Search

The urinary normetanephrine to creatinine ratio (uNMN/Cr) and urinary metanephrine to creatinine ratio (uMN/Cr) are commonly evaluated for the diagnosis of pheochromocytomas (PCC) in dogs. This study aimed to establish reference intervals for uNMN/Cr and uMN/Cr in 56 healthy dogs in Japan and to investigate the effect of urine collection methods on these measurements in 15 non-PCC dogs. The upper limits of reference intervals for uNMN/Cr and uMN/Cr were 124.4 nmol/mmol (90% confidence interval [CI] 107.7-137.0) and 121.1 nmol/mmol (90% CI 102.8-145.1), respectively. Both uNMN/Cr and uMN/Cr were significantly higher when urine was collected in the hospital compared to at home. Several factors, including the method of urine collection, should be considered when utilizing these reference intervals.

Pheochromocytomas are rare neuroendocrine tumors that derive from the chromaffin cells of the adrenal medulla and secrete catecholamines. The measurement of plasma or fractionated urine metanephrines is the hormonal determination of choice for the biochemical diagnosis. Once the biochemical diagnosis is confirmed, the next step is the localization study. It is recommended to request a genetic study in all patients with pheochromocytomas since 40% of cases are hereditary. Once the diagnostic study is completed, preoperative treatment with alpha blockers should be instituted at least 7-14 days before adrenalectomy. However, in low-risk patients, the omission of presurgical treatment could be considered if the surgery is performed in centers with experience and a strict monitoring of the patient is carried out during the perioperative period. This document offers a practical guide on the diagnosis and perioperative approach in patients with pheochromocytomas., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

Background: The prevalence of metastatic pheochromocytoma and paraganglioma (PPGL) is approximately 15%-20%. Although there are indicators to assess metastatic risks, none of them predict metastasis reliably. Therefore, we aimed to develop and validate a scoring system using clinical, genetic, and biochemical risk factors to preoperatively predict the metastatic risk of PPGL., Methods: In the cross-sectional cohort (n = 180), clinical, genetic, and biochemical risk factors for metastasis were identified using multivariate logistic regression analysis, and a novel scoring system was developed. The scoring system was validated and compared with the age, size of tumor, extra-adrenal location, and secretory type (ASES) score in the longitudinal cohort (n = 114)., Results: In the cross-sectional cohort, pseudohypoxia group-related gene variants (SDHB, SDHD, or VHL), methoxytyramine >0.16 nmol/L, and tumor size >6.0 cm were independently associated with metastasis after multivariate logistic regression. Using them, the gene variant, methoxytyramine, and size of tumor (GMS) score were developed. In the longitudinal cohort, Harrell's concordance index of the GMS score (0.873, 95% confidence interval [CI]: 0.738-0.941) was higher than that of the ASES score (0.713, 95% CI: 0.567-0.814, p = 0.007). In the longitudinal cohort, a GMS score ≥2 was significantly associated with a higher risk of metastasis (hazard ratio = 25.07, 95% CI: 5.65-111.20). A GMS score ≥2 (p < 0.001), but not ASES score ≥2 (p = 0.090), was associated with shorter progression-free survival., Conclusion: The GMS scoring system, which integrates gene variant, methoxytyramine level, and tumor size, provides a valuable preoperative approach to assess metastatic risk in PPGL., (© 2024 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Introduction: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Pheochromocytoma (PHEO) is a tumor from the chromaffin tissue of the adrenal medulla, capable of hyperproduction of catecholamines. The increased production of hormones by the tumor leads to catecholamine crises, which have a pathological effect on all organs and systems. In the primary diagnosis of pheochromocytomas, it is important to determine the level of the metabolite of catecholamines - metanephrines. Currently, in clinical practice, various methods are used to determine the level of this metabolite: in blood plasma or in urine, total or only free form, fractionated analysis or unfractionated., Aim: Comparison of the effectiveness of various methods for determining the level of metanephrines for the diagnosis of pheochromocytomas., Materials and Methods: A retrospective single-center cohort study was conducted on a sample of patients who were initially operated on for adrenal neoplasm at the Pirogov St. Petersburg State University High Medical Technology Clinic from November 2007 to December 2022 and who passed analysis to determine the level of blood or urine metanephrins before surgical treatment. The results of tests for metanephrine and tumor size were evaluated., Results: 1088 patients with adrenal neoplasms who underwent surgical treatment were examined, of which 348 had histologically confirmed the presence of pheochromocytoma. Four types of metanephrine assays were compared: free fractionated plasma metanephrines (232 patients), unfractionated daily urine metanephrines (431 patients), fractionated total daily urine metanephrines (427 patients) and fractionated free daily urine metanephrines (178 patients). The greatest sensitivity was demonstrated by the analysis of free fractionated plasma methanephrines (95.4%). Unlike others, the sensitivity of this analysis did not decrease in the group of patients with small pheochromocytomas (3 cm or less). The greatest specificity was demonstrated by the analysis of unfractionated metanephrines in daily urine (97.8%), with the lowest sensitivity among all tests (67.6%). The study of fractionated total daily urine metanephrins showed good results of sensitivity and specificity, only slightly inferior to the best indicators, and the analysis of free daily urine metanephrins demonstrated unexpectedly low efficiency. There is a positive correlation between the level of metanephrine in the blood and the size of the tumor., Conclusion: Based on the data obtained, the preferred assays for the primary diagnosis of pheochromocytoma can be considered the determination of fractionated free plasma metanephrines and fractionated total daily urine metanephrines, which is consistent with relevant clinical recommendations. It was found that the size of the tumor correlates with the severity of an increase in the level of metanephrins determined by any of the described methods.

Pheochromocytoma and paraganglioma (PPGL) require prompt consideration and efficient diagnosis and treatment to minimize associated morbidity and mortality. Once considered, appropriate biochemical testing is key to diagnosis. Advances in understanding catecholamine metabolism have clarified why measurements of the O-methylated catecholamine metabolites rather than the catecholamines themselves are important for effective diagnosis. These metabolites, normetanephrine and metanephrine, produced respectively from norepinephrine and epinephrine, can be measured in plasma or urine, with choice according to available methods or presentation of patients. For patients with signs and symptoms of catecholamine excess, either test will invariably establish the diagnosis, whereas the plasma test provides higher sensitivity than urinary metanephrines for patients screened due to an incidentaloma or genetic predisposition, particularly for small tumors or in patients with an asymptomatic presentation. Additional measurements of plasma methoxytyramine can be important for some tumors, such as paragangliomas, and for surveillance of patients at risk of metastatic disease. Avoidance of false-positive test results is best achieved by plasma measurements with appropriate reference intervals and preanalytical precautions, including sampling blood in the fully supine position. Follow-up of positive results, including optimization of preanalytics for repeat tests or whether to proceed directly to anatomic imaging or confirmatory clonidine tests, depends on the test results, which can also suggest likely size, adrenal vs extra-adrenal location, underlying biology, or even metastatic involvement of a suspected tumor. Modern biochemical testing now makes diagnosis of PPGL relatively simple. Integration of artificial intelligence into the process should make it possible to fine-tune these advances., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Pheochromocytoma (PCC) is rare in cats and plasma (PL) and urinary (U) metanephrines (metanephrine [MN]; normetanephrine [NMN]) measurement is rarely described in cats., Objectives: We evaluated the utility of PL and U MNs measurement in 10 healthy cats and a cat with a confirmed diagnosis of pheochromocytoma (PheoCat), using liquid chromatography with tandem mass spectrometry (LC-MS-MS)., Methods: Urine and EDTA PL samples collected from each of the 10 cats and the PheoCat were promptly stored at -80°C and remained frozen until analysis. To evaluate U MNs stability, an additional urine sample collected from the healthy cats was refrigerated for 24 hours before freezing. Urinary creatinine concentration (Creat) was assessed using the same spot urine samples to calculate U MNs-to-creatinine ratios., Results: The PL-MN and PL-NMN median concentrations of the healthy cats were 2.73 and 7.02 nmol/L, respectively. The median U-MN/Creat and U-NMN/Creat ratios were 70 and 139 μg/g, respectively. The PheoCat had a PL-MN of 3.68 nmol/L, PL-NMN of 66.27 nmol/L, U-MN/Creat of 179 μg/g, and U-NMN/Creat of 1262 μg/g. The PheoCat had markedly increased concentrations of both PL and U MNs when compared to the healthy cats. No significant difference was found between U MNs measured in urine samples that underwent 24 hours of refrigeration in comparison to those that were frozen immediately., Conclusions: We report preliminary reference intervals for PL and U MNs in cats using LC-MS-MS and the potential clinical applicability of these biomarkers for the diagnosis of PCC in cats., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Introduction: Metanephrines (MTNs) are metabolites of catecholamines and are constantly produced in high amounts by pheochromocytomas and paragangliomas (PPGLs). Marked MTN elevations (> 3 times the upper limit of normal [ULN]) are highly suggestive of PPGL. The frequency of marked MTN elevations in non-PPGL hypertensive emergencies (HTNEs) is unknown., Methods: We retrospectively analyzed plasma free metanephrine (PMTN) and 24-h urinary fractionated metanephrine (UMTN) levels in 48 consecutive patients (59.7 ± 15.6 years; 48% female; BMI: 31 ± 9.7 kg/m 2 ) hospitalized for HTNE, defined as systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 120 mmHg with end-organ damage. PMTNs were measured in 47 patients, UMTNs were measured in 16 patients, and both PMTNs and UMTNs were measured in 15 patients., Results: PMTN/UMTN levels were not associated with SBP/DBP, comorbidities, end-organ damage, or interfering medications, the exception being that plasma normetanephrines (PNMNs) were significantly associated with comorbidities (Adj. R 2  = 0.16; p = 0.04) and interfering medications (Adj. R 2  = 0.15; p = 0.03), although with weak correlation. Marked MTN (specifically PNMN) elevations (647, 521, and 453 pg/mL; normal ≤ 148 pg/mL) were noted in only three patients (6%)., Discussion: Marked MTN elevations in HTNE are uncommon. Therefore, we recommend against measuring MTN in the setting of an apparent precipitating cause of HTNE to avoid unnecessary testing and imaging. Testing for MTN in HTNE should be pursued only when there is no clear precipitating cause and in cases where there is strong underlying clinical suspicion for PPGL. However, should testing be performed, marked MTN elevations should not be disregarded as being a commonly occurring result of HTNE., (© 2022. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

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 A NMN /A Cr and A MN /A Cr between d-SPE and SPE were both higher than 0.95. In addition, the areas under the receiver operator curves for spot urine A NMN /A Cr , A MN /A Cr 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.

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., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We aimed to identify presurgical and surgical risk factors for intraoperative complications in patients with pheochromocytomas. A retrospective study of patients with pheochromocytomas who underwent surgery in ten Spanish hospitals between 2011 and 2021 was performed. One hundred and sixty-two surgeries performed in 159 patients were included. The mean age was 51.6 ± 16.4 years old and 52.8% were women. Median tumour size was 40 mm (range 10-110). Laparoscopic adrenalectomy was performed in 148 patients and open adrenalectomy in 14 patients. Presurgical alpha- and beta-blockade was performed in 95.1% and 51.9% of the surgeries, respectively. 33.3% of the patients (n = 54) had one or more intraoperative complications. The most common complication was the hypertensive crisis in 21.0%, followed by prolonged hypotension in 20.0%, and hemodynamic instability in 10.5%. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more commonly than patients pre-treated with other antihypertensive drugs (51.1% vs 26.5%, P = 0.002). Intraoperative complications were more common in patients with higher levels of urine metanephrine (OR = 1.01 for each 100 μg/24 h, P = 0.026) and normetanephrine (OR = 1.00 for each 100 μg/24 h, P = 0.025), larger tumours (OR = 1.4 for each 10 mm, P < 0.001), presurgical blood pressure > 130/80 mmHg (OR = 2.25, P = 0.027), pre-treated with doxazosin (OR = 2.20, P = 0.023) and who had not received perioperative hydrocortisone (OR = 3.95, P = 0.008). In conclusion, intraoperative complications in pheochromocytoma surgery are common and can be potentially life-threatening. Higher metanephrine and normetanephrine levels, larger tumour size, insufficient blood pressure control before surgery, pre-treatment with doxazosin, and the lack of treatment with perioperative hydrocortisone are associated with higher risk of intraoperative complications.

Background: Pheochromocytoma is a rare cause of acute cardiovascular disease; however, any severe illness may have high catecholamines, simulating pheochromocytoma. We determined the spectrum of urine metanephrines from inpatient and outpatient collections without pheochromocytoma, compared with confirmed pheochromocytoma patients., Methods: Retrospective analysis using centralized laboratory data serving all outpatients and hospitals in southern Alberta. The analysis comprised 24-hour urine normetanephrine and metanephrine (UNM-UMN) results collected from hospital inpatients, community outpatients, and patients from a comprehensive provincial pheochromocytoma registry., Results: There were 974 unique inpatients (including 132 from intensive care), 6802 outpatients, and 58 pheochromocytoma patients. Among outpatient, general ward, and intensive care unit (ICU) patients, 18.7%, 34.4%, and 67.4% of results, respectively, were supranormal. Although pheochromocytoma patients had higher median UNM-UMN vs inpatients, there was substantial overlap. Receiver operating characteristic (ROC) analysis showed area under the curve (AUC) of 0.64-0.91 to detect true pheochromocytoma (P < .0001), with progressively poorer discrimination among hospitalized and ICU-dependent patients. A 24-hour urine normetanephrine >6.95 nmol/d had 98% specificity for pheochromocytoma when inpatient general ward samples were included, but only 46% sensitivity and 13% positive predictive value for pheochromocytoma. Considering ICU collections, 98% specificity required results more than fivefold above the upper reference limit and still had poor positive predictive value. A model combining both UNM and UMN results as a cross-product marginally improved the ROC AUC, but improved sensitivity in outpatients and ward patients but not ICU patients., Conclusion: There is a high degree of overlap in UNM-UMN between hospitalized patients and pheochromocytoma; high test specificity is not achieved in this population unless >3-5 times the upper reference limit., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The management of blood pressure is a significant concern for surgeons and anesthesiologists performing adrenalectomy for pheochromocytoma. We evaluated clinical factors in pheochromocytoma patients to identify the predictors of postoperative hypotension. The medical records of patients who underwent adrenalectomy for pheochromocytoma between 2001 and 2017 were retrospectively reviewed and clinical and biochemical data were evaluated. Of 29 patients, 13 patients needed catecholamine support in the perisurgical period while 16 patients did not. There were significant differences in median age, tumor size, and blood pressure drop (maxmin) between the 2 groups (68 vs 53 years old, p=0.045; 50 vs 32 mm diameter, p=0.022; 110 vs 71 mmHg, p=0.015 respectively). In univariate logistic analysis, age > 65.5 years, tumor size > 34.5 mm, urine metanephrine > 0.205 mg/day and urine normetanephrine > 0.665 mg/day were significant predictors of prolonged hypotension requiring postoperative catecholamine support. Tumor size and urine metanephrine and urine normetanephrine levels were correlated with postoperative hypotension. These predictors may help in the safe perioperative management of pheochromocytoma patients treated with adrenalectomy., Competing Interests: No potential conflict of interest relevant to this article was reported.

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.

Pheochromocytoma occasionally engenders catecholamine-induced hypertension crisis. Pheochromocytoma is clinically identified in 0.1%-5.7% of patients with neurofibromatosis type 1 (NF1), which is 10 times more frequently than in healthy individuals. This report describes a case of newly diagnosed NF1 presenting with pheochromocytoma crisis, with severe electrolyte depletion and deteriorating recurrent ventricular tachycardia storm. Characteristic skin lesions such as café-au-lait macules and neurofibromas contributed to the diagnosis of NF1 and pheochromocytoma. No recurrence of electrolyte depletion was found after the adrenalectomy. Primary care physicians must distinguish the characteristic skin lesions of NF1, such as café-au-lait macules and neurofibromas and recognise the risk for pheochromocytoma., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To analyze the clinical and analytical features, diagnostic tests, therapies, and outcomes of pheochromocytoma (PCC)., Design and Methods: A multicenter retrospective study in surgically treated patients with PCC followed in 3 Spanish tertiary referral hospitals., Results: A total of 106 patients (61 [57.5%] women, mean age 52.3 ± 14.8 years) were evaluated. At diagnosis, PCC was symptomatic in 62% and sporadic in 83%. Patients with familial PCC were significantly younger than those with sporadic disease (40.8 ± 14.2 years vs 54.5 ± 13.9 years, p < .001). Familial PCCs were more frequently associated with MEN2A (n = 8). Levels of 24-h urinary fractionated metanephrines were positively related to tumor size. The maximum tumor diameter was 4.3 cm (3-6 cm); 27.7% of the patients had tumors ≥6 cm. Incidental PCCs were significantly smaller than symptomatic PCCs (3.4 cm [2.4-5.0 cm] vs 5.6 cm [4.0-7.0 cm], p < .001). Scintigraphy by ¹²³I-metaiodobenzylguanidine showed a high sensitivity (81.9%). Preoperative alpha blockade with phenoxybenzamine was used in 93.6% and doxazosin in the rest. Laparoscopic surgery was used in 2/3 of the patients, with a low conversion (1.9%) to open surgery. Perioperative complications appeared in approximately 20% of patients, mainly hypertensive crisis (9.4%). Recurrent disease appeared in 10%, and malignant PCC was uncommon (6.3%)., Conclusions: PCCs surgically treated in Spain are usually large, symptomatic, and sporadic tumors diagnosed around the sixth decade of life. Hereditary PCC is usually associated with MEN2A. The main type of surgical technique used is laparoscopic surgery, and the prevalence of metastatic PCC is low., (Copyright © 2020 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Detection of normetanephrine (NMN), metanephrine (MN) and 3-methoxytyramine (3-MT) could be used to diagnose pheochromocytomas and paragangliomas (PPGLs). The accuracy for the diagnosis of PPGLs is only 6% by virtue of the classic symptom triad. In addition, false-positive results were found using plasma free MNs as biomarkers. Spot urinary free metanephrines (MNs) presented high specificity for PPGLs diagnosis in our previous work by HPLC with the electrochemical detection. Whereas, MNs and creatinine (Cr) need to be detected separately. A simple and specific method was urgently needed for the diagnosis of PPGLs. Here, we established a new HPLC method for spot urinary free MNs and 3-MT by the fluorescence detection and Cr by the ultraviolet detection simultaneously. It was worth mentioning that Cr for the virtue of being fairly constant in a given subject was used as an internal reference correction to eliminate the effect of spot urine volume for the diagnosis of PPGLs. Thirty-seven patients with PPGLs and 164 control subjects were detected by the established method and the peak area ratios of MNs and 3-MT to Cr were used innovatively for the diagnosis of PPGLs. The results showed acceptable precisions and recoveries. The sensitivities of the method were 94.6%, 91.9% and 86.5% and the specificities were 96.3%, 93.9% and 82.3%, respectively by the peak area of NMN/Cr, MN/Cr and 3-MT/Cr for the diagnosis. The established method provides a promising way for simple, rapid and accurate diagnosis of PPGLs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Phaeochromocytoma may present with uncontrolled hypertension leading to haemorrhagic stroke (HS), ischaemic stroke (IS) and transient ischaemic attack (TIA). False elevation in the levels of CATS/ METS has been reported in acute cerebrovascular disease. Our aim was to analyse the frequency and pattern of elevations of CATS/METS in patients with acute cerebrovascular disease and to determine associated factors., Materials and Methods: This is a retrospective study of 112 samples of CATS/ METS received by the laboratory over a two-year period, from patients with acute cerebrovascular disease. CATS/METS were measured using LC/MS/MS method. Clinical details and CATS/METS level were obtained from the database. Mann-Whitney U test and Kruskal Wallis test were used for statistical analysis. These statistical analyses were performed using SPSS v.20.0 (IBM Corp., Armonk, NY, USA)., Results: Of the 112 patients, 39% had HS, 54% had IS and 7% had TIA. A total of 29% of patients had elevated CATS/ METS. Elevated levels of CATS/METS were noted in 41% and 25% of HS and IS patients, respectively (p=0.53). Median norepinephrine, epinephrine and metanephrine levels in HS were significantly higher than IS (p< 0.05). Systolic blood pressure was higher in those who had elevated CATS/ METS (p=0.04). Only for two patients with elevated CATS/METS repeat testing was performed. Age, diastolic blood pressure and the time of sample collection in relation to the presentation, for CATS/METS were not significantly different between groups that had elevated levels of CATS/ METS versus those who did not., Conclusion: We noted that CATS/METS were elevated in one-third of patients, especially in patients with high systolic blood pressure. Increase in CATS/METS should be appropriately followed up with repeat testing. Since false elevation in CATS/METS has been reported in cerebrovascular disease, screening for phaeochromocytoma is best deferred for a month.

Background: In patients with phaeochromocytomas or paragangliomas (PPGLs), 24-h urine collections for metanephrines (uMNs) are cumbersome., Objective: To evaluate the diagnostic utility of ratios to creatinine of 'spot' uMNs., Methods: Concentrations of uMNs and plasma metanephrines (pMNs) were measured by HPLC-mass-spectrometry. We retrospectively compared correlations of 24-h-urine output and ratio to creatinine in historical specimens and prospectively assessed 24-h and contemporaneous spot urines and, where possible, pMNs. Using trimmed log-transformed values, we derived reference intervals based on age and sex for spot urines. We used multiples of upper limit of normal (ULNs) to compare areas under curves (AUCs) for receiver-operator characteristic curves of individual, and sum and product of, components., Results: In 3143 24-h-urine specimens on 2416 patients, the correlation coefficients between the ratios and outputs of metanephrine, normetanephrine and 3-methoxytyramine in 24-h urines were 0.983, 0.905 and 0.875, respectively. In 96 patients, the correlations between plasma concentrations, urine output and ratios in spot specimens were similar to those for raw output or ratios in 24-h specimens. Of the 160 patients with PPGLs, the CIs for AUCs for individual metabolites overlapped for all four types of measurement, as did those for the sum of the multiple ULNs although these were slightly higher (AUC for spot urine: 0.838 (0.529-1), plasma: 0.929 (0.874-0.984) and output: 0.858 (0.764-0.952))., Conclusions: Ratios of fractionated metanephrines to creatinine in spot urine samples appear to have a similar diagnostic power to other measurements. The ease of spot urine collection may facilitate diagnosis and follow-up of PPGLs through improved patient compliance.

A 63-year-old woman with multiple endocrine neoplasia type 2A (MEN2A) presented with recurrent spells of headaches, sweats and palpitations decades after right adrenalectomy for phaeochromocytoma, and total thyroidectomy for medullary thyroid cancer. She was hypertensive and in sinus rhythm. DOTA-TATE positron-emission tomography (PET) demonstrated a 12mm enhancing left adrenal incidentaloma. 24 hours urine catecholamines, and multiple plasma metanephrine and normetanephrine measurements were all within normal reference ranges. Based on her symptoms and imaging findings, left adrenalectomy was performed and found a 40 mm phaeochromocytoma. Her symptoms have since completely resolved and plasma metanephrine is now undetectable MEN2-associated phaeochromocytomas are often bilateral and may be metachronous. Patients at high risk of phaeochromocytoma who develop symptoms of catecholamine excess should be carefully evaluated even if plasma or urinary metanephrines are within the normal reference range. Biochemical reference ranges for metanephrines need to be adjusted accordingly in patients who have had prior unilateral total adrenalectomy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Urinary measurement of fractionated metanephrines is one of the best available biochemical tests for the diagnosis of pheochromocytoma and paraganglioma; however, false-positive results remain an issue. In addition, despite their convenience, there is no evidence to suggest that spot urine samples should replace the standard 24-h urine collection method. The objective of this study is to elucidate clinical variables that may influence the levels of spot urine fractionated metanephrines and to examine their instability. The study is a retrospective review of prospectively collected data from 949 patients whose spot urine fractionated metanephrines were measured under suspicion of pheochromocytoma or paraganglioma at our institution from January 2011 to June 2017. The effects of clinical factors such as age, sex, renal function, and medications on the level of spot urine fractionated metanephrines were evaluated. Urinary fractionated metanephrines were significantly higher in female subjects. They correlated with age but not with estimated glomerular filtration rate (eGFR). A multivariate regression model for urinary fractionated metanephrine levels revealed that age, female sex, eGFR, and the presence of α1-blocker medication were significantly positively correlated with urinary metanephrine (M) levels. Age, female sex, eGFR, and presence of α1-blockers and antidepressant and antipsychotic medications positively correlated with urinary normetanephrine (NM). In addition, age, female sex, eGFR, and presence of α1-blockers and antidepressant and antipsychotic medications were positively correlated with urinary M + NM. In conclusion, sex, age, eGFR, and treatment with α1-blockers, antidepressants, and antipsychotics may affect the levels of urinary fractionated metanephrines. When assessing urinary fractionated metanephrines in patients with suspected PPGLs, we must consider these factors.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors arising from adrenal and extra-adrenal chromaffin cells. They produce excessive amounts of catecholamines and their metabolites. A newly analytical procedure based on the semi-automated microextraction by packed sorbent (MEPS) technique, using a digitally controlled syringe (eVol) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), was developed to quantify free urinary catecholamines and metanephrines. The important parameters affecting MEPS performance, namely the type of sorbent material (porous graphitized carbon (PGC), polar enhanced polymer (PEP), cation-exchange (CX) and C18), number of extraction cycles, and elution solvent system, were evaluated. The optimal experimental conditions involved the loading of sample mixture in seven extraction cycles through a C18 sorbent in a MEPS syringe, followed by using elution solutions (water/acetonitrile/formic acid, 95/4.75/0.25). The entire sample preparation took about 4 min. Chromatographic separation was well achieved with an HSS PFP column using the gradient elution. The linearity range of the method was 0.167-33.4 ng/mL for epinephrine, 0.650-130 ng/mL for norepinephrine, 1.53-306 ng/mL for dopamine, 1.34-268 ng/mL for metanephrine, 3.43-686 ng/mL for normetanephrine, and 1.33-265 ng/mL for 3-methoxytyramine. The intra- and interassay precisions were ≤ 12.8%, and the respective accuracies were 88.4-112.0% and 89.0-109.5%. The carryover and sample stability without acidification were also investigated. Validation using clinical urine specimens showed that the proposed method had higher sensitivity compared with other urinary biochemical tests. The developed MEPS-LC-MS/MS method was simple, fast, and cost-effective; it helped to obtain information about multiple metabolites. It is applicable in routine clinical laboratories for the screening of PPGL. Graphical abstract.

Introduction: Pheochromocytoma is a tumour arising from the adrenal medulla, which secretes catecholamines. Approximately 20% of pheochromocytomas are cystic and more likely to be asymptomatic. They should be surgically resected as all have a malignant potential and pose cardiovascular risk. Case presentation: We report the case of a 61-year-old female patient admitted electively for laparoscopic adrenalectomy for a large cystic pheochromocytoma detected incidentally. Diagnosis was confirmed preoperatively by elevated 24-h urinary metanephrines. The patient was treated preoperatively with alpha and beta blockade. Surgery was without complication; she had an uneventful postoperative recovery and no evidence of recurrence at one-year follow-up., Conclusion: This case highlights the necessity of investigating for biochemical function in all adrenal lesions by measuring metanephrines, even when entirely cystic on imaging. Given the surgical and anaesthetic risk in resection of pheochromocytoma, attaining a preoperative diagnosis allows for careful preoperative planning and safe surgery.

Objective: Sympathoadrenal activity is decreased during overnight rest. This study assessed whether urinary-free normetanephrine, metanephrine and methoxytyramine in overnight/first-morning urine collections might offer an alternative to measurements in 24-h collections or plasma for diagnosis of pheochromocytoma and paraganglioma (PPGL)., Design and Methods: Prospective multicenter cross-sectional diagnostic study involving 706 patients tested for PPGL, in whom tumors were confirmed in 79 and excluded in 627 after follow-up. Another 335 age- and sex-matched volunteers were included for reference purposes. Catecholamines and their free O-methylated metabolites were measured in 24-h collections divided according to waking and sleeping hours and normalized to creatinine. Plasma metabolites from blood sampled after supine rest were measured for comparison., Results: Urinary outputs of norepinephrine, normetanephrine, epinephrine and metanephrine in the reference population were respectively 50 (48-52)%, 35 (32-37)%, 76 (74-78)% and 15 (12-17)% lower following overnight than daytime collections. Patients in whom PPGLs were excluded showed 28 (26-30)% and 6 (3-9)% day-to-night falls in normetanephrine and metanephrine, while patients with PPGLs showed no significant day-to-night falls in metabolites. Urinary methoxytyramine was consistently unchanged from day to night. According to receiver-operating characteristic curves, diagnostic accuracy of metabolite measurements in overnight/first-morning urine samples did not differ from measurements in 24-h urine collections, but was lower for both than for plasma. Using optimized reference intervals, diagnostic specificity was higher for overnight than daytime collections at similar sensitivities., Conclusions: Measurements of urinary-free catecholamine metabolites in first-morning/overnight urine collections offer an alternative for diagnosis of PPGL to 24-h collections but remain less accurate than plasma measurements.

Pheochromocytomas are rare neuroendocrine chromaffin-derived tumors that arise within the adrenal medulla. They are usually benign, but if not diagnosed or if left untreated, they can have devastating consequences. Clinical consideration of the diagnosis is paramount, as they may have protean manifestations, and a high index of suspicion is essential if serious consequences are to be avoided. An accurate biochemical diagnosis is crucial for the management of these patients: either plasma or urinary metanephrines are both highly sensitive and specific if correctly employed, but knowledge of pre- and post-analytic interference is essential. Diagnostic imaging with cross-sectional CT and/or MRI offers high sensitivity in their detection, but lack specificity. The introduction of PET/CT/MR has led to a dramatic improvement in the localization of both pheochromocytomas and paragangliomas, together with the increasing availability of new functional imaging radionuclides. Optimal investigation and accurate diagnosis is best achieved at 'centers of excellence' with expert multidisciplinary teams., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: Pheochromocytoma/Paraganglioma (PPGL) is a rare tumor with non-specific presentations overlapping common entities like anxiety, hypertension, acute illness and episodic "spells." Assessment of urine normetanephrine or metanephrine (UNM-UMN) in real-life, where PPGL is very rare and PPGL mimics extremely common, may show overlap in results with loss of specificity depending on the reference range. We determined the extent to which UNM-UMN are high in people undergoing screening for PPGL., Design and Methods: Retrospective review of all UNM-UMN performed in a central lab serving Southern Alberta over 8 years., Results: After excluding pediatric ages and patients with CKD, there were 12,572 unique patients with 14,383 measures of UNM-UMN. 85 patients (0.7%) had markedly high UNM-UMN compatible with likely PPGL. Depending on the age category (in decades), 10-22% of all UNM results were above the upper reference limit(URL), particularly between ages of 40-60. Less than 3% had elevations in both UNM and UMN. Of those with high UNM, 99% were less than 3-fold the URL. Based on the population data, a potential new reference range for UNM is suggested, which may be more appropriate to the types of patient who undergo this form of testing., Conclusions: There is an extraordinarily high prevalence of high UNM seen in real-life use of the test. However, the vast majority of high UNM are unlikely to be PPGL given the disease rarity and the massive number of tests ordered. This suggests the current laboratory URL may be too low (poor specificity) and/or the reference range may not be appropriate to the type of patient being screened for PPGL. Depending on the frequency of use of any screening test in a population, if the disease is rare and the specificity of the test is poor, a high rate of false positive results will be expected., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Although currently the primary strategy for the treatment of pheochromocytomas is surgery, it is associated with a high risk of intraoperative hemodynamic instability (IHD), even with adequate preoperative medical preparation, which may result in life-threatening situations. The aim of this study was to develop and validate a nomogram for preoperative prediction of IHD related to pheochromocytoma surgery. The development cohort consisted of 283 patients with pheochromocytoma who underwent unilateral laparoscopic or open adrenaletomy at our center between January 1, 2007 and December 31, 2016. The clinicopathological characteristics of each patient were recorded. The least absolute shrinkage and selection operator binary logistic regression model was used for data dimension reduction and feature selection, while multivariable logistic regression analysis was used to develop the prediction model. An independent cohort consisting of 119 consecutive patients from January 1, 2017 to December 31, 2018 was used for validation. The performance of the prediction model was assessed in regards to discrimination, calibration, and clinical usefulness. The predictors of this model included body mass index, coronary heart disease, tumor size, and preoperative use of crystal/colloid fluid. For the validation cohort, the model showed good discrimination with an area under the receiver operating characteristic of 0.767 (95% CI, 0.667-0.857) and good calibration (unreliability test, p = 0.852; Hosmer-Lemeshow test, p = 0.9309). Decision curve analysis demonstrated that the model was clinically useful. This nomogram to facilitate preoperative individualized prediction of IHD in patients with pheochromocytoma may help to improve the perioperative strategy and treatment outcome.

We recently conducted an open-label phase I/II study to evaluate the efficacy and safety of preoperative and chronic treatment with metyrosine (an inhibitor of catecholamine synthesis) in pheochromocytoma/paraganglioma (PPGL) in Japan. We compared creatinine-corrected metanephrine fractions in spot urine and 24-hour urine samples (the current standard for the screening and diagnosis of PPGLs) from 16 patients to assess the therapeutic effect of metyrosine. Percent changes from baseline in urinary metanephrine (uMN) or normetanephrine (uNMN) were compared between spot and 24-hour urine samples. Mean percent changes in uMN or uNMN in spot and 24-hour urine were -26.36% and -29.27%, respectively. The difference in the percent change from baseline between uMN or uNMN in spot and 24-hour urine was small (-2.90%). The correlation coefficient was 0.87 for percent changes from baseline between uMN or uNMN measured in spot and 24-hour urine. The area under the receiver operator characteristic (ROC) curve of uMN or uNMN measured in spot urine vs. 24-hour urine (reference standard) to assess the efficacy of metyrosine treatment was 0.93. Correlations and ROCs between 24-hour urinary vanillylmandelic acid, adrenaline, and noradrenaline and 24-hour uMN or uNMN were similar to those between spot uMN or uNMN and 24-hour uMN or uNMN. No large difference was observed between spot and 24-hour urine for the assessment of metyrosine treatment by quantifying uMN or uNMN in Japanese patients with PPGLs. These results suggest that spot urine samples may be useful in assessing the therapeutic effect of metyrosine.

The diagnostic utility of different thresholds of elevated urinary fractionated metanephrine (UFM) for pheochromocytoma-paraganglioma (PPGL) was evaluated in 10 164 community-dwelling subjects (2012-2017). Levels were ≥1.5× the upper normal limit (UNL) in 276 subjects (2.7%) and ≥2×UNL in 138 (1.4%). PPGL was subsequently diagnosed in 59 (mean age 51.9 ± 14.3, 64% female); 58 (98.3%) with UFM ≥ 2×UNL. Positive predictive values (PPV) were 42% for UFM ≥ 2×UNL, 55% for UFM ≥ 2.5×UNL, and 69% for UFM ≥ 3×UNL. The main reason for PPGL screening (52.5%) was adrenal incidentaloma. Mean (median) metanephrine/normetanephrine levels were 6.7 ± 9×UNL (3 × UNL) and 6.1 ± 8.9×UNL (2.5 × UNL). Six patients (10.2%) had an extra-adrenal tumor (one malignant paraganglioma); one had bilateral pheochromocytoma. Only one patient presented with the "classic triad" (headache, palpitations, sweating). In conclusion, after excluding obvious reasons for false-positive results, thorough diagnostic assessment for PPGL is justified in all subjects with UFM ≥ ×2UNL. The PPV of milder UFM elevations is very low., (©2019 Wiley Periodicals, Inc.)

Pheochromocytoma during pregnancy, although rare, is a perilous condition. The wellbeing of mother and fetus are at stake if not diagnosed and treated antenatally and timely. The diagnosis is frequently overlooked because of the aspecific nature of signs and symptoms and confusion with pregnancy-related hypertension. Measurements of plasma or urinary free metanephrines have the highest diagnostic accuracy. MRI is preferred over ultrasonography. The optimal time for surgical removal is before 24 weeks of gestation or at/after delivery. Laparoscopic adrenalectomy should be preceded by medical pretreatment. Cesarean delivery is preferred in these patients; vaginal delivery might be considered in selected pretreated patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The effects of catecholamine excess due to pheochromocytoma on body composition, including skeletal muscle mass, are unknown. Here, we investigated the effects of catecholamine metabolites on body composition in subjects with pheochromocytoma. After body compositions using bioelectrical impedance analysis, urinary metanephrine (UM), and urinary normetanephrine (UNM) were measured in 16 patients with pheochromocytoma and 224 patients with nonfunctioning adrenal incidentaloma (NFAI), we compared skeletal muscle mass and fat mass (FM) between the two groups. After adjustments for confounders, UM (β = - 0.171, P = 0.006) and UNM (β = - 0.249, P < 0.001) levels were correlated inversely with skeletal muscle mass index (SMI), but not FM or percentage FM (pFM), in all subjects. Patients with pheochromocytoma had lower ASM by 7.7% (P = 0.022) and SMI by 6.6% (P = 0.001) than patients with NFAI. Conversely, FM and pFM were not statistically different between the two groups. The odds ratio for low skeletal muscle mass in the presence of pheochromocytoma was 10.33 (95% confidence interval, 2.65-40.22). Our results indicate that patients with pheochromocytoma have a reduced skeletal muscle mass and suggest that catecholamine excess has adverse effects on skeletal muscle metabolism.

Compared with the general population, rates of pheochromocytoma are higher in neurofibromatosis type 1 (NF1) patients. However, pheochromocytoma testing is often plagued by false positive results. Here we present a patient with NF1, elevated urinary metanephrine levels, and an indeterminate adrenal nodule. Clonidine suppression testing aided diagnosis and led to definitive surgical treatment that confirmed a pheochromocytoma. Pheochromocytoma screening and clonidine suppression testing can both aid in the evaluation for catecholamine-secreting tumours., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Pheochromocytoma and paraganglioma are uncommon tumors whose best known symptoms include high blood pressure, palpitations, headache, and sweating. Clinical identification is not easy, however, and requires biochemical tests that allow for early diagnosis, including measurement of metanephrines levels. The aim of this study was to assess the diagnostic performance of plasma free metanephrines (PMETs) and to verify the transferability of the reference values used., Methods: PMETs levels were measured by liquid chromatography coupled to tandem mass spectrometry. Other biochemical tests evaluated (plasma catecholamine, urine metanephrine, catecholamine and vanilmandelic acid levels) were performed by liquid chromatography with electrochemical detection. Requests of these tests from 01/09/2015 to 31/10/2017 were reviewed, and both the reference values (document EP28-A3c) and the parameters of biological variation (Fraser method) for PMETs were estimated., Results: The study sample consisted of 1,279 patients (61.3% females) aged 0-90 years, including 19 with pheochromocytoma/paraganglioma. Tests requested included: PMETs (n=662), catecholamines (n=589), metanephrines (n=586), and vanilmandelic acid (n=513) in urine, and plasma catecholamines (n=228). Tests with higher sensitivity were urinary fractionated metanephrines (91.7%) and PMETs (82.4%). When performance was compared in patients with both tests (n=243), they detected the same number of tumors (90.9%), but PMETs showed greater specificity (93.5% vs 88.8%). Plasma normetanephrine levels showed a significant association with age (rho=0.19, P<.0001)., Conclusion: PMETs and urinary fractionated metanephrines are the biochemical tests with better performance in diagnosis of pheochromocytomas/paragangliomas., (Copyright © 2018 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Pheochromocytoma is a rare neuroendocrine tumor, clinically characterized by high blood pressure, palpitations, and headache. It is often associated with abnormalities of the ventricular repolarization phase; the dispersion of ventricular repolarization is the basis for ventricular arrhythmias (torsion de point, ventricular tachycardia or ventricular fibrillation)., Objectives: Analysis of abnormal ventricular repolarization focused on the presence and amount of U wave in patients affected by pheochromocytoma and its modification after surgery., Materials and Methods: We reviewed pathology records of 722 patients admitted for adrenal nodule or suspected chromaffin-cell tumor and identified 39 patients affected by pheochromocytoma. Metanephrine, normetanephrine, and 3-methoxytyramine have been assessed by determining concentrations in 24-hour urine collection. Standard 12-lead electrocardiogram records have been reviewed with analysis of heart rate, P wave, PR interval, QRS duration, QTc, and U wave. Then we selected and compared 22 patients of 39 affected by pheochromocytoma, with both clinical and electrocardiographic data before and after surgery., Results: In our cohort of 39 patients affected by pheochromocytoma, we found U wave in ECG, before treatment, in 82.8 percent of patients, while only 37.0 percent after treatment (p<0.001) and we observed a statistically significant correlation between this wave and the urinary metanephrine. After surgery, in the selected 22 patients, we observed a clear significant reduction in systemic blood pressure, fasting glucose, metanephrine, normetanephrine, and 3-methoxytyramine. We found a significant reduction of U wave presence and leads involved in these patients after surgery (90.9% versus 9%). We observed a linear correlation between the amount of U waves in 12-lead electrocardiogram and metanephrine (r 2 =0.333, p=0.015), 3-methoxytyramine levels (r 2 =0.458, p=0.006), and tumor size (r 2 =0.429, p=0.003)., Conclusions: In our retrospective analysis, patients affected by pheochromocytoma presented U wave in electrocardiogram. The presence and amount of U wave were associated with the metanephrine levels and the tumor size with significant reduction after surgical removal.

Glucose intolerance is often observed in patients with pheochromocytoma. However, it remains controversial issue that glucose intolerance on pheochromocytoma is caused by impaired insulin secretion and/or by increased insulin resistance. We aimed to reveal the mechanism of glucose intolerance on pheochromocytoma with regard to the type and amount of catecholamines released. We evaluated 12 individuals diagnosed with pheochromocytoma and who underwent surgery to remove it. We examined glycemic parameters before and after surgery and investigated the association between the change of parameters of insulin secretion (homeostasis model assessment of β-cell function (HOMA-β)), insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR)) and that of urinary levels of metanephrine/normetanephrine before and after surgery. Overall, fasting plasma glucose, glycated hemoglobin (HbA1c), HOMA-β, and HOMA-IR were improved significantly after surgery. Regression analysis showed that the improvement in HOMA-β from before to after surgery was significantly positively associated with an improvement in urinary levels of metanephrine from before to after surgery and showed a significantly negative association with improvement in urinary levels of normetanephrine from before to after surgery. The improvement in HOMA-IR from before to after surgery was significantly positively associated with an improvement in urinary levels of normetanephrine from before to after surgery. Our results showed that pheochromocytoma extirpation improved glycemic parameters. Furthermore, the different effects elicited by excess amounts of adrenaline and noradrenaline on glucose intolerance were demonstrated.

Background Plasma-free metanephrines (PFM) or urinary fractionated metanephrines (UFM) are the preferred biochemical tests for the diagnosis of phaeochromocytoma and paraganglioma (PPGL). Borderline increased results should be followed up to either exclude or confirm diagnosis. Methods We extracted all PFM and UFM results reported by our laboratory over a six-month period from the laboratory information system. We categorized patients with borderline increased results according to whether follow-up testing had been performed as suggested in the initial laboratory report. Questionnaires were then sent to all requesting doctors and medical notes reviewed where available. Results Two hundred and four patients with borderline increased PFM or UFM were identified. Sixty-five (38.5%) of 169 patients with borderline increased PFM had a repeat test out of which 36 were normal and 29 did not normalize. Of 35 patients with borderline increased UFM, 17 (48.6%) had subsequent PFM measurement, out of which 15 were normal. Questionnaires were returned to 106 (52%) patients. Of these, the most frequent indication for testing was hypertension ( n = 50); 15 patients had an incidental adrenal mass and two of these patients were diagnosed with a phaeochromocytoma. Conclusion Only 38% of patients with borderline increased PFM had a repeat PFM measurement. This was not significantly higher when compared with the 28% in a previous audit that we reported in 2010 ( P = 0.10). Forty-nine per cent of patients with a borderline increased UFM had a repeat UFM or PFM measurement. There remains a substantial possibility of missed detection of PPGL.

Pheochromocytoma and paraganglioma are neuroendocrine tumors characterized by a catecholamine production potential. The biochemical diagnosis for this type of tumor is carried out through the metanephrine titration on 24-hours urines. Some authors have suggested that the sensitivity of the test could be improved by sampling and analyzing urines 3 days in a row (cycle) versus a unique measurement but this method has never been fully evaluated. The goal of this study was to establish a comparison of diagnosis performances between urinary metanephrines measurement for 3 consecutive days, and metanephrines measurement on a unique 24-hour sample. Patients of Brest Regional University Hospital whose 3-consecutive day 24-hour urine samples had been analyzed from January 2011 to May 2017 were included in this study. The primary endpoint was the comparison of diagnostic performances of urinary metanephrine titration over a single day versus 3 consecutive days. Eighty-two patients for a total of 103 cycles among which 7 revealed a pheochromocytoma were analyzed. ROC curve analysis shows that the metanephrine cycle titration method is more efficient than the metanephrine single titration method (metanephrine: AUC=0.881 against 0.826 respectively; normetanephrine: AUC=0.946 against 0.901 respectively). Urinary titration over 3 days allows the diagnosis of 100% (7/7) of pheochromocytomas against 85.7% (6/7) for the the single urinary titration. In conclusion, metanephrine titration over 3 consecutive days of 24-hours urine samples shows a better sensitivity and better diagnosis performances for detecting pheochromocytoma and paraganglioma than the single titration method.

Background: The metanephrines (MNs) in plasma and urine were proposed as biomarkers for the diagnosis of pheochromocytomas and paragangliomas (PPGLs). However, plasma free MNs and 24h urinary fractionated MNs were not satisfactory enough in specificity for the diagnosis of PPGLs. Moreover, the collection of 24h urine was inconvenient. This work examined the diagnostic and prognostic efficiency of free MNs in spot urine for PPGLs., Methods: We measured free MNs concentration in spot urine and plasma of 28 PPGLs patients and 155 control subjects by HPLC with electrochemical detection. Postoperative free MNs levels in spot urine and plasma of 14 PPGLs patients were also determined. Creatinine (Cr) concentration was used for the correction of urine volume., Results: The specificity of spot urinary free MNs/Cr in the diagnosis of PPGLs was significantly higher than that of plasma free MNs [normetanephrine (NMN), 98.7% (95.4%-99.8%) vs 93.0% (87.4%-96.6%); metanephrine (MN), 93.6% (88.5%-96.9%) vs 84.5% (77.5%-90.0%)]. Meanwhile, the positive likelihood ratios for spot urinary free NMN/Cr and MN/Cr were 69.21 and 13.29, compared with 12.68 and 5.30 for plasma free NMN and MN, respectively. For the PPGLs patients underwent surgery, the plasma free MNs level appeared an abnormal elevation and yielded false-positive results for some patients. Our findings were validated in an independent cohort, resulting in the specificity of 100% for both urinary free NMN/Cr and MN/Cr, and 97.3% and 83.8% for plasma free NMN and MN, respectively., Conclusions: Spot urinary free MNs/Cr, superior to plasma free MNs, presented a promising biomarker for the diagnosis and prognosis of PPGLs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Our objective was to improve molecular diagnostics in patients with hereditary pheochromocytoma and paraganglioma (PPGL) by using next-generation sequencing (NGS) multi-gene panel analysis. Derived from this study, we here present three cases that were diagnosed with NF1 germline mutations but did not have a prior clinical diagnosis of neurofibromatosis type 1 (NF1)., Design: We performed genetic analysis of known tumor predisposition genes, including NF1 , using a multi-gene NGS enrichment-based panel applied to a total of 1029 PPGL patients. We did not exclude genes known to cause clinically defined syndromes such as NF1 based on missing phenotypic expression as is commonly practiced., Methods: Genetic analysis was performed using NGS (TruSight Cancer Panel/customized panel by Illumina) for analyzing patients' blood and tumor samples. Validation was carried out by Sanger sequencing., Results: Within our cohort, three patients, who were identified to carry pathogenic NF1 germline mutations, attracted attention, since none of the patients had a clinical suspicion of NF1 and one of them was initially suspected to have MEN2A syndrome due to co-occurrence of a medullary thyroid carcinoma. In these cases, one splice site, one stop and one frameshift mutation in NF1 were identified., Conclusions: Since phenotypical presentation of NF1 is highly variable, we suggest analysis of the NF1 gene also in PPGL patients who do not meet diagnostic NF1 criteria. Co-occurrence of medullary thyroid carcinoma and PPGL was found to be a clinical decoy in NF1 diagnostics. These observations underline the value of multi-gene panel NGS for PPGL patients., (© 2018 European Society of Endocrinology.)

The measurement of urine catecholamine and metanephrine concentrations is important for biochemical screening and diagnosis of pheochromocytoma. The goal of this work was to develop a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining catecholamines and metanephrines in urine to replace an existing liquid chromatographic method using electrochemical detection. Urine samples were prepared using Oasis weak-cation-exchange cartridges. The eluate was analyzed on an Agilent ZORBAX Eclipse Plus Phenyl-Hexyl column in 3 min. Adrenaline, noradrenaline, dopamine, metanephrine, normetanephrine, and their deuterated internal standards were monitored in positive electrospray ionization mode by multiple reaction monitoring (MRM). No evidence of ion suppression was observed. The assay was linear up to 5μmol/L for adrenaline, 5μmol/L for noradrenaline, 6.1μmol/L for dopamine, 5.6μmol/L for metanephrine, and 34.6μmol/L for normetanephrine, with lower limits of quantification of 5, 5, 12, 6 and 7 nmol/L, respectively. The intra-day and inter-day precisions for all analytes ranged from 0.59% to 4.64% and 1.98% to 4.80%, respectively. External quality assurance samples were assayed and showed excellent agreement with the target values. This simple method provides an improved assay for determining urine catecholamines and metanephrines.

Metanephrines (MNs) were suggested as a potential first-line biochemical index for the diagnosis of phaeochromocytomas (PHEO). In this study, we developed a simple electrochemical method for the quantitative measurement of MNs in spot urine samples. As MNs contain a hydroxyphenyl group, they could be oxidized at a certain potential to quinines, which could be further detected by the differential pulse voltammetry (DPV) method using unmodified screen-printed carbon electrode (SPCE). Meanwhile, the solid phase extraction (SPE) technique was used to eliminate the matrix effect in the samples. Consequently, free MNs from the extracted urine sample were screened in a linear range from 0.25 mg/L to 12.5 mg/L. The lowest limit of quantification (LLOQ) for MNs was 0.25 mg/L and the limit of detection (LOD) was 0.05 mg/L. Both the precisions and recoveries were sufficient for clinical applications. The urine samples from 22 patients with PHEO and 63 controls were analyzed by the proposed method. The area under the ROC curve was 0.981 (95% CI, 0.958-1.000) with the sensitivity of 95.5% and the specificity of 92.4% at the cut-off value of 0.404 mg/L in these urine samples. Overall, the proposed method provides a cost-effective, rapid and simple tool for clinical diagnosis of PHEO.

Objective: Pentraxin 3 (PTX3) is an acute-phase glycoprotein, which is increased in patients with cardiovascular disease (CVD) and considered as a predictor of CVD in the general population. Both functional and nonfunctional adrenal tumors are associated with a higher risk of cardiovascular events and mortality. We aimed to investigate plasma PTX3 levels in patients with functioning and nonfunctioning adrenal tumors and determine its relationship with cardiovascular risk factors., Methods: Twenty-one patients with functional adrenal tumors (11 pheochromocytomas, 9 Cushing syndrome, and 1 primary hyperaldosteronism), 28 patients with nonfunctional adrenal incidentalomas, and 40 healthy controls were enrolled in the study. Serum PTX3 levels were measured using a human PTX3 enzyme-linked immunosorbent assay., Results: PTX3 concentrations were significantly higher in the adrenal tumor group compared with the control group (3,001.64 ± 374.64 pg/mL vs. 1,173.59 ± 168.89 pg/mL; P<.001). PTX3 concentrations were positively correlated with carotid intima media thickness (CIMT) (r 2 , 0.464; P<.001), high-sensitivity C-reactive protein (hsCRP) (r 2 , 0.551; P<.001), diastolic blood pressure (r 2 , 0.334; P = .003), systolic blood pressure (r 2 , 0.312; P = .006), and urinary metanephrine concentrations (r 2 , 0.320; P = .041). Serum PTX3 concentrations in patients with functional adrenal tumors and comorbidities including hypertension, diabetes mellitus, or CVD were higher than in those without comorbidities (3,654.54 ± 447 pg/mL vs. 1,026.96 ± 447.97 pg/mL; P = .008)., Conclusion: We found that serum PTX3 concentrations increased in both functional and nonfunctional adrenal tumors. PTX3 levels were correlated with cardiovascular risk factors such as CIMT, hsCRP, and blood pressure., Abbreviations: BMI = body mass index; CIMT = carotid intima-media thickness; CRP = C-reactive protein; CT = computed tomography; CVD = cardiovascular disease; FGF2 = fibroblast growth factor 2; hsCRP = high-sensitivity C-reactive protein; PA = primary hyperaldosteronism; PTX3 = pentraxin 3.