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Original article
Performance of plasma free metanephrines in diagnosis of pheochromocytomas and paragangliomas in the population of Asturias
Rendimiento de las metanefrinas libres plasmáticas en el diagnóstico de los feocromocitomas y paragangliomas en la población asturiana
Eduardo Martínez-Morilloa,
Corresponding author
edumartinezmorillo@gmail.com

Corresponding author.
, Nuria Valdés Gallegob, Edwin Eguia Ángelesa, Juan Carlos Fernández Fernándeza, Belén Prieto Garcíaa,c, Francisco V. Álvareza,c
a Laboratorio de Medicina, Servicio de Bioquímica Clínica, Hospital Universitario Central de Asturias, Oviedo, Spain
b Servicio de Endocrinología, Hospital Universitario Central de Asturias, Oviedo, Spain
c Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Association of plasma normetanephrine levels with patient age&#46; The suggested cut-off points are added based on patient age&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pheochromocytomas &#40;PCTs&#41; and paragangliomas &#40;PGLs&#41; are infrequent tumours&#44; with 1&#8211;2 cases per 100&#44;000 inhabitants and year&#44; and are mainly derived from the chromaffin cells of the sympathetic nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> These neoplasms are located in the adrenal gland medulla &#40;80&#8211;85&#37; of all PCTs&#41; or in the sympathetic nervous system ganglia of the chest&#44; abdomen and pelvis &#40;15&#8211;20&#37; of all PGLs&#41;&#44; and usually produce abnormally high levels of catecholamines and their metabolites&#46; Paragangliomas located in the head and skull base are of parasympathetic origin&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The typical signs and symptoms of PCTs&#47;PGLs are well known&#44; but are not very specific&#46; The episodic secretion of catecholamines is responsible for most of the symptoms&#44; including major fluctuations in blood pressure<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">3&#44;4</span></a> and the classic triad of palpitations &#40;58&#37;&#41;&#44; headache &#40;52&#37;&#41; and perspiration &#40;49&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a> However&#44; only 30&#8211;40&#37; of all patients experience these three symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">3&#44;6</span></a> The clinical identification of PCT&#47;PGL is not easy&#44; because approximately half of all patients experience paroxysmal arterial hypertension &#40;AHT&#41; or have normal blood pressure&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">7&#44;8</span></a> and necropsy studies have shown that approximately 0&#46;05&#37; of all deceased individuals have undiagnosed PCT&#47;PGL&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a> At present&#44; up to 40&#37; of all PCTs&#47;PGLs are considered to be hereditary&#44; while the remaining 60&#37; correspond to spontaneous cases&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Pheochromocytomas&#47;paragangliomas occur more frequently in individuals between 40 and 50 years of age&#44; with a slight female predominance &#40;55&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> The prevalence differs according to the population studied&#46; Thus&#44; in the general population&#44; the prevalence of PCT&#47;PGL is less than 0&#46;1&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">8</span></a> while in patients with AHT the figure increases to 0&#46;2&#8211;0&#46;6&#37;&#44; and in patients with adrenal incidentalomas the prevalence is usually 3&#8211;7&#37;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> but can reach 20&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The most common reasons for the biochemical study of PCT&#47;PGL are the presence of AHT and episodic symptoms attributable to excess catecholamine output&#44; as well as treatment-resistant AHT&#46; Other indications are the determination of functionality of an adrenal incidentaloma&#44; the assessment of genetic predisposition&#44; the exclusion of tumour recurrence&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> young patients with AHT&#44; and individuals with a history of hypertensive crises during anaesthesia&#46; The traditionally used biochemical techniques have been the analysis of vanillylmandelic acid &#40;VMA&#41; and total catecholamines and metanephrines &#40;MNs&#41; in urine&#44; and plasma catecholamines&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">However&#44; in recent years several publications have shown fractionated MNs in 24-h urine and plasma free metanephrines &#40;PFMs&#41; to afford a better diagnostic performance&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">14&#8211;18</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In fact&#44; according to the current recommendations of the American Society of Endocrinology&#44; the initial biochemical study of PCT&#47;PGL should include one of these two tests&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Since PCTs&#47;PGLs are potentially fatal tumours&#44; especially if the patient suffers an adrenergic crisis&#44; the establishment of an early diagnosis is very important&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a> The availability of biochemical tests with a good diagnostic performance&#44; in which sample extraction is fast and simple&#44; is very useful for obtaining such an early diagnosis&#46; To the best of our knowledge&#44; the Medicine laboratory of the Department of Clinical Biochemistry of Hospital Universitario Central de Asturias &#40;HUCA&#41; was the first laboratory in Spain to incorporate the mass spectrometry measurement of PFMs within its range of services&#46; The objective of the present study was to clinically validate the PFM test&#44; introduced in 2015&#44; based on a review of its diagnostic performance during its first two years of use&#44; and to compare it with other classical biochemical tests used for the same purpose&#46; In addition&#44; the transferability of the reference values used for plasma MNs and normetanephrine &#40;NMN&#41; was verified and their biological variability parameters were assessed&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Pre-analytical conditions</span><p id="par0040" class="elsevierStylePara elsevierViewall">A sample collection for the determination of plasma MNs and catecholamines was made in a purple stopper tube containing K3-EDTA&#46; The patients were instructed to avoid chocolate&#44; bananas&#44; vanilla&#44; pineapple&#44; nuts&#44; coffee and tea before sampling&#46; They were also instructed to avoid alcohol consumption&#46; In addition&#44; the suppression of drugs such as levodopa&#44; hydrazine and its derivatives&#44; monoamine oxidase inhibitors &#40;MAOIs&#41; and prochlorperazine was requested&#46; Sampling was performed with the patient in the supine position after at least 15<span class="elsevierStyleHsp" style=""></span>min of rest&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Urinary MNs&#44; catecholamines and VMA were determined from 24-h urine collected in specific 3-l amber containers with a vacuum port&#44; holding 10<span class="elsevierStyleHsp" style=""></span>ml of HCl 6N as a stabilizing preservative&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Analytical methods</span><p id="par0050" class="elsevierStylePara elsevierViewall">Plasma free metanephrines were quantified with a triple quadrupole mass spectrometer &#40;QTRAP 5500&#44; AB Sciex&#41; coupled to a liquid chromatograph &#40;Ekspert ultra LC 100&#44; Eksigent&#41;&#46; The method was developed and validated in our laboratory&#46; Briefly&#44; the technique includes the initial separation of MNs &#40;500<span class="elsevierStyleHsp" style=""></span>&#956;l of plasma EDTA&#41; using solid phase extraction cartridges &#40;SampliQ WCX&#44; 30<span class="elsevierStyleHsp" style=""></span>mg&#44; 1<span class="elsevierStyleHsp" style=""></span>ml &#91;Agilent&#93;&#41;&#46; After extraction&#44; the MNs are subjected to gradient chromatographic separation using two mobile phases&#58; ammonium formate with 0&#46;2&#37; formic acid&#44; pH<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;2 &#40;solution A&#41; and methanol with 0&#46;2&#37; formic acid &#40;solution B&#41;&#46; These mobile phases are prepared with high purity reagents&#58; LiChrosolv<span class="elsevierStyleSup">&#174;</span> methanol &#40;Merck-Millipore&#41;&#44; ultrapure Milli-Q<span class="elsevierStyleSup">&#174;</span> water&#44; Suprapur<span class="elsevierStyleSup">&#174;</span> formic acid &#40;Merck-Millipore&#41; and ammonium formate&#44; purity &#8805;99&#37; &#40;Fluka&#41;&#46; The chromatographic precolumn and column used are&#58; Pursuit 3 PFP MetaGuard 10<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm and Pursuit 3 PFP&#44; 2<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>mm &#40;Agilent&#41;&#44; respectively&#46; The calibrators are prepared from certified reference material&#58; Catecholamine Mix 2 &#40;Metanephrines&#41; solution &#40;Sigma&#8211;Aldrich&#41;&#46; In addition&#44; isotopic &#40;deuterium&#41; labelled internal standards are used for the standardization of all the steps of the analytical process&#58; &#40;&#177;&#41;-Metanephrine-D3 hydrochloride solution and &#40;&#177;&#41;-Normetanephrine-D3 hydrochloride solution&#44; 100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml in methanol &#40;Sigma&#8211;Aldrich&#41;&#46; Software is used to operate the mass spectrometer and analyze the results&#58; Analyst<span class="elsevierStyleSup">&#174;</span> &#40;version 1&#46;6&#46;2&#41; and MultiQuant&#8482; &#40;version 2&#46;1&#46;1296&#46;0&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The linearity of the method is 20&#8211;2000<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for both MN and NMN&#44; with correlation coefficients &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleSup">2</span>&#41;<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;995&#46; The inter-assay coefficients of variation &#40;CV&#41; are &#8804;4&#46;1&#37; and 6&#46;2&#37; for MN and NMN&#44; respectively&#46; The limit of quantitation &#40;LoQ&#41; was established at 20<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The remaining biochemical tests evaluated &#40;catecholamines in plasma and MN&#44; catecholamines and VMA in urine&#41; were analyzed using commercial analytical methods previously implemented in our laboratory&#46; Specifically&#44; these tests are quantified using high-performance liquid chromatography &#40;HPLC&#41; with electrochemical detection&#46; The equipment used is a liquid chromatograph &#40;model 1200 series&#44; Agilent&#41; with an electrochemical detector &#40;model 1640&#44; Bio-Rad<span class="elsevierStyleSup">&#174;</span>&#41;&#46; Bio-Rad<span class="elsevierStyleSup">&#174;</span> kits are used for sample preparation and analysis&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The reference values used for all these tests are&#58; &#60;100 and &#60;165<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;for plasma MN and NMN&#44; respectively&#41;&#44; 10&#8211;67 and 95&#8211;446<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;for plasma epinephrine and norepinephrine&#44; respectively&#41;&#44; 64&#8211;302 and 162&#8211;528<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;24<span class="elsevierStyleHsp" style=""></span>h &#40;for urinary MN and NMN&#44; respectively&#41;&#44; 0&#46;6&#8211;20 and 15&#8211;80<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;24<span class="elsevierStyleHsp" style=""></span>h &#40;for urinary epinephrine and norepinephrine&#44; respectively&#41;&#44; and 1&#46;8&#8211;6&#46;7<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h &#40;for urinary VMA&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Patients</span><p id="par0070" class="elsevierStylePara elsevierViewall">A review of the medical records of the patients commented on below was made with the purpose of determining whether they had or had had PCT&#47;PGL&#44; based on the medical reports&#44; imaging tests and pathology findings&#58;</p><p id="par0075" class="elsevierStylePara elsevierViewall">- <span class="elsevierStyleItalic">Inclusion criteria</span>&#58; Patients with 24-h urine and&#47;or plasma samples received at the Department of Clinical Biochemistry of HUCA between 1 September 2015 and 31 October 2017 &#40;25 months&#41;&#44; and a request for at least one of the following tests&#58; PFM&#44; plasma catecholamines&#44; MN&#44; catecholamines and VMA in urine&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">- <span class="elsevierStyleItalic">Exclusion criteria</span>&#58; Patients for whom data could not be obtained from the medical records&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The following software was used to review the electronic medical records&#58; PowerChart &#40;Cerner Millennium<span class="elsevierStyleSup">&#174;</span>&#41; for reviewing the case histories of the patients seen at HUCA&#44; and Cerner Selene<span class="elsevierStyleSup">&#174;</span> for reviewing the case histories of the patients seen at other district hospitals of the Asturian health service system&#44; which refer these tests to our Department&#44; our hospital being the corresponding reference centre&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">During the study period&#44; requests for some of the selected biochemical tests were received corresponding to 1794 patients&#46; However&#44; only 71&#46;3&#37; of the case histories &#40;1279 patients&#41; could be accessed&#44; since the remainder corresponded to patients seen at the district hospitals and who had not received previous care at HUCA&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">This situation prevented us from accessing their electronic medical records from PowerChart &#40;Cerner Millennium<span class="elsevierStyleSup">&#174;</span>&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The final 1279 patients with a known history ranged in age from 0 to 90 years&#46; The median age was 60 years&#44; with an interquartile range &#40;IQR&#41; of 49&#8211;70 years&#46; A little over one-half of the patients &#40;61&#46;3&#37;&#41; were women&#46; The following biochemical tests were requested in these patients&#58; PFMs &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>662&#41;&#44; urinary catecholamines &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>589&#41;&#44; urinary fractionated MNs &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>586&#41;&#44; urinary VMA &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>513&#41; and plasma catecholamines &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>228&#41;&#46; In the cases of patients who had any of these tests performed more than once during the study period&#44; we used the first of the biochemical test results&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The indications for these biochemical studies were&#58; adrenal gland mass &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>445&#59; 34&#46;8&#37;&#41;&#44; AHT &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>234&#59; 18&#46;3&#37;&#41;&#44; known or suspected neuroendocrine tumour &#40;NET&#41; other than a PCT&#47;PGL &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>186&#59; 14&#46;5&#37;&#41;&#44; the clinical triad &#40;headache&#44; perspiration and&#47;or palpitations&#41; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>73&#59; 5&#46;7&#37;&#41;&#44; PCT&#47;PGL &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>64&#59; 5&#46;0&#37;&#41;&#44; genetic disorder &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>44&#59; 3&#46;4&#37;&#41;&#44; and other reasons &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>233&#59; 18&#46;3&#37;&#41;&#46; Thus&#44; more than half of the requests &#40;53&#46;1&#37;&#41; referred to patients with an adrenal mass or AHT&#46; The main reasons for studies in patients with AHT were&#58; hypertensive crisis&#44; AHT difficult to control and&#47;or resistant to drugs&#44; AHT in young patients&#44; and the exclusion of secondary causes of AHT in patients with chronic kidney disease or heart disease&#46; Patients in which the reason for study was PCT&#47;PGL&#44; NET or carcinoid tumour were often individuals with an already known tumour and subjected to follow-up&#44; or cases with simple clinical suspicions that were not subsequently confirmed&#46; Many of the patients with possible NETs were studied in the context of suspected carcinoid tumour due to the presence of flushing and&#47;or gastrointestinal disorders &#40;mainly chronic diarrhoea and important weight losses&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Nineteen cases of PCT&#47;PGL were finally detected in the study period &#40;13 PCTs and 6 PGLs&#41; &#40;13 women and 6 men&#41; and diagnosed by a combination of biochemical tests and imaging studies&#44; with subsequent histopathological confirmation &#40;immunohistochemical markers&#41; after surgery&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Biological variability for MN and NMN was estimated based on serial plasma samples &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#41; corresponding to 8 individuals &#40;3 samples per patient except for one individual with 4 samples&#41;&#44; 7<span class="elsevierStyleHsp" style=""></span>males and one female between 19 and 82 years of age&#46; These were patients subjected to periodic follow-up due to RET gene mutation &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; or an adrenal gland mass &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41; with no growth or functionality&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0120" class="elsevierStylePara elsevierViewall">A review was made of the appropriateness of the reference values used for PFM &#40;&#60;100<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for MN and &#60;165<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for NMN&#41;&#44; which were values established internally and used by the Mayo Clinic &#40;Rochester&#41; &#40;<a href="https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/81609">https&#58;&#47;&#47;www&#46;mayomedicallaboratories&#46;com&#47;test-catalog&#47;Clinical&#43;and&#43;Interpretive&#47;81609</a>&#41; and published in the literature&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> To this effect&#44; the results of all the patients with PFM test requests during the study period and with no presence of PCT&#47;PGL were used&#44; and a series of statistical analyses were made with MedCalc<span class="elsevierStyleSup">&#174;</span>&#44; version 12&#46;5&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The search for aberrant values was performed using the Reed test&#46; Normal data distribution was assessed using the Kolmogorov&#8211;Smirnov test&#46; Since the MN and NMN values did not follow a normal distribution&#44; nonparametric tests were used for the remaining analyses&#46; Thus&#44; the Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span>-test and the Kruskal&#8211;Wallis test were used to compare two or more groups of values of independent variables&#44; respectively&#46; Associations between variables were established based on the Spearman correlation coefficient&#46; Lastly&#44; the reference values were estimated according to the recommendations of document EP28-A3c of the Clinical and Laboratory Standards Institute&#44; which provides methodological guidelines and statistical procedures to establish and verify values and reference ranges for quantitative analytical methods applied to clinical tests&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The reference values were calculated using the nonparametric method&#44; which required data ordering from lower to higher&#46; The reference limits were then defined as percentiles 2&#46;5 and 97&#46;5 of the previously ordered data&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Accordingly if the data &#40;<span class="elsevierStyleItalic">x</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#8230;<span class="elsevierStyleItalic">n</span>&#41; are ordered from 1 to <span class="elsevierStyleItalic">n</span>&#44; the order number is obtained according to the following formula&#58;<elsevierMultimedia ident="eq0005"></elsevierMultimedia><elsevierMultimedia ident="eq0010"></elsevierMultimedia></p><p id="par0140" class="elsevierStylePara elsevierViewall">The datum corresponding to that order number or the nearest whole number is the reference limit obtained&#46; In this case&#44; for PFM only the upper reference limit was used&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The biological variability parameters for MN and NMN were estimated&#44; based on the Fraser method&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a> The intra- &#40;CV<span class="elsevierStyleInf">I</span>&#41; and inter-individual coefficients of variation &#40;CV<span class="elsevierStyleInf">G</span>&#41; were calculated using the following formulas&#58;<elsevierMultimedia ident="eq0015"></elsevierMultimedia><elsevierMultimedia ident="eq0020"></elsevierMultimedia>where SA&#43;I2 is the experimental variance obtained with the results of each individual&#59; SA2 is the analytical variance&#59; ST2 is the total variance obtained with the results of all the individuals&#59; and <span class="elsevierStyleItalic">M</span> is the mean concentration&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The individuality index &#40;II&#41; was calculated using the following formula&#58;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">24</span></a><elsevierMultimedia ident="eq0025"></elsevierMultimedia></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Biochemical diagnostic performance</span><p id="par0155" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the diagnostic performance of the different biochemical tests&#44; in decreasing order of sensitivity&#46; The tests showing the greatest sensitivity were urinary fractionated MN &#40;91&#46;7&#37;&#41; followed by PFM &#40;82&#46;4&#37;&#41;&#46; As regards specificity&#44; VMA showed the best results &#40;96&#46;7&#37;&#41;&#44; followed by PFM &#40;94&#46;7&#37;&#41;&#46; On considering the 24-h urine results&#44; MN showed far greater sensitivity than the other tests &#40;catecholamines and VMA&#41;&#44; but with lower specificity&#46; Similarly&#44; the results in plasma showed MN to offer better sensitivity &#40;82&#46;4&#37; vs&#46; 71&#46;4&#37;&#41; and specificity &#40;94&#46;7&#37; vs&#46; 83&#46;3&#37;&#41; than catecholamines&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">On comparing only the results obtained in urine samples involving the simultaneous request for MN and catecholamines &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>452&#41;&#44; urinary MN continued to show greater diagnostic sensitivity &#40;90&#46;9&#37; &#91;10&#47;11&#93; vs&#46; 81&#46;8&#37; &#91;9&#47;11&#93;&#41; despite poorer specificity &#40;84&#46;4&#37; &#91;372&#47;441&#93; vs&#46; 91&#46;4&#37; &#91;403&#47;441&#93;&#41;&#46; Similarly&#44; on comparing only the results obtained in plasma samples involving the simultaneous request for MN and catecholamines &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>129&#41;&#44; MN continued to show better results in terms of sensitivity &#40;85&#46;7&#37; &#91;6&#47;7&#93; vs&#46; 71&#46;4&#37; &#91;5&#47;7&#93;&#41; and specificity &#40;93&#46;4&#37; &#91;114&#47;122&#93; vs&#46; 78&#46;7&#37; &#91;96&#47;122&#93;&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Since MN measurement showed the greatest diagnostic sensitivity&#44; we compared the results obtained in patients with this measurement in both urine and plasma &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>243&#41;&#46; In these patients&#44; both tests detected the same cases &#40;90&#46;9&#37; &#91;10&#47;11&#93;&#41;&#44; but PFM proved comparatively more specific &#40;93&#46;5&#37; &#91;217&#47;232&#93; vs&#46; 88&#46;8&#37; &#91;206&#47;232&#93;&#41;&#46; It should be noted that there were only three false positives &#40;FPs&#41; showing high MNs in both samples &#40;plasma and urine&#41;&#44; while in the remaining cases MNs were found to be elevated only in plasma or urine&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">On plotting the diagnostic performance curves for the different biochemical tests analyzed in the 1279 patients&#44; and focusing on the tests with the highest performance &#40;NMN&#44; norepinephrine and AVM&#41;&#44; urinary NMN exhibited the greatest area under the curve &#40;AUC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;954&#41;&#44; followed by plasma NMN &#40;AUC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;893&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; In addition&#44; the Youden index calculated for plasma NMN was found to be 0&#46;715 &#40;sensitivity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>76&#46;5&#37;&#59; specificity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>95&#46;0&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">This result was obtained using a cut-off point for plasma NMN of 168<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#44; which is very similar to that currently used &#40;165<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#41;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">On plotting the diagnostic performance curves for urinary and plasma MN and NMN in patients with both measurements &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>243&#41;&#44; the AUC of the urine tests was greater than that of the plasma tests&#44; though statistical significance was not reached &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Furthermore&#44; on combining MN and NMN&#44; the AUCs obtained in urine and plasma were nearly equal &#40;0&#46;972 and 0&#46;971&#44; respectively&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Reference values and biological variability</span><p id="par0185" class="elsevierStylePara elsevierViewall">In the subjects &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>645&#41; in which no PCT&#47;PGL was identified&#44; and who were between 9 and 90 years of age&#44; the plasma levels ranged from 20 to 479<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for MN and 20 to 3626<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for NMN&#44; respectively&#46; One MN value &#40;479<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#41; and one NMN value &#40;3626<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#41; were identified as aberrant values and were excluded&#46; Therefore&#44; the range of results in the remaining 644 samples was 20&#8211;165<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for MN&#44; with a median of 25<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#44; and 20&#8211;612<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for NMN&#44; with a median of 67<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">In the case of MN&#44; significant gender differences were observed &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41;&#44; with a median and interquartile range of 29 &#40;21&#8211;40&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for males &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>237&#41; and 24 &#40;20&#8211;33&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for females &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>407&#41;&#46; However&#44; no significant association was observed between MN levels and patient age &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;67&#41;&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">In the case of NMN&#44; no significant gender differences were observed &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;95&#41;&#44; with a median and interquartile range of 68 &#40;44&#8211;96&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for males &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>237&#41; and 67 &#40;47&#8211;91&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for females &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>407&#41;&#46; By contrast&#44; a significant positive association was observed between NMN levels and patient age &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;19&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; On comparing the NMN results stratified according to age groups &#40;&#60;40 years&#44; 40&#8211;60 years and &#62;60 years&#41;&#44; significant differences were observed among the three groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41;&#44; with a median and interquartile range of 48 &#40;40&#8211;61&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for patients &#60;40 years &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>66&#41;&#44; 65&#46;5 &#40;46&#8211;89&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for individuals aged 40&#8211;60 years &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>250&#41;&#44; and 76 &#40;51&#8211;101&#46;5&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for those &#62;60 years &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>328&#41;&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0200" class="elsevierStylePara elsevierViewall">The reference value obtained for MN according to the nonparametric method &#40;Clinical and Laboratory Standards Institute&#44; EP28-A3c&#41; was &#40;value and 90&#37; confidence interval&#41;&#58; 55 &#40;53&#8211;60&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for all individuals &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>644&#41;&#44; regardless of age or gender&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">The reference values obtained for NMN were&#58; 168 &#40;146&#8211;187&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for all individuals &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>644&#41;&#44; 97<span class="elsevierStyleHsp" style=""></span>&#40;85&#8211;129&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for individuals &#60;40 years &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>66&#41;&#44; 164 &#40;134&#8211;188&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for individuals aged 40&#8211;60 years &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>250&#41;&#44; and 180 &#40;157&#8211;223&#41;<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for individuals &#62;60 years of age &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>328&#41;&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">With regard to the biological variability study&#44; NMN exhibited values between 23 and 119<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#44; with a mean value of 72&#46;4<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#46; The analytical coefficient of variation &#40;CV&#41; was 8&#46;2&#37;&#46; The CV<span class="elsevierStyleInf">I</span> and CV<span class="elsevierStyleInf">G</span> obtained based on the formulas described above were 32&#37; and 19&#46;6&#37;&#44; respectively&#46; Therefore&#44; the individuality index &#40;II&#41; obtained was 1&#46;63&#46; Since this index was greater than 1&#46;4&#44; the individuality of the test is considered to be low&#44; and it is not advisable to use the reference value of the change to detect significant changes&#59; rather&#44; the use of population reference values is considered more appropriate&#46; The results for MN were similar&#44; with CV<span class="elsevierStyleInf">I</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>CV<span class="elsevierStyleInf">G</span>&#44; and therefore the individuality index &#40;II&#41; obtained was &#62;1&#46;4&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0215" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; this is the first study in Spain to assess the diagnostic performance obtained with the routine measurement of PFMs using a reference method &#40;liquid chromatography coupled to tandem mass spectrometry&#41; and other classical biochemical tests&#46; The results obtained show that MNs&#44; in both plasma and urine&#44; are better markers of PCT&#47;PGL than the other biochemical parameters &#40;plasma and urinary catecholamines&#44; and urinary VMA&#41;&#46; This supports the notion that catecholamines and VMA provide little additional information beyond that already afforded by MNs&#44; and consequently should not be used for the diagnosis of PCT&#47;PGL&#46; However&#44; many clinicians still request these tests&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">The determination of PFMs constitutes a test with a good performance in diagnosing these tumours&#46; However&#44; their quantification represents an analytical challenge for the laboratory&#44; due to their low plasma concentration&#46; Mass spectrometry offers excellent sensitivity and specificity in the determination of these analytes&#44; and has been established as a reference method&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Plasma free metanephrines have some advantages over urinary MNs&#44; such as relatively easy sample collection&#44; easier control regarding the effects of diet and medication&#44; and the possibility of using the test in patients with chronic kidney disease&#44; where urinary MNs are of no use&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">25</span></a> However&#44; one of its main limitations is the need for very strict control of the pre-analytical conditions in which sample collection occurs&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">26&#44;27</span></a> A recent meta-analysis concluded that PFM sensitivity is significantly higher when the blood samples are obtained with the patient in the supine rather than in the sitting position &#40;95&#37; vs&#46; 89&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41;&#46; In addition&#44; the specificity of PFMs in the supine position is significantly higher than that of urinary MNs &#40;95&#37; vs&#46; 90&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">28</span></a> Our study obtained results very similar to those described above&#44; with the two tests showing the same sensitivity &#40;91&#37;&#41;&#44; and PFM exhibiting greater specificity &#40;94&#37;&#41; than urinary MNs &#40;89&#37;&#41;&#44; on considering those patients where both tests were requested&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Another key aspect for achieving optimal performance in determining PFMs is the use of adequate reference values&#46; In this regard&#44; the ideal reference population comprises patients who are studied for suspected PCT&#47;PGL and in whom the disease is finally discarded&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">The results of our study show that the plasma MN levels exhibit no differences according to age&#44; though there are gender differences&#44; with significantly higher &#40;but clinically irrelevant&#41; levels in males&#46; By contrast&#44; the NMN levels increase significantly with advancing patient age&#46; Accordingly&#44; the reference value obtained was close to 100<span class="elsevierStyleHsp" style=""></span>pg&#47;ml in younger patients &#40;&#60;40 years of age&#41; versus 164<span class="elsevierStyleHsp" style=""></span>pg&#47;ml in patients aged 40&#8211;60 years &#40;very similar to the currently used reference value&#41;&#44; and 180<span class="elsevierStyleHsp" style=""></span>pg&#47;ml in older patients &#40;&#62;60 years&#41;&#46; Therefore&#44; using age-differentiated reference values can reduce the number of false negative findings in younger patients and false positive readings in older individuals&#46; Other authors have obtained similar results&#44; with stable MN levels over the entire age range and NMN levels that increase with age&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">29</span></a> Specifically&#44; Lenders and Eisenhofer<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> recommend the use of a single reference value for MN &#40;88&#46;8<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#41; and a variable value for NMN conditioned to patient age&#58; 86&#46;1<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;5&#8211;17 years&#41;&#59; 106&#46;3<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;18&#8211;29 years&#41;&#59; 128&#46;2<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;30&#8211;39 years&#41;&#59; 144&#46;7<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;40&#8211;49 years&#41;&#59; 159&#46;4<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;50&#8211;59 years&#41;&#59; and 192&#46;4<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;&#62;60 years&#41;&#46; Based on our results and those reported in the literature&#44; it seems clear that in order to maximize the sensitivity of this test without significantly reducing its specificity&#44; we should lower the NMN reference value in patients &#60;40 years of age from 165<span class="elsevierStyleHsp" style=""></span>pg&#47;ml to 100<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">With regard to biological variability&#44; since CV<span class="elsevierStyleInf">I</span> for both MN and NMN is greater than CV<span class="elsevierStyleInf">G</span>&#44; it is not advisable to use the reference value of the change to detect individual significant changes that may be associated with the presence of PCT&#47;PGL&#59; instead&#44; it is more appropriate to use population-based clinical decision values&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">The greatest challenge in interpreting the biochemical results of MNs occurs when results close to the normal limit are obtained&#46; In these cases&#44; the reading obtained is more likely to be a false positive result due to drug treatment or a physiological increase in catecholamine levels than a true positive result&#44; due to the low prevalence of PCT&#47;PGL&#46; The results of our study show that the combination of PFM with urinary fractionated MN is an adequate strategy for differentiating between true positive and false positive readings&#44; since an elevation evidenced by both tests is strongly suggestive of PCT&#47;PGL&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Regarding the possible causes of false negative results&#44; it is important to remember that PGL of the head and neck are non-secretory tumours&#44; and these tests are therefore normally of little use in such cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">2&#44;13</span></a> In the present study&#44; one of the three cases of PCT&#47;PGL not detected with PFM testing corresponded to a patient with a jugular &#40;non-secretory&#41; PGL&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">Another case was a 38-year-old woman with NMN 110<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;&#62;100<span class="elsevierStyleHsp" style=""></span>pg&#47;ml being proposed as the reference value in individuals &#60;40 years of age&#41;&#46; Therefore&#44; with reference values adjusted for age and excluding non-secretory tumours&#44; the sensitivity obtained is 94&#37; &#40;16&#47;17 cases&#41;&#44; with a decrease in specificity of only 0&#46;4&#37; &#40;94&#46;3&#37;&#41;&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">The limitations of our study include the small number of patients with plasma catecholamine measurement and the small number of cases of PCT with the determination of VMA in urine&#46; This is because in the event of the simultaneous measurement of plasma and urinary catecholamines&#44; our laboratory cancels the former test because it does not offer information complementary to that provided by urinary catecholamine testing&#46; Furthermore&#44; VMA measurement in urine is performed concomitantly with the determination of homovanillic acid and 5-hydroxy-indoleacetic acid&#59; as a result&#44; many of the VMA measurements were performed in patients with a suspected NET&#47;carcinoid tumour&#46; Another possible limitation is that the PFM reference values have been calculated taking into account all the patients studied&#44; this being a population that probably includes some individuals on different drug treatments as well as patients for whom the other pre-analytical and sample extraction conditions might not have been recommended&#46; However&#44; we feel that the sample size involved&#44; and the statistical tests applied&#44; guarantee that the results obtained are reliable and representative of our population&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">To sum up&#44; this study validates the diagnostic usefulness of PFM determination in the routine clinical practice of a real-life working environment&#46; Adjusting the clinical decision values for plasma NMN in younger patients allows for the increased sensitivity of this test&#46; All clinicians should focus the biochemical diagnosis of PCT&#47;PGL on the analysis of PFMs and urinary fractionated MNs&#44; when available&#44; avoiding the other classical biochemical tests&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflicts of interest</span><p id="par0270" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1120002"
          "palabras" => array:4 [
            0 => "Feocromocitoma"
            1 => "Paraganglioma"
            2 => "Catecolaminas"
            3 => "Metanefrinas"
          ]
        ]
      ]
    ]
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pheochromocytoma and paraganglioma are uncommon tumours whose best known symptoms include high blood pressure&#44; palpitations&#44; headache&#44; and sweating&#46; Clinical identification is not easy&#44; however&#44; and requires biochemical tests that allow for early diagnosis&#44; including measurement of metanephrines levels&#46; The aim of this study was to assess the diagnostic performance of plasma free metanephrines &#40;PMETs&#41; and to verify the transferability of the reference values used&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">PMETs levels were measured by liquid chromatography coupled to tandem mass spectrometry&#46; Other biochemical tests evaluated &#40;plasma catecholamine&#44; urine metanephrine&#44; catecholamine and vanilmandelic acid levels&#41; were performed by liquid chromatography with electrochemical detection&#46; Requests of these tests from 01&#47;09&#47;2015 to 31&#47;10&#47;2017 were reviewed&#44; and both the reference values &#40;document EP28-A3c&#41; and the parameters of biological variation &#40;Fraser method&#41; for PMETs were estimated&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The study sample consisted of 1279 patients &#40;61&#46;3&#37; females&#41; aged 0&#8211;90 years&#44; including 19 with pheochromocytoma&#47;paraganglioma&#46; Tests requested included&#58; PMETs &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>662&#41;&#44; catecholamines &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>589&#41;&#44; metanephrines &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>586&#41;&#44; and vanilmandelic acid &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>513&#41; in urine&#44; and plasma catecholamines &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>228&#41;&#46; Tests with higher sensitivity were urinary fractionated metanephrines &#40;91&#46;7&#37;&#41; and PMETs &#40;82&#46;4&#37;&#41;&#46; When performance was compared in patients with both tests &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>243&#41;&#44; they detected the same number of tumours &#40;90&#46;9&#37;&#41;&#44; but PMETs showed greater specificity &#40;93&#46;5&#37; vs&#46; 88&#46;8&#37;&#41;&#46; Plasma normetanephrine levels showed a significant association with age &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;19&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">PMETs and urinary fractionated metanephrines are the biochemical tests with better performance in diagnosis of pheochromocytomas&#47;paragangliomas&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "identificador" => "abst0020"
            "titulo" => "Conclusion"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Los feocromocitomas y paragangliomas son tumores poco frecuentes cuyos s&#237;ntomas m&#225;s conocidos son hipertensi&#243;n arterial&#44; palpitaciones&#44; cefalea y diaforesis&#46; Sin embargo&#44; su identificaci&#243;n cl&#237;nica no es f&#225;cil&#46; Por ello&#44; se utilizan pruebas bioqu&#237;micas que permitan un diagn&#243;stico precoz&#44; destacando las metanefrinas&#46; El objetivo de este estudio fue evaluar el rendimiento diagn&#243;stico de las metanefrinas libres plasm&#225;ticas &#40;MLP&#41; y verificar la transferibilidad de los valores de referencia utilizados&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Las MLP fueron cuantificadas mediante cromatograf&#237;a l&#237;quida de alta resoluci&#243;n acoplada a espectrometr&#237;a de masas&#46; Otras pruebas bioqu&#237;micas evaluadas &#40;catecolaminas en plasma&#44; metanefrinas&#44; catecolaminas y &#225;cido vanilmand&#233;lico en orina&#41; fueron analizadas por cromatograf&#237;a l&#237;quida de alta resoluci&#243;n con detecci&#243;n electroqu&#237;mica&#46; Se revisaron las solicitudes de dichas pruebas del 01&#47;09&#47;2015 al 31&#47;10&#47;2017 y se estimaron los valores de referencia &#40;documento EP28-A3c&#41; y los par&#225;metros de variabilidad biol&#243;gica &#40;m&#233;todo de Fraser&#41; de las MLP&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se estudiaron 1&#46;279 pacientes &#40;61&#44;3&#37; mujeres&#41;&#44; con edades entre 0-90 a&#241;os&#44; incluyendo 19 casos de feocromocitoma&#47;paraganglioma&#46; Las solicitudes bioqu&#237;micas fueron&#58; MLP &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>662&#41;&#44; catecolaminas urinarias &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>589&#41;&#44; metanefrinas urinarias &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>586&#41;&#44; &#225;cido vanilmand&#233;lico urinario &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>513&#41; y catecolaminas plasm&#225;ticas &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>228&#41;&#46; Las pruebas con mayor sensibilidad fueron las metanefrinas fraccionadas urinarias &#40;91&#44;7&#37;&#41; y las MLP &#40;82&#44;4&#37;&#41;&#46; Cuando se compar&#243; el rendimiento en pacientes con ambas pruebas &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>243&#41;&#44; estas detectaron los mismos casos &#40;90&#44;9&#37;&#41;&#44; pero las MLP fueron m&#225;s espec&#237;ficas &#40;93&#44;5 vs&#46; 88&#44;8&#37;&#41;&#46; Para la normetanefrina plasm&#225;tica se observ&#243; una asociaci&#243;n significativa con la edad &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;19&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Las MLP y las metanefrinas fraccionadas urinarias son las pruebas bioqu&#237;micas que ofrecen un mayor rendimiento en el diagn&#243;stico de los feocromocitomas&#47;paragangliomas&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0025"
            "titulo" => "Introducci&#243;n"
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            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
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            "identificador" => "abst0035"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusi&#243;n"
          ]
        ]
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    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Please cite this article as&#58; Mart&#237;nez-Morillo E&#44; Vald&#233;s Gallego N&#44; Eguia &#193;ngeles E&#44; Fern&#225;ndez Fern&#225;ndez JC&#44; Prieto Garc&#237;a B&#44; &#193;lvarez FV&#46; Rendimiento de las metanefrinas libres plasm&#225;ticas en el diagn&#243;stico de los feocromocitomas y paragangliomas en la poblaci&#243;n asturiana&#46; Endocrinol Diabetes Nutr&#46; 2019&#59;66&#58;312&#8211;319&#46;</p>"
      ]
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Association of plasma normetanephrine levels with patient age&#46; The suggested cut-off points are added based on patient age&#46;</p>"
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        "etiqueta" => "Figure 2"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Box plots corresponding to plasma normetanephrine levels by age range &#40;&#60;40 years&#44; 40&#8211;60<span class="elsevierStyleHsp" style=""></span>years&#44; &#62;60 years&#41;&#46;</p>"
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                  \t\t\t\t">Urinary metanephrines&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">91&#46;7&#37; &#40;11&#47;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">86&#46;6&#37; &#40;497&#47;574&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Plasma metanephrines&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">82&#46;4&#37; &#40;14&#47;17&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">94&#46;7&#37; &#40;611&#47;645&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Plasma catecholamines&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">71&#46;4&#37; &#40;5&#47;7&#41;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Diagnostic performance of the different biochemical tests&#46;</p>"
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t">0&#46;954&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;934&#8211;0&#46;970 &#40;&#60;0&#46;0001&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0&#46;893&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;866&#8211;0&#46;915 &#40;&#60;0&#46;0001&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Urinary norepinephrine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;833&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;800&#8211;0&#46;862 &#40;&#60;0&#46;0001&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Urinary VMA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Plasma norepinephrine&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Pheochromocytoma&#58; diagnostic and therapeutic update"
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Oleaga"
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                    0 => array:2 [
                      "doi" => "10.1016/S1575-0922(08)70669-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Endocrinol Nutr"
                        "fecha" => "2008"
                        "volumen" => "55"
                        "paginaInicial" => "202"
                        "paginaFinal" => "216"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22967914"
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                          ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Update on modern management of pheochromocytoma and paraganglioma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;W&#46;M&#46; Lenders"
                            1 => "G&#46; Eisenhofer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Endocrinol Metab &#40;Seoul&#41;"
                        "fecha" => "2017"
                        "volumen" => "32"
                        "paginaInicial" => "152"
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                      ]
                    ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Clinical and pathological characteristics of hypertensive and normotensive adrenal pheochromocytomas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Lu"
                            1 => "P&#46; Li"
                            2 => "W&#46; Gan"
                            3 => "X&#46; Zhao"
                            4 => "S&#46; Shen"
                            5 => "W&#46; Feng"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-0042-100911"
                      "Revista" => array:6 [
                        "tituloSerie" => "Exp Clin Endocrinol Diabetes"
                        "fecha" => "2016"
                        "volumen" => "124"
                        "paginaInicial" => "372"
                        "paginaFinal" => "379"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27219882"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Causes of secondary hypertension in the young population&#58; a monocentric study"
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                          "autores" => array:6 [
                            0 => "C&#46; Noilhan"
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                            2 => "L&#46; Bieler"
                            3 => "J&#46; Amar"
                            4 => "B&#46; Chamontin"
                            5 => "B&#46; Bouhanick"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
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                      "Revista" => array:5 [
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                        "volumen" => "65"
                        "paginaInicial" => "159"
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                      "titulo" => "Pheochromocytoma in Italy&#58; a multicentric retrospective study"
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                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46; Mannelli"
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                            2 => "A&#46; Cilotti"
                            3 => "A&#46; Conti"
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                  ]
                  "host" => array:1 [
                    0 => array:1 [
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                        "tituloSerie" => "Eur J Endocrinol"
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                        "paginaInicial" => "619"
                        "paginaFinal" => "624"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical presentations&#44; biochemical phenotypes&#44; and genotype&#8211;phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46;J&#46; Timmers"
                            1 => "A&#46; Kozupa"
                            2 => "G&#46; Eisenhofer"
                            3 => "M&#46; Raygada"
                            4 => "K&#46;T&#46; Adams"
                            5 => "D&#46; Solis"
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                      ]
                    ]
                  ]
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Article information
ISSN: 25300180
Original language: English
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