{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:07:18Z","timestamp":1789762038800,"version":"4.0.1"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Pheochromocytoma (PhC) and Paraganglioma (PG) are rare neuroendocrine tumors characterized by uncontrolled catecholamine secretion. Although rare, much attention is still devoted to identifying a unique biochemical signature of these diseases to reduce false positives, thus improving patient outcomes, and customizing clinical laboratory practices to available resources and specific diagnostic needs. Emerging knowledge into catecholamine metabolism has greatly improved diagnostic strategies, with current international guidelines recognizing plasma free or urinary fractionated metanephrine measurements as the recommended first-line biochemical tests. This narrative review highlights the clinical utility of measuring plasma free metanephrines compared to urinary catecholamines in the diagnosis of these conditions. Plasma free metanephrines offer superior sensitivity and specificity compared to catecholamines due to their continuous secretion, which is independent from tumor size and catecholamine fluctuations. This review also addresses preanalytical and methodological challenges, emphasizing patient preparation, sample stability and advanced analytical techniques currently available. Methodologies such as LC-MS\/MS have demonstrated improved diagnostic accuracy compared to traditional immunoassays, offering enhanced analytical performance in terms of sensitivity, specificity, and reduced susceptibility to interferences.<\/jats:p>","DOI":"10.3390\/diagnostics16091263","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:09:12Z","timestamp":1776935352000},"page":"1263","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Catecholamines and Metanephrines: Quantification in the Diagnosis of Pheochromocytoma and Paraganglioma, Considerations and Critical Issues"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7756-6241","authenticated-orcid":false,"given":"Sandra","family":"Rufolo","sequence":"first","affiliation":[{"name":"University Hospital \u201cSan Giovanni di Dio e Ruggi d\u2019Aragona\u201d, 84131 Salerno, Italy"},{"name":"Post-Graduate School in Clinical Pathology and Clinical Biochemistry, University of Salerno, 84081 Baronissi, Campania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Chiara","family":"Balsamo","sequence":"additional","affiliation":[{"name":"University Hospital \u201cSan Giovanni di Dio e Ruggi d\u2019Aragona\u201d, 84131 Salerno, Italy"},{"name":"Post-Graduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Campania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Parisi","sequence":"additional","affiliation":[{"name":"Post-Graduate School in Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Campania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2724-8212","authenticated-orcid":false,"given":"Albino","family":"Coglianese","sequence":"additional","affiliation":[{"name":"Post-Graduate School in Clinical Pathology and Clinical Biochemistry, University of Salerno, 84081 Baronissi, Campania, Italy"},{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Baronissi, Campania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5076-3220","authenticated-orcid":false,"given":"Bruno","family":"Charlier","sequence":"additional","affiliation":[{"name":"University Hospital \u201cSan Giovanni di Dio e Ruggi d\u2019Aragona\u201d, 84131 Salerno, Italy"},{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Baronissi, Campania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6066-7569","authenticated-orcid":false,"given":"Viviana","family":"Izzo","sequence":"additional","affiliation":[{"name":"University Hospital \u201cSan Giovanni di Dio e Ruggi d\u2019Aragona\u201d, 84131 Salerno, Italy"},{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Baronissi, Campania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1530\/EJE-20-0628","article-title":"Epidemiology of pheochromocytoma and paraganglioma: Population-based cohort study","volume":"184","author":"Leung","year":"2021","journal-title":"Eur. J. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s12022-022-09704-6","article-title":"Overview of the 2022 WHO Classification of Paragangliomas and Pheochromocytomas","volume":"33","author":"Mete","year":"2022","journal-title":"Endocr. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1530\/EJE-19-0159","article-title":"Pheochromocytoma and paraganglioma: Clinical feature-based disease probability in relation to catecholamine biochemistry and reason for disease suspicion","volume":"181","author":"Geroula","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1056\/NEJMra1806651","article-title":"Pheochromocytoma and Paraganglioma","volume":"381","author":"Neumann","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_5","first-page":"271","article-title":"Pheochromocytoma and Paraganglioma: From Clinical Findings to Diagnosis","volume":"54","author":"Aygun","year":"2020","journal-title":"Sisli Etfal Hast. Tip Bul."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1196\/annals.1353.009","article-title":"Characteristics of blood pressure in pheochromocytoma","volume":"1073","author":"Zelinka","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s40618-022-01905-4","article-title":"Neuroendocrine neoplasms in the context of inherited tumor syndromes: A reappraisal focused on targeted therapies","volume":"46","author":"Ruggeri","year":"2023","journal-title":"J. Endocrinol. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.sleep.2010.09.015","article-title":"Increased sympathetic activity in children with obstructive sleep apnea: Cardiovascular implications","volume":"12","author":"Horne","year":"2011","journal-title":"Sleep Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1023\/A:1011572617314","article-title":"Understanding catecholamine metabolism as a guide to the biochemical diagnosis of pheochromocytoma","volume":"2","author":"Eisenhofer","year":"2001","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Eisenhofer, G., Peitzsch, M., Bechmann, N., and Huebner, A. (2022). Biochemical Diagnosis of Catecholamine-Producing Tumors of Childhood: Neuroblastoma, Pheochromocytoma and Paraganglioma. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.901760"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.clinbiochem.2014.07.009","article-title":"Amoxicillin-associated interference in an HPLC-EC assay for urinary fractionated metanephrines: Potential pitfall in pheochromocytoma biochemical diagnosis","volume":"47","author":"Barco","year":"2014","journal-title":"Clin. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.21037\/jxym-20-88","article-title":"Metabolism and secretion mechanism of catecholamine syndrome and related treatment strategies","volume":"5","author":"Liu","year":"2020","journal-title":"J. Xiangya Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1124\/pr.56.3.1","article-title":"Catecholamine metabolism: A contemporary view with implications for physiology and medicine","volume":"56","author":"Eisenhofer","year":"2004","journal-title":"Pharmacol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.jamcollsurg.2009.09.022","article-title":"Clinical spectrum of pheochromocytoma","volume":"209","author":"Guerrero","year":"2009","journal-title":"J. Am. Coll. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1210\/jc.2007-1354","article-title":"Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the diagnostic accuracy of plasma fractionated metanephrines for pheochromocytoma","volume":"93","author":"Preissner","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s10286-010-0065-7","article-title":"Catecholamines 101","volume":"20","author":"Goldstein","year":"2010","journal-title":"Clin. Auton. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.abb.2010.12.017","article-title":"Tyrosine hydroxylase and regulation of dopamine synthesis","volume":"508","author":"Daubner","year":"2011","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1210\/endrev\/bnad011","article-title":"Biochemical Assessment of Pheochromocytoma and Paraganglioma","volume":"44","author":"Eisenhofer","year":"2023","journal-title":"Endocr. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1046\/j.1471-4159.1996.66041565.x","article-title":"Mesenteric organ production, hepatic metabolism, and renal elimination of norepinephrine and its metabolites in humans","volume":"66","author":"Eisenhofer","year":"1996","journal-title":"J. Neurochem."},{"key":"ref_20","first-page":"3009","article-title":"Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines","volume":"80","author":"Eisenhofer","year":"1995","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10377","DOI":"10.1073\/pnas.93.19.10377","article-title":"A novel nonneuronal catecholaminergic system: Exocrine pancreas synthesizes and releases dopamine","volume":"93","author":"Mezey","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3864","DOI":"10.1210\/jcem.82.11.4339","article-title":"Substantial production of dopamine in the human gastrointestinal tract","volume":"82","author":"Eisenhofer","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S93","DOI":"10.1291\/hypres.18.SupplementI_S93","article-title":"Is there a third peripheral catecholaminergic system? Endogenous dopamine as an autocrine\/paracrine substance derived from plasma DOPA and inactivated by conjugation","volume":"18","author":"Goldstein","year":"1995","journal-title":"Hypertens. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1093\/clinchem\/47.6.988","article-title":"Free or total metanephrines for diagnosis of pheochromocytoma: What is the difference?","volume":"47","author":"Eisenhofer","year":"2001","journal-title":"Clin. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1001\/jama.287.11.1427","article-title":"Biochemical diagnosis of pheochromocytoma: Which test is best?","volume":"287","author":"Lenders","year":"2002","journal-title":"JAMA"},{"key":"ref_26","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":"ref_27","doi-asserted-by":"crossref","first-page":"e28081","DOI":"10.1002\/pbc.28081","article-title":"Biochemical testing for neuroblastoma using plasma free 3-O-methyldopa, 3-methoxytyramine, and normetanephrine","volume":"67","author":"Peitzsch","year":"2020","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1056\/NEJMoa012277","article-title":"Neuroblastoma screening at one year of age","volume":"346","author":"Schilling","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.clinbiochem.2014.04.015","article-title":"Urinary homovanillic and vanillylmandelic acid in the diagnosis of neuroblastoma: Report from the Italian Cooperative Group for Neuroblastoma","volume":"47","author":"Barco","year":"2014","journal-title":"Clin. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ejca.2016.12.002","article-title":"Catecholamines profiles at diagnosis: Increased diagnostic sensitivity and correlation with biological and clinical features in neuroblastoma patients","volume":"72","author":"Verly","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_31","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"},{"key":"ref_32","unstructured":"Goldman, L., and Cooney, K.A. (2024). Adrenal medulla, catecholamines, and pheochromocytoma. Goldman-Cecil Medicine, Elsevier. [27th ed.]. Chapter 209."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E170","DOI":"10.1002\/pbc.24671","article-title":"Interchangeability between 24-hour collection and single spot urines for vanillylmandelic and homovanillic acid levels in the diagnosis of neuroblastoma","volume":"60","author":"Cangemi","year":"2013","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1111\/j.1365-2265.2007.02805.x","article-title":"The diagnostic efficacy of urinary fractionated metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma","volume":"66","author":"Perry","year":"2007","journal-title":"Clin. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1530\/EJE-14-0730","article-title":"Measurements of plasma metanephrines by immunoassay vs liquid chromatography with tandem mass spectrometry for diagnosis of pheochromocytoma","volume":"172","author":"Weismann","year":"2015","journal-title":"Eur. J. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1515\/cclm-2017-1120","article-title":"Quantification of vanillylmandelic acid, homovanillic acid and 5-hydroxyindoleacetic acid in urine using a dilute-and-shoot and ultra-high pressure liquid chromatography tandem mass spectrometry method","volume":"56","author":"Grouzmann","year":"2018","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1196\/annals.1353.040","article-title":"Multicenter study on the diagnostic value of a new RIA for the detection of free plasma metanephrines in the work-up for pheochromocytoma","volume":"1073","author":"Lenz","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_38","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":"ref_39","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":"Eisenhofer","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1515\/cclm-2019-0020","article-title":"Short-term stability of free metanephrines in plasma and whole blood","volume":"58","author":"Danese","year":"2020","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1373\/clinchem.2003.023135","article-title":"Stability of plasma free metanephrines during collection and storage as assessed by an optimized HPLC method with electrochemical detection","volume":"49","author":"Willemsen","year":"2003","journal-title":"Clin. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1373\/clinchem.2006.075218","article-title":"Stability of urinary fractionated metanephrines and catecholamines during collection, shipment, and storage of samples","volume":"53","author":"Willemsen","year":"2007","journal-title":"Clin. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1097\/00004872-200106000-00006","article-title":"Lessons from an unpleasant surprise: A biochemical strategy for the diagnosis of pheochromocytoma","volume":"19","author":"Gardet","year":"2001","journal-title":"J. Hypertens."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4602","DOI":"10.1210\/jc.2005-2668","article-title":"Comparison of diagnostic accuracy of urinary free metanephrines, vanillyl mandelic acid, and catecholamines and plasma catecholamines for diagnosis of pheochromocytoma","volume":"92","author":"Boyle","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.cca.2012.12.031","article-title":"Simultaneous liquid chromatography tandem mass spectrometric determination of urinary free metanephrines and catecholamines, with comparisons of free and deconjugated metabolites","volume":"418","author":"Peitzsch","year":"2013","journal-title":"Clin. Chim. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.sleep.2021.09.007","article-title":"Catecholamines and children obstructive sleep apnea: A systematic review","volume":"87","author":"Sica","year":"2021","journal-title":"Sleep Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3892\/etm.2024.12784","article-title":"Clinical exome next-generation sequencing panel for hereditary pheochromocytoma and paraganglioma diagnosis","volume":"29","author":"Melli","year":"2025","journal-title":"Exp. Ther. Med."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/9\/1263\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:21:53Z","timestamp":1776936113000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/9\/1263"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,23]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["diagnostics16091263"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16091263","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,23]]}}}