‐MN became apparent. Conclusions: A 24‐hour urine NM‐MN measurement is unlikely to be affected by mild‐to‐moderate renal impairment and may be used as a reliable diagnostic test. With more advanced renal impairment, CKD‐specific reference ranges or an alternative test may be needed. [ABSTRACT FROM AUTHOR]

The article describes the case of suspected pheochromocytoma and pituitary pars intermedia dysfunction in a 27-year-old Shetland pony. Topics discussed include brief information on the cause of excessive secretion of catecholamines, clinical symptoms that led to the diagnosis of suspected pheochromocytoma, and the usefulness of measurement of catecholamines and their metabolites in plasma and urine in detecting suspected pheochromocytoma.

Background Adrenomegaly and hypertension are common clinical entities in canine medicine for which testing for pheochromocytoma is recommended. Yet, a validated biochemical test for the diagnosis of pheochromocytoma in dogs does not exist. In human medicine, plasma free metanephrine testing is the diagnostic standard for the biochemical diagnosis of pheochromocytoma. Objectives The purpose of this study was to investigate the utility of measurement of plasma free metanephrines in dogs for the diagnosis of pheochromocytoma. Methods Plasma free metanephrines were measured in 11 healthy dogs and in 3 dogs confirmed to have a pheochromocytoma. The metanephrine assays were performed at a reference laboratory using high-performance liquid chromatography with electrochemical detection. Results The plasma free metanephrine and normetanephrine concentrations in 11 healthy dogs were normally distributed and were used to create tentative reference intervals. All 3 dogs with histologically confirmed pheochromocytoma clearly had higher concentrations of plasma free metanephrines. Conclusions This pilot study demonstrates the potential utility of plasma free metanephrines levels for the biochemical diagnosis of pheochromocytoma in dogs. [ABSTRACT FROM AUTHOR]

ABSTRACT (1 R)-Normetanephrine is the natural stereoisomeric substrate for sulfotransferase 1A3 (SULT1A3)-catalyzed sulfonation. Nothing appears known on the enantioselectivity of the reaction despite its potential significance in the metabolism of adrenergic amines and in clinical biochemistry. We confronted the kinetic parameters of the sulfoconjugation of synthetic (1 R)-normetanephrine and (1 S)-normetanephrine by recombinant human SULT1A3 to a docking model of each normetanephrine enantiomer with SULT1A3 and the 3′-phosphoadenosine-5′-phosphosulfate cofactor on the basis of molecular modeling and molecular dynamics simulations of the stability of the complexes. The KM, Vmax, and kcat values for the sulfonation of (1 R)-normetanephrine, (1 S)-normetanephrine, and racemic normetanephrine were similar. In silico models were consistent with these findings as they showed that the binding modes of the two enantiomers were almost identical. In conclusion, SULT1A3 is not substrate-enantioselective toward normetanephrine, an unexpected finding explainable by a mutual adaptability between the ligands and SULT1A3 through an 'induced-fit model' in the catalytic pocket. Chirality, 25:28-34, 2012.© 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Urinary catecholamines and metanephrines have been proposed as a diagnostic tool for identifying canine pheochromocytomas, but the effects of critical illness on urine concentrations of catecholamines and metanephrines currently are unknown. To examine the effects of illness on urine concentrations of catecholamines and metanephrines in dogs. Twenty-five critically ill dogs and 25 healthy age- and sex-matched control dogs. Prospective observational study. Urine was collected from healthy and critically ill dogs, and urine concentrations of epinephrine, norepinephrine, metanephrine, and normetanephrine were measured by high-performance liquid chromatography with electrochemical detection. Urinary catecholamine and metanephrine : creatinine ratios were calculated and compared between groups. Urinary epinephrine, norepinephrine, metanephrine, and normetanephrine : creatinine ratios were higher in critically ill dogs when compared with a healthy control population ( P= .0009, P < 0.0001, P < 0.0001, and P < 0.0001, respectively). Illness has a significant impact on urinary catecholamines and their metabolites in dogs. Further investigation of catecholamine and metanephrine concentrations in dogs with pheochromocytomas is warranted to fully evaluate this test as a diagnostic tool; however, the findings of this study suggest that the results may be difficult to interpret in dogs with concurrent illness. [ABSTRACT FROM AUTHOR]

Background: Urinary catecholamines and metanephrines are used for the diagnosis of pheochromocytoma (PHEO) in dogs. Hyperadrenocorticism (HAC) is an important differential diagnosis for PHEO. Objectives: To measure urinary catecholamines and metanephrines in dogs with HAC. Animals: Fourteen dogs with HAC, 7 dogs with PHEO, and 10 healthy dogs. Methods: Prospective clinical trial. Urine was collected during initial work-up in the hospital; in dogs with HAC an additional sample was taken at home 1 week after discharge. Parameters were measured using high-pressure liquid chromatography and expressed as ratios to urinary creatinine concentration. Results: Dogs with HAC had significantly higher urinary epinephrine, norepinephrine and normetanephrine to creatinine ratios than healthy dogs. Urinary epinephrine, norepinephrine, and metanephrine to creatinine ratios did not differ between dogs with HAC and dogs with PHEO, whereas the urinary normetanephrine to creatinine ratio was significantly higher ( P= .011) in dogs with PHEO (414, 157.0–925.0, median, range versus (117.5, 53.0–323.0). Using a cut-off ratio of 4 times the highest normetanephrine to creatinine ratio measured in controls, there was no overlap between dogs with HAC and dogs with PHEO. The variables determined in urine samples collected at home did not differ from those collected in the hospital. Conclusion and Clinical Importance: Dogs with HAC might have increased concentrations of urinary catecholamines and normetanephrine. A high concentration of urinary normetanephrine (4 times normal), is highly suggestive of PHEO. [ABSTRACT FROM AUTHOR]

Tragically as many as 50% of pheochromocytomas are discovered at autopsy, mainly because the diagnosis of this neuroendocrine tumor was not considered. Missing the diagnosis almost invariably results in devastating cardiovascular complications or death. Clinicians must always think of pheochromocytoma whenever evaluating a patient with sustained or paroxysmal hypertension or any manifestations suggesting hypercatecholaminemia. Very rarely, familial pheochromocytomas may cause no hypertension, symptoms, or signs. But biochemical testing can always establish the presence or absence of a pheochromocytoma, and localization with magnetic resonance imaging, computed tomography, or 131I or 123I-MIBG is almost always possible. [ABSTRACT FROM AUTHOR]

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

Abstract Background Exaggerated sympathoadrenal function has been accused of contributing to hypertension in type-2 diabetes. Recently, plasma unconjugated (free) metanephrines were reported to be stable markers of catecholamine hypersecretion. Thus, we aimed to examine whether unconjugated metanephrines are reliable markers of stress response induced by standardized cycling exercise and to identify differences in such stress responses between hypertensive and/or diabetic patients. Design Type-2 diabetic patients with (DM/H; n = 8, 50 ± 7 years, HbA1c: 7·7 ± 0·6%) or without hypertension (DM/N; n = 6, 48 ± 10 years, 7·5 ± 1·8%) and nondiabetic hypertensive patients (H; n = 8, 56 ± 4 years) were studied during incremental cycling exercise (15 min) to 75% of individual VO2 max and during recovery (60 min). Plasma catecholamines and unconjugated metanephrines were measured by high-performance liquid chromatography with electrochemical detection. Hormone responses were quantified from the areas under the concentration-time curves and compared with those of age-, sex- and BMI-matched healthy volunteers (CON, n = 22). Results Blood pressure responses of DM/H and H, but not DM/N, were greater than those of CON (P < 0·01), whereas heart rates increased similarly in all groups. Unconjugated normetanephrine responses were only increased (P = 0·04) in DM/H (2156 vs. 1133 pg mL-1 min-1 ) but not in DM/N (1528 vs. 1300 pg mL-1 min-1 ) and H (1960 vs. 1425 pg mL-1 min-1 ) when compared with respective CON. Unconjugated metanephrines did not change from baseline, whereas catecholamine responses were comparable in all groups. Conclusions The excessive response of plasma unconjugated normetanephrine to cycling may serve as a marker of exaggerated sympathoadrenal function in hypertensive type-2 diabetic patients. [ABSTRACT FROM AUTHOR]