Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension.

Introduction: Neuroblastoma (NB) is a pediatric cancer of the developing sympathetic nervous system. It produces and releases metanephrines, which are used as biomarkers for diagnosis in plasma and urine. However, plasma catecholamine concentrations remain generally normal in children with NB. Thus, unlike pheochromocytoma and paraganglioma (PHEO/PGL), two other non-epithelial neuroendocrine tumors, hypertension is not part of the usual clinical picture of patients with NB. This suggests that the mode of production and secretion of catecholamines and metanephrines in NB is different from that in PHEO/PGL, but little is known about these discrepancies. Here we aim to provide a detailed comparison of the biosynthesis, metabolism and storage of catecholamines and metanephrines between patients with NB and PHEO. Method: Catecholamines and metanephrines were quantified in NB and PHEO/PGL patients from plasma and tumor tissues by ultra-high pressure liquid chromatography tandem mass spectrometry. Electron microscopy was used to quantify neurosecretory vesicles within cells derived from PHEO tumor biopsies, NB-PDX and NB cell lines. Chromaffin markers were detected by qPCR, IHC and/or immunoblotting. Results: Plasma levels of metanephrines were comparable between NB and PHEO patients, while catecholamines were 3.5-fold lower in NB vs PHEO affected individuals. However, we observed that intratumoral concentrations of metanephrines and catecholamines measured in NB were several orders of magnitude lower than in PHEO. Cellular and molecular analyses revealed that NB cell lines, primary cells dissociated from human tumor biopsies as well as cells from patient-derived xenograft tumors (NB-PDX) stored a very low amount of intracellular catecholamines, and contained only rare neurosecretory vesicles relative to PHEO cells. In addition, primary NB expressed reduced levels of numerous chromaffin markers, as compared to PHEO/PGL, except catechol O-methyltransferase and monoamine oxidase A. Furthermore, functional assays through induction of chromaffin differentiation of the IMR32 NB cell line with Bt2cAMP led to an increase of neurosecretory vesicles able to secrete catecholamines after KCl or nicotine stimulation. Conclusion: The low amount of neurosecretory vesicles in NB cytoplasm prevents catecholamine storage and lead to their rapid transformation by catechol O-methyltransferase into metanephrines that diffuse in blood. Hence, in contrast to PHEO/PGL, catecholamines are not secreted massively in the blood, which explains why systemic hypertension is not observed in most patients with NB.

Decrease in Salivary Serotonin in Response to Probiotic Supplementation With Saccharomyces boulardii in Healthy Volunteers Under Psychological Stress: Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Bacterial probiotics are thought to exert a serotonergic effect relevant to their potential antidepressant and pro-cognitive action, but yeast probiotics have not been tested. The aim of the present study was to determine whether 30-day supplementation with Saccharomyces boulardii affects the level of salivary serotonin under psychological stress and identify the factors associated with it. Methods: Healthy medical students were randomized to ingest Saccharomyces boulardii CNCM I-1079 or placebo before a stressful event. Salivary serotonin concentration was assessed before and at the end of supplementation. Moreover, obtained results were compared to psychological, biochemical, physiological and sociodemographic study participants data. Results: Data of thirty-two participants (22.8 ± 1.7 years of age, 16 males) was available for the main analysis. Supplementation with Saccharomyces boulardii decreased salivary serotonin concentration under psychological stress by 3.13 (95% CI 0.20 to 6.07) ng/mL, p = 0.037, as compared to placebo. Salivary serotonin was positively correlated with salivary metanephrine (ß = 0.27, 95% CI 0.02 to 0.52, p = 0.031) and pulse rate (ß = 0.28, 95% CI 0.05 to 0.50, p = 0.018), but insignificantly with anxiety, depression, eating attitudes and information retrieval. Conclusions: Saccharomyces boulardii CNCM I-1079 may be distinct from bacterial probiotics in its salivary serotonergic effect, which appears positively linked to symapathoadrenal markers. The study requires cautious interpretation, and further investigation.

A 3-min UPLC-MS/MS method for the simultaneous determination of plasma catecholamines and their metabolites: Method verification and diagnostic efficiency.

OBJECTIVE: To verify a rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantification of catecholamines and their metabolites, and to validate its efficiency for the diagnosis of phaeochromocytomas and paragangliomas (PPGLs). METHODS: Plasma samples were pretreated with solid-phase extraction, followed by a 3-min UPLC-MS/MS analysis to quantify epinephrine (E), norepinephrine (NE), dopamine (DA), metanephrine (MN), normetanephrine (NMN) and 3-methoxytyramine (3-MT), simultaneously. The UPLC-MS/MS method was comprehensively verified and its diagnostic efficiency on PPGLs was tested using 7 PPGLs and 408 non-PPGLs patient plasma samples. RESULTS: Using the developed method, the limit of detections (LODs) of the 6 analytes ranged from 0.0002 nmol/L (MN) to 0.0250 nmol/L (NE), while the lower limit of measuring intervals (LLMIs) ranged from 0.05 nmol/L (E, MN and NMN) to 0.10 nmol/L (NE and DA). The reportable ranges were 0.05-30.00 nmol/L for E, MN and NMN, 0.10-30.00 nmol/L for NE and DA, 1.00-300.00 pg/mL for 3-MT. No significant matrix effect was detected after correcting using internal standard. Besides, intra-day and inter-day precision were also within acceptance criteria with coefficient of variations (CVs) ≤ 15% and recoveries ranged from 95% to 115% for all the 6 analytes. The carryover effect was lower than 10%. Its diagnostic efficiency for PPGLs was significantly increased, the areas under the receiver operating characteristic (ROC) curves were increased from 68.7% to 89.1% (using E, NE and DA) to 75.2%-99.9% (using MN, NMN and 3-MT). CONCLUSION: This study verified a rapid UPLC-MS/MS method for the determination of catecholamines and their metabolites in human plasma. It showed high diagnostic efficiency and will serve as an important tool to avoid the risk for missing patients with PPGLs.

Síndrome de vasoconstricción cerebral reversible secundario a un paraganglioma yugular secretor de metanefrinas / Reversible cerebral vasoconstriction syndrome secondary to secreting jugular paraganglioma

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Effects of Trilostane on urinary Catecholamines and their metabolites in dogs with Hypercortisolism.

BACKGROUND: Glucocorticoids influence the synthesis and metabolism of catecholamines (epinephrine and norepinephrine) and metanephrines (metanephrine and normetanephrine). The aim of this study was to measure urinary catecholamines and metanephrines in dogs with hypercortisolism before and during trilostane therapy. Urine samples were collected during initial work up and during therapy with trilostane in 14 dogs with hypercortisolism and in 25 healthy dogs. Epinephrine, norepinephrine, metanephrine and normetanephrine were measured using high-pressure liquid chromatography and expressed as ratios to urinary creatinine concentration. RESULTS: Untreated dogs with hypercortisolism had significantly higher epinephrine, norepinephrine, and normetanephrine:creatinine ratios compared to healthy dogs. During trilostane therapy, urinary catecholamines and their metabolites did not decrease significantly. However, dogs with low post-ACTH cortisol concentrations during trilostane therapy had less increased epinephrine, norepinephrine and normetanephrine:creatinine ratios compared to healthy dogs. There was no correlation of urinary catecholamines and their metabolites with baseline or post-ACTH cortisol or endogenous ACTH concentrations during trilostane therapy. CONCLUSION: Influences between steroid hormones and catecholamines seem to occur, as dogs with hypercortisolism have significantly higher urinary epinephrine, norepinephrine, and normetanephrine:creatinine ratios. Once-daily trilostane therapy does not lead to a significant decrease in catecholamines and their metabolites. Trilostane-treated dogs still have increased urinary epinephrine, norepinephrine and normetanephrine:creatinine ratios during trilostane therapy.

Autoimmune Voltage-Gated Potassium Channelopathy Presenting With Catecholamine Excess.

BACKGROUND: Autoimmune voltage-gated potassium channelopathies have been associated with a range of neurological presenting symptoms, including central, peripheral, and autonomic dysfunction. PATIENT DESCRIPTION: We describe a 12-year-old boy who presented with nine months of pain, anxiety, and 30-pound weight loss. He was admitted for failure to thrive, then noted to be persistently hypertensive and tachycardic. Plasma metanephrines and urine metanephrines and catecholamines were elevated. Extensive investigation for causes of elevated catecholamines, such as hyperthyroidism or catecholamine-secreting tumor, was negative. A paraneoplastic panel was positive for voltage-gated potassium channel antibodies. Treatment with intravenous immunoglobulin and pulse methylprednisolone led to complete resolution of symptoms, weight gain, and normalization of vital signs and plasma metanephrines. CONCLUSION: Voltage-gated potassium channel antibodies should be considered as part of the differential in patients presenting with elevated metanephrine and catecholamine secretion.

Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels.

AIM: The present study was to compare the effects of nicotinic acid and nicotinamide on the plasma methyl donors, choline and betaine. METHODS: Thirty adult subjects were randomly divided into three groups of equal size, and orally received purified water (C group), nicotinic acid (300 mg, NA group) or nicotinamide (300 mg, NM group). Plasma nicotinamide, N1-methylnicotinamide, homocysteine, betaine and choline levels before and 1.5-h and 3-h post-dosing, plasma normetanephrine and metanephrine concentrations at 3-h post-dosing, and the urinary excretion of N1-methyl-2-pyridone-5-carboxamide during the test period were examined. RESULTS: The level of 3-h plasma nicotinamide, N1-methylnicotinamide, homocysteine, the urinary excretion of N1-methyl-2-pyridone-5-carboxamide and pulse pressure (PP) in the NM group was 221%, 3972%, 61%, 1728% and 21.2% higher than that of the control group (P < 0.01, except homocysteine and PP P < 0.05), while the 3-h plasma betaine, normetanephrine and metanephrine level in the NM group was 24.4%, 9.4% and 11.7% lower (P < 0.05, except betaine P < 0.01), without significant difference in choline levels. Similar but less pronounced changes were observed in the NA group, with a lower level of 3-h plasma N1-methylnicotinamide (1.90 ± 0.20 µmol/l vs. 3.62 ± 0.27 µmol/l, P < 0.01) and homocysteine (12.85 ± 1.39 µmol/l vs. 18.08 ± 1.02 µmol/l, P < 0.05) but a higher level of betaine (27.44 ± 0.71 µmol/l vs. 23.52 ± 0.61 µmol/l, P < 0.05) than that of the NM group. CONCLUSION: The degradation of nicotinamide consumes more betaine than that of nicotinic acid at identical doses. This difference should be taken into consideration in niacin fortification.

Catecholamines and their O-methylated metabolites in vitreous humor in hypothermia cases.

PURPOSE: The aim of this study was to assess the diagnostic value of catecholamines and their O-methylated metabolites in vitreous humor samples in identifying antemortem cold exposure and fatal hypothermia in the forensic casework. METHODS: A total of 80 autopsy cases (40 hypothermia fatalities and 40 cases in which hypothermia as the main or contributory cause of death was excluded) were selected for this study. Catecholamines and their O-methylated metabolites were measured in urine and vitreous humor samples collected at autopsy. RESULTS: Urine catecholamine and their O-methylated metabolite concentrations were significantly higher in hypothermia-related deaths. On the other hand, measurements in vitreous humor samples did not reveal statistically significant differences between hypothermia-related deaths and controls. CONCLUSIONS: Globally considered, our findings seem to suggest that, contrary to urine catecholamines and their O-methylated metabolites, vitreous levels of these compounds appear to be of limited value in characterizing human antemortem stress reactions due to cold exposure and can hardly be used in the forensic setting to support the diagnosis of hypothermia.

Mass spectrometric quantification of salivary metanephrines-A study in healthy subjects.

BACKGROUND: Determination of metanephrine (MN), normetanephrine (NMN), and 3-methoxytyramine (3-MT) in saliva may offer potential diagnostic advantages in diagnosing pheochromocytoma. METHODS: In this preliminary study, we determined metanephrine concentrations in saliva of healthy subjects and the relationship with simultaneously measured plasma metanephrines. We also studied the possible influence of pre-analytical conditions such as a collection device, awakening, posture, and eating on the salivary metanephrine levels. RESULTS: Eleven healthy subjects were included. Fasting blood and saliva samples were collected in seated position and after 30min of horizontal rest. Plasma and salivary MN, NMN, and 3-MT concentrations were determined using a high-performance liquid chromatography tandem mass spectrometric technique (LC-MS/MS) with automated solid phase extraction sample preparation. Metanephrines were detectable in saliva from all participants both in seated and supine position. No significant correlations were observed between the MN, NMN, and 3-MT concentrations in saliva and plasma in seated or supine position. Furthermore, there was no difference between MN, NMN, and 3-MT samples collected with or without a collection device. CONCLUSION: Metanephrines can be detected in saliva with LC-MS/MS with sufficient sensitivity and precision. Our findings warrant evaluation of salivary metanephrine measurement as a novel laboratory tool in the work-up of patients suspected of having a pheochromocytoma.

Metanephrine neuroendocrine tumor marker detection by SERS using Au nanoparticle/Au film sandwich architecture.

Neuroendocrine tumors, such as pheochromocytoma or paraganglioma, are dangerous tumors that constitute a potential threat for a large number of patients. Currently, the biochemical diagnosis of neuroendocrine tumors is based on measurement of the direct secretory products of the adrenomedullary-sympathetic system or of their metabolites, such as catecholamines or their metanephrine derivatives, from plasma or urine. The techniques used for analysis of plasma free metanephrines, i.e. high-performance liquid chromatography or high-performance liquid chromatography coupled with mass-spectrometry are technically-demanding and time consuming, which limit their availability. Here we demonstrate a simple, fast and low-cost method for detecting metanephrine by Surface Enhanced Raman Scattering (SERS). The protocol consists in using evaporation-induced self-assembly of gold (Au) nanoparticles incubated with the analyte, on planar gold films. The assembly process produces regions with a dense distribution of both inter-particle gaps and particle-film gaps. Finite-difference time-domain simulations confirm that both kinds of gaps are locations of enhanced electromagnetic fields resulting from inter-particle and particle-film plasmonic coupling, useful for SERS amplification. Metanephrine vibrational bands assignment was performed according to density functional theory calculations. Metanephrine metabolite was detected in liquid at concentration levels lower than previously reported for other similar metabolites. The obtained results demonstrate that the Au nanoparticle/Au film exhibits noticeable SERS amplification of the adsorbed metabolite and can be used in the design of efficient, stable SERS-active substrates for the detection and identification of specific tumor markers.

Is Preoperative Biochemical Testing for Pheochromocytoma Necessary for All Adrenal Incidentalomas?

This study examined whether imaging phenotypes obtained from computed tomography (CT) can replace biochemical tests to exclude pheochromocytoma among adrenal incidentalomas (AIs) in the preoperative setting.We retrospectively reviewed the medical records of all patients (n = 251) who were admitted for operations and underwent adrenal-protocol CT for an incidentally discovered adrenal mass from January 2011 to December 2012. Various imaging phenotypes were assessed for their screening power for pheochromocytoma. Final diagnosis was confirmed by biopsy, biochemical tests, and follow-up CT.Pheochromocytomas showed similar imaging phenotypes as malignancies, but were significantly different from adenomas. Unenhanced attenuation values ≤10 Hounsfield units (HU) showed the highest specificity (97%) for excluding pheochromocytoma as a single phenotype. A combination of size ≤3 cm, unenhanced attenuation values ≤ 10 HU, and absence of suspicious morphology showed 100% specificity for excluding pheochromocytoma.Routine noncontrast CT can be used as a screening tool for pheochromocytoma by combining 3 imaging phenotypes: size ≤3 cm, unenhanced attenuation values ≤10 HU, and absence of suspicious morphology, and may substitute for biochemical testing in the preoperative setting.

Angiotensin II status and sympathetic activation among hypertensive patients in Uganda: a cross-sectional study.

BACKGROUND: Sympathetic activation and renin-angiotensin system are essential for development and sustenance of hypertension. However, the status of these systems has not been well evaluated among patients in an African setting. This study therefore set out to assess the angiotensin II status and sympathetic activation among hypertensive patients in Uganda. METHODS: In this cross sectional study conducted at Mulago, the national referral hospital, blood samples were taken to measure angiotensin II, metanephrines and normetanephrines. Urine samples were also taken for measuring urine creatinine and sodium. The angiotensin II categories were defined using the Mosby's Diagnostic and Laboratory Test References. 9th ed while the metanephrines and normetanephrine categories were defined using the Makerere University Biosafety II Immunology Laboratory reference values. RESULTS: 162 patients were consented and enrolled into the study, of these 136 (84 %) had low, 15 (9 %) had normal, while, 11 (7 %) had high angiotensin II levels. 142 (88 %) participants had normal levels of metanephrine, while 20 (12 %) had high levels. Only 88 were assessed for metanephrines and of these 85 (97 %) had normal, while 3 (3 %) had raised levels. Urine sodium was associated with low and normal angiotensin II levels (P value 0.007). Female gender and diastolic blood pressure were associated with a protective effect against high normetanephrines (OR 0.29, P value 0.015), 80-89 mmHg (OR 0.19, p value 0.053), above 100 mmHg (OR 0.27, p value 0.022). Current smoking status was associated with high risk for abnormal normetanephrines (OR 17.6, P value -0.022) while former smoking was associated with high risk for abnormal metanephrines (OR 18.7, p value 0.022). After multivariate analysis, all the significant variables at bivariate analysis were still significant except those who stopped smoking and those with a BP at 80-89 which were not significant. CONCLUSIONS: Hypertensive patients in this setting have predominantly low angiotensin II hypertension as a result of high salt intake. Sympathetic activation is not a significant mechanism of hypertension in this study population, more so in the females, with the exception of smokers who have a highly activated sympathetic system. Therefore, the use of agents targeting renin angiotensin and sympathetic systems as single first line antihypertensive agents in this setting should be re-evaluated if such patients are to be treated effectively.

Pheochromocytoma: clinical review based on a rare case in adolescence.

Pheochromocytomas are rare tumours originating in chromaffin cells, representing 0.1-1% of all secondary hypertension (HT) cases. The majority are benign and unilateral, characterised by the production of catecholamines and other neuropeptides. Mainly located in the adrenal gland, they are more frequent between the 3rd and 5th decades of life; however, 10-25% can be associated with genetic familial syndromes (multiple endocrine neoplasia type 2 (MEN 2), type 1 neurofibromatosis and Von-Hippel-Landau disease in younger ages. The authors present a rare case of secondary HT due to a pheochromocytoma in a 15-year-old patient, whose metanephrine assay confirmed the diagnosis, and abdominal ultrasound and CT localised the tumour in the adrenal gland. HT was controlled with α and ß blockers, with posterior retroperitoneal laparoscopic surgical intervention and subsequent resolution of HT. Age and concomitant hyperparathyroidism compelled genetic testing for the exclusion of MEN 2, which was negative.

Adrenal incidentalomas: a disease of modern technology offering opportunities for improved patient care.

Adrenal incidentalomas (AIs) are found in approximately 4% of patients undergoing abdominal imaging, with peak prevalence in the sixth and seventh decades of life. Detection of AI warrants clinical, biochemical, and radiological evaluation to establish its secretory status and risk of malignancy. Careful review of the lipid content, size, and imaging phenotype of an adrenal mass is needed to evaluate the risk for malignancy. Identification of an AI may be an opportunity to identify an underlying secretory tumor that may have been otherwise unrecognized. A practical approach to investigation and follow-up of AIs is presented in this article.

Catecholamine metabolism in paraganglioma and pheochromocytoma: similar tumors in different sites?

Pheochromocytoma (PHEO) and paraganglioma (PGL) are catecholamine-producing neuroendocrine tumors that arise respectively inside or outside the adrenal medulla. Several reports have shown that adrenal glucocorticoids (GC) play an important regulatory role on the genes encoding the main enzymes involved in catecholamine (CAT) synthesis i.e. tyrosine hydroxylase (TH), dopamine ß-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT). To assess the influence of tumor location on CAT metabolism, 66 tissue samples (53 PHEO, 13 PGL) and 73 plasma samples (50 PHEO, 23 PGL) were studied. Western blot and qPCR were performed for TH, DBH and PNMT expression. We found a significantly lower intra-tumoral concentration of CAT and metanephrines (MNs) in PGL along with a downregulation of TH and PNMT at both mRNA and protein level compared with PHEO. However, when PHEO were partitioned into noradrenergic (NorAd) and mixed tumors based on an intra-tumoral CAT ratio (NE/E >90%), PGL and NorAd PHEO sustained similar TH, DBH and PNMT gene and protein expression. CAT concentration and composition were also similar between NorAd PHEO and PGL, excluding the use of CAT or MNs to discriminate between PGL and PHEO on the basis of biochemical tests. We observed an increase of TH mRNA concentration without correlation with TH protein expression in primary cell culture of PHEO and PGL incubated with dexamethasone during 24 hours; no changes were monitored for PNMT and DBH at both mRNA and protein level in PHEO and PGL. Altogether, these results indicate that long term CAT synthesis is not driven by the close environment where the tumor develops and suggest that GC alone is not sufficient to regulate CAT synthesis pathway in PHEO/PGL.

Diagnostic accuracy of plasma free metanephrines in a seated position compared with 24-hour urinary metanephrines in the investigation of pheochromocytoma.

The aim of this study was to determine the diagnostic efficacy of free metanephrines in plasma samples drawn in the seated position compared with 24-h urinary metanephrines in detecting pheochromocytomas in Asian patients. This prospective study was conducted at Samsung Medical Center between May 2010 and July 2011. The study contained 245 subjects, including 28 patients with histologically-proven pheochromocytoma, 44 with histologically-proven non-pheochromocytoma, 112 controls suspected of having tumors but with negative investigations during two or more years of follow-up, and 45 healthy normotensive volunteers. Plasma-free metanephrines were measured by LC-MS/MS. The cut-off values with optimal sensitivity and specificity for plasma metanephrine and plasma normetanephrine were 0.33 nmol/L and 0.61 nmol/L, respectively. Both the plasma metanephrines measurement and urinary metanephrines measurement had a sensitivity of 96.4% (p = 1.00). However, the urinary metanephrines measurement was significantly more specific than the plasma metanephrines measurement (94.2% vs. 75.6%; p < 0.001). When we applied cut-off values based on BMI, specificity improved from 75.6% to 87.2%, with a comparable gain in sensitivity. From a diagnostic perspective, measurement of free metanephrines in plasma drawn in the seated position is highly sensitive but insufficiently specific when compared with measurement of 24-h urinary fractionated metanephrines. The specificity may be improved by applying cut-off values based on BMI. We suggest that free metanephrines in plasma drawn from seated position can also be used as an initial screening test to ensure that pheochromocytomas are not missed in Asian patients.

Enzyme and acid deconjugation of plasma sulfated metanephrines.

BACKGROUND: Total (i.e. free+sulfated) metanephrines in plasma is a biomarker for the diagnosis of pheochromocytoma/paraganglioma. Sulfated metanephrines must be completely deconjugated by perchloric acid hydrolysis or sulfatase treatment prior to analytical measurement to enable quantification by current techniques. In this report, we compare the yield and efficiency of both methods. METHODS: The deconjugation rate of synthetic sulfated metanephrines (normetanephrine (S-NMN), metanephrine (S-MN) and methoxytyramine (S-MT)) spiked in charcoal-stripped plasma was determined by boiling perchloric acid and compared to sulfatase treatment. Total plasma metanephrines (MN, NMN and MT) were also determined in patient samples by both methods. RESULTS: The complete deconjugation of sulfated metanephrines is achieved after 30 min incubation with 0.1M boiling perchloric acid or upon sulfatase treatment. Ten minutes of acid hydrolysis (gold-standard) leads to a 30% underestimation of metanephrine concentrations. The enzyme hydrolysis is time and amount of sulfatase dependent. The rate of hydrolysis is analyte-dependent (MT>>NMN>MN), although it must contain at least 0.8 U/ml of sample. The Deming regression curves comparing acid versus enzyme hydrolysis on patient samples assessed that both methods gave similar unbiased concentrations. CONCLUSION: Enzyme and acid treatments are equivalent and efficient for removing sulfate from metanephrines as long as the optimal protocol is used for each method. However, the gold standard method for acid hydrolysis at 10 min established more than 20 years ago was not satisfactory regarding the hydrolysis of metanephrines in plasma.

Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of biochemically active HNPGL than 24-h urinary excretion rates of catecholamines and metabolites.

CONTEXT: A substantial number of patients with head and neck paragangliomas (HNPGLs) have biochemically active tumors, evidenced by increased urinary excretion of catecholamines and metabolites, including 3-methoxytyramine (3MT). It is unclear whether plasma levels of these parameters are more sensitive to detect biochemical activity in HNPGL patients than urinary excretion rates. OBJECTIVE: To compare plasma free levels vs urinary excretion rates of deconjugated 3MT and combined metanephrines (MNs) in patients with HNPGL. PATIENTS AND METHODS: We included 124 consecutive patients with HNPGL for screening of catecholamine excess by measurement of 24-h urinary excretion rates of deconjugated (nor)metanephrine, (nor)epinephrine, dopamine, vanillylmandelic acid, 3MT, and plasma free levels of (nor)metanephrine and 3MT. RESULTS: Plasma free 3MT levels were increased in 35 of the 124 patients (28%), whereas 24-h urinary excretion of deconjugated 3MT was increased in 30 patients (24%) (P=0.13). Plasma free MN levels were increased in seven patients (6%) and urinary deconjugated MN levels in six patients (5%) (P=1.00). Plasma free normetanephrine (NMN) levels were increased in seven patients (6%), and five patients had increased urinary excretion of deconjugated NMN (4%) (P=0.69). Plasma free combined MN levels (NMN, MN, and 3MT) were increased in 41 patients (33%), whereas 24-h urinary excretion rates of deconjugated combined MNs were increased in 33 patients (27%, P<0.05). CONCLUSIONS: The combined levels of free MNs and free 3MT in plasma indicate a higher number of biochemically active HNPGLs than the 24-h urinary excretion rates of these markers.