Normetanephrine Concentrations Research Articles

Case of functional paraganglioma with intraoperative hypertensive crisis during robot-assisted thoracoscopic resection

BackgroundMediastinal paragangliomas are rare. Their dangerousness may unfold during surgery, especially if hormonal activity was previously unknown. We report our experience with this case in context to the incidence and localization of atypically located mediastinal paragangliomas in the literature.Case presentationA 69-year-old female patient who was scheduled for thoracoscopic resection due to a posterior mediastinal tumor that had been progressing in size for several years and increasing symptoms. The induction of anesthesia, the ventilation of the lungs and the gas exchange after lung separation was uneventful. After initially stable circulatory conditions, there was a sudden increase in blood pressure up to 300/130 mmHg and tachycardia up to 130/min. This hypertensive phase was difficult to influence and required a rapid and consistent use of antihypertensive medication to bring down the blood pressure to reasonable values. The patient stabilized after tumor resection. The postoperative course was unremarkable. During the intraoperative blood pressure crisis, blood was drawn for analysis. These samples showed elevated concentrations of normetanephrine and metanephrine. The tumor subsequently presented as a catecholamine-secreting paraganglioma.ConclusionIn order to avoid life-threatening blood pressure crises, hormone activity should be ruled out preoperatively in the case of mediastinal tumor, in which a paraganglioma could be considered in the differential diagnosis, especially if there are indications of hypertension in the medical history. Robotic-assisted thoracoscopic resection of the posterior mediastinal tumor was a feasible surgical method, even in the case of unexpected functional paraganglioma.

Association of Fetal Catecholamines With Neonatal Hypoglycemia

Perinatal stress and fetal growth restriction increase the risk of neonatal hypoglycemia. The underlying pathomechanism is poorly understood. In a sheep model, elevated catecholamine concentrations were found to suppress intrauterine insulin secretion, followed by hyperresponsive insulin secretion once the adrenergic stimulus subsided. To determine whether neonates with risk factors for hypoglycemia have higher catecholamine concentrations in umbilical cord blood (UCB) and/or amniotic fluid (AF) and whether catecholamines are correlated with postnatal glycemia. In a prospective cohort study of 328 neonates at a tertiary perinatal center from September 2020 through May 2022 in which AF and UCB were collected immediately during and after delivery, catecholamines and metanephrines were analyzed using liquid chromatography with tandem mass spectrometry. Participants received postnatal blood glucose (BG) screenings. Risk factor for neonatal hypoglycemia. Comparison of catecholamine and metanephrine concentrations between at-risk neonates and control participants, and correlation of concentrations of catecholamines and metanephrines with the number and severity of postnatal hypoglycemic episodes. In this study of 328 neonates (234 in the risk group: median [IQR] gestational age, 270 [261-277] days; and 94 in the control group: median [IQR] gestational age, 273 [270-278] days), growth-restricted neonates showed increased UCB median (IQR) concentrations of norepinephrine (21.10 [9.15-42.33] vs 10.88 [5.78-18.03] nmol/L; P < .001), metanephrine (0.37 [0.13-1.36] vs 0.12 [0.08-0.28] nmol/L; P < .001), and 3-methoxytyramine (0.149 [0.098-0.208] vs 0.091 [0.063-0.149] nmol/L; P = .001). Neonates with perinatal stress had increased UCB median (IQR) concentrations of norepinephrine (22.55 [8.99-131.66] vs 10.88 [5.78-18.03] nmol/L; P = .001), normetanephrine (1.75 [1.16-4.93] vs 1.25 [0.86-2.56] nmol/L; P = .004), and 3-methoxytyramine (0.120 [0.085-0.228] vs 0.091 [0.063-0.149] nmol/L; P = .008) (P < .0083 was considered statistically significant). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were negatively correlated with AF C-peptide concentration (rs = -0.212, P = .005; rs = -0.182, P = .016; and rs = -0.183, P = .016, respectively [P < .017 was considered statistically significant]). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were positively correlated with the number of hypoglycemic episodes (BG concentration of 30-45 mg/dL) (rs = 0.146, P = .01; rs = 0.151, P = .009; and rs = 0.180, P = .002, respectively). Concentrations of UCB metanephrine and 3-methoxytyramine were negatively correlated with the lowest measured BG concentration (rs = -0.149, P = .01; and rs = -0.153, P = .008, respectively). Neonates at risk for hypoglycemia displayed increased catecholamine and metanephrine concentrations that were correlated with postnatal hypoglycemic episodes and lower BG levels; these results are consistent with findings in a sheep model that fetal catecholamines are associated with neonatal β-cell physiology and that perinatal stress or growth restriction is associated with subsequent neonatal hyperinsulinemic hypoglycemia. Improving the pathomechanistic understanding of neonatal hypoglycemia may help to guide management of newborns at risk for hypoglycemia.

Acute Hemodynamic, Metabolic, and Hormonal Responses to a Boxing Exergame with and without Blood Flow Restriction in Non-Athlete Young Individuals.

This study aimed to compare acute hemodynamic, metabolic (glucose and blood lactate concentrations), hormonal (growth hormone and normetanephrine), heart rate variability (HRV), and rating of perceived exertion (RPE) responses before and after bouts of a boxing exergame with and without blood flow restriction (BFR) in non-athlete young individuals. Fourteen participants (age: 30 ± 10 y; BMI: 21 ± 3 kg.m-2) participated in two sessions of a 20 min boxing exergame. During week one, the participants were randomly divided into two groups and played against one another under normal (n = 7) and BFR (n = 7) conditions. Over the next exercise session, participants were then reallocated to the opposite condition (normal vs. BFR) for data collection. Hemodynamic, metabolic, HRV, and hormonal parameters were measured before and immediately after the exercise protocols. Playing exergame led to a significant increase in hemodynamic variables (except for diastolic blood pressure) regardless of BFR condition with no between-group differences. Regarding HRV, significant reductions in total power (TP) and low-frequency (LF) waves were identified in the non-BFR group (p < 0.0001) compared with the BFR group. Conversely, a significant increase in very LF (VLF) waves was noted for the BFR group (p = 0.050), compared with the non-BFR group. Significant increases were observed in serum concentrations of growth hormone, normetanephrine, and blood lactate concentration from pre- to post-exercise under both conditions (p ≤ 0.05), with no significant differences between the groups. Moreover, no statistically significant changes were observed in glucose levels. RPE responses were significantly greater (p ≤ 0.05) in the BFR group compared with the non-BFR group throughout the exercise session. We observed similar hemodynamic, hormonal, and metabolic responses after an acute boxing exergame session in young individuals, whether conducted with or without BFR. However, notable differences were observed in certain HRV markers and RPE. Specifically, the inclusion of BFR resulted in an elevation of VLF and a heightened perceived exertion. These findings suggest that BFR may alter cardiac autonomic and perceptual responses during exergaming. Further research is warranted to understand the long-term implications and potential benefits of incorporating BFR into exergaming routines.

A HYPERADRENERGIC STATE IN HYPERTENSION IS ASSOCIATED WITH MOOD DISTURBANCE AND IMPAIRED STRESS-MODULATED VASOMOTOR RESPONSES

Objective: Increasing evidence suggests a high prevalence of affective disorders in hypertension, however, the physiological associations remain unclear. Noradrenergic activation in the central and peripheral nervous systems is a putative mechanism that may explain the link between both conditions. Here, we investigate whether these stress-sensitive co-morbidities may be dependent on basal noradrenergic activity and whether vascular responses to centrally acting stimuli vary according to noradrenergic activity. Design and method: We examined the relation of affective disorders and stress-mediated vascular responses to plasma concentrations of normetanephrine (NMN), a measure of noradrenergic activity, in subjects with primary hypertension. Subjects on antidepressant medication, alpha- and beta-blockers were excluded. The Patient Health Questionnaire (PHQ-9), the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDSSR-16), and Generalised Anxiety Disorder-7 (GAD-7) questionnaires were used for the evaluation of symptoms of depression and anxiety. Forearm blood flow (strain gauge plethysmography) was used to assess vascular responses to mental stress (Stroop colour-word test) and slow breathing (by biofeedback), interventions that respectively increase or decrease noradrenergic activity in the pre-frontal cortex and locus coeruleus. Results: 100 subjects (53% male) with (mean ± SD) age 43.4 ± 10.9 years were recruited. 88% of subjects were treated with anti-hypertensive medications and 4% had type 2 diabetes. 31% and 34% of the study population scored moderate to severe depression for PHQ-9 and QIDSSR-16 respectively indicating significant mood disturbance. Scores representing low mood and high anxiety were 2-3-fold higher for hypertensive subjects in the highest compared to lowest NMN tertiles (PHQ-9: 9.2 ± 5.8 vs 3.8 ± 2.7, P &lt; 0.001; QIDSSR-16: 12.3 ± 4.9 vs 4.5 ± 3.5, P = 0.003; GAD-7: 9.0 ± 5.5 vs 4.6 ± 3.8, P = 0.003). Forearm vasodilator responses to mental stress and vasoconstrictor responses to slow breathing were attenuated in those with high compared to low NMN (28.3 ± 21% vs. 47.1 ± 30% increases for mental stress and 3.7 ± 21% vs. 18.6 ± 15% decreases for slow breathing for highest vs. lowest tertiles of NMN, both P &lt; 0.01). Conclusions: A hyperadrenergic state in hypertension is associated with mood disturbance and impaired stress-modulated vasomotor responses. This association may be mediated by chronic stress impinging on pathways regulating central arousal and peripheral sympathetic nerve activity.

Plasma-free metanephrines, nerve growth factor, and renalase significance in patients with PCOS.

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

Plasma and urinary metanephrine and normetanephrine concentrations using liquid chromatography with tandem mass spectrometry in healthy cats and in a cat with pheochromocytoma

Pheochromocytoma (PCC) is rare in cats and plasma (PL) and urinary (U) metanephrines (metanephrine [MN]; normetanephrine [NMN]) measurement is rarely described in cats. 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). 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. 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. 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.

Correlation between the size of pheochromocytoma and the level of metanephrines.

Objective. Pheochromocytomas (PHEO) and paraganglioma (PGLs) are rare neuroendocrine catecholamine-producing tumors that arise from the chromaffin cells of either the adrenal medulla or extra-adrenal paraganglionic tissues. Despite the recent advances in imaging technologies, biochemical evidence of excessive catecholamine production by the tumor is considered the most important test for the diagnosis of these tumors. The aim of the present study is to investigate the role of the catecholamine metabolites (normetanephrine and metanephrine) levels in the diagnosis of PHEO/PGLs and to evaluate if their levels correlate with the size of these tumors. Patients and Methods. Twenty-five patients were included in the study during the time period of 10 years. Their data were compared with another set of 25 patients to obtain the sensitivity and specificity of metanephrine and normetanephrine in the diagnosis of PHEO/PGLs. The tumor size was reviewed in every patient to obtain the correlation coefficient between the tumor sizes and the plasma/24-hour urinary metanephrine levels. Results. The sensitivity and specificity rates for plasma metanephrine were 80-92% and 92-96%, respectively; while for 24-hour urinary metanephrine were 80-90% and 95-100%, respectively. We found a strong positive relationship between the tumor size and the plasma levels of normetanephrine (r=0.518, p<0.01), and metanephrine (r=0.577, p<0.01). While the relation with the 24-hour urinary concentrations of normetanephrine (r=0.384, p=0.01) and 24-h urinary meta-nephrine (r=0.138, p<0.01) was low. Conclusion. The determination of plasma and 24-hour urinary levels of metanephrines is a reliable test for the diagnosis of PHEO, as they are continuously produced by the tumor cells in contrast to catecholamines.

Reliability of biomarkers of physiological stress at rest and post-exertional heat stress.

The purpose of this study was to assess the reliability of blood biomarkers that can signify exercise-induced heat stress in hot conditions. Fourteen males completed two heat stress tests separated by 5-7 days. Venous blood was drawn pre- and post- heat stress for the concentration of normetanephrine, metanephrine, serum osmolality, copeptin, kidney-injury molecule 1 and neutrophil gelatinase-associated lipocalin. No biomarker, except copeptin, displayed systematic trial order bias (p ≥ 0.05). Normetanephrine, copeptin and neutrophil gelatinase-associated lipocalin presented acceptable reliability (CV range: 0.9-14.3%), while greater variability was present in metanephrine, osmolality and kidney-injury molecule 1 (CV range: 28.6-43.2%). Normetanephrine exhibited the largest increase (p <0.001) in response to heat stress (trial 1 = 1048 ± 461 pmol. L-1; trial 2 = 1067 ± 408 pmol. L-1), whilst kidney-injury molecule 1 presented trivial changes (trial 1 = -4 ± 20 ng. L-1; trial 2 = 2 ± 16 ng. L-1, p >0.05). Normetanephrine, copeptin and neutrophil gelatinase-associated lipocalin demonstrated good reliability and sensitivity to an acute bout of heat stress. These biomarkers may be suitable for application in laboratory and field research to understand the efficacy of interventions that can attenuate the risk of thermal injury whilst exercising in the heat.

The most common indications for measuring metanephrine and normetanephrine in plasma - a rational approach.

Aim To determine the most common indications for measuring metanephrine and normetanephrine in plasma by gender and age and to compare the concentrations of metanephrine and normetanephrine by indication, gender and age. Methods The study was conducted on 224 patients whose plasma metanephrine and normetanephrine concentrations were measured at the Clinical Institute for Laboratory Diagnostics at the University Hospital Centre Osijek for one year, until 1st January 2020. Results The most frequent indications for biochemical testing were adrenal incidentaloma, 138 (6.6 %), and symptoms of pheochromocytoma, 41 (18.3%). Metanephrine concentration was lower in females (p=0.009). No significant correlation was found between age and metanephrine concentration, while age and normetanephrine concentration were positively correlated (p=0.01). Of the 224 patients, only one patient was diagnosed with pheochromocytoma, whose indication for measurement of metanephrine and normetanephrine was adrenal incidentaloma. Conclusion Adrenal incidentalomas and symptoms suggestive of pheochromocytoma are very common in the general population, while the incidence of pheochromocytoma is extremely low. Clear guidelines for the referral of patients for biochemical testing are needed to avoid unnecessary costs and to identify the correct diagnosis promptly.

PSAT006 Two Cases of Pheochromocytoma Associated Takotsubo Syndrome- Importance of Early Recognition and Treatment

Abstract Introduction Pheochromocytoma is a rare catecholamine producing adrenal medullary tumor that classically presents with hypertension. Takutsubo cardiomyopathy (TC) is a rare but increasingly recognized presentation of pheochromocytoma. We present two cases of TC likely caused by pheochromocytoma. Case 1 A 60 y/o male who presented with acute onset nausea, vomiting and abdominal pain. Systolic BP was 150-160 mm Hg, and diastolic BP was 100 mmHg. Troponin was elevated (4.15 ng/ml; nl = 0-0.04). An echocardiogram showed a reduced left ventricular ejection fraction (LVEF) of 15-20% (nl = 50-75%), a mildly dilated left ventricle, and apical ballooning suggestive of TC. Coronary arteries were normal on cardiac catheterization. CT scan identified a 5.3×5.6×5.7 cm adrenal mass of 50 HU pre-contrast. Further evaluation revealed markedly elevated plasma metanephrine concentration of 858 pg/ml (nl&amp;lt;57) and normetanpehrine concentration of 1729 pg/ml (&amp;lt;148). His presentation was strongly suggestive of pheochromocytoma associated TC. He was prepared for surgery with doxazosin 2 mg twice daily followed by metoprolol succinate and metyrosine up to 500 mg/d. Final pathology revealed a 5.3 cm left pheochromocytoma with negative surgical margins. Germline genetic testing was negative for pheochromocytoma/paraganglioma pathogenic gene mutations, and an MIBG scan did not reveal metastatic disease. Echocardiogram one month after adrenalectomy showed a marked improvement in LVEF to 55-60% with no regional wall motion abnormalities, and plasma metanephrine concentrations normalized. Case 2 A 61 y/o female smoker with type 2 diabetes mellitus, hypertension, Graves disease and obesity presented with sudden onset of nausea followed by chest discomfort, bilateral shoulder discomfort and shortness of breath. Troponin was 0.6 ng/ml (nl = 0-0.04), EKG showed ST elevations in leads I, 2, V5 V6 with hyperacute T waves. Coronary arteries were normal on catheterization. She required intubation, and systolic BP ranged from 110 to 200 mm Hg. On echocardiogram the LVEF was 35% to 40% (nl = 50-75), and there was diffuse hypokinesis of the mid to apical LV myocardium with hypercontractility of the LV base, suggestive of TC. The plasma metanephrine concentration was 3.31 nmol/l (nl= 0-0.49), and normetanephrine concentration was 5.02 nmol/l (nl= 0-0.89). CT imaging revealed a 2.9 cm left adrenal mass. She underwent successful left adrenalectomy after preparation with alpha, beta blockade and metyrosine. Germline genetic testing was negative for pheochromocytoma/paraganglioma pathogenic gene mutations . Echocardiogram nine months post-adrenalectomy showed normal EF of 50-55% and resolution of apical hypokinesis. Discussion We present two pheochromocytoma patients presenting with TC that reversed following appropriate pheochromocytoma management. Few case series report the association of pheochromocytoma and TC. These patients usually present acutely without prodromal stressors commonly found with classic TC. Conclusion In the setting of TC, pheochromocytoma should be considered. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSIII-A-5 Blood Catecholamine Profiling of Transportation Stress in Goats Previously Habituated to Livestock Trailer

Abstract Long distance transportation can cause significant physiological changes in goats that can impact their wellbeing. This experiment was conducted to determine the effects of habituation to livestock trailer on plasma catecholamine profile in goats transported for long periods. A total of 168 intact male Spanish goats were separated into two treatment (TRT) groups and maintained on two different paddocks in a split-plot design. Concentrate supplement was fed to one group inside two livestock trailers (5.0 × 2.3 m each; habituated group, H), while the other group received the concentrate supplement, but not inside the trailers (non-habituated, NH). After 4 weeks of habituation period, goats were subjected to a 10-hour transportation stress in 4 replicates (n = 21 goats/replicate/TRT). Blood samples were collected prior to loading (Preload), 20 min after loading (0 h), and at 2, 4, 6, 8, and 10 h of transportation (Time) for catecholamine analysis using a sensitive, high-throughput GC-MS/MS method. Habituation did not have any significant effect on dopamine, norepinephrine, and normetanephrine concentrations, while there was a tendency for TRT effect (P &amp;lt; 0.1) on epinephrine, tyramine, and metanephrine concentrations. Phenyethylamine and 5-methoxytryptamine concentrations were significantly higher (P &amp;lt; 0.05) in the H group compared to the NH group, which may enhance emotional wellbeing and energy levels. While both dopamine and 5-methoxytryptamine concentrations decreased (P &amp;lt; 0.05) with transportation time, dopamine concentrations increased again at 10 h. Plasma metanephrine concentrations were 0.86, 0.85, 4.22, 3.68, 2.30, 2.05, 2.14 (SEM = 0.327) nM, respectively at Preload, 0, 2, 4, 6, 8, and 10 h, indicating that stress peaked during the initial hours and decreased thereafter. Interaction effects were not significant. Habituation to trailer may be beneficial in mood and energy stabilization in goats during long-distance transportation. Metanephrine concentrations may more accurately reflect stress levels in goats.

The concentration of metanephrine and normetanephrine in the most common indications for biochemical monitoring

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Systemic inflammation and sympathetic activation in gestational diabetes mellitus with obstructive sleep apnea

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

Influence of nitisinone and its metabolites on l-tyrosine metabolism in a model system

Nitisinone (NTBC) is currently used for the treatment of tyrosinemia type 1, a rare disease. It also exhibits potential in the treatment of other orphan diseases as well as nervous system disorders – this is however limited by its side effects. In all living organisms, NTBC inhibits 4-hydroxyphenylpyruvate dioxygenase activity, thereby affecting l-tyrosine (L-TYR) catabolism, which results in the therapeutic effect. The NTBC metabolites formed in patient's body is one of the causes of its side effects. The influence of NTBC and its metabolites; 2-amino-4-(trifluoromethyl)benzoic acid, 2-nitro-4-(trifluoromethyl)benzoic acid, and cyclohexane-1,3-dione on L-TYR catabolism was investigated in Raphanus sativus var. longipinnatus. Based on targeted LC–MS/MS analysis the concentration of NTBC and its metabolites in exposed plant tissues was determined. Based on non-targeted LC-MS/MS analysis the concentrations of products of L-TYR catabolism: levodopa, epinephrine, norepinephrine, normetanephrine, dopamine, tyramine and vitamins C, B5 and B6, additionally leucine and valine were identified as influenced by the NTBC or its metabolites.NTBC and its metabolites influenced L-TYR catabolism differently. Particularly significant changes were found in the content of epinephrine and normetanephrine: in the plant tissues exposed to NTBC, an increase in the content of these neurotransmitters was found (+42%), whereas in the plant treated with 2-amino-4-(trifluoromethyl)benzoic acid or 2-nitro-4-(trifluoromethyl)benzoic acid a decrease in concentration (−39% and 55%, respectively) was observed. Cyclohexane-1,3-dione does not influence epinephrine and normetanephrine concentration. The conclusions of this study provide a platform for expanded research on the causes of side effects of NTBC treatment.

Optimized procedures for testing plasma metanephrines in patients on hemodialysis

Diagnosis of pheochromocytomas and paragangliomas in patients receiving hemodialysis is troublesome. The aim of the study was to establish optimal conditions for blood sampling for mass spectrometric measurements of normetanephrine, metanephrine and 3-methoxytyramine in patients on hemodialysis and specific reference intervals for plasma metanephrines under the most optimal sampling conditions. Blood was sampled before and near the end of dialysis, including different sampling sites in 170 patients on hemodialysis. Plasma normetanephrine concentrations were lower (P < 0.0001) and metanephrine concentrations higher (P < 0.0001) in shunt than in venous blood, with no differences for 3-methoxytyramine. Normetanephrine, metanephrine and 3-methoxytyramine concentrations in shunt and venous blood were lower (P < 0.0001) near the end than before hemodialysis. Upper cut-offs for normetanephrine were 34% lower when the blood was drawn from the shunt and near the end of hemodialysis compared to blood drawn before hemodialysis. This study establishes optimal sampling conditions using blood from the dialysis shunt near the end of hemodialysis with optimal reference intervals for plasma metanephrines for the diagnosis of pheochromocytomas/paragangliomas among patients on hemodialysis.

Diagnostic Accuracy of Salivary Metanephrines in Pheochromocytomas and Paragangliomas

Measurements of plasma free metanephrines are recommended for diagnosing pheochromocytomas and paragangliomas (PPGL). Metanephrines can be detected in saliva with LC-MS/MS with sufficient analytical sensitivity and precision. Because collecting saliva is noninvasive and less cumbersome than plasma or urine sampling, we assessed the diagnostic accuracy of salivary metanephrines in diagnosing PPGL. This 2-center study included 118 healthy participants (44 men; mean age: 33 years (range: 19--74 years)), 44 patients with PPGL, and 54 patients suspected of PPGL. Metanephrines were quantified in plasma and saliva using LC-MS/MS. Diagnostic accuracy; correlation between plasma and salivary metanephrines; and potential factors influencing salivary metanephrines, including age, sex, and posture during sampling, were assessed. Salivary metanephrines were significantly higher in patients with PPGL compared with healthy participants (metanephrine (MN): 0.19 vs 0.09 nmol/L, P < 0.001; normetanephrine (NMN): 2.90 vs 0.49 nmol/L, P < 0.001). The diagnostic sensitivity and specificity of salivary metanephrines were 89% and 87%, respectively. Diagnostic accuracy of salivary metanephrines was 88%, with an area under the ROC curve of 0.880. We found a significant correlation between plasma and salivary metanephrines (Pearson correlation coefficient: MN, 0.86, P < 0.001; NMN, 0.83, P < 0.001). Salivary NMN concentrations were higher when collected in a seated position compared with supine (P < 0.001) and increased with age (P < 0.001). Salivary metanephrines are a promising tool in the biochemical diagnosis of PPGL. Salivary metanephrines correlate with plasma free metanephrines and are increased in patients with PPGL. At this time, however, salivary metanephrines cannot replace measurement of plasma free metanephrines.

Multivariate Statistical Approach for Nephrines in Women with Obesity.

Catecholamines are physiological regulators of carbohydrate and lipid metabolism during stress, but their chronic influence on metabolic changes in obese patients is still not clarified. The present study aimed to establish the associations between the catecholamine metabolites and metabolic syndrome (MS) components in obese women as well as to reveal the possible hidden subgroups of patients through hierarchical cluster analysis and principal component analysis. The 24-h urine excretion of metanephrine and normetanephrine was investigated in 150 obese women (54 non diabetic without MS, 70 non-diabetic with MS and 26 with type 2 diabetes). The interrelations between carbohydrate disturbances, metabolic syndrome components and stress response hormones were studied. Exploratory data analysis was used to determine different patterns of similarities among the patients. Normetanephrine concentrations were significantly increased in postmenopausal patients and in women with morbid obesity, type 2 diabetes, and hypertension but not with prediabetes. Both metanephrine and normetanephrine levels were positively associated with glucose concentrations one hour after glucose load irrespectively of the insulin levels. The exploratory data analysis showed different risk subgroups among the investigated obese women. The development of predictive tools that include not only traditional metabolic risk factors, but also markers of stress response systems might help for specific risk estimation in obesity patients.

Incremental "Therapeutic" Myocardial Exposure to Catecholamines: Incidence and Impact in Takotsubo Syndrome.

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 1149pmol/L vs 938pmol/L; p = 0.03). Long-term survival (median follow-up 3years) 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.

Prevalence and progression of carbohydrate disorders in patients with pheochromocytoma/paraganglioma: retrospective single-center study

BackgroundCarbohydrate disorders are the most frequent metabolic disorders, affecting a significant proportion of patients with pheochromocytoma. ObjectiveA retrospective study assessed the prevalence and progression of carbohydrate disorders in 204 patients (92 men, 112 women) with histologically proven pheochromocytoma diagnosed in a single specialized tertiary center during a 40-year period (1978–2017). One hundred were followed-up after tumor removal. ResultsCarbohydrate disorders were diagnosed in 49.5% of cases: 30.4% with diabetes and, 19.1% prediabetes. Subjects with carbohydrate disorders had significantly greater age at diagnosis and higher 24-hour urine metanephrine and normetanephrine concentrations than those with normal glucose tolerance. One-third of patients with diabetes achieved good glycemic control under oral treatment (54% on metformin monotherapy). One-third of patients overall required preoperative insulin treatment. Postoperative follow-up (100 patients; 5-year mean duration) showed reduced prevalence of diabetes (13% vs. 33%; P=0.0007) and prediabetes (12% vs. 24%; P=0.027). Almost 60% of subjects initially diagnosed with carbohydrate disorders recovered normal glucose tolerance after surgery; these subjects had significantly higher preoperative urine metanephrine/normetanephrine levels than those with persistent diabetes/prediabetes. Correlation analysis revealed a moderate negative relationship between urine metanephrine/normetanephrine concentration and the outcome of the carbohydrate disorders (Spearmen's Rho=−0.507; P=0.013). There was no significant difference according to pre- or postoperative prevalence of obesity (15% vs. 16%; P=0.845) or dyslipidemia (46% vs. 39%; P=0.316). ConclusionsCarbohydrate disorders affect approximately 50% of pheochromocytoma patients; 30% develop overt diabetes, which may be the only clinical manifestation in some rare cases. Pheochromocytoma-related diabetes is more likely to affect patients with predominant adrenaline secretion. It is often easy to control and usually requires oral antidiabetic treatment. Reversibility of carbohydrate disorders depend on severity, preoperative metanephrine level, age and weight.

Antecedent cancer in Takotsubo syndrome predicts both cardiovascular and long-term mortality

BackgroundTakotsubo syndrome (TTS), primarily an acute myocardial inflammatory condition engendered by catecholamine exposure, is associated with similar long-term mortality rates to those of patients with acute myocardial infarction. However, there is increasing evidence of a nexus between TTS and underlying malignancies:- many patients have antecedent cancer (A/Ca), while incremental risk of late cancer-related death has also been reported.PurposeTo evaluate potential interactions between A/Ca among TTS patients and both early and late clinical course.MethodsThree hundred forty-six consecutive TTS patients [aged 69 ± 13 (SD) years, males: 8.2%] were prospectively followed up for a median duration of 4.1 (IQR 2.2–6.4) years. Associations between A/Ca and severity of acute attacks, in-hospital complications and long-term death rates were sought utilising univariate analyses followed by multiple logistic regression analysis.ResultsA/Ca (present in 16.8% of patients) was associated with (i) greater elevation of hs-CRP and NT-proBNP concentrations (p = 0.01 and 0.04, respectively), (ii) more complicated in-hospital clinical course, with major adverse cardiac events (MACE) in 30.9% of patients, compared to 18.2% in non-A/Ca patients (p = 0.04). Long-term all-cause mortality rate was also greater [hazard ratio (HR) = 2.4, p = 0.0001] in A/Ca patients, with an excess cardiovascular (CVS) fatality rate (HR = 3.1, p = 0.001). On multivariate analysis, male gender, peak plasma concentrations of normetanephrine and hs-CRP, early arrhythmias and development of shock, but not A/Ca per se, were all independently associated with increased long-term mortality rate. Furthermore, patients discharged on β-adrenoceptor antagonists (βBl) or angiotensin converting enzyme inhibitors/ angiotensin receptor blockers (ACEi/ARB) had lower long-term mortality rates (β = − 0.2, p = 0.01; β = − 0.14, p = 0.05, respectively).Conclusions(1) A/Ca is associated with greater clinical severity of initial TTS attacks and substantially greater long-term CVS-related as well as all-cause mortality.(2) Post-discharge therapy with either βBl or ACEi/ARB is associated with reductions in long-term mortality rates.Overall, the current data suggest operation of substantial interactions between neoplasia and TTS, both at the level of pathogenesis and of outcomes.