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Background: Moderately elevated plasma normetanephrine (NMN) levels are frequent among patients with suspected pheochromocytoma and paraganglioma (PPGL). Clonidine suppression testing (CST) is recommended to distinguish patients with from those without PPGL. We aimed at evaluating the diagnostic outcome of CST in patients with moderate NMN elevations. Methods: Data from patients participating in the PMT study (Prospective Monoamine-Producing Tumor) and the ENSAT (European Network for the Study of Adrenal Tumours) registry in 6 European reference centers were analyzed retrospectively. Eighty-nine patients with suspected PPGL and moderate NMN elevations upon screening were included. During follow-up, PPGL was confirmed in 16 and excluded in 73 cases. Plasma NMN was measured by liquid chromatography tandem mass spectrometry before and 180 minutes after oral clonidine. Receiver operating characteristic analysis was performed to identify optimal cutoffs. Results: If published diagnostic criteria for CST (ie, NMN ≥112 ng/L and NMN suppression Conclusions: This study, involving one of the largest cohorts of patients with suspected PPGL and moderately elevated NMN, confirmed the diagnostic accuracy of CST. The application of an adapted cutoff further improved sensitivity.

OBJECTIVE To compare clinical, biochemical, tumoural and mutational characteristics of Von Hippel Lindau Syndrome (VHL)-associated pheochromocytoma (PCC) to multiple endocrine neoplasia 2A (MEN2A)-associated pheochromocytoma. DESIGN Retrospective study design in a tertiary health care centre in Northern India. METHODS A total of 47 patients with biochemical and histologically proven pheochromocytoma/paraganglioma (PCC/PGL): 29 associated with VHL and 18 with MEN2A, were divided in two cohorts, respectively. Analysis of their medical records along with a prospective follow-up was done. RESULTS There were more children

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

Acne vulgaris, a chronic inflammatory skin disease, has been associated with not only sebaceous gland dysfunction but also various endogenous and exogenous stresses. Since sebaceous glands are under neuroendocrine control, including the hypothalamic-pituitary-adrenal axis and neuro-autocrine mechanisms, it remains unclear how psychological stress relates to the pathogenesis of acne. In this study, we investigated the relationship between psychological stress and catecholamine in acne lesions from 18 patients with mild or moderate acne. The State-Trait Anxiety Inventory (STAI) revealed that all patients were anxious, with six having low anxiety and 12 high anxiety. Salivary α-amylase activity (sAA), which is regulated by the sympatho-adrenal medullary (SAM) system, positively correlated with the STAI State Anxiety scores (STAI-S) and was significantly detectable in acne patients with high rather than low anxiety. In addition, the level of normetanephrine, but not metanephrine, both of which are catecholamine metabolites, in hair follicles of acne lesions also positively correlated with the STAI-S. Furthermore, the normetanephrine level was higher in patients with high rather than low anxiety, whereas there was no change in metanephrine in the hair follicles of the acne lesions. Moreover, neither the sAA nor metanephrine and normetanephrine in the acne lesions was related to acne severity in the patients. Thus, these results provide novel evidence that a SAM system-associated increase of normetanephrine level in hair follicles is involved in the acne pathology of patients with anxiety.

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 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 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

Objective Despite the significant morbidity and mortality associated with pheochromocytoma and paraganglioma, little is known about their epidemiology. The primary objective was to determine the incidence of pheochromocytoma and paraganglioma in an ethnically diverse population. A secondary objective was to develop and validate algorithms for case detection using laboratory and administrative data. Design Population-based cohort study in Alberta, Canada from 2012 to 2019. Methods Patients with pheochromocytoma or paraganglioma were identified using linked administrative databases and clinical records. Annual incidence rates per 100 000 people were calculated and stratified according to age and sex. Algorithms to identify pheochromocytoma and paraganglioma, based on laboratory and administrative data, were evaluated. Results A total of 239 patients with pheochromocytoma or paraganglioma (collectively with 251 tumors) were identified from a population of 5 196 368 people over a period of 7 years. The overall incidence of pheochromocytoma or paraganglioma was 0.66 cases per 100 000 people per year. The frequency of pheochromocytoma and paraganglioma increased with age and was highest in individuals aged 60–79 years (8.85 and 14.68 cases per 100 000 people per year for males and females, respectively). An algorithm based on laboratory data (metanephrine >two-fold or normetanephrine >three-fold higher than the upper limit of normal) closely approximated the true frequency of pheochromocytoma and paraganglioma with an estimated incidence of 0.54 cases per 100 000 people per year. Conslusion The incidence of pheochromocytoma and paraganglioma in an unselected population of western Canada was unexpectedly higher than rates reported from other areas of the world.

Borderline isolated norepinephrine (NE) and normetanephrine (NMT) elevation is common among patients with suspected pheochromocytoma and paraganglioma (PPGL). The clonidine suppression test (CST) may help establish the etiology in these cases. Prolonged laboratory processing and/or paucity of reliable biochemical assays may limit the utility of CST. The aim of this study was to evaluate whether blood pressure (BP) reduction during CST is associated with alterations in plasma NMT/NE, thereby potentially providing an immediate indication of CST results. In this cross-sectional study, the authors included all consecutive patients with suspected PPGL who underwent CST from January 1, 2014, to December 31, 2019. Linear regression models were conducted to evaluate the association between BP reduction and decrease in plasma NMT/NE. The final analysis included 36 patients (17 males). The decrease in systolic BP (SBP) 90 minutes postclonidine was associated with a decrease in plasma NMT (R = 0.668, P = .025) and NE (R = 0.562, P = .005). A 40% decrease in NMT and NE correlated with a 9.74% and 7.16% decrease in SBP, respectively. Subgroup analyses demonstrated that the association between SBP reduction and the decrease in plasma NMT (R = 0.764, P = .046) and NE (R = 0.714, P = .003) strengthens among patients with hypertension and among those with diabetes mellitus (R = 0.974, P = .026 for NMT). In conclusion, SBP reduction during CST is associated with plasma NMT and NE decrease. Therefore, the decrease in SBP 90 minutes postclonidine may serve as an immediate complementary clinical tool for PPGL diagnosis.

Introduction: 177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) is a promising therapy for metastatic and/or inoperable pheochromocytoma and paraganglioma (PPGL). We aim to evaluate the efficacy and safety of and identify predictors of response to 177Lu-DOTATATE therapy in metastatic and/or inoperable PPGL. Methods: This retrospective study involved 15 patients of metastatic or unresectable PPGL, who received 177Lu-DOTATATE PRRT therapy. Clinical, biochemical (plasma-free normetanephrine), and radiological (anatomical and functional) responses were compared before and after the last therapy. Results: A total of 15 patients (4 PCC, 4 sPGL, 5 HNPGL, 1 PCC + sPGL, 1 HNPGL + sPGL) were included. The median duration of follow up was 27 (range: 11–62) months from the start of PRRT. Based on the RECIST (1.1) criteria, progressive disease was seen in three (20%), stable disease in eight (53%), partial response in one (7%), and minor response in three (20%) and controlled disease in 12 (80%). On linear regression analysis the presence of PGL (P= 0.044) and baseline SUVmax >21 (P < 0.0001) were significant positive predictors of early response to PRRT. Encouraging safety profiles were noted with no long term nephrotoxicity and hematotoxicity. Conclusion: 177Lu-DOTATATE therapy is an effective and safe modality of treatment for patients with metastatic/inoperable PPGL. Although it is not prudent to withhold PRRT in metastatic PPGL with baseline SUVmax < 21, baseline SUVmax >21 can be used to predict early response to PRRT.

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 40-year-old woman presented with a left adrenal incidentaloma. Based on the presence of café-au-lait spots, cutaneous neurofibroma, and family history, she was diagnosed with neurofibromatosis type 1 (NF1). Adrenal incidentaloma screening showed an elevated normetanephrine level; the left adrenal mass showed the uptake of I-123 meta-iodobenzylguanidine. She underwent left adrenalectomy, and pheochromocytoma was diagnosed. One year later, the results of a biopsy of a palpable mass in the left breast suggested invasive ductal carcinoma. The patient underwent neoadjuvant chemotherapy followed by left breast-conserving surgery. We herein report a rare case of an NF1 patient who developed both pheochromocytoma and breast cancer.

Background Takotsubo-like cardiomyopathy associated with pheochromocytoma (Pheo-TTS) is a recognized but uncommon disorder. While Pheo-TTS might more often recur and the pattern of left ventricular (LV) wall motion abnormality is more diverse compared with primary TTS, it remains to be elucidated whether coronary functional abnormalities are also involved. Case summary A 50-year-old woman was referred with a chief complaint of transient chest pain, dyspnoea, and paroxysmal thyroid swelling that usually developed after meals. In the past, she had been admitted to emergency rooms three times due to pulmonary oedema following the above attacks. Serial cardiac catheterizations showed normal coronary arteries and morphologically different types of LV dysfunction each time; apical LV ballooning at the first, basal LV ballooning at the second, and diffuse LV hypokinesis at the last admission. Acetylcholine (ACh) provocation testing for coronary vasospasm was negative at the second admission. During hospitalization in our department, abdominal ultrasonography for screening detected a right adrenal mass and the urinary normetanephrine level was increased. The adrenal tumour was urgently removed surgically and finally she was diagnosed as having norepinephrine-secreting pheochromocytoma. Acetylcholine testing was again performed just after the operation, showing both epicardial and microvascular coronary spasms. Since the operation, she has been free of symptoms. Importantly, ACh testing at 1-year follow-up showed that epicardial spasm was no longer noted, whereas coronary microvascular spasm persisted. Discussion Adrenal pheochromocytoma could cause recurrent attacks of catecholamine surges with different patterns of LV dysfunction, where coronary vasospasm may also be involved along the coronary arteries.

OBJECTIVE A 24-hour urine nor/metanephrine (urine NM-MN) measurements are a recommended first step in pheochromocytoma diagnosis. We hypothesized the presence of renal impairment (CKD) significantly confounds the results obtained in a urine NM-MN collection, giving artificially lower measurements. DESIGN Retrospective review of a comprehensive laboratory database with all urine NM-MN results from Southern Alberta from 2010 to 2018 (n = 15 505). After excluding high probability pheochromocytoma cases, results from patients with three levels of CKD (n = 796) were compared to those without CKD to determine the potential CKD effect. PATIENTS All patients having urine NM-MN collection during the time period, irrespective of ordering physician or test indication. MEASUREMENTS Urine NM-MN was measured by liquid chromatography-tandem mass spectrometry and glomerular filtration rate determined within a median of 1.9 days, as estimated by CKD-EPI equation. RESULTS In subjects with mild-to-moderate renal impairment, there was no continuous gradient between subnormal renal function and urine NM-MN measures. When the estimated GFR was

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.

Background Neuroblastoma is a common solid tumor of childhood and is often associated with hypertension. Potential etiologies contributing to hypertension include renal compression, pain, volume overload, and catecholamine secretion. Cases We completed a single center retrospective review of children with neuroblastoma and ≥stage II hypertension (per Hypertension Canada guidelines) over a 2-year period. All patients (n = 10) had elevated urine normetanephrine levels and eight had intra-abdominal tumors. Four patients had refractory hypertension requiring > three agents, of which three required alpha/beta blockade. Conclusion Although multifactorial, hypertension in neuroblastoma often has a neuroendocrine component. Excess normetanephrine production in neuroblastoma may be a more common hypertensive mechanism than previously appreciated. Urinary normetanephrine elevation could suggest potential neuroendocrine-mediated hypertension.

Objective Measurements of plasma free metanephrines (MNs), including MN and normetanephrine, provide high sensitivity and specificity for the diagnosis of pheochromocytoma and paraganglioma (PPGL). 3-Methoxytyramine (3-MT) and chromogranin A (CgA) may allow the detection of dopamine-producing or biochemically silent PPGL. The aim of this study was to evaluate whether measurements of plasma 3-MT or CgA as a supplement of plasma MNs offer a better diagnostic strategy for initial testing of PPGL. Patients and design We enroled 125 patients who underwent surgery from 2015 to 2016 for our study and identified 33 patients with PPGL and 92 patients with non-PPGL masses. Measurement The levels of plasma free MNs and 3-MT were measured for all 125 patients using liquid chromatography-tandem mass spectrometry. Plasma CgA concentrations were determined using a radioimmunoassay. To evaluate the diagnostic performance of plasma free MNs, 3-MT and CgA, sensitivity and specificity were determined, and receiver operating characteristic curves were constructed. Results We found that combining 3-MT and MNs increased the diagnostic sensitivity from 93.9% (95% confidence interval [CI]: 78.4%-98.9%) to 97.0% (95% CI: 82.5%-99.8%). In contrast, addition of plasma CgA test reduced the diagnostic specificity significantly from 91.3% (95% CI: 83.1%-95.9%) to 75.0% (95% CI: 64.7%-83.2%). Conclusion Here, we demonstrated that 3-MT represents a valuable supplementary test to plasma MNs, which can further enhance the sensitivity of the assay, while plasma CgA added no additional diagnostic value to MNs due to the lowered diagnostic specificity.

Background Pheochromocytomas (PCCs) and paragangliomas (PGLs) are known to physicians as the “great mimickers” because of their variable presentation, especially in the pediatric population. Rarely, they co-secrete other hormones. Case presentation An 11-year-old boy presented with severe hypertension (HTN) with cardiac target organ damage. Signs of genital and cutaneous androgenization were observed, but the gonadal volume was prepubertal (2 mL). Urine normetanephrine and norepinephrine levels were elevated. Increased beta-human chorionic gonadotropin (β-HCG) and pubertal testosterone values with suppressed values of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) suggested an androgenization secondary to HCG hyperproduction. Imaging revealed a right adrenal mass, suggestive for PCC. Histopathology confirmed a PCC with positive staining for β-HCG. Postoperative resolution of symptoms of β-HCG and catecholamine excess and normalization of hormonal levels confirmed the diagnosis. Conclusions Ectopic hormone secretion from PCC is possible, even if rare. Signs and symptoms attributable to ectopic hormones should be investigated in PCC patients. To date, this is the first case of a β-HCG-secreting PCC.

Pheochromocytoma is a tumor of chromaffin tissue that produces a large amount of biologically active substances (adrenaline, noradrenaline, dopamine), clinically manifested by hypertension and various metabolic disorders. Quite often the diagnosis is made only after autopsy. One of the reasons for late diagnosis is a great number of different clinical masks of the disease. Usually pheochromocytoma is suspected in patients with paroxysmal hypertension. We present a 37-year-old pregnant female (week 8 of pregnancy) with pheochromocytoma and permanent hypertension and sustained elevation of blood pressure up to 220/150 mm Hg. Her only complaint was vision disorder that started 3 months ago. Also, she noted a weight loss of 4 kg over the last 6 months. Retinopathy, left ventricle hypertrophy, tumor of right adrenal gland and glucose level disorders were revealed. Pregnancy was terminated for medical reasons. The patient took combination of doxazosin 0.4 mg, metoprolol 100 mg and moxonidin 0.4 mg per day and blood pressure was normalized to 130/90 mm Hg. Due to hypertension and tumor of right adrenal gland that are accompanied by retinopathy and metabolic disorders, pheochromocytoma was suspected. Contrast-enhanced computed tomography confirmed the tumor (60×73×70 mm) of right adrenal gland. Urinary normetanephrine level was 5.5 times higher than the norm. Magnetic resonance angiography of cerebral vessels was done because of malignant hypertension and family history (the patient’s sister had died of cerebral hemorrhage). Fusiform aneurysm of right internal carotid artery was revealed. The patient underwent laparoscopic resection of right adrenal gland. Histologic examination: pronounced cellular and nuclear polymorphism, invasion of tumor cells into a fibrous capsule, which does not exclude the malignant nature of pheochromocytoma. Follow-up period lasted for 8 months and was characterized by normalization of blood pressure, glucose level and weight gain of 3.5 kg. Computed tomography of retroperitoneal space and normal urinary metanephrine tests revealed no recurrent pheochromocytoma.

Several confounders must be considered in the evaluation of urinary catecholamine excretion. However, literature is contradictory about potential confounders. The aim of the present study was to assess correlations between catecholamine excretion and anthropometric or clinical parameters with special attention to urine volume. A total of 967 24-h urinary catecholamine measurements were performed in 593 patients for diagnostic purposes. The indication for urine examination was suspicion of secondary hypertension, phaeochromocytoma, or paraganglioma. From the patients examined, 57% were females and 43% were males. The patients’ age ranged between 15 and 87 years with a median [Q1; Q3] of 51 [39; 62] years. Seventy-eight percent of the patients suffered from hypertension. Seventy percent of patients took one or more antihypertensive drugs. The most commonly used drugs were ACE inhibitors (43%), while α-blockers (15%) were the least used drugs. Urinary excretion was between 500 and 11 950 ml/24 h with a median of 2200 [1600; 2685] ml/24 h. The median body mass index (BMI) was 26.7 [24.0; 30.4] kg/m2. The excretion of all catecholamines was greater in men than in women (all p

Thyroid hormones can affect the cardiovascular system directly by binding to nuclear thyroid receptors, as well as indirectly by changing the neuro – humoral status of the body as a whole. The aim of the work was to assess the effect of levothyroxine suppressive therapy on the regulation of the heart rate and activity of the sympathoadrenal system, as well as the level of cortisol in the blood of young patients with thyroid cancer. It is shown that the effect of suppressive therapy with levothyroxine on the state of the cardiovascular system is manifested in an increase in the risk of tachycardia and changes in heart rate variability associated with the body mass index. Patients with thyroid cancer had a sharp decrease in normetanephrine (norepinephrine metabolite) in the urine. The levels of metanephrine (metabolite of adrenaline) and dopamine in the urine was dependent on the tonus of the autonomic nervous system and blood pressure. The revealed shifts indicate that against the background of subclinical hyperthyroidism, the mechanisms aimed at stabilizing the heart rate and preventing the effects of hyperstimulation of thyroid and beta-adrenoreceptors of the myocardium are included.

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 (p2=0.333, p=0.015), 3-methoxytyramine levels (r2=0.458, p=0.006), and tumor size (r2=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.

The protein kinase A (PKA) signaling system mediates the effects of numerous hormones, neurotransmitters, and other molecules to regulate metabolism, cardiac function, and more. PKA defects may lead to diverse phenotypes that largely depend on the unique expression profile of the affected subunit. Deletion of the Prkarcb gene, which codes for PKA catalytic subunit β (Cβ), protects against diet-induced obesity (DIO), yet the mechanism for this phenotype remains unclear. We hypothesized that metabolic rate would be increased in Cβ knockout (KO) mice, which could explain DIO resistance. Male, but not female, CβKO mice had increased energy expenditure, and female but not male CβKO mice had increased subcutaneous temperature and increased locomotor activity compared with wild-type (WT) littermates. Urinary norepinephrine (NE) and normetanephrine were elevated in female CβKO mice. CβKO mice had increased heart rate (HR); blocking central NE release normalized HR to that of untreated WT mice. Basal and stimulated PKA enzymatic activities were unchanged in adipose tissue and heart and varied in different brain regions, suggesting that Prkacb deletion may mediate signaling changes in specific brain nuclei and may be less important in the peripheral regulation of PKA expression and activity. This is a demonstration of a distinct effect of the PKA Cβ catalytic subunit on catecholamines and sympathetic nerve signaling. The data provide an unexpected explanation for the metabolic phenotype of CβKO mice. Finally, the sexual dimorphism is consistent with mouse models of other PKA subunits and adds to the importance of these findings regarding the PKA system in human metabolism.

Background Asfotase alfa (STRENSIQ®, Alexion Pharmaceuticals, Inc.) is the only approved treatment for patients with pediatric-onset hypophosphatasia, a disease caused by a mutation in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. ALP is often used as signaling system in routine immunoassays. Because asfotase alfa contains the active site of the full ALP enzyme, it can catalyze the substrate as the antibody-conjugated ALP would within an assay. Therefore, its presence in a treated patient’s sample may generate false positive or false negative results. We investigated whether the presence of asfotase alfa within a sample induced interference in immunoassays that utilize ALP or alternative detection systems. Methods Asfotase alfa was added to samples at concentrations from 0.08–5 µg/mL and analysed on various immunoassays following manufacturer’s instructions. Results Asfotase alfa was detected in all ALP assays but ALKP1 (RayBiotech). We observed no changes in normetanephrine and noradrenaline (IBL) at any asfotase alfa concentration. However, asfotase alfa notably interfered in an oxytocin (ENZO) assay in nonextracted samples. Extraction using a C18 column eliminated the interference. No interference was observed on automated analyzers using alternative detection system (COBAS fT4 and TSH; Advia Centaur FSH, fT4; Architect LH; FSH). Immulite 2000 fT4, TSH, testosterone and hCG (ALP-based) showed no interference. However, the presence of asfotase alfa resulted in a dose-dependent increase of Troponin I signal. Conclusion The presence of asfotase alfa must be taken into consideration when analyzing blood samples in treated patients to avoid any risk of misinterpretation of false positive/negative results. It is essential that assays be tested for this possible interference.

Purpose Pheochromocytoma, a catecholamine-secreting tumour leading to neurological and cardiovascular life-threatening conditions through hypertension crisis, occurs in 0.1-0.5% of hypertensive patients, but it is extremely rare in pregnancy (0.0018-0.006%). Some classes of drugs, even commonly used in pregnancy, can trigger catecholamine secretion, precipitating the clinical situation. Materials and methods and results We report a 33-year-old woman, gravida 2 para 1, with previous mild hypertension, was admitted to the emergency room, at 28 2/7 weeks of gestation due to headache, tachycardia and severe arterial hypertension (220/120 mm Hg) triggered by the antiemetic metoclopramide used for a week because of nausea. In the emergency room, a paradoxical rise in blood pressure followed intravenous labetalol infusion was observed. Both metoclopramide and labetalol-triggered hypertensive crisis raised the suspicion of an undiagnosed pheochromocytoma. Diagnostic work-up showed elevated normetanephrine urinary excretion ​​and a right adrenal pheochromocytoma by abdominal magnetic resonance imaging. Oral alpha-1 and beta-1-adrenergic antagonist and calcium-channel blocker were started. At 33-weeks of gestation, she underwent a caesarean section giving birth to a female child. Seven weeks later she underwent a video-laparoscopic right adrenalectomy which normalised her blood pressure. Conclusions Both metoclopramide, a selective dopamine type-2 receptor antagonist and partial agonist of 5-hydroxytryptamine 4 receptor, and labetalol, a non-selective β-adrenoreceptor-blocker with weak α1-adrenergic antagonism, exacerbated an acute hypertensive crisis revealing an unrecognised pheochromocytoma in a pregnant patient. Careful attention to potential drug-triggered catecholamine crises and especially early recognition of pheochromocytomas, are mandatory in hypertensive pregnant women. A missed or delayed diagnosis could result in catastrophic results affecting foetal and maternal outcomes.

Introduction We sought to characterize the prevalence and factors characteristic of head and neck paragangliomas (HNPGLs) that secrete catecholamines to inform best practices for diagnosis and management. Methods This was a retrospective cohort study from 2000 to 2020 at a single‐institution tertiary centre. One‐hundred fifty‐two patients (182 tumours) with HNPGLs with at least one measurement of urine or plasma catecholamines and/or catecholamine metabolite levels prior to treatment were included. We differentiated and characterized those patients with increased level(s) of any nature and those with ‘clinically significant’ versus ‘clinically insignificant’ catecholamine production. Results Thirty‐one (20.4%) patients had increased catecholamine and/or catecholamine metabolite levels. In most patients, these levels were ≤5‐fold above the upper limit of the reference range. Four of these 31 patients with increased levels were ultimately found to have an additional catecholamine secreting mediastinal paraganglioma or pheochromocytoma. Fourteen of 31 patients with HNPGL were deemed clinically significant secretors of catecholamines based on hyper‐adrenergic symptoms and/or profound levels of normetanephrines. This cohort was enriched for patients with paragangliomas of the carotid body or cervical sympathetic chain and those with SDHB genetic mutations. Ultimately, the prevalence of clinically significant catecholamine secreting Hangs was determined to be 9.2% and 7.7% based on a per‐patient and per‐tumour basis, respectively. Conclusions The rate of catecholamine excess in the current cohort of patients with HNPGLs was higher than previously reported. Neuroendocrine tumours of any anatomic subsite may secrete catecholamines, although not all increased laboratory level(s) are indicative of clinically significant catecholamine secretion causing symptoms or warranting adrenergic blockade., The prevalence of clinically significant catecholamine secreting head and neck paragangliomas was determined to be 7.7%–9.2% based on a per‐patient and per‐tumour basis, respectively. The rate of catecholamine excess in the current cohort of patients with HNPGLs was higher than previously reported. Neuroendocrine tumours of any anatomic subsite may secrete catecholamines, though not all increased laboratory level(s) are indicative of clinically significant catecholamine secretion causing symptoms or warranting adrenergic blockade.

No research has explored the role of catecholamine metabolites in the stratification of cardiovascular risk. We aimed to evaluate the relationship between urine metanephrines and cardiometabolic risk/complications. In this retrospective cross-sectional study, we collected the data of 1374 patients submitted to the evaluation of urine metanephrines at the City of Health and Science University Hospital of Turin between 2007 and 2015, mainly for investigating the suspicion of secondary hypertension or the secretion of an adrenal lesion. The univariate analysis showed associations between metanephrines and cardiometabolic variables/parameters, particularly considering noradrenaline metabolite. At univariate regression, normetanephrine was associated with hypertensive cardiomyopathy (OR = 1.18, 95% CI 1.11–1.25, p &lt, 0.001) and metabolic syndrome (OR = 1.11, 95% CI 1.03–1.20, p = 0.004), while metanephrine was associated with hypertensive cardiomyopathy (OR = 1.23, 95% CI 1.06–1.43, p = 0.006) and microalbuminuria (OR = 1.30, 95% CI 1.03–1.60, p = 0.018). At multivariate regression, considering all major cardiovascular risk factors as possible confounders, normetanephrine retained a significant association with hypertensive cardiomyopathy (OR = 1.14, 95% CI 1.07–1.22, 0.001) and metabolic syndrome (OR = 1.10, 95% CI 1.02–1.19, p = 0.017). Moreover, metanephrine retained a significant association with the presence of hypertensive cardiomyopathy (OR = 1.18, 95% CI 1.01–1.41, p = 0.049) and microalbuminuria (OR = 1.34, 95% CI 1.03–1.69, p = 0.019). The study showed a strong relationship between metanephrines and cardiovascular complications/metabolic alterations. Individuals with high levels of these indirect markers of sympathetic activity should be carefully monitored, and they may benefit from an aggressive treatment to reduce the cardiometabolic risk.

Background: Paroxysmal sympathetic hyperactivity (PSH) is one of the important reasons for the high mortality and morbidity of traumatic brain injury (TBI). We aim to explore the role of the neutrophil extracellular traps (NETs) in the pathogenesis of sympathetic hyperexcitability after TBI and the underlying mechanisms, providing evidence for clinical treatment.Methods: Enzyme-linked immunosorbent assay was used to assess the plasma metanephrine and normetanephrine levels which represented the variation of the sympathetic system after TBI with rat diffuse axonal injury (DAI) model. NETs in the paraventricular nucleus (PVN) and circulating blood were examined using immunofluorescence and flow cytometry. Neutrophils-microglia co-culture system was established to further explore the effect of NETs on PSH and its mechanisms.Results: After TBI, metanephrine and normetanephrine levels began to increase at 9 h and peaked at 72 h. After the injury, the level of NETs kept increasing at 24 and 72 h in the PVN. A positive correlation was found between the concentration of the PVN NETs and blood catecholamine. Flow cytometry of peripheral blood cells revealed that NETs level in the injury group was higher than that in the control group. Immunofluorescence results confirmed the presence of NETs in the PVN after TBI. The positive result of immunoprecipitation suggested a correlation effect between LL37 and P2 × 7. Peptidyl arginine deiminase-4 (PAD4) inhibitor could inhibit the expression levels of MST1, YAP, and IL-1β. The hippo/MST1 pathway inhibitor could inhibit the expression levels of YAP and IL-1β.Conclusion: NETs formation in the PVN might be associated with sympathetic hyperactivity after TBI, which might relate to the activation of microglia cells and increased secretion of IL-1β via the hippo/MST1 pathway.

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 mu g/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.

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.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.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 normetanephrine6.95 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.There is a high degree of overlap in UNM-UMN between hospitalized patients and pheochromocytoma; high test specificity is not achieved in this population unless3-5 times the upper reference limit.

The aim of our study was to assess the sympathetic nervous system’s involvement in the evolution of gastric carcinoma in patients by analyzing the mediators of this system (epinephrine and norepinephrine), as well as by analyzing the histological expression of the norepinephrine transporter (NET). We conducted an observational study including 91 patients diagnosed with gastric carcinoma and an additional 200 patients without cancer between November 2017 and October 2018. We set the primary endpoint as mortality from any cause in the first two years after enrolment in the study. The patients were monitored by a 24-h Holter electrocardiogram (ECG) to assess sympathetic or parasympathetic predominance. Blood was also collected from the patients to measure plasma free metanephrine (Meta) and normetanephrine (N-Meta), and tumor histological samples were collected for the analysis of NET expression. All of this was performed prior to the application of any antineoplastic therapy. Each patient was monitored for two years. We found higher heart rates in patients with gastric carcinoma than those without cancer. Regarding Meta and N-Meta, elevated levels were recorded in the patients with gastric carcinoma, correlating with the degree of tumor differentiation and other negative prognostic factors such as tumor invasion, lymph node metastasis, and distant metastases. Elevated Meta and N-Meta was also associated with a poor survival rate. All these data suggest that the predominance of the sympathetic nervous system’s activity predicts increased gastric carcinoma severity.

Aims It is well‐accepted that takotsubo syndrome (TS) is characterized by a massive surge of plasma catecholamines despite lack of solid evidence. The objective of this study was to examine the hypothesis of a massive catecholamine elevation in TS by studying plasma‐free catecholamine metabolites in patients participating in the Stockholm myocardial infarction (MI) with normal coronaries 2 (SMINC‐2) study where TS constituted more than one third of the patients. Methods and results The patients included in the SMINC‐2 study were classified, according to cardiac magnetic resonance (CMR) imaging findings (148 patients), which was performed at a median of 3 days after hospital admission. Plasma‐free catecholamine metabolites; metanephrine, normetanephrine, and methoxy‐tyramine were measured on day 2–4 after admission. Catecholamine metabolite levels were available in 125 patients. One hundred and ten (88%) of the 125 patients included in SMINC‐2 study, and 38 (86.4%) of the 44 patients with TS had completely normal plasma metanephrine and normetanephrine levels. All patients had normal plasma methoxy‐tyramine levels. Fourteen (11.2%) of the 125 patients included in SMINC‐2 study, and 5 (11.6%) of the 43 patients with TS had mild elevations (approximately 1.2 times the upper normal limits) of either plasma metanephrine or normetanephrine. One patient with pheochromocytoma‐triggered TS had marked elevation of plasma metanephrine and mild elevation of plasma normetanephrine. There were no significant differences between the number or degree of catecholamine metabolite elevations between the different groups of patients with CMR imaging diagnosis included in SMINC‐2 study. Conclusion There was no evidence of massive catecholamine elevations in the acute and subacute stages of TS apart from one patient with pheochromocytoma‐induced TS. Most of the TS patients had normal catecholamine metabolites indicating that blood‐borne catecholamines do not play a direct role in the pathogenesis of TS.

Context Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine tumors with discrete catecholamine profiles that cause incompletely understood metabolic and physiologic changes. Objective The objective was to evaluate relationships between plasma catecholamines, body weight, and hemoglobin A1c (HbA1c). We hypothesized that individual catecholamines would correlate negatively with weight and glucose control. Design A retrospective cohort study was performed (1999-2020). Wilcoxon rank-sum tests compared nonparametric, continuous variables; mixed-effect linear modeling (MEM) evaluated relationships between catecholamines and weight or HbA1c. The median study duration was 54.2 months [interquartile range (IQR) 19.0-95.1]. Setting Tertiary academic hospital. Patients 360 patients were identified prospectively by referral to our center for management or surveillance of PCC/PGL. The median age was 59 years (IQR 45-67) and 56.4% (n = 203) were female. Main outcome measures The primary and secondary outcomes were weight and HbA1c, respectively. Results On multivariable MEM, norepinephrine (P Conclusion Plasma norepinephrine and its metabolite directly correlate with HbA1c and inversely correlate with weight in PCC/PGL. After resection, declining normetanephrine levels correlate with improving HbA1c despite an increase in patient body weight. Persistently elevated catecholamines and decreasing weight are observed in MRD.

Metanephrines (MNs; normetanephrine (NMN), metanephrine (MN) and methoxytyramine (MT)) detected in urine or plasma represent the best biomarker for neuroblastoma (NB) diagnosis, however the metabolism of both catecholamine (CAT) and MNs remains enigmatic in NB. Using patient-derived xenograft (PDX) models derived from primary NB cells, we observed that the plasma levels of MNs in NB-PDX-bearing mice were comparable as in patients. Interestingly, murine plasma displayed an elevated fraction of glucuronidated forms of MNs relative to human plasma where sulfonated forms prevail. In tumors, the concentration ranges of MNs and CAT and the expression levels of the main genes involved in catecholamine metabolism were similar between NB-PDX and human NB tissues. Likewise, plasma and intratumoral profiles of individual MNs, with increased levels of MT and NMN relative to MN, were also conserved in mouse models as in patients. We further demonstrated the downregulation of the Phenylethanolamine N-Methyltransferase gene in NB biopsies and in NB-PDX explaining this biochemical phenotype, and giving a rational to the low levels of epinephrine and MN measured in NB affected patients. Thus, our subcutaneous murine NB-PDX models not only reproduce the phenotype of primary NB tumors, but also the metabolism of catecholamine as observed in patients. This may potentially open new avenues in preclinical studies for the follow up of novel therapeutic options for NB through the quantification of plasma MNs.

To study the prognostic value of determining Chromogranin A blood level in the diagnosis of PHEO.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.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.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.Цель. Изучить прогностическую ценность определения хромогранина А (ХрА) в диагностике феохромоцитомы (ФХЦ). Материалы и методы. Выполнено сравнительное аналитическое исследование с участием 157 пациентов с подозрением на ФХЦ, проводилась статистическая обработка результатов анализа суточной мочи на метанефрин (МН) и норметанефрин, а также анализа крови на ХрА по группам, которые включали пациентов без ФХЦ, с первичной опухолью или ее рецидивом, подтвержденными по данным мультиспиральной компьютерной томографии, и/или сцинтиграфии с метайодбензилгуанидином, и/или пробы с клонидином. Результаты. Рассчитаны показатели эффективности методов по группам и отмечено, что наиболее низкие цифры чувствительности метода определения ХрА наблюдаются в группе с рецидивом ФХЦ (43,8%). При ее исключении из общей выборки специфичность метода сохранилась на высоком уровне (85,45%), а чувствительность значимо возросла до 87,1%. Также значимо повысился и показатель чувствительности метода определения МН в суточной моче до 96,8% при специфичности в 98,2%. Получены данные о наличии корреляционной связи между диаметром опухоли и ее секреторной активностью: слабая с уровнем ХрА [коэффициент корреляции Спирмена (rho) 0,491] и сильная с суммарным уровнем метилированных катехоламинов МКА (rho 0,765). Ложноположительные результаты чаще отмечались у пациентов с другими нейроэндокринными опухолями (37,5%), а также у принимающих ингибиторы протонной помпы (43,75%). Чувствительность и специфичность метода определения ХрА в группе пациентов с результатами анализа на МН в пределах серой зоны оказались 50 и 86,1% соответственно. Заключение. Анализ крови на ХрА можно рекомендовать в качестве подтверждающего теста для диагностики ФХЦ при сомнительных показателях МКА или при подозрении на рецидив ФХЦ. Применение теста в качестве метода 1-го ряда только при отсутствии возможности исследования МКА. При интерпретации ХрА необходимо учитывать состояния, вызывающие ложноположительные результаты.

Multiple stressors, including 24-h-shifts characterise the working environment of physicians, influencing well-being, health and performance. We aimed to evaluate the effect of the stressor 24-h-shift on the adrenal medullary and sympathoneural system in physicians with the hypothesis that shift work might have different impacts on both systems. Twenty-two physicians collected two 12-h-urine samples (“daytime” and “nighttime”) during a 24-h shift (“on-duty”) and on a free weekend (“off-duty”), respectively. Urinary excretion rates per m2 body surface area were assessed for the catecholamines epinephrine, norepinephrine and their respective free O-methylated metabolites metanephrine and normetanephrine by LC-MS/MS-analysis. The stressor provoked differential responses of epinephrine and norepinephrine. Epinephrine excretion rates showed significant increases from off to on duty. The largest proportional change (off-duty to on-duty) for epinephrine was observed for nighttime (205%), the increase for daytime was 84%. An increase in norepinephrine from off to on duty was only visible for nighttime collections. For the catecholamine metabolites, normetanephrine paralleled norepinephrine and exhibited an increase in excretion from off to on duty during nighttime collections of 53% whereas there was no change during daytime collections (3%). In conclusion: Whilst the 24-h-shift-work stressor in physicians activates the sympatho-adrenomedullary system, represented by epinephrine, the sympathoneural response through norepinephrine reflects mainly an ambulatory position during working hours.

Summary We report the case of a 76-year-old male with a remote history of papillary thyroid cancer who developed severe paroxysmal headaches in the setting of episodic hypertension. Brain imaging revealed multiple lesions, initially of inconclusive etiology, but suspicious for metastatic foci. A search for the primary malignancy revealed an adrenal tumor, and biochemical testing confirmed the diagnosis of a norepinephrine-secreting pheochromocytoma. Serial imaging demonstrated multiple cerebral infarctions of varying ages, evidence of vessel narrowing and irregularities in the anterior and posterior circulations, and hypoperfusion in watershed areas. An exhaustive work-up for other etiologies of stroke including thromboembolic causes or vasculitis was unremarkable. There was resolution of symptoms, absence of new infarctions, and improvement in vessel caliber after adequate alpha-adrenergic receptor blockade for the management of pheochromocytoma. This clinicoradiologic constellation of findings suggested that the etiology of the multiple infarctions was reversible cerebral vasoconstriction syndrome (RCVS). Pheochromocytoma remains a poorly recognized cause of RCVS. Unexplained multifocal cerebral infarctions in the setting of severe hypertension should prompt the consideration of a vasoactive tumor as the driver of cerebrovascular dysfunction. A missed or delayed diagnosis has the potential for serious neurologic morbidity for an otherwise treatable condition. Learning points: The constellation of multifocal watershed cerebral infarctions of uncertain etiology in a patient with malignant hypertension should trigger the consideration of undiagnosed catecholamine secreting tumors, such as pheochromocytomas and paragangliomas. Reversible cerebral vasoconstriction syndrome is a serious but reversible cerebrovascular manifestation of pheochromocytomas that may lead to strokes (ischemic and hemorrhagic), seizures, and cerebral edema. Alpha-adrenergic receptor blockade can reverse cerebral vasoconstriction and prevent further cerebral ischemia and infarctions. Early diagnosis of catecholamine secreting tumors has the potential for reducing neurologic morbidity and mortality in patients presenting with cerebrovascular complications.

Cardiomyopathy is a frequent complication of pheochromocytoma, and echocardiography is the most accessible method for its evaluation. The objective of this study was to assess the clinical significance of classical and novel echocardiographic parameters of cardiac function in 24 patients with pheochromocytomas (PPGL) compared to 24 subjects with essential hypertension (EH). Fourteen PPGL patients were reassessed after successful surgery. Left ventricular hypertrophy was four times more prevalent in patients with PPGL vs EH (75% vs 17%; P = 0.00005). Left ventricular mass index (LVMi) significantly correlated with urine metanephrine (MN) (rs = 0.452, P = 0.00127) and normetanephrine (NMN) (rs = 0.484, P = 0.00049). Ejection fraction (EF) and endocardial fractional shortening (EFS) were normal in all participants and did not correlate with urine metanephrines. Global longitudinal strain (GLS) was significantly lower in PPGL compared to EH group (−16.54 ± 1.83 vs −19.43 ± 2.19; P < 0.00001) and revealed a moderate significant positive correlations with age (rs = 0.489; P = 0.015), LVMi (rs = 0.576, P < 0.0001), MN (rs = 0.502, P = 0.00028) and NMN (rs = 0.580, P < 0.0001). Relative wall thickness (RWT) showed a strong positive correlation with urine MN (rs = 0.559, P < 0.0001) and NMN (rs = 0.689, P < 0.00001). Markedly decreased LVMi (118.2 ± 26.9 vs 102.9 ± 22.3; P = 0.007) and significant improvement in GLS (−16.64 ± 1.49 vs −19.57 ± 1.28; P < 0.001) was observed after surgery. ΔGLS depended significantly on the follow-up duration. In conclusion, classical echocardiographic parameters usually used for assessment of systolic cardiac function are not reliable tests in pheochromocytoma patients. Instead, GLS seems to be a better predictor for the severity and the reversibility of catecholamine-induced myocardial function damage in these subjects. RWT should be measured routinely as an early indicator of cardiac remodeling.

Previously, we reported that morning plasma glucose (PG) elevation before wake-up(W1) and after wake-up(W2), occur through different mechanisms in patients with type 2 diabetes. We measured three point PGs by Point-of-Care Testing (POCT) and flash glucose monitoring system (FreeStyle Libre Pro™); midnight (3 am), the time of awakening (about 6 am) and just before breakfast (8 am), hormones and their metabolites in 32 hospitalized patients with type 2 diabetes. Those with insulin therapy or overtly elevated fasting PG (>11 mmol/L) were excluded. W1 could be explained by relative insulin deficiency. Urinary normetanephrine, reflects a sum of production of norepinephrine was significantly correlated with W2 (R=0.422, p0.05). The Urinary normetanephrine was increased by the treatment (0.19±0.19 mg/gCre to 0.26±0.11 mg/gCre, p0.05). Further, eplerenone(50mg), a selective mineralocorticoid receptor antagonist affected neither W1 nor W2 in 2 male diabetes patients with hypertension. These results suggested that nonselective mineralocorticoid receptor antagonist may affect glucose metabolism via change of alpha-adrenergic tone. Disclosure K. Yamauchi: None.

Pheochromocytomas (PHEO) and paragangliomas (PGL) are rare tumors originated in cells derived from the neural crest. The first ones are located in the adrenal medulla, and the second ones in the sympathetic and parasympathetic nervous system. These kind of tumors may secrete excess catecholamines, including epinephrine, norepinephrine, dopamine and/or their metabolite metanephrine, normetanephrine and 3-methoxytyramine, respectively. Its clinical manifestations depend on the location, the secretory profile and the malignant potential of the tumor. These tumors are frequently benign in their presentation. Some arise in the context of familiar syndromes, accounting for up to one-third of the total of diagnosis. The metastatic form is the most common presentation of the tumors with familiar origin and due to their rarity, their diagnosis and management is often difficult. Over the years, our knowledge and perception of PHEO and PGL has greatly expanded and changed. This review article aims to focus on the genetic, clinical, diagnostic, therapeutic and prognostic approaches, to give the clinician knowledge of the most recent updates regarding these themes.

Summary Pheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both 18F-fluorodeoxyglucose (18F-FDG) PET/CT and 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. 18F-FDOPA PET/CT may be beneficial for localization in these patients. Learning points: 18F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients. Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions. MEN1 is implicated in the tumorigenesis of PHEO in this patient.

Summary Ectopic adrenocorticotropic hormone (ACTH) production is an uncommon cause of Cushing’s syndrome and, rarely, the source can be a phaeochromocytoma. A 55-year-old man presented following an episode of presumed gastroenteritis with vomiting and general malaise. Further episodes of diarrhoea, joint pains and palpitations followed. On examination, he was hypertensive with no clinical features to suggest hypercortisolaemia. He was subsequently found to have raised plasma normetanephrines of 3.98 nmol/L (NR Learning points: Phaeochromocytomas are a rare source of ectopic ACTH secretion. A high clinical index of suspicion is therefore required to make the diagnosis. Ectopic ACTH secretion from a phaeochromocytoma can rapidly progress to severe Cushing’s syndrome, thus complicating tumour removal. Removal of the primary tumour often leads to full recovery. The limited literature suggests that the presence of ectopic Cushing’s syndrome does not appear to have any long-term prognostic implications.

Although Takotsubo syndrome (TS) was once considered to be rare and largely benign, it is now recognized to represent a major cause of cardiac morbidity and mortality, especially in ageing women. The biochemical precipitant of attacks of TS is an increase in catecholamine concentrations within the myocardium, engendering inflammatory activation via biased post-receptor signalling at myocardial β2-adrenoceptor level. Cases of TS have been reported in patients treated with catecholamines, and with antidepressants which limit catecholamine re-uptake. In the current investigation, we sought to delineate the extent and potential impact of this “iatrogenic” form of TS. Patients’ data from a regional registry of 301 consecutive cases of TS were evaluated after exclusion of patients (n = 20) in whom TS had occurred in association with life threatening extracardiac disease states. A total of 55 (18%) of patients were identified as having antecedent exposure to potentially “iatrogenic” agents (tricyclic antidepressants in 24 cases, β2-adrenoceptor agonists in 15). Demographics, including proportion of male patients, did not differ significantly between patients with and without “iatrogenic” TS, but plasma concentrations of the catecholamine metabolite normetanephrine tended to be greater (median 1149 pmol/L vs 938 pmol/L; p = 0.03). Long-term survival (median follow-up 3 years) was marginally (p = 0.13) worse for patients with “iatrogenic” TS. Potentially iatrogenic precipitation of TS attacks (via iatrogenic elevation of catecholamine levels and β2-adrenoceptor stimulation) is common, associated with greater elevation of plasma normetanephrine concentrations, and also with a trend towards increased long-term mortality when compared to the remainder of TS patients.

Cardiac paraganglioma (PGL) is a rare neuroendocrine tumour causing significant morbidity primarily due to norepinephrine secretion potentially causing severe hypertension, palpitations, lethal tachyarrhythmias, stroke and syncope. Cardiologists are faced with two clinical scenarios. The first is the elevated norepinephrine, whose actions must be properly counteracted by adrenoceptor blockade to avoid catastrophic consequences. The second is to evaluate the precise location of a cardiac PGL and its spread since compression of cardiovascular structures may result in ischaemia, angina, non-noradrenergic-induced arrhythmia, cardiac dysfunction or failure. Thus, appropriate assessment of elevated norepinephrine by its metabolite normetanephrine is a gold biochemical standard at present. Furthermore, dedicated cardiac CT, MRI and transthoracic echocardiogram are necessary for the precise anatomic information of cardiac PGL. Moreover, a cardiologist needs to be aware of advanced functional imaging using 68Ga-DOTA(0)-Tyr(3)-octreotide positron emission tomography/CT, which offers the best cardiac PGL-specific diagnostic accuracy and helps to stage and rule out metastasis, determining the next therapeutic strategies. Patients should also undergo genetic testing, especially for mutations in genes encoding succinate dehydrogenase enzyme subunits that are most commonly present as a genetic cause of these tumours. Curative surgical resection after appropriate α-adrenoceptor and β-adrenoceptor blockade in norepinephrine-secreting tumours is the primary therapeutic strategy. Therefore, appropriate and up-to-date knowledge about early diagnosis and management of cardiac PGLs is paramount for optimal outcomes in patients where a cardiologist is an essential team member of a multidisciplinary team in its management.

The majority of pheochromocytoma (PCC) and paraganglioma (PGL) are endocrine active tumors, and they cause clinical symptoms by secreting excess one or more catecholamines (epinephrine, norepinephrine, and dopamine) and their inactive metabolites (metanephrine, normetanephrine, 3-metoxythromine). Although signs and symptoms regarding excess catecholamine often develop in PCC and PGL (PPGL), non-functional PPGLs may present with local compression symptoms. Persistent, sometimes worsening hypertension is the most common finding and occurs in 80-90% of the patients. Classically defined symptom triad; headache, sweating and palpitations are seen in only 25% of the patients with PCC. The difference of clinical symptoms may be related to the tumor secretion, epinephrine or norepinephrine. All patients with signs and symptoms suggestive of catecholamine excess should be screened by biochemical tests regardless of whether they have hypertension or not. Not all patients with newly diagnosed hypertension need to be screened, but only patients with additional tips for catecholamine excess should be screened. Approximately 20% of the PPGLs are diagnosed in childhood, and the male/female ratio is 2/1. 60-90% of pediatric patients present with hypertension. PPGL in pregnancy is rare, and the estimated incidence ranges between 1/15000-1/54000. Although early diagnosis is the most important factor in preventing mortality, diagnosis is not as easy as it is a rare condition. Hypertension is a common complication in pregnancy, occurring in 5-10%. Computed tomography should not be used as the imaging method during pregnancy; the first choice is magnetic resonance imaging with gadolinium or without contrast. Plasma free metanephrine or 24-hour urinary fractionated metanephrine level is recommended as a screening test for the diagnosis of PPGL in the Endocrine Society Clinical Practice Guideline. In suspicious situations, tests should be repeated. Since 40% of these patients have germline mutations, genetic tests are recommended for all patients with PPGL regardless of family history and age. Preoperative knowledge of germline mutations affects the surgical approach and the extent of adrenalectomy. After the biochemical diagnosis is made in PPGL, the tumor is localized with imaging methods to make the operation plan. In this review, we aimed to evaluate the clinical findings, diagnostic tests, and imaging studies for tumor localization in PPGL.

Since activation of the sympathetic nervous system is associated with both impaired insulin secretion and insulin resistance, or namely with diabetes, evaluation of such activation in ordinary clinical settings may be important. Therefore, we evaluated the relationships between urinary concentrations of the catecholamine metabolites, urinary normetanephrine (U-NM) and urinary metanephrine (U-M), and glucose metabolism in a general population. From 1,148 participants in the 2016 population-based Iwaki study of Japanese, enrolled were 733 individuals (gender (M/F): 320/413; age: 52.1±15.1), who were not on medication affecting serum catecholamines, not diabetic, and had complete data-set and blood glucose levels appropriate for the evaluation of insulin secretion and resistance, using homeostasis model assessment (HOMA-β and HOMA-R, respectively). Univariate linear regression analyses revealed significant correlations between both U-NM and U-M, and HOMA-β, but adjustment for multiple factors correlated with HOMA indices abolished these (β = -0.031, p = 0.499, and β = -0.055, p = 0.135, respectively). However, the correlation between U-NM and HOMA-R observed using univariate linear regression analysis (β = 0.132, p1.6) determined by ROC analysis (0.2577 mg/gCr) showed that individuals at risk had an odds ratio of 2.65 (confidence interval: 1.42–4.97) after adjustment for the same factors used above. Higher U-NM concentrations within the physiologic range are a significant risk factor for increased insulin resistance in a general Japanese population.

Introduction: The effect of renal sympathetic denervation (RDN) on neurohormonal responses is largely unknown. We aimed to assess the effect of RDN on the renin–angiotensin–aldosterone system (RAAS) and endogenous catecholamines. Methods: A total of 60 patients with hypertension underwent RDN and remained on a stable antihypertensive drug regimen. Samples for plasma aldosterone, plasma renin and urine (nor)metanephrine were collected at baseline and at 6 months post procedure. Ambulatory blood pressure (BP) recordings were obtained at baseline and at 6 months post procedure. Results: Mean age was 64±9 years, and 30/60 patients were male. At 6 months, average daytime systolic and diastolic ambulatory BP decreased by 10 and 6 mmHg, respectively ( pConclusion: Despite significant reductions in ambulatory BP, RDN did not result in a significant change in endogenous catecholamines or in RAAS hormones at 6 months.

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.

Catecholamines can be used to evaluate neuroendocrine tumors, stress, and potentially pain, but catecholamines degrade rapidly. Their metabolites normetanephrine (NME) and metanephrine (ME) have better stability in urine. In cats, urine sampling in a home environment would be beneficial to reduce effects of clinical stress and simplify sampling. We evaluated a human urine ELISA for analysis of NME and ME in feline urine, and investigated the effects of acidification, cat tray pellets, and storage time at room temperature up to 8.5 h. In 26 feline urine samples, mean NME concentration was 192 ± 80 ng/mL, mean intra- and inter-assay CV was 6.5% and 4.2%, respectively, and spike recovery was 98–101%, but dilutional recovery was unsatisfactory. For ME, mean intra- and inter-assay CV was 10.2% and 4.1%, respectively. Mean urine ME concentration was 32.1 ± 18.3 ng/mL, close to the kit’s lowest standard, and spike recovery was 65–90%; the ELISA could not be validated for ME. The stability study, performed for NME on 12 urine samples, did not identify differences between acidified and non-acidified samples, cat tray pellets, or storage time, and no interaction effects. The ME ELISA was not suitable for feline urine; performance of the NME ELISA was acceptable, except for dilution recovery. For analysis of NME, feline urine can be sampled at home using cat tray pellets and stored at room temperature up to 8.5 h without acidification.

Introduction In the MEN 2A syndrome, which is the most common of the three types of MEN, three endocrine systems are affected simultaneously or subsequently by the development of tumours manifested by medullary thyroid gland carcinoma, pheochromocytoma (often bilateral) and hyperparathyroidism. Material and methods 27 patients from 3 families affected by MEN 2A syndrome were examined clinically (by detecting the effects of catecholamine overproduction), biochemically (screening for metanephrine and normetanephrine in the serum), visualization (CT, MRI, MIBG, PET CT) and some of them also genetically (DNA fragment analysis obtained by PCR amplification). Results Familial incidence of pheochromocytoma was confirmed in 10 patients (4 males, 5 females and one girl) aged 6 to 54 years (average 22.8 years) . In 5 patients, the pheochromocytoma occurred on both sides, in one patient, with genetically proved MEN 2A syndrome, only one adrenal gland was affected by pheochromocytoma. In 10 patients, mutations were detected in the exon 10, 11 and 16 RET of the proto-oncogene in the centromeric region of the 10th chromosome. After proper preparation, 5 patients underwent bilateral adrenalectomy (unilateral adrenalectomy in one patient). Histological examination of the removed tumours in all cases excluded the malignant pheochromocytoma.The first of the operated patients (54 yr) died after surgery for cardiovascular failure. Others have lived 5 to 15 years after bilateral adrenalectomy without signs of local recurrence of the disease, and have no clinical signs of over-production of catecholamines. Conclusion Bilateral pheochromocytoma and thyroid carcinoma are indications for detailed clinical and genetic examination of all family members. Bilateral adrenalectomy with lifetime supplementation of adrenal hormones is indicated in symptomatic patients and/or patients asymptomatic with tumours larger than 3 cm in diameter (Tab. 1, Fig. 11, Schema 1, Ref. 31).

Pheochromocytomas are catecholamine-secreting tumors. These tumors are rare in children, and they may be associated with hereditary syndromes such as von Hippel-Lindau (VHL) disease. Most pediatric patients with pheochromocytoma present with sustained hypertension, while 10% to 69% of adult patients are asymptomatic. Herein, we present the case of a 12-yr-old Japanese girl with pheochromocytoma due to a germline mutation in the VHL (Arg161Gln). The only complaint was loss of weight. Pyrexia, anemia, and increases in C-reactive protein (CRP) and ferritin were observed. Abdominal ultrasonography revealed a right adrenal gland tumor. Fractionated catecholamines and metanephrines in plasma and 24-h collected urine revealed elevated levels of norepinephrine and normetanephrine. Although hypertension and tachycardia were inapparent by an ordinary physical examination, paroxysmal mild hypertension and tachycardia were identified by a thorough examination after walking and abdominal compression. Paroxysmal hypertension and tachycardia were profound during operation. In conclusion, pheochromocytoma can be a consideration in the differential diagnosis of weight loss. Hypertension and tachycardia can be inapparent and paroxysmal in pediatric patients as well as in adults; thus, thorough assessment should be repeated.

Background With the increasing access to imaging more pheochromocytomas are diagnosed in the workup of adrenal incidentalomas. This may have changed the occurrence of the classic presentation with hypertension and the classic triad (headaches, sweating and palpitation). Methods We reviewed 94 consecutive cases of pheochromocytomas. Two cases of ectopic ACTH-syndrome were subsequently excluded. Results Of the 92 cases included 64% had presented as an incidentaloma, 32% as a suspected pheochromocytoma and 4% had been screened because of previously diagnosed MEN2A. Those screened were youngest while those with incidentalomas were oldest. The females were more common in the incidentaloma and the screening groups, and males in the suspected pheochromocytoma group. Measurements of noradrenaline/normetanephrine levels were highest in the suspected pheocromocytoma group and lowest in the screening group. Hypertension was present in 63% of the incidentalomas, 79% of suspected pheochromocytomas and in none of the screening group. Paroxysmal symptoms were present in almost all with suspected pheochromocytoma while only in half of the other groups. The suspected pheocromocytoma group had most symptoms and the screening group least. The classic triad was present in 14% of the incidentalomas, in 28% of the suspected and in none of the screening group, while no symptoms at all was present in 12%, 0% and 25%, respectively. Pheochromocytoma crisis occurred in 5%. There was a positive correlation between tumor size vs hormone levels, and catecholamine levels vs blood pressure. Conclusion Clinicians need to be aware of the modern presentation of pheochromocytomas since early identification can be life-saving.