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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]

Paragangliomas (PGs) are rare neuroendocrine tumors that originate in the autonomic nervous system. Functionally, they are highly vascular and may be parasympathetic or sympathetic. Parasympathetic tumors are usually asymptomatic and inactive, located mostly in the skull base in the distribution of IX and X cranial nerves. In contrast, sympathetic tumors are highly active (secretes norepinephrine) and symptomatic and mainly located in the abdomen and pelvic regions. Surgical removal of these tumors is curative and key to favorable outcomes. Some of these tumors have malignant potential as well. Meticulous preoperative preparation is needed but many patients may still land up in hypertensive crises intraoperatively which should be managed promptly and cautiously by the anesthesia team to reduce morbidity and mortality during surgery. Here, we describe the successful anesthetic management of a patient diagnosed with large aortocaval PG abutting the aorta and compressing the inferior vena cava and bilateral renal veins.

Elevated metanephrine and catecholamine levels 3-fold upper limit of normal (ULN) are diagnostic for pheochromocytoma. We sought to determine whether size correlates with biochemical activity or symptoms which could guide timing of surgery. Data from consecutive patients undergoing adrenalectomy for pheochromocytoma at our institution over a 10-year period were retrospectively collected. These included maximal lesion diameter on preoperative imaging, plasma/urine metanephrine and/or catecholamine levels, demographic variables and presence of typical paroxysmal symptoms. Receiver operating characteristic curves were used to assess predictive accuracy. Sixty-three patients were included in the analysis (41 females and 22 males). Median age was 56 (43, 69) years. Due to various referring practices, 31 patients had documented 24-h urine metanephrine, 26 had 24-h urine catecholamine, and 52 had fractionated plasma metanephrine levels available for review. Values were converted to fold change compared to ULN and the maximum of all measured values was used for logistic regression. Median tumor size was 3.40 (2.25, 4.55) cm in greatest dimension. Tumor size at which pheochromocytoma produced > 3-fold ULN was ≥2.3 cm (AUC of 0.84). Biochemical activity increased with doubling tumor size (odds ratio = 8, P = 0.0004) or ≥ 1 cm increase in tumor size (odds ratio = 3.03, P = 0.001). 40 patients had paroxysmal symptoms, but there was no significant correlation between tumor size/biochemical activity and symptoms. In our study, tumor size directly correlated with the degree of biochemical activity and pheochromocytomas ≥2.3 cm produced levels 3 times ULN. These findings may allow clinicians to adjust timing of operative intervention. [ABSTRACT FROM AUTHOR]

Functionalized carbon quantum dots with tunable optical properties widely used in sensor applications. In this study, carbon quantum dots were synthesized from Zelkova serrata leaves (ZCQDs) in an aqueous medium via a single-step hydrothermal reaction with essential reactive functional groups. As-synthesized ZCQDs (average size, 3–7 nm) were characterized and confirmed to contain hydroxyl/amine and carboxylic acid functional groups. Photoluminescence spectral analysis revealed that the fluorescence intensity of ZCQDs drastically decreased after the addition of different concentrations of normetanephrine (NM) in deionized water and geriatric plasma samples. Our developed strategy could detect NM with a limit of detection of 7.96 and 86.2 nM in deionized water and geriatric plasma samples, respectively. Interestingly, Fourier transform infrared spectroscopy revealed a new peak at 1660 cm−1, confirming the formation of the keto (C=O) group in NM. In addition, significant peak shifts were observed in the C 1s, and O 1s deconvoluted X-ray photoelectron spectra. Bandgap calculations also revealed significant interactions between NM and ZCQDs. Antibacterial activities of ZCQDs were investigated in Escherichia coli and Staphylococcus aureus, and potent activities were observed in Staphylococcus aureus at a half-maximal inhibitory concentration of 32 μg/mL via the generation of intracellular reactive oxygen species. By enabling specific therapies and improving our understanding of intricate biological processes at the nanoscale, these materials have the potential to completely transform the biomedical field. Our findings suggest the involvement of a working mechanism in transferring electrons between the conductance band of ZCQDs and the acidic protons of N, to produce the oxidized form NM for photoluminescence quenching of ZCQDs. [ABSTRACT FROM AUTHOR]

Measurements of plasma metanephrines and methoxytyramine provide a sensitive test for diagnosis of pheochromocytoma/paraganglioma. False-positive results remain a problem, particularly in patients taking norepinephrine reuptake-blocking drugs. Therefore, in this retrospective observational study, we measured plasma metanephrines and methoxytyramine in 61 patients taking norepinephrine reuptake blockers (tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors) and 17 others taking selective serotonin reuptake inhibitors, all without pheochromocytoma/paraganglioma. We highlight a singular case with strongly elevated plasma normetanephrine and methoxytyramine concentrations associated with norepinephrine reuptake blockade. Data were compared to results from 252 and 1804 respective patients with and without tumors. Plasma normetanephrine was 40% higher (P < 0.0001) in patients on norepinephrine reuptake blockers and methoxytyramine was 127% higher (P = 0.0062) in patients taking tricyclic antidepressants compared to patients not taking uptake blockers and without tumors. The corresponding false-positive rates rose (P < 0.0001) from 4.8% to 23.0% for normetanephrine and from 0.9% to 28.6% for methoxytyramine. Selective serotonin reuptake inhibitors did not increase plasma concentrations of metabolites. In the highlighted case, plasma normetanephrine and methoxytyramine were elevated more than six times above upper reference limits. A pheochromocytoma/paraganglioma, however, was excluded by functional imaging. All biochemical test results normalized after discontinuation of norepinephrine reuptake blockers. These findings clarify that norepinephrine reuptake blockers usually result in mild elevations of normetanephrine and methoxytyramine that, nevertheless, significantly increase the number of false-positive results. There can, however, be exceptions where increases in normetanephrine and methoxytyramine reach pathological levels. Such exceptions may reflect failure of centrally mediated sympathoinhibition that normally occurs with the norepinephrine reuptake blockade. [ABSTRACT FROM AUTHOR]

Abstract 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.

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]

Purpose: Polycystic ovarian syndrome (PCOS) is a common heterogeneous condition with probably multifactorial genesis. Animal studies have proven the essential role of the sympathetic nervous system in the syndrome development, while human studies are still contradictory. The present study aims to investigate the possible influence of plasma-free metanephrine (MN), and normetanephrine (NMN), nerve growth factor (NGF), and renalase (RNL) on the hormonal and metabolic parameters in women with PCOS and healthy controls. Methods: Fifty patients with PCOS and 30 healthy women participated in the study. The plasma-free MN and NMN, NGF, RNL, anti-Mullerian hormone (AMH), gonadotropin, androgen levels, and metabolic parameters were investigated. Results: Plasma-free NMN and NGF concentrations were increased in PCOS individuals, while RNL levels were decreased compared to healthy volunteers. Increased plasma-free NMN (OR = 1.0213 [95%CI 1.0064–1.0364], p = 0.005) and NGF (OR = 1.0078 [95%CI 1.0001–1.0155], p = 0.046) but not MN or RNL levels were associated with a higher risk of PCOS after adjustment for age. Plasma-free NMN levels were positively associated with the LH (r = +0.253; p = 0.039). androstenedione (r = +0.265; p = 0.029), 17-OH progesterone (r = +0.285; p = 0.024), NGF (r = +0.320; p = 0.008), and AMH (r = +0.417; p < 0.001) concentrations of the investigated women. RNL levels were inversely related to the BMI (r = −0.245; p = 0.029), HOMA-IR (r = −0.250; p = 0.030), free testosterone (r = −0.303; p = 0.006) levels. systolic (r = −0.294; p = 0.008) and diastolic (r = −0.342; p = 0.002) blood pressure. Conclusions: Increased sympathetic noradrenergic activity and NGF synthesis might be related to the increased AMH and delta-4 androgen levels in a subgroup of PCOS patients. RNL levels might influence the metabolic status of PCOS patients. Further studies are needed to explore the significance of adrenal medullar and autonomic dysfunction for developing different PCOS phenotypes and their subsequent cardiovascular complications. [ABSTRACT FROM AUTHOR]

Abstract 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 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.

A 52-year-old Chinese woman was admitted to a cardiac intensive care unit (CCU) due to nausea, vomiting, and dyspnea, which began a day before her hospitalization. Metoprolol succinate and conventional treatment for acute myocardial infarction (AMI) were initially administered to the patient based on electrocardiogram (ECG) findings and elevated cardiac troponin I (cTnI). However, the following day, she developed aggravated nausea, vomiting, fever, sweating, a flushed face, a rapid heart rate, and a significant rise in blood pressure. Furthermore, ultrasonic cardiography (UCG) displayed takotsubo-like changes; nevertheless, ECG indicated inconsistent cTnI peaks with extensive infarction. After coronary computed tomography angiography (CTA) ruled out (AMI), and in conjunction with the uncommon findings, we strongly suspected that the patient had a secondary condition of pheochromocytoma-induced takotsubo cardiomyopathy (Pheo-TCM). In the meanwhile, the use of metoprolol succinate was promptly discontinued. This hypothesis was further supported by the subsequent plasma elevation of multiple catecholamines and contrast-enhanced computed tomography (CECT). After one month of treatment with high-dose Phenoxybenzamine in combination with metoprolol succinate, the patient met the criteria for surgical excision and successfully underwent the procedure. This case report demonstrated that pheochromocytoma could induce TCM and emphasized the significance of distinguishing it from AMI (in the context of beta-blocker usage and anticoagulant management).

Objective: To validate urinary Vanillylmandelic acid (VMA) for screening adrenal medullary disorders, taking plasma-free Metanephrine as the gold standard. Study Design: Cross-sectional validation study. Place and Duration of Study: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, in collaboration with Armed Forces Institute of Urology, Rawalpindi from Pakistan, Jan 2020 to Mar 2021. Methodology: One hundred and thirty (130) symptomatic hypertensive patients with adrenal masses on ultrasound were selected Urine and blood samples were collected under specified conditions after taking necessary precautions and subsequently analyzed. Taking plasma Metanephrine as a reference, sensitivity, specificity and predictive values were calculated at predefined cut-off values. Results: In a young population with a mean age of 28.55±5.54 years, headache, palpitations and sweating were the predominant symptoms having a frequency of 130(100%), 116(89.2%) and 111(85.4%), respectively. Twenty-four hours urinary Vanillylmandelic acid had lower sensitivity (66.3%) than a random urinary VMA/cr ratio (72.1%) but similar specificity (97.7%). On the other hand, plasma-free Normetanephrine had 100% sensitivity but lower specificity (93.2%). ROC curve was plotted, and AUC for 24 hours urinary VMA, urinary VMA/cr ratio and plasma-free Normetanephrine were 0.820, 0.849 and 0.966, respectively. Conclusion: Plasma-free Metanephrine could be used for screening pheochromocytoma and other adrenal medullary disorders like paraganglionoma. In addition, VMA/cr ratio can be used for biochemical confirmation of the disease owing to the high specificity found in our study. [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]

Aims: The present study aims to investigate the association between catecholamine metabolites (normetanephrine [NMN] and metanephrine [MN]) and polycystic ovarian syndrome (PCOS) and its clinical manifestations.

Paraganglioma is a rare neuroendocrine tumor arising outside the adrenal gland from the primitive neural crest cells. The pediatric form is an exceptional entity. Here we report a case of a 15-year-old boy presenting with hypertensive crisis. Computed tomography scan revealed a left lateral-aortic paraganglioma, with significantly elevated plasmatic catecholamine levels. Preoperative management was conducted in our patient with selective alpha-1 blockers, then complete resection of the tumor was achieved without complications. The histological and immunohistochemical examination confirmed the diagnosis of a paraganglioma. Paranganglioma management should be started as soon as possible to prevent high blood pressure complications. It is based on preoperative medication with alpha-blocker to prevent adrenegeric discharge, followed by a complete and safe surgical removal of the tumor. Functional paraganglioma remains a rare entity among pediatric population. Preoperative management is mandatory to avoid postoperative morbidity. • A rare case of lateral-aortic paraganglioma in an adolescent which is rarely reported in the literature and which is the first Moroccan case to our knowledge. • Our experience in the management of functional paraganglioma in an adolescent boy. • The importance of pre operative management to prevent post operative morbidity. [ABSTRACT FROM AUTHOR]

As cortisol and metanephrine are involved in the stress response, it is often recommended that individuals are relaxed at the time of venepuncture, however, evidence behind these recommendations is lacking. We investigated the effects of acute psychological stress on serum cortisol and plasma metanephrine concentrations in healthy individuals exposed to varying levels of psychological stress and compared these results to self-reported measures of stress.Ten medical students completed two medical in-person simulations (one low-complexity, one high-complexity) in a random order. At four times, participants completed the State-Trait Anxiety Inventory (STAI) and serum cortisol and plasma metanephrine/normetanephrine were tested.Median (interquartile range) STAI prior to the low-complexity simulation was 44 (18) versus 33 (13) afterwards (P = 0.050). STAI prior to the high-complexity simulation was 33 (10) versus 48 (17) afterwards (P = 0.007). Cortisol prior to the low-complexity simulation was 272 nmol/L (115) versus 247 (115) afterwards (P = 0.333). Prior to the high-complexity simulation, cortisol was 246 (70) versus 261 (137) afterwards (P = 0.859). Metanephrine prior to the low-complexity simulation was 242 pmol/L (79) versus 247 (93) afterwards (P = 0.515). Metanephrine prior to the high-complexity simulation was 220 (81) versus 251 pmol/L (120) afterwards (P = 0.074). Normetanephrine prior to the low-complexity simulation was 593 pmol/L (247) versus 682 (281) afterwards (P = 0.047 for the difference). Normetanephrine prior to the high-complexity simulation was 696 (123) versus 705 pmol/L (224) afterwards (P = 0.169).The trend in cortisol levels largely reflected changes in STAI. We outline some implications of these findings for current practice and future research. [ABSTRACT FROM AUTHOR]

Abstract Background Although some evidence suggests an association between obstructive sleep apnea (OSA) and gestational diabetes mellitus (GDM), its consequences still remain largely unknown. We sought to determine whether OSA is associated with higher inflammation and sympathetic levels in GDM, and to relate them with insulin resistance and perinatal outcomes. Methods OSA was identified by polysomnography and defined as an apnea–hypopnea index of ≥ 5 h−1. Plasma cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-10), metanephrine, and normetanephrine were determined by immunoassays. Results We included 17 patients with GDM and OSA and 34 without OSA. Women with GDM and OSA had higher normetanephrine concentrations [81 IQR (59–134) vs. 68 (51–81) pg/mL]. No differences in the inflammatory profile were found, while IL-1β was higher in patients with mean nocturnal oxyhemoglobin saturation ≤ 94%. We found positive correlations between increased sympathetic activation and IL-1β, with obstructive apneas, while time in REM showed an inverse relationship with IL-1β and metanephrine. Furthermore, IL-10 was inversely related with time in sleep stages 1–2, and with the arousal index, and it was positively related with time in slow-wave sleep. Significant correlations were also found between IL-1β and insulin resistance. There were no significant differences in neonatal characteristics; however, we found inverse relationships between IL-10 and birth weight (BW), and percentile of BW. Conclusions OSA increased sympathetic activity, and IL-1β concentration was higher in patients with GDM with lower nocturnal oxygenation, all of which were related with obstructive events, and time in REM. Moreover, IL-1β was related with insulin resistance, and IL-10 inversely correlated with neonatal BW.

Objective: To validate urinary Vanillylmandelic acid (VMA) for screening adrenal medullary disorders, taking plasma-free Metanephrine as the gold standard. Study Design: Cross-sectional validation study. Place and Duration of Study: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology,Rawalpindi, in collaboration with Armed Forces Institute of Urology, Rawalpindi from Pakistan, Jan 2020 to Mar 2021. Methodology: One hundred and thirty (130) symptomatic hypertensive patients with adrenal masses on ultrasound were selected Urine and blood samples were collected under specified conditions after taking necessary precautions and subsequently analyzed. Taking plasma Metanephrine as a reference, sensitivity, specificity and predictive values were calculated at predefined cut-off values. Results: In a young population with a mean age of 28.55±5.54 years, headache, palpitations and sweating were the predominant symptoms having a frequency of 130(100%), 116(89.2%) and 111(85.4%), respectively. Twenty-four hours urinary Vanillylmandelic acid had lower sensitivity (66.3%) than a random urinary VMA/cr ratio (72.1%) but similar specificity(97.7%). On the other hand, plasma-free Normetanephrine had 100% sensitivity but lower specificity (93.2%). ROC curve was plotted, and AUC for 24 hours urinary VMA, urinary VMA/cr ratio and plasma-free Normetanephrine were 0.820, 0.849 and0.966, respectively. Conclusion: Plasma-free Metanephrine could be used for screening pheochromocytoma and other adrenal medullary disorders like paraganglionoma. In addition, VMA/cr ratio can be used for biochemical confirmation of the disease owing to the high specificity found in our study.

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]

Background & Aims: Despite the fact that researchers have recently turned their attention to the new style of video games with movement (exergames) and considering that these games have been recently accepted as a kind of sports activity with a wide range of people as audience of these games both male and female in various ages, the influence of gender in response to various parameters, including hemodynamic factors, has not been addressed. Therefore, the above study was conducted with the aim of comparing the effect of gender on hemodynamic factors and normetanephrine after video boxing game with movement, with and without blood flow restriction. Methods: Fourteen healthy young people (Female: 8, Male: 6; Age: 30±10 years; BMI: 21±3 kg.m2 ) were divided into two groups of men and women and participated in two training sessions of boxing with Microsoft Kinect Xbox 360. Normetanephrine and some hemodynamic factors such as HR, SBP, DBP, RPP and MAP were measured before and after. At the beginning of each session, the subjects performed 5 minutes of warm-up exercises with stretching. Blood samples were taken from serum before training to test for serum Normetanephrine. A Cardiac Holter monitoring system was used to measure Heart Rate. All measurement instructions were followed in the measurement process; before the start of the game, the Avecinna My Patch Holter device with four cables were installed on the subjects' chests by f-55 SKINTACT chest leads made in Austria and poly)gel ultrasound gel to measure the heart rate. The selected exergame was boxing from Kinect Sports with Microsoft's Kinect X BOX360. Subjects were two groups of men and women and competed against each other for 20 minutes, the separated groups of women and men were fighting against each other. In the first week, seven subjects with BFR, which was imposed by an Iranian-made inflatable cuff with 15 to 20% systolic blood pressure restriction by a sphygmomanometer, played against seven competitors without BFR. After seven days, the training session was repeated, but this time the two groups were changed regarding BFR. At intervals of 5, 10, 15, and 20 games, the cuffs were opened and closed again. The Rate of Perceived Exertion (RPE) was also recorded by the Borg 10-point scale at the minutes of 0, 5, 10, 15, and 20 minutes. Accordingly, the subjects were supposed to indicate the rate of perceived exertion by numbers when implementing the protocol. Blood samples were taken again by specialists present at the laboratory immediately after the game. Shapiro-Wilk test was used to evaluate the normality of data distribution. Independent t-test was used to compare before and after data of the two groups and the Analysis of variance with repeated measures was used to evaluate the data of RPE and the significance level was considered as p≤0.05 for all statistical analyses. Data were analyzed using SPSS software version 22. Results: Statistical analysis of the present study showed that boxing exergame in both protocols with and without BFR led to a significant increase in hemodynamic variables except DBP in both men and women, but comparing the increase between the two groups of women and Men did not show significant outcomes. The results showed that although the comparison of increase in SBP, MAP, HR, RPP indices during both protocols in both groups of men and women was not significant; Men showed a greater increase in SBP, HR, RPP in the protocol with BFR compared to without BFR, while in the group of women it was quite the opposite. The group of women in the protocol without BFR showed a greater increase in these parameters compared to the protocol with BFR. Regarding MAP parameter, men in both protocols showed more increase than women. The results of the DBP data, showed an insignificant increase in both groups in the two protocols and no significant difference was observed between men and women. Regarding normetanephrine, like other parameters, the comparison of increase in normetanephrine in women and men during both protocols was not significant and, like the MAP parameter, in men, the increase in both protocols was greater than in women. The results of independent t-test related to hemodynamic and normathephrine indices are presented in the table below. Regarding the comparison of reported RPE, both groups of men and women reported significantly higher values in the session with BFR, but the comparison of the values reported in women and men did not show a significant difference in both protocols (without and with BFR, respectively F4,48=0.039, p=0.997; F4,48=1.426, p=0.240). However, in the protocol without BFR, women reported higher values of RPE in all the above minutes. Conversely, in the protocol with BFR, men reported higher values of PRE at different minutes. Conclusion: In general, it can be concluded that a exergame session in both with and without restriction of blood flow in the arteries of the hand, could not cause significant results in increasing hemodynamic factors, normetanephrine and RPE in both men and women. However, there were differences in the responses of some factors between the two groups. The reason for this insignificancy can be due to various factors such as the type of game chosen, the duration of training protocols or the competitiveness of the game that caused excitement in both groups and the degree of obstruction of blood flow and opening and closing the cuffs during the protocol with BFR. the comparison of hemodynamic responses of men and women in the proposed protocol in the combination of exergame with different training methods such as BFR that was presented in this study has recently come to many researchers attention, that proves the potential of this new style of games with sports activities that appeals to a wide range of audiences. Therefore a closer look at the effects of this proposed protocol on the cardiovascular system and hemodynamic factors in long-term protocols and the comparison of gender responses in other age groups is required. [ABSTRACT FROM AUTHOR]

Introduction: Pheochromocytoma is a rare neuroendocrine tumor that originates from the adrenal medulla, less commonly from extraadrenal chromaffin cells (paraganglioma). In about 90% of cases, the tumor produces abnormal amounts of catecholamines. Pheochromocytomas are usually benign, but in rare cases can be malignant. Typical clinical manifestations are the result of the haemodynamic and metabolic effects of catecholamines and usually include paroxysmal hypertension with the classic triad (headache, excessive sweating, palpitations), carbohydrate disorders, etc. Elevated levels of catecholamine metabolites (metanephrine and normetanephrine) tested in plasma or in 24-hour urine confirm the diagnosis. Surgical removal of the tumor is the only radical treatment. Follow-up of patients postoperatively should be lifelong and performed by a multidisciplinary team in a specialized center of expertise. Case report: A 36-year-old female patient referred to the clinic for decompensated diabetes mellitus. Detailed history revealed paroxysmal hypertension and the classic triad of pheochromocytoma. Тhe diagnosis was confirmed by high urinary metanephrine levels and an abdominal CT scan, showing a tumor in the right adrenal gland with features typical of pheochromocytoma. Surgical removal of the pheochromocytoma and normalization of catecholamine levels led to normalization of blood pressure and reversal of diabetes mellitus. Conclusion: Pheochromocytoma is a difficult diagnosis in endocrinology practice as it can mimic many other diseases. Early detection and surgical removal of the tumor are crucial to avoid complications caused by elevated serum catecholamine levels. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the specificity/sensitivity and predictive values of urine spot metanephrines-to-creatinine ratios to diagnose canine pheochromocytomas and to determine whether there is a correlation between urine catecholamine levels and tumor volume., Methods: In a retrospective study, 32 client-owned dogs with adrenal tumors were identified (13 nonpheochromocytoma and 19 pheochromocytoma). Medical records were evaluated for patients undergoing adrenalectomy between August 2020 and August 2023. Patients were divided into groupings of pheochromocytoma and other adrenal tumor diagnosis on the basis of histopathology., Results: Urine spot normetanephrine concentrations were significantly elevated in dogs with pheochromocytomas compared to dogs with other adrenal tumors. Sensitivity was 78.9%, specificity 76.9%, positive predictive value 83.3%, and negative predictive value 71.4% for discriminating between pheochromocytoma and nonpheochromocytoma. Spot urine metanephrine concentrations were not significantly different between the 2 groups. Only 5 of 19 pheochromocytoma patients had urine normetanephrine concentrations > 4 times the upper reference limit, which is the previously established diagnostic cutoff. Median tumor volume did not correlate with normetanephrine values, nor did those values correlate to patients that experienced intraoperative complications. Twenty-one percent of cases were biochemically silent pheochromocytomas., Conclusions: Urine normetanephrine-to-creatinine levels but not metanephrine-to-creatinine levels can potentially differentiate a pheochromocytoma from a nonpheochromocytoma., Clinical Relevance: Previously published guidelines of 4 times the upper reference limit in spot urine metanephrines testing used to diagnose pheochromocytomas will lead to a significant number of missed diagnoses.

Background and Aim: Inactivity increases the risk of chronic diseases. The aim of the present study was to investigate the acute changes in Normetanephrine and glucose in boxing with Kinect Xbox with and without blood flow restriction as an alternative to aerobic exercise during quarantine in young non-athletes. Material and Methods: Fourteen healthy non-athlete individuals with a range of 20 to 40 years of age were randomly and purposefully selected. And on two different days with and without restriction of blood flow, they played boxing with Xbox 360 for 20 minutes. Blood samples were taken before and immediately after Results: There was a significant increase in serum Normetanephrine playing compared to before the test in both training groups, but the amount of changes between the two groups with and without blood flow restriction was not significant (P≤0.05). Exergames, in the case of unrestricted blood flow, has a significant effect on glucose, but the restriction of blood flow did not lead to a significant difference in the amount of glucose (P≤0.05). Conclusion: Exergames provide the necessary stimulus for catecholamine secretion and glucose response, and it is recommended for people with limited blood flow. Further studies are needed on the effect of restricting blood flow as a new training method on video game with movement.

Background: To identify candidate external quality assessment (EQA) materials for normetanephrine and metanephrine measurements, we assessed the commutability of eight processed human plasma samples. The agreement between routine assays and the candidate reference measurement procedure (cRMP) was also evaluated. Methods: Fifty-three clinical samples and eight processed plasma samples were prepared. The processed samples included pooled and individual plasma samples spiked with pure normetanephrine and metanephrine and non-spiked pooled and individual plasma samples. The clinical and processed samples were subjected to four routine isotope dilution tandem mass spectrometry assays and cRMP. Commutability was assessed based on two approaches recommended by the CLSI and International Federation of Clinical Chemistry (IFCC). Passing–Bablok regression and Bland–Altman analysis were used to evaluate the agreement between the routine assays and cRMP. Results: The commutability results of the CLSI approach were better than those of the IFCC approach. For the CLSI approach, spiked individual plasma samples and spiked high-concentration pooled plasma samples were commutable for all routine assays for both analytes. The non-spiked pooled plasma sample was commutable for two out of four routine assays for metanephrine and three out of four routine assays for normetanephrine. The agreement between the routine assays and the cRMP was satisfactory, except for one routine assay showing significant bias. Conclusions: High-concentration spiked pooled plasma samples and spiked individual plasma samples are candidate EQA materials for normetanephrine and metanephrine measurements. [ABSTRACT FROM AUTHOR]

Context: Sampling of blood in the supine position for diagnosis of pheochromocytoma and paraganglioma (PPGL) results in lower rates of false positives for plasma normetanephrine than seated sampling. It is unclear how inpatient vs outpatient testing and other preanalytical factors impact false positives. Objective: We aimed to identify preanalytical precautions to minimize false-positive results for plasma metanephrines. Methods: Impacts of different blood sampling conditions on plasma metanephrines were evaluated, including outpatient vs inpatient testing, sampling of blood in semi- vs fully recumbent positions, use of cannulae vs direct venipuncture, and differences in outside temperature. A total of 3147 patients at 10 tertiary referral centers were tested for PPGL, including 278 with and 2869 without tumors. Rates of false-positive results were analyzed. Results: Outpatient rather than inpatient sampling resulted in 44% higher plasma concentrations and a 3.4-fold increase in false-positive results for normetanephrine. Low temperature, a semi-recumbent position, and direct venipuncture also resulted in significantly higher plasma concentrations and rates of false-positive results for plasma normetanephrine than alternative sampling conditions, although with less impact than outpatient sampling. Higher concentrations and rates of false-positive results for plasma normetanephrine with low compared with warm temperatures were only apparent for outpatient sampling. Preanalytical factors were without impact on plasma metanephrines in patients with PPGL.Conclusion: Although inpatient blood sampling is largely impractical for screening patients with suspected PPGL, other preanalytical precautions (eg, cannulae, warm testing conditions) may be useful. Inpatient sampling may be reserved for follow-up of patients with difficult to distinguish true- from false-positive results. [ABSTRACT FROM AUTHOR]

Background Pheochromocytoma and paraganglioma (PPGL) is diagnosed through biochemical confirmation of excessive catecholamines in urine and plasma. Recent technological developments have allowed us to measure urinary free metanephrines; however, the diagnostic accuracy of these new methods and the diagnostic cutoff values have not been evaluated. Methods This is a retrospective study of 595 subjects, including 71 PPGL cases and 524 controls. PPGL was based on pathological confirmation. Subjects with no evidence of PPGL over 2 years were included in the control group. Results Urinary free metanephrines yielded similar area under the curve (AUC) to urinary fractionated metanephrines and plasma free metanephrines. However, urinary free normetanephrine yielded a better AUC than did urinary fractionated normetanephrine. The optimal cutoff for urinary free metanephrine and normetanephrine corrected for urinary creatinine yielded 97.2% sensitivity and 98.1% specificity. Conclusion Urinary free metanephrines are a reliable method for diagnosing PPGL in Asian populations compared with existing biochemical methods.

Aim. To study the prognostic value of determining Chromogranin A blood level in the diagnosis of PHEO. Materials and methods. We conducted a comparative analytical study of 157 patients with suspected PHEO, statistical analysis of 24-hour urinary metanephrine and normetanephrine excretion test was performed, as well as a blood test for CrA, in groups that included patients without PHEO, with primary tumor or its recurrence, confirmed according to MSCT and/or scintigraphy with MIBG and/or the clonidine suppression test. Results. The parameters of efficiency of these methods were calculated by groups and it was noted that the lowest sensitivity of the CrA determination method was observed in the group with recurrence of PHEO (43.8%), their exclusion from the entire sample didnt change specificity of the method and it remained at a high level (85.45%), though sensitivity significantly increased up to 87.1%. Sensitivity of determining 24-hour urinary metanephrine excretion also increased significantly up to 96.8%, with 98.2% of specificity. The correlation between diameter of the tumor and its secretory activity was identified: small with CrA level (rho 0.491) and strong with total level of methylated catecholamines (rho 0.765). False positive results were more often observed in patients present with other neuroendocrine tumors (37.5%), as well as those taking proton-pump inhibitors (43.75%). The sensitivity and specificity of CrA determining method in the group of patients with methanephrins elevated within gray zone appeared to be 50 and 86.1%, respectively. Conclusion. A blood test for CrA can be recommended as a confirmatory test for diagnosing PHEO in cases of questionable methylated catecholamines indicators or in cases of suspected relapse of PHEO. The use of the test as a first-line method is only possible if there is no possibility to study methylated catecholamines. When interpreting CrA level, it is necessary to take into account the conditions that may cause false-positive results.

A novel dual-template magnetic molecularly imprinted polymer (MMIP) was synthesized to extract normetanephrine (NMN), metanephrine (MN) and 3-methoxytyramine (3-MT) from spot urine samples. As the adsorbent of dispersive solid-phase extraction (d-SPE), the MMIP was prepared using dopamine and MN as dual templates, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as the crosslinking reagent and magnetic nanoparticles as the magnetic core. NMN, MN, 3-MT and creatinine (Cr) in spot urine samples were selectively enriched by d-SPE and detected by HPLC-fluorescence detection/ultraviolet detection. The peak area (A) ratios of NMN, MN and 3-MT to Cr were used for the diagnosis of pheochromocytomas and paragangliomas (PPGLs). The results showed that the adsorption efficiencies of MMIP for target analytes were all higher than 89.0%, and the coefficient variation precisions of intra-assay and inter-assay for the analytes were within 4.9% and 6.3%, respectively. The recoveries of the analytes were from 93.2% to 112.8%. The MMIP was still functional within 14 days and could be reused at least seven times. The d-SPE and recommended solid-phase extraction (SPE) were both used to pretreat spot urine samples from 18 PPGLs patients and 22 healthy controls. The correlation coefficients of ANMN/ACr and AMN/ACr between d-SPE and SPE were both higher than 0.95. In addition, the areas under the receiver operator curves for spot urine ANMN/ACr, AMN/ACr and plasma free NMN and MN were 0.975, 0.773 and 0.990, 0.821, respectively, indicating the two methods had the similar performances. The d-SPE method took only 20 min, which was effective in clinical application. [ABSTRACT FROM AUTHOR]

Head and neck paragangliomas (HNPGLs) are tumors of parasympathetic origin that occur at variable locations and are often secondary to germline mutations in succinate dehydrogenase (SDH) subunit genes. Occasionally, these tumors produce catecholamines. Here, we assessed whether different locations of HNPGLs relate to the presence of SDHx mutations, catecholamine production and other presentations. In this multicenter study, we collected clinical and biochemical data from 244 patients with HNPGLs and 71 patients without HNPGLs. We clarified that jugulotympanic HNPGLs have distinct features. In particular, 88% of jugulotympanic HNPGLs arose in women, among whom only 24% occurred due to SDHx mutations compared to 55% in men. Jugulotympanic HNPGLs were also rarely bilateral, were of a smaller size and were less often metastatic compared to carotid body and vagal HNPGLs. Furthermore, we showed that plasma concentrations of methoxytyramine (MTY) were higher (P < 0.0001) in patients with HNPGL than without HNPGL, whereas plasma normetanephrine did not differ. Only 3.7% of patients showed strong increases in plasma normetanephrine. Plasma MTY was positively related to tumor size but did not relate to the presence of SDHx mutations or tumor location. Our findings confirm that increases in plasma MTY represent the main catecholamine-related biochemical feature of patients with HNPGLs. We expect that more sensitive analytical methods will make biochemical testing of HNPGLs more practical in the future and enable more than the current 30% of patients to be identified with dopa mine-producing HNPGLs. The sex-dependent differences in the development of HNPGLs may have relevance to the diagnosis, management and outcomes of these tumors. [ABSTRACT FROM AUTHOR]

Background: Although some evidence suggests an association between obstructive sleep apnea (OSA) and gestational diabetes mellitus (GDM), its consequences still remain largely unknown. We sought to determine whether OSA is associated with higher inflammation and sympathetic levels in GDM, and to relate them with insulin resistance and perinatal outcomes. Methods: OSA was identified by polysomnography and defined as an apnea–hypopnea index of ≥ 5 h−1. Plasma cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-10), metanephrine, and normetanephrine were determined by immunoassays. Results: We included 17 patients with GDM and OSA and 34 without OSA. Women with GDM and OSA had higher normetanephrine concentrations [81 IQR (59–134) vs. 68 (51–81) pg/mL]. No differences in the inflammatory profile were found, while IL-1β was higher in patients with mean nocturnal oxyhemoglobin saturation ≤ 94%. We found positive correlations between increased sympathetic activation and IL-1β, with obstructive apneas, while time in REM showed an inverse relationship with IL-1β and metanephrine. Furthermore, IL-10 was inversely related with time in sleep stages 1–2, and with the arousal index, and it was positively related with time in slow-wave sleep. Significant correlations were also found between IL-1β and insulin resistance. There were no significant differences in neonatal characteristics; however, we found inverse relationships between IL-10 and birth weight (BW), and percentile of BW. Conclusions: OSA increased sympathetic activity, and IL-1β concentration was higher in patients with GDM with lower nocturnal oxygenation, all of which were related with obstructive events, and time in REM. Moreover, IL-1β was related with insulin resistance, and IL-10 inversely correlated with neonatal BW. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the usefulness of metanephrine (MN) and normetanephrine (NMN) in bilateral simultaneous adrenal vein sampling (AVS) with and without ACTH stimulation. The study was conducted in a single referral center. Prospective recruited patients with PA were treated with AVS. The effects of cortisol, MN and NMN on selectivity catheterization were assessed and determined by lateralization. We enrolled 54 patients with PA who were treated with simultaneous bilateral AVS with ACTH. The Selectivity Index (SI) calculated by MN was higher than that calculated by other indicators (p<0.001), the catheterization success rate of MN at baseline was the same as that of cortisol after ACTH stimulation, and in lateralization diagnosis, MN was not inferior to cortisol. In conclusion, among the studied indicators, MN is the best index for determining the catheterization selectivity in AVS, especially in the absence of ACTH stimulation. [ABSTRACT FROM AUTHOR]

Catecholamine release increases in dogs with pheochromocytomas and in situations of stress. Although plasma catecholamines degrade rapidly, their metabolites, normetanephrine (NME) and metanephrine (ME), are stable in acidified urine. Our aim was to verify a human urine ELISA kit for the quantification of NME and ME in canine urine and to determine the effects on metabolite stability of sampling time (morning or midday) and day (ordinary or day spent in a clinic). We analyzed 179 urine samples from 17 healthy dogs. For NME, the mean intra-assay CV was 6.0% for all samples and 4.3% for the canine control; inter-assay CVs were 3.3, 3.8, and 12% for high and low concentration human urine positive controls supplied in the ELISA kit and a positive canine control, respectively; spike-recovery was 90–101%. For ME, mean intra-assay CV was 6.5% for samples and 9.0% for the canine control; inter-assay CVs were 12.7, 7.2, and 22.5% for high and low concentration human urine positive controls supplied in the ELISA kit and a positive canine control, respectively; spike-recovery was 85–89%. Dilution recovery was unsatisfactory for both metabolites. Based on our verification results, NME was selected for remaining analyses. We found no effect on NME concentrations of acidification or room temperature storage for up to 24 h. The NME:creatinine ratio was higher after the first of 3 clinic days compared to the same morning (111.2 ± 5.5 vs. 82.9 ± 5.3; p < 0.0001), but not on the other days. NME verification results were generally superior to ME. Dilution studies were unsatisfactory for both metabolites. Given that NME was stable without acidification at room temperature, urine samples can be collected at home. The clinic environment can cause higher NME:creatinine ratios, especially in unaccustomed dogs. [ABSTRACT FROM AUTHOR]

Accurate diagnosis of pheochromocytoma and paraganglioma (PPGLs) is highly dependent on the detection of metanephrines and catecholamines. However, the systematic investigation on influencing factors including specimen (plasma or whole blood), anticoagulant, storage conditions, and interference factors need further confirmation. Blood with heparin-lithium or EDTA-K2 were collected, stability of epinephrine (EPI), norepinephrine (NE), dopamine (DA), metanephrine (MN), normetanephrine (NMN), 3-methoxytyramine (3-MT) in whole blood and plasma at room temperature and 4 °C for different storage times, stability of plasma MN, NMN and 3-MT at −20 °C and −80 °C were investigated. Plasma with hemoglobin (1 g/L, 2 g/L, 3 g/L, 4 g/L, 6 g/L), TG (<5 mmol/L, 5–8 mmol/L, >8 mmol/L) were prepared. EPI, NE, DA were prone to degrade at room temperature, samples should be centrifuged at 4 °C. EPI and NE were stable in whole blood at 4 °C for 4 h and in plasma for 2 h. For MN, NMN, 3-MT, plasma can be stable at room temperature and 4 °C for at least 6 h, which is better than whole blood; there was no significant difference when stored at −20 °C and −80 °C for 7 days. Heparin-lithium had a slight advantage over EDTA-K2. EPI, NE, DA should not be performed when Hb > 1 g/L or TG > 5 mmol/L. MN, NMN, 3-MT should not be performed when Hb > 2 g/L, whereas TG had no interference. According to the actual clinical application scenario, this study provided a reliable basis for the accurate diagnosis of PPGLs. [ABSTRACT FROM AUTHOR]

Background and Aim: Inactivity increases the risk of chronic diseases. The aim of the present study was to investigate the acute changes in Normetanephrine and glucose in boxing with Kinect Xbox with and without blood flow restriction as an alternative to aerobic exercise during quarantine in young non-athletes. Material and Methods: Fourteen healthy non-athlete individuals with a range of 20 to 40 years of age were randomly and purposefully selected. And on two different days with and without restriction of blood flow, they played boxing with Xbox 360 for 20 minutes. Blood samples were taken before and immediately after Results: There was a significant increase in serum Normetanephrine playing compared to before the test in both training groups, but the amount of changes between the two groups with and without blood flow restriction was not significant (P≤0.05). Exergames, in the case of unrestricted blood flow, has a significant effect on glucose, but the restriction of blood flow did not lead to a significant difference in the amount of glucose (P≤0.05). Conclusion: Exergames provide the necessary stimulus for catecholamine secretion and glucose response, and it is recommended for people with limited blood flow. Further studies are needed on the effect of restricting blood flow as a new training method on video game with movement. [ABSTRACT FROM AUTHOR]

Objectives: Biochemical testing of urinary metanephrines is useful in the diagnosis and monitoring of pheochromocytoma and paragangliomas. We investigated the feasibility of mixture decomposition (ie, indirect) methods in verifying clinically derived reference intervals for urinary deconjugated metanephrine metabolites.Methods: Urinary 24-hour metanephrine and normetanephrine excretion results were extracted from our data warehouse and intervals were estimated by the modern variant of the Hoffmann method, maximum likelihood estimation (MLE), and gamma mixture model using R software.Results: Hoffmann, MLE, and gamma mixture models provided metanephrine and normetanephrine intervals that closely matched those derived from clinical studies. However, three-component MLE and gamma models were required for normetanephrine in adult women because the Hoffmann method was not suitable. Some data transformations caused blending of the mixed distributions and subsequent widening of the reference interval estimation, emphasizing the importance of careful data transformation for Hoffmann and MLE analyses. Gamma mixture models gave overall good agreement without the need for data transformation.Conclusions: Indirect methods have utility in verifying reference intervals in 24-hour urine specimens collected by patients. We emphasize the benefits of applying multiple decomposition methods to corroborate findings and careful application of data transformation when using Gaussian-based models. [ABSTRACT FROM AUTHOR]

Context: False-positive results are common for pheochromocytoma/paraganglioma (PPGL) real-world screening.Objective: Determine the correlation between screening urine and seated plasma metanephrines in outpatients where PPGL was absent, compared to meticulously prepared and supine-collected plasma metanephrines with age-adjusted references.Design: Retrospective cohort study.Setting: Databases from a single-provider provincial laboratory (2012-2018), a validated PPGL registry, and a manual chart review from a specialized endocrine testing unit.Patients: PPGL registry data excluded known PPGL cases from the laboratory database. Outpatients having both urine and plasma metanephrines <90 days apart.Methods: The correlation between urine and seated plasma measures along with the total positivity rate. All cases of plasma metanephrines drawn in the endocrine unit were reviewed for test indication and test positivity rate.Results: There were 810 non-PPGL pairs of urine and plasma metanephrines in the laboratory database; 46.1% of urine metanephrines were reported high. Of seated outpatient plasma metanephrines drawn a median of 5.9 days later, 19.2% were also high (r = 0.33 and 0.50 for normetanephrine and metanephrine, respectively). In contrast, the meticulously prepared and supine collected patients (n = 139, 51% prior high urine metanephrines) had <3% rate of abnormal high results in patients without known PPGL/adrenal mass.Conclusions: There was a poor-to-moderate correlation between urine and seated plasma metanephrines. Up to 20% of those with high urine measures also had high seated plasma metanephrines in the absence of PPGL. Properly prepared and collected supine plasma metanephrines had a false-positive rate of <3% in the absence of known PPGL/adrenal mass. [ABSTRACT FROM AUTHOR]

Pheochromocytoma is a neuroendocrine tumor characterized by the excessive production of catecholamines (epinephrine, norepinephrine, and dopamine). The diagnosis is suspected due to hypertensive paroxysms, associated with vegetative phenomena, due to the catecholaminergic hypersecretion. Diagnosis involves biochemical tests that reveal elevated levels of catecholamine metabolites (metanephrine and normetanephrine). Functional imaging, such as 123I-metaiodobenzylguanidine scintigraphy (123I-MIBG), has increased specificity in identifying the catecholamine-producing tumor and its metastases. The gold-standard treatment for patients with pheochromocytoma is represented by the surgical removal of the tumor. Before surgical resection, it is important to optimize blood pressure and intravascular volume in order to avoid negative hemodynamic events.

Measurement of urinary metanephrines in spot samples is used for the diagnosis of canine pheochromocytoma (PC). We describe a simple analytical method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) for measuring free metanephrine (MN) and normetanephrine (NMN) in spot urine samples. Using the developed method, we evaluated the stability of urinary free-MN and free-NMN at various storing conditions. In addition, we assessed the feasibility of urinary free-MN and -NMN measurement for diagnosing PC. Urine samples were mixed with stable isotope internal standards and thereafter purified by ultrafiltration. The purified samples were analyzed by LC-MS/MS in the multiple reaction monitoring mode after separation on a multimode octa decyl silyl column. The coefficient of variation of free-MN and -NMN measurement was 7.6% and 5.5%, respectively. The linearity range was 0.5-10 µg/l for both analytes. Degradation was less than 10% for both analytes under any of the storage conditions. The median free-NMN ratio to creatinine of 9 PC dogs (595, range 144--47,961) was significantly higher (P<0.05) than that of 13 dogs with hypercortisolism (125, range 52--224) or 15 healthy dogs (85, range 50--117). The developed method is simple and may not require acidification of spot urine. The results of this preliminary retrospective study suggest that the measurement of urinary free metanephrines is a promising tool for diagnosing canine PC. [ABSTRACT FROM AUTHOR]

A novel dual-template magnetic molecularly imprinted polymer (MMIP) was synthesized to extract normetanephrine (NMN), metanephrine (MN) and 3-methoxytyramine (3-MT) from spot urine samples. As the adsorbent of dispersive solid-phase extraction (d-SPE), the MMIP was prepared using dopamine and MN as dual templates, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as the crosslinking reagent and magnetic nanoparticles as the magnetic core. NMN, MN, 3-MT and creatinine (Cr) in spot urine samples were selectively enriched by d-SPE and detected by HPLC-fluorescence detection/ultraviolet detection. The peak area (A) ratios of NMN, MN and 3-MT to Cr were used for the diagnosis of pheochromocytomas and paragangliomas (PPGLs). The results showed that the adsorption efficiencies of MMIP for target analytes were all higher than 89.0%, and the coefficient variation precisions of intra-assay and inter-assay for the analytes were within 4.9% and 6.3%, respectively. The recoveries of the analytes were from 93.2% to 112.8%. The MMIP was still functional within 14 days and could be reused at least seven times. The d-SPE and recommended solid-phase extraction (SPE) were both used to pretreat spot urine samples from 18 PPGLs patients and 22 healthy controls. The correlation coefficients of ANMN/ACr and AMN/ACr between d-SPE and SPE were both higher than 0.95. In addition, the areas under the receiver operator curves for spot urine ANMN/ACr, AMN/ACr and plasma free NMN and MN were 0.975, 0.773 and 0.990, 0.821, respectively, indicating the two methods had the similar performances. The d-SPE method took only 20 min, which was effective in clinical application.

Pheochromocytomas are tumors that develop from the chromaffin cells of the adrenal medulla. More than 40% of cases of pheochromocytomas are associated with genetic conditions such as neurofibromatosis type 1 (NF1) or von Hippel-Lindau syndrome. Cystic pheochromocytomas are rare, generally asymptomatic, and thus of bigger size at the time of diagnosis. Surgical treatment is necessary to prevent cardiovascular morbidity and malignancy risk. We report the case of a 27-year-old patient admitted for further examination of a left adrenal mass that was discovered by an abdominal CT scan in the context of abdominal pain associated with hypertension evolving for three years. The clinical examination showed the presence of multiple café au lait spots, axillary and inguinal freckling with two dermal neurofibromas diagnosed clinically, as well as Lisch nodules on bilateral ophthalmic examination, thus meeting the clinical criteria for the diagnosis of NF1. The clinical laboratory investigation showed elevated urinary metanephrine and normetanephrine levels. CT scan examination showed a 10 cm left adrenal cystic mass on abdominal CT. This mass uptake of the radioligand in metaiodobenzylguanidine (MIBG) scintigraphy without secondary extra-adrenal localization allowed the diagnosis of a seemingly benign cystic pheochromocytoma to be made. The patient was put on presurgical drug preparation with volume expansion and then underwent left unilateral adrenalectomy. The histopathological study was in favor of a rather aggressive cystic pheochromocytoma with a pheochromocytoma of the adrenal gland scaled (PASS) score of 9. Blood pressure and urine catecholamines at seven days, three months, six months, and one year after surgery were normalized. Cystic pheochromocytoma is a rare tumor with a potentially poor prognosis. It is characterized by a more insidious evolution and a larger volume at diagnosis. It should be considered a diagnosis in patients with a cystic adrenal mass or an extra-adrenal mass with fluctuating blood pressure during surgery. This case illustrates the importance of both presurgical preparation and screening for pheochromocytoma in neurofibromatosis type 1., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Serhane et al.)

This study aimed to elucidate the clinical diagnostic value of plasma catecholamines and their metabolites for pheochromocytoma and paraganglioma (PPGL)-induced secondary hypertension using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS). The study population included 155 patients with PPGL that were divided into the PPGL with hypertension (n = 79) and a PPGL without hypertension (n = 76) groups, and 90 healthy volunteers and 90 patients with primary hypertension as the control groups. UPLC-MS/MS was performed to detect plasma levels of catecholamines and their metabolites, including dopamine, vanillylmandelic acid (VMA), norepinephrine, metanephrine, and normetanephrine. Receiver operating characteristic curves were generated to analyze the diagnostic value of the plasma levels of catecholamines and their metabolites in PPGL-induced secondary hypertension. Patients in the primary hypertension and PPGL without hypertension groups had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal group (all p < .05). On the other hand, patients in the PPGL with hypertension group had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal, primary hypertension, and PPGL without hypertension groups (all p < .05). Collectively, our findings showed that dopamine, VMA, norepinephrine, metanephrine, and normetanephrine are all effective biomarkers for the diagnosis of PPGL and PPGL-induced secondary hypertension., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

We previously highlighted the problem of frequent false positives in 24 h urine normetanephrine(UNM) measurements owing to reference intervals that are inappropriately low for the population being screened for pheochromocytoma. Using a large population database, we devised new age-stratified reference intervals for the 24 h UNM test that were higher compared to previous. However, it was uncertain as to whether this would compromise test sensitivity for true pheochromocytoma cases. Retrospective analysis of all pheochromocytoma cases from a recently constructed provincial registry. All confirmed cases had their diagnostic UNM results retrospectively re-analysed according to the newly proposed UNM reference intervals to determine the percentage and phenotype of cases that might have been theoretically missed with the new reference range. After excluding pediatric and non-secretory head and neck paragangliomas, there were 60 confirmed pheochromocytoma cases. Using prior reference intervals, 51/60 (85%) had an abnormally high UNM. Of the 9 with normal UNM, 4 had a high urine metanephrine(UMN), 5 had normal levels of both UNM and UMN such that 55/60 had abnormal test results, representing the historical combined test sensitivity of 92%. Using the proposed reference interval, 43/60 (72%) had high UNM results. Of the 17 with normal UNM, 12 had high UMN, 5 had normal levels of both UNM and UMN. Therefore, 55/60 patients had had elevations in either UNM or UMN, corresponding to an identical combined test sensitivity of 92%. Reference intervals for UNM derived from actual clinical population screening data are higher than in traditional healthy volunteers. Use of these more appropriate reference intervals can significantly reduce the false positive rate without compromising test sensitivity for true pheochromocytoma. [ABSTRACT FROM AUTHOR]