J W Lenders

Carl Gustav Carus-Institut, Pforzheim, Baden-Württemberg, Germany

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Publications (265)1311.58 Total impact

  • A van Berkel, K Pacak, J W M Lenders
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    ABSTRACT: Localization of phaeochromocytomas and paragangliomas (PPGLs) should involve functional imaging since anatomical imaging modalities can either fail to locate the tumor or can be suboptimal due to an anatomical abnormality or previous surgery. Functional imaging is particularly useful to fully delineate the extent of disease by using the whole body scan and the evaluation of multifocality, metastatic or recurrent disease. An increasing number of radiolabeled tracers have become available for tumor visualization during the past decade. (123) I-meta-iodobenzylguanidine scintigraphy is the most widely used functional imaging modality and its sensitivity to identify chromaffin cell tumors varies from 85-88% for phaeochromocytomas and 56-76% for paragangliomas, while specificity ranges between 70-100% and 84-100%, respectively. This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 05/2014; · 3.40 Impact Factor
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    ABSTRACT: Context: Somatic mutations in genes that influence cell entry of calcium have been identified in aldosterone-producing adenomas (APAs) of adrenal cortex in primary aldosteronism (PA). Many adrenal glands removed for suspicion of APA do not contain a single adenoma but nodular hyperplasia. Objective: The objective of the study was to assess multinodularity and phenotypic and genotypic characteristics of adrenals removed because of the suspicion of APAs. Design and Methods: We assessed the adrenals of 53 PA patients for histopathological characteristics and immunohistochemistry for aldosterone (P450C18) and cortisol (P450C11) synthesis and for KCNJ5, ATP1A1, ATP2B3, and CACNA1D mutations in microdissected nodi. Results: Glands contained a solitary adenoma in 43% and nodular hyperplasia in 53% of cases. Most adrenal glands contained only one nodule positive for P450C18 expression, with all other nodules negative. KCNJ5 mutations were present in 22 of 53 adrenals (13 adenoma and nine multinodular adrenals). An ATP1A1 and a CACNA1D mutation were found in one multinodular gland each and an ATP2B3 mutation in five APA-containing glands. Mutations were always located in the P450C18-positive nodule. In one gland two nodules containing two different KCNJ5 mutations were present. Zona fasciculata-like cells were more typical for KCNJ5 mutation-containing nodules and zona glomerulosa-like cells for the other three genes. Conclusions: Somatic mutations in KCNJ5, ATP1A1, or CACNA1D genes are not limited to APAs but are also found in the more frequent multinodular adrenals. In multinodular glands, only one nodule harbors a mutation. This suggests that the occurrence of a mutation and nodule formation are independent processes. The implications for clinical management remain to be determined.
    The Journal of Clinical Endocrinology and Metabolism 04/2014; · 6.31 Impact Factor
  • Jacques W M Lenders, Graeme Eisenhofer
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    ABSTRACT: The principal function of the adrenal medulla is the production and secretion of catecholamines. During stressful challenging conditions, catecholamines exert a pivotal homeostatic role. Although the main adrenomedullary catecholamine, epinephrine, has a wide array of adrenoreceptor-mediated effects, its absence does not cause life-threatening problems. In contrast, excess production of catecholamines due to an adrenomedullary tumor, specifically pheochromocytoma, results in significant morbidity and mortality. Despite being rare, pheochromocytoma has a notoriously bad reputation because of its potential devastating effects if undetected and untreated. The paroxysmal signs and symptoms and the risks of missing or delaying the diagnosis are well known for most physicians. Nevertheless, even today the diagnosis is still overlooked in a considerable number of patients. Prevention and complete cure are however possible by early diagnosis and appropriate treatment but these patients remain a challenge for physicians. Yet, biochemical proof of presence or absence of catecholamine excess has become more easy and straightforward due to developments in assay methodology. This also applies to radiological and functional imaging techniques for locating the tumor. The importance of genetic testing for underlying germline mutations in susceptibility genes for patients and relatives is increasingly recognized. Yet, the effectiveness of genetic testing, in terms of costs and benefits to health, has not been definitively established. Further improvement in knowledge of genotype-phenotype relationships in pheochromocytoma will open new avenues to a more rationalized and personalized diagnostic approach of affected patients. © 2014 American Physiological Society. Compr Physiol 4:691-713, 2014.
    Comprehensive Physiology. 04/2014; 4(2):691-713.
  • Hypertension 04/2014; 63(4):e89. · 6.87 Impact Factor
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    ABSTRACT: Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To explore whether phenotypic differences among PPGLs reflect a MAX-mediated mechanism and opposing influences of HIF2α and HIF1α, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2α and mature phenotypic features and the other with high expression of HIF2α and immature phenotypic features due to mutations stabilizing HIFs. Max-mutated tumors distributed to a distinct sub-cluster of the former group. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2α, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α had opposing actions to HIF2α in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2α in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 03/2014; · 6.20 Impact Factor
  • B.J. Kramers, C. Kramers, J.W.M. Lenders, J. Deinum
    Clinical Therapeutics. 01/2014; 36(8):e12.
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    ABSTRACT: Higher plasma concentrations of catecholamines in winter than in summer have been established, but whether this impacts the plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown. In this study, we examined seasonal variations in the plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming ('arterialization' of venous blood) on blood flow and measured concentrations. The measurements of the plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for the measurements of plasma metanephrines and forearm blood flow before and after forearm warming. There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, the plasma concentrations of normetanephrine were higher (P<0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P<0.0001). These differences resulted in a twofold higher (P=0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (P=0.0010). Forearm warming increased blood flow and lowered (P=0.0020) plasma normetanephrine concentrations. The plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.
    European Journal of Endocrinology 01/2014; 170(3):349-57. · 3.14 Impact Factor
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    ABSTRACT: Adrenal phaechromocytomas and extra-adrenal sympathetic paragangliomas (PPGLs) are rare neuroendocrine tumours characterised by production of the catecholamines noradrenaline, adrenaline and dopamine. Tumoural secretion of catecholamines determines their clinical presentation which is highly variable among patients. Up to 10-15% of patients present entirely asymptomatically and in 5% of all adrenal incidentalomas a PPGL is found. Therefore, prompt diagnosis of PPGL remains a challenge for every clinician. Early consideration of the presence of a PPGL is of utmost importance since missing the diagnosis can be devastating due to potential lethal cardiovascular complications of disease. First step in diagnosis is proper biochemical analysis to confirm or refute the presence of excess production of catecholamines or their metabolites. Biochemical testing is not only indicated in symptomatic patients, but also in asymptomatic patients with adrenal incidentalomas or identified genetic predispositions. Measurements of metanephrines in plasma or urine offers the best diagnostic performance and are the tests of first choice. Paying attention to sampling conditions, patient preparation and use of interfering medications is important since these factors can largely influence test results. When initial test results are inconclusive, additional tests can performed such as the clonidine suppression test. Test results can also be used for estimation of tumour size or prediction of tumor location and underlying genotype. Furthermore, tumoural production of 3-methoxytyramine is associated with presence of an underlying SDHB mutation and may be a biomarker of malignancy.
    European Journal of Endocrinology 12/2013; · 3.14 Impact Factor
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    ABSTRACT: Adrenal venous sampling is recommended by current guidelines to identify surgically curable causes of hyperaldosteronism but remains markedly underused. Key factors contributing to the poor use of adrenal venous sampling include the prevailing perceptions that it is a technically challenging procedure, difficult to interpret, and can be complicated by adrenal vein rupture. In addition, the lack of uniformly accepted standards for the performance of adrenal venous sampling contributes to its limited use. Hence, an international panel of experts working at major referral centers was assembled to provide updated advice on how to perform and interpret adrenal venous sampling. To this end, they were asked to use the PICO (Patient or Problem, Intervention, Control or comparison, Outcome) strategy to gather relevant information from the literature and to rely on their own experience. The level of evidence/recommendation was provided according to American Heart Association gradings whenever possible. A consensus was reached on several key issues, including the selection and preparation of the patients for adrenal venous sampling, the procedure for its optimal performance, and the interpretation of its results for diagnostic purposes even in the most challenging cases.
    Hypertension 11/2013; · 6.87 Impact Factor
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    ABSTRACT: Adrenal vein sampling is used to establish the origins of excess production of adrenal hormones in primary aldosteronism. Correct catheter positioning is confirmed using adrenal vein measurements of cortisol, but this parameter is not always reliable. Plasma metanephrine represents an alternative parameter. The objective of our study was to determine the use of plasma metanephrine concentrations to establish correct catheter positioning during adrenal vein sampling with and without cosyntropin stimulation. We included 52 cosyntropin-stimulated and 34 nonstimulated sequential procedures. Plasma cortisol and metanephrine concentrations were measured in adrenal and peripheral venous samples. Success rates of sampling, using an adrenal to peripheral cortisol selectivity index of 3.0, were compared with success rates of metanephrine using a selectivity index determined by receiver operating characteristic curve analysis. Among procedures assessed as selective using cortisol, the adrenal to peripheral vein ratio of metanephrine was 6-fold higher than that of cortisol (94.0 versus 15.5; P<0.0001). There were significant positive relationships between adrenal to peripheral vein ratios of cortisol and metanephrine for cosyntropin-stimulated samplings but not for nonstimulated samplings. Receiver operating characteristic curve analysis indicated a plasma metanephrine selectivity index cutoff of 12. Using this cutoff, concordance in sampling success rates determined by cortisol and metanephrine was substantially higher in cosyntropin-stimulated than in nonstimulated samplings (98% versus 59%). For the latter procedures, sampling success rates determined by metanephrine were higher (P<0.01) than those determined by cortisol (91% versus 56%). In conclusion, metanephrine provides a superior analyte compared with cortisol in assessing the selectivity of adrenal vein sampling during procedures without cosyntropin stimulation.
    Hypertension 09/2013; · 6.87 Impact Factor
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    ABSTRACT: To document the influences of blood sampling under supine fasting versus seated non-fasting conditions on diagnosis of phaeochromocytomas and paragangliomas (PPGL) using plasma concentrations of normetanephrine, metanephrine and methoxytyramine. Biochemical testing for PPGL was performed on 762 patients at six centres, two of which complied with requirements for supine sampling after an overnight fast and four of which did not. PPGL were found in 129 patients (67 non-compliant, 62 compliant) and not in 633 patients (195 non-compliant, 438 compliant). Plasma concentrations of normetanephrine and methoxytyramine did not differ between compliant and non-compliant sampling conditions in patients with PPGL, but were 49-51% higher in patients without PPGL sampled under non-compliant compared to compliant conditions. The 97.5-percentiles of distributions were also higher under non-compliant compared to compliant conditions for normetanephrine (1.29 vs 0.79 nmol/l), metanephrine (0.49 vs 0.41 nmol/l) and methoxytyramine (0.42 vs 0.18 nmol/l). Use of upper cut-offs established from seated non-fasting sampling conditions resulted in substantially decreased diagnostic sensitivity (98% vs 85%). In contrast, use of upper cut-offs established from supine fasting conditions resulted in decreased diagnostic specificity for testing under non-compliant compared to compliant conditions (71% vs 95%). High diagnostic sensitivity of plasma normetanephrine, metanephrine and methoxytyramine for detection of PPGL can only be guaranteed using upper cut-offs of reference intervals established with blood sampling under supine fasting conditions. With such cut-offs, sampling under seated non-fasting conditions can lead to a 5.7-fold increase in false-positive results necessitating repeat sampling under supine fasting conditions. This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 09/2013; · 3.40 Impact Factor
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    ABSTRACT: PURPOSE: Pheochromocytomas and paragangliomas (PGLs) are neuroendocrine tumors of sympathetic and parasympathetic paraganglia. The present study investigated the relationships between genotype-specific differences in mitochondrial function and catecholamine content in PGL tumors. EXPERIMENTAL DESIGN: Respiratory chain enzyme assays and 1H-NMR spectroscopy at 500 MHz, were performed on homogenates of 35 sporadic PGLs and 59 PGLs from patients with hereditary mutations in SDHB, SDHD, SDHAF-2, VHL, RET, NF1 and MAX. RESULTS: In SDHx related PGLs, a significant decrease in complex II activity (p<0.0001) and a significant increase in complex I, III and IV enzyme activities were observed when compared to sporadic, RET and NF1 tumors. Also, a significant increase in citrate synthase (p<0.0001) enzyme activity was observed in SDHx related PGLs when compared to sporadic, VHL, RET and NF1 related ones. An increase in succinate accumulation (p<0.001) and decrease in ATP/ADP/AMP accumulation (p<0.001) was observed when compared to sporadic PGLs and PGLs of other genotypes. Positive correlations (p<0.01) were observed between respiratory chain complex II activity and total catecholamine content and ATP/ADP/AMP and total catecholamine contents in tumor tissues. CONCLUSIONS: The present study for the first time establishes relationship between determinants of energy metabolism like activity of respiratory chain enzyme complex II, ATP/ADP/AMP content and catecholamine content in PGL tumors. Also, the present study for the first time successfully uses NMR spectroscopy to detect catecholamines in PGL tumors and provides ex vivo evidence for the accumulation of succinate in PGL tumors with a SDHx mutation.
    Clinical Cancer Research 05/2013; · 7.84 Impact Factor
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    ABSTRACT: BACKGROUND: Adrenal vein sampling (AVS) is the preferred test for subtyping primary aldosteronism. However, the procedure is technically demanding and costly. In AVS it is common practice to take duplicate blood samples at each location. In this paper we explore whether a single sample procedure leads to a different conclusion concerning the location of adrenal aldosterone secretion than a duplicate sample procedure. METHODS: AVS procedures with duplicate measurements performed in our university medical centre between 2005 and 2010 were evaluated retrospectively. We compared the conclusions regarding selectivity and lateralization based on the first sample taken (A) to the conclusions based on the average of duplicate samples (AB). We also calculated the number needed to sample in duplicate to prevent one misclassification. RESULTS: Ninety-six AVS procedures of 82 patients were included. The concordance in AVS conclusions between sample A and AB was 98-100%, depending on the criteria used for selectivity and lateralization. With permissive and strict criteria the number needed to sample in duplicate were infinite and 48, respectively. CONCLUSIONS: The incremental benefit of duplicate sampling compared to single sampling is low. Therefore, in case of technical difficulties during AVS, conclusions can also be reliably drawn from a single blood sample.
    Clinica chimica acta; international journal of clinical chemistry 04/2013; · 2.54 Impact Factor
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    ABSTRACT: BACKGROUND: The diagnosis of phaeochromocytoma is commonly performed by measurements of plasma free normetanephrine and metanephrine. Plasma deconjugated normetanephrine and metanephrine have been proposed as alternative, equivalent, but easier to measure biomarkers. OBJECTIVE: The aim of this study was to compare the diagnostic performance of plasma free versus deconjugated normetanephrine and metanephrine in patients tested for phaeochromocytoma. METHODS: The study population included a reference group of 262 normotensive and hypertensive volunteers, 198 patients with phaeochromocytoma and 528 patients initially suspected of having the tumour, but with negative investigations after at least 2 years of follow up. Measurements were performed using liquid chromatography with electrochemical detection. RESULTS: Plasma concentrations of free normetanephrine were 17-fold higher in patients with phaeochromocytoma than in the reference population, a 72% larger (p<0.001) difference than that for the 10-fold higher levels of plasma deconjugated normetanephrine. In contrast, relative increases of plasma concentrations of free and deconjugated metanephrine were similar. Using upper cut-offs established in the reference population, measurements of plasma free metabolites provided superior diagnostic performance than deconjugated metabolites according to measures of both sensitivity (97% vs 92%, p=0.002) and specificity (93 vs 89%, p=0.012). The area under the receiver operating characteristic curve for the free metabolites was larger than that for the deconjugated metabolites (0.986 vs 0.965, p<0.001). CONCLUSION: Measurements of plasma free normetanephrine and metanephrine are superior to the deconjugated metabolites for diagnosis of phaeochromocytoma © 2013 Blackwell Publishing Ltd.
    Clinical Endocrinology 03/2013; · 3.40 Impact Factor
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    ABSTRACT: Background: It is generally accepted that pheochromocytoma is associated with an increased cardiovascular risk. This is however not based on studies with an appropriate control group of patients with essential hypertension. Aim of the Study: We examined whether patients with pheochromocytoma have an excess cardiovascular morbidity as compared to hypertensive patients. Methods: In a retrospective case-control study we reviewed the medical charts of 109 pheochromocytoma patients for cardiovascular events within 5 years prior to the diagnosis. These patients were matched to control patients with essential hypertension for gender and year of birth and diagnosis. Outcome variables were ischemic heart disease, cerebrovascular accidents, and transient ischemic attacks. Classical cardiovascular risk factors were also assessed. Results: A significantly higher rate of patients with pheochromocytoma suffered a cardiovascular event (13.8%; 95% confidence interval: 7.9%-21.6%) as compared to hypertensive patients (1.1%, 95% confidence interval: 0.1%-3.9%) (P < .001). Blood pressure level was lower in pheochromocytoma patients (153/91 ± 35/15 mm Hg) than in hypertensive patients (170/103 ± 18/8 mm Hg) (P < .001), even after correction for use of antihypertensive medication (P < .02). The difference in event rates could not be attributed to differences in other cardiovascular risk factors. Conclusions: Pheochromocytoma patients have a clearly higher rate of cardiovascular events than patients with essential hypertension. This cannot be attributed to differences in blood pressure or other cardiovascular risk factors. The most likely explanation for the excess event rate is the prolonged exposure to the toxic effects of tumoral catecholamines. These data underpin the importance of a timely diagnosis and treatment of pheochromocytoma.
    The Journal of Clinical Endocrinology and Metabolism 03/2013; 98(3):1100-6. · 6.31 Impact Factor
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    ABSTRACT: BACKGROUND: Neurofibromatosis I may rarely predispose to pheochromocytoma and gastrointestinal stromal tumors. METHODS: A 59-year-old woman with neurofibromatosis I presented with pheochromocytoma of the left adrenal gland. During surgery, 3 gastrointestinal stromal tumors adjacent to the stomach and small intestine were removed. Despite appropriate thrombosis prophylaxis, the patient died of a pulmonary embolus 2 days postoperatively. The second patient, a 55-year-old man with neurofibromatosis I and bilateral pheochromocytomas, had several small gastrointestinal stromal tumors adjacent to the jejunum during surgery. A review of the literature was conducted to identify patients with neurofibromatosis I with concurrence of pheochromocytoma and gastrointestinal stromal tumors and to define the specific clinical features of these patients. RESULTS: In addition to our 2 patients, 12 other cases of neurofibromatosis I with concomitant occurrence of pheochromocytomas and gastrointestinal stromal tumors have been reported. Pheochromocytomas had adrenal locations in all patients. Two of the 14 patients had a mixed pheochromocytoma/ganglioneuroma. In 4 of the 14 patients, gastrointestinal stromal tumors were located along the stomach. The gastrointestinal stromal tumors in our 2 patients showed no somatic mutations in KIT and PDGFRA genes. A pulmonary embolism was diagnosed in 4 patients. CONCLUSIONS: The simultaneous occurrence of pheochromocytoma and gastrointestinal stromal tumor should be considered in all patients with neurofibromatosis I presenting with an abdominal mass with symptoms suggestive of pheochromocytoma. Therefore, a pheochromocytoma should be excluded before a patient with neurofibromatosis I undergoes surgery for a gastrointestinal stromal tumor because an undiagnosed pheochromocytoma carries a high risk of life-threatening cardiovascular complications during surgery. Finally, this combination may be associated with an increased risk for thromboembolic events, but more studies are necessary to confirm this.
    The American journal of medicine 02/2013; 126(2):174-180. · 5.30 Impact Factor
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    ABSTRACT: Two major categories of mortality are distinguished in patients with phaeochromocytoma. First, the effects of excessive circulating catecholamines may result in lethal complications if the disease is not diagnosed and/or treated timely. The second category of mortality is related to development of metastatic disease or other neoplasms. Improvements in disease recognition and diagnosis over the past few decades have reduced mortality from undiagnosed tumours. Nevertheless, many tumours remain unrecognised until they cause severe complications. Death resulting from unrecognised or untreated tumour is caused by cardiovascular complications. There are also numerous drugs and diagnostic or therapeutic manipulations that can cause fatal complications in patients with phaeochromocytoma. Previously it has been reported that operative mortality was as high as 50% in unprepared patients with phaeochromocytoma who were operated and in whom the diagnosis was unsuspected. Today mortality during surgery in medically prepared patients with the tumour is minimal. Phaeochromocytomas may be malignant at presentation or metastases may develop later, but both scenarios are associated with a potentially lethal outcome. Patients with phaeochromocytoma run an increased risk to develop other tumours, resulting in an increased mortality risk compared to the general population. Phaeochromocytoma during pregnancy represents a condition with potentially high maternal and foetal mortality. However, today phaeochromocytoma in pregnancy is recognised earlier and in conjunction with improved medical management, maternal mortality has decreased to less than 5%.
    Hormone and Metabolic Research 01/2013; · 2.15 Impact Factor
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    ABSTRACT: Background: Measurements of plasma free metanephrines provide a sensitive test for the diagnosis of pheochromocytoma/paraganglioma (P/PGL), with highly elevated levels diagnostic of the disease. However, there is less diagnostic certainty in patients with mild elevations of these catecholamine metabolites.Patients and methods: Here we report use of the clonidine suppression test (CST) as a second-tier diagnostic test in 24 patients with mild elevations of plasma free metanephrines and/or catecholamines. Blood samples before and 3 hours after clonidine were analyzed for plasma concentrations of metanephrines and catecholamines with a negative test result defined as either a clonidine-induced fall in normetanephrine or noradrenaline by more than 40 % and 50 % respectively or to below the upper cut-offs of reference intervals.Results: P/PGLs were confirmed in 9 patients and excluded in 15 by independent criteria. More than half of the patients without P/PGL showed normalized plasma concentrations of normetanephrine at baseline before clonidine compared to initial screening; all showed appropriate clonidine-induced falls in normetanephrine and noradrenaline or levels after the drug below upper cut-offs, indicating a diagnostic specificity of 100 % (CI 78-100 %). However, similar responses for noradrenaline were noted in 7 patients with P/PGL, indicating a diagnostic sensitivity of only 22 % (CI 2,8-60 %) compared to 100 % (CI 66-100 %) for normetanephrine.Conclusion: These results support use of the CST in combination with measurements of normetanephrine for confirming or excluding P/PGL in patients with borderline elevated test results, which should, however, first be confirmed by sampling blood under standardized resting conditions.
    DMW - Deutsche Medizinische Wochenschrift 01/2013; 138(3):76-81. · 0.65 Impact Factor
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    ABSTRACT: BACKGROUND AND OBJECTIVE: We hypothesized that bronchodilation in patients with chronic obstructive pulmonary disease (COPD) increases the smoke-related risk to develop cardiovascular disease and aimed to study the effect of short-acting anticholinergic bronchodilation and smoking on cardiovascular events. METHODS: We performed a secondary analysis on data from the Lung Health Study, a large randomized clinical trial of smokers with mild to moderate pulmonary obstruction, 35 to 60 years old, without cardiovascular co-morbidity. We used Cox proportional survival analysis, controlling for several confounders, to study the effect on 5-year risk of fatal and/or nonfatal cardiovascular events. Secondary outcome encompassed fatal and nonfatal coronary events. RESULTS: Of 2,745 participants, 23 (0.8%) died of cardiovascular disease. One hundred and sixty two participants were hospitalized for a cardiovascular event, and 94 participants due to a coronary event. Survival analysis revealed no effect between smoking and short-acting anticholinergic bronchodilation on fatal and/or nonfatal cardiovascular events, HR=1.12 (0.58-2.19), nor on coronary events: HR=1.46 (0.60-3.56). CONCLUSIONS: Our study results show that short-acting anticholinergic bronchodilation had no detrimental effect on cardiovascular disease in smokers with mild to moderate pulmonary obstruction.
    Respirology 12/2012; · 2.78 Impact Factor
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    ABSTRACT: BACKGROUND: Measurements of plasma normetanephrine and metanephrine provide a useful diagnostic test for phaeochromocytoma, but this depends on appropriate reference intervals. Upper cut-offs set too high compromise diagnostic sensitivity, whereas set too low, false-positives are a problem. This study aimed to establish optimal reference intervals for plasma normetanephrine and metanephrine. METHODS: Blood samples were collected in the supine position from 1226 subjects, aged 5-84 y, including 116 children, 575 normotensive and hypertensive adults and 535 patients in whom phaeochromocytoma was ruled out. Reference intervals were examined according to age and gender. Various models were examined to optimize upper cut-offs according to estimates of diagnostic sensitivity and specificity in a separate validation group of 3888 patients tested for phaeochromocytoma, including 558 with confirmed disease. RESULTS: Plasma metanephrine, but not normetanephrine, was higher (P < 0.001) in men than in women, but reference intervals did not differ. Age showed a positive relationship (P < 0.0001) with plasma normetanephrine and a weaker relationship (P = 0.021) with metanephrine. Upper cut-offs of reference intervals for normetanephrine increased from 0.47 nmol/L in children to 1.05 nmol/L in subjects over 60 y. A curvilinear model for age-adjusted compared with fixed upper cut-offs for normetanephrine, together with a higher cut-off for metanephrine (0.45 versus 0.32 nmol/L), resulted in a substantial gain in diagnostic specificity from 88.3% to 96.0% with minimal loss in diagnostic sensitivity from 93.9% to 93.6%. CONCLUSIONS: These data establish age-adjusted cut-offs of reference intervals for plasma normetanephrine and optimized cut-offs for metanephrine useful for minimizing false-positive results.
    Annals of Clinical Biochemistry 10/2012; · 1.92 Impact Factor

Publication Stats

5k Citations
1,311.58 Total Impact Points


  • 2013–2014
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 1988–2013
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 1986–2013
    • Radboud University Nijmegen
      • • Department of Medical Oncology
      • • Department of General Internal Medicine
      Nijmegen, Provincie Gelderland, Netherlands
  • 2012
    • University of Florence
      • Dipartimento di Scienze Biomediche, Sperimentali e Cliniche
      Florence, Tuscany, Italy
  • 2008–2012
    • Technische Universität Dresden
      • Institut für Chemie und Laboratoriumsmedizin
      Dresden, Saxony, Germany
  • 2003–2008
    • Maastricht University
      • Interne Geneeskunde
      Maastricht, Provincie Limburg, Netherlands
  • 2007
    • St. Antonius Ziekenhuis
      Nieuwegen, Utrecht, Netherlands
  • 2003–2007
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 2006
    • University of Toronto
      • Department of Medicine
      Toronto, Ontario, Canada
  • 1993–2005
    • National Institutes of Health
      • Branch of Behavioral Neuroscience
      Maryland, United States
  • 1991
    • Leiden University Medical Centre
      • Department of Cardiology
      Leiden, South Holland, Netherlands