{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:23:39Z","timestamp":1787318619722,"version":"build-2736575974"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T00:00:00Z","timestamp":1623024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Von Hippel-Lindau Alliance"},{"name":"Intramural Research Program"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Measurements of plasma free metanephrines are recommended for diagnosing pheochromocytomas and paragangliomas (PPGL). Metanephrines can be detected in saliva with LC-MS\/MS with sufficient analytical sensitivity and precision. Because collecting saliva is noninvasive and less cumbersome than plasma or urine sampling, we assessed the diagnostic accuracy of salivary metanephrines in diagnosing PPGL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This 2-center study included 118 healthy participants (44 men; mean age: 33 years (range: 19--74 years)), 44 patients with PPGL, and 54 patients suspected of PPGL. Metanephrines were quantified in plasma and saliva using LC-MS\/MS. Diagnostic accuracy; correlation between plasma and salivary metanephrines; and potential factors influencing salivary metanephrines, including age, sex, and posture during sampling, were assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Salivary metanephrines were significantly higher in patients with PPGL compared with healthy participants (metanephrine (MN): 0.19 vs 0.09\u2009nmol\/L, P\u2009&amp;lt;\u20090.001; normetanephrine (NMN): 2.90 vs 0.49\u2009nmol\/L, P\u2009&amp;lt;\u20090.001). The diagnostic sensitivity and specificity of salivary metanephrines were 89% and 87%, respectively. Diagnostic accuracy of salivary metanephrines was 88%, with an area under the ROC curve of 0.880. We found a significant correlation between plasma and salivary metanephrines (Pearson correlation coefficient: MN, 0.86, P\u2009&amp;lt;\u20090.001; NMN, 0.83, P\u2009&amp;lt;\u20090.001). Salivary NMN concentrations were higher when collected in a seated position compared with supine (P\u2009&amp;lt;\u20090.001) and increased with age (P\u2009&amp;lt;\u20090.001).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Salivary metanephrines are a promising tool in the biochemical diagnosis of PPGL. Salivary metanephrines correlate with plasma free metanephrines and are increased in patients with PPGL. At this time, however, salivary metanephrines cannot replace measurement of plasma free metanephrines.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/clinchem\/hvab064","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T14:34:46Z","timestamp":1619102086000},"page":"1090-1097","source":"Crossref","is-referenced-by-count":8,"title":["Diagnostic Accuracy of Salivary Metanephrines in Pheochromocytomas and Paragangliomas"],"prefix":"10.1093","volume":"67","author":[{"given":"Karin","family":"Eijkelenkamp","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thamara E","family":"Osinga","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn","family":"van Faassen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ido P","family":"Kema","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel N","family":"Kerstens","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel","family":"Pacak","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim J","family":"Sluiter","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thera P","family":"Links","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anouk N A","family":"van der Horst-Schrivers","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"},{"name":"Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,7]]},"reference":[{"key":"2021080609121929400_hvab064-B1","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1001\/jamaoncol.2017.0222","article-title":"Pheochromocytoma and paraganglioma susceptibility genes: estimating the associated risk of disease","volume":"3","author":"Fishbein","year":"2017","journal-title":"JAMA Oncol"},{"key":"2021080609121929400_hvab064-B2","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nrc3648","article-title":"Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity","volume":"14","author":"Dahia","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"2021080609121929400_hvab064-B3","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1210\/jc.2014-1498","article-title":"Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline","volume":"99","author":"Lenders","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"2021080609121929400_hvab064-B4","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1097\/HJH.0000000000002438","article-title":"Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension","volume":"38","author":"Lenders","year":"2020","journal-title":"J Hypertens"},{"key":"2021080609121929400_hvab064-B5","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1373\/clinchem.2018.291369","article-title":"Biochemical diagnosis of chromaffin cell tumors in patients at high and low risk of disease: plasma versus urinary free or deconjugated O-methylated catecholamine metabolites","volume":"64","author":"Eisenhofer","year":"2018","journal-title":"Clin Chem"},{"key":"2021080609121929400_hvab064-B6","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.cca.2018.12.019","article-title":"Reference intervals for LC-MS\/MS measurements of plasma free, urinary free and urinary acid-hydrolyzed deconjugated normetanephrine, metanephrine and methoxytyramine","volume":"490","author":"Eisenhofer","year":"2019","journal-title":"Clin Chim Acta"},{"key":"2021080609121929400_hvab064-B7","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1373\/clinchem.2006.076489","article-title":"Is supine rest necessary before blood sampling for plasma metanephrines?","volume":"53","author":"Lenders","year":"2007","journal-title":"Clin Chem"},{"key":"2021080609121929400_hvab064-B8","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1210\/jc.2009-0303","article-title":"Dietary influences on plasma and urinary metanephrines: implications for diagnosis of catecholamine-producing tumors","volume":"94","author":"de Jong","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"2021080609121929400_hvab064-B9","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1365-2265.2009.03761.x","article-title":"Influence of various confounding variables and storage conditions on metanephrine and normetanephrine levels in plasma","volume":"73","author":"Deutschbein","year":"2010","journal-title":"Clin Endocrinol"},{"key":"2021080609121929400_hvab064-B10","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1515\/cclm-2020-0022","article-title":"Blood sampling for metanephrines comparing venipuncture vs. indwelling intravenous cannula in healthy subjects","volume":"58","author":"Eijkelenkamp","year":"2020","journal-title":"Clin Chem Lab Med"},{"key":"2021080609121929400_hvab064-B11","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/cen.12587","article-title":"Supine or sitting? Economic considerations regarding patient position during plasma metanephrine analysis for the exclusion of chromaffin tumours","volume":"82","author":"Chortis","year":"2015","journal-title":"Clin Endocrinol"},{"key":"2021080609121929400_hvab064-B12","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.cca.2007.04.011","article-title":"Saliva specimen: a new laboratory tool for diagnostic and basic investigation","volume":"383","author":"Chiappin","year":"2007","journal-title":"Clin Chim Acta"},{"key":"2021080609121929400_hvab064-B13","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.clinbiochem.2016.02.003","article-title":"Mass spectrometric quantification of salivary metanephrines\u2014a study in healthy subjects","volume":"49","author":"Osinga","year":"2016","journal-title":"Clin Biochem"},{"key":"2021080609121929400_hvab064-B14","doi-asserted-by":"crossref","first-page":"9072","DOI":"10.1021\/acs.analchem.0c01263","article-title":"In matrix derivatization combined with LC-MS\/MS results in ultrasensitive quantification of plasma free metanephrines and catecholamines","volume":"92","author":"Faassen","year":"2020","journal-title":"Anal Chem"},{"key":"2021080609121929400_hvab064-B15","first-page":"431","article-title":"Salivary free catecholamines metabolites as possible biochemical markers in pheochromocytoma diagnosis","volume":"7","author":"Stefanescu","year":"2011","journal-title":"Acta Endocrinol"},{"key":"2021080609121929400_hvab064-B16","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.cca.2012.09.031","article-title":"Influence of saliva flow rate stimulated by gum-chewing on salivary concentrations of catecholamine metabolites","volume":"414","author":"Higashi","year":"2012","journal-title":"Clin Chim Acta"},{"key":"2021080609121929400_hvab064-B17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0024-3205(01)01111-0","article-title":"Catecholamines in human saliva","volume":"69","author":"Kennedy","year":"2001","journal-title":"Life Sci"},{"key":"2021080609121929400_hvab064-B18","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1258\/acb.2012.012066","article-title":"Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma","volume":"50","author":"Eisenhofer","year":"2013","journal-title":"Ann Clin Biochem"},{"key":"2021080609121929400_hvab064-B19","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.cca.2019.03.1620","article-title":"Age-specific pediatric reference intervals for plasma free normetanephrine, metanephrine, 3-methoxytyramine and 3-O-methyldopa: particular importance for early infancy","volume":"494","author":"Peitzsch","year":"2019","journal-title":"Clin Chim Acta"}],"container-title":["Clinical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/clinchem\/article-pdf\/67\/8\/1090\/39588792\/hvab064.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/clinchem\/article-pdf\/67\/8\/1090\/39588792\/hvab064.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T11:31:59Z","timestamp":1698924719000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/clinchem\/article\/67\/8\/1090\/6294198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,7]]},"references-count":19,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,6,7]]},"published-print":{"date-parts":[[2021,8,5]]}},"URL":"https:\/\/doi.org\/10.1093\/clinchem\/hvab064","relation":{},"ISSN":["0009-9147","1530-8561"],"issn-type":[{"value":"0009-9147","type":"print"},{"value":"1530-8561","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,8,1]]},"published":{"date-parts":[[2021,6,7]]}}}