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Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma

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Eisenhofer, Graeme, Lattke, Peter, Herberg, Maria, Siegert, Gabriele, Qin, Nan, Därr, Roland, Hoyer, Jana, Villringer, Arno, Prejbisz, Aleksander, Januszewicz, Andrzej, Remaley, Alan, Martucci, Victoria, Pacak, Karel, Ross, H Alec, Sweep, Fred C G J, Lenders, Jacques W M·2013·Annals of Clinical Biochemistry International Journal of Laboratory Medicine
DOI 10.1258/acb.2012.012066PMC PMC4714582
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Abstract

BACKGROUND: Measurements of plasma normetanephrine and metanephrine provide a useful diagnostic test for phaeochromocytoma, but this depends on appropriate reference intervals. Upper cut-offs set too high compromise diagnostic sensitivity, whereas set too low, false-positives are a problem. This study aimed to establish optimal reference intervals for plasma normetanephrine and metanephrine. METHODS: Blood samples were collected in the supine position from 1226 subjects, aged 5-84 y, including 116 children, 575 normotensive and hypertensive adults and 535 patients in whom phaeochromocytoma was ruled out. Reference intervals were examined according to age and gender. Various models were examined to optimize upper cut-offs according to estimates of diagnostic sensitivity and specificity in a separate validation group of 3888 patients tested for phaeochromocytoma, including 558 with confirmed disease. RESULTS: Plasma metanephrine, but not normetanephrine, was higher (P < 0.001) in men than in women, but reference intervals did not differ. Age showed a positive relationship (P < 0.0001) with plasma normetanephrine and a weaker relationship (P = 0.021) with metanephrine. Upper cut-offs of reference intervals for normetanephrine increased from 0.47 nmol/L in children to 1.05 nmol/L in subjects over 60 y. A curvilinear model for age-adjusted compared with fixed upper cut-offs for normetanephrine, together with a higher cut-off for metanephrine (0.45 versus 0.32 nmol/L), resulted in a substantial gain in diagnostic specificity from 88.3% to 96.0% with minimal loss in diagnostic sensitivity from 93.9% to 93.6%. CONCLUSIONS: These data establish age-adjusted cut-offs of reference intervals for plasma normetanephrine and optimized cut-offs for metanephrine useful for minimizing false-positive results.

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  1. Whiting MJ, 2009, Clin Biochem Rev, 30, 3

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Authors
Eisenhofer, G., Lattke, P., Herberg, M., Siegert, G., Qin, N., Därr, R., Hoyer, J., Villringer, A., Prejbisz, A., Januszewicz, A., Remaley, A., Martucci, V., Pacak, K., Ross, H. A., Sweep, F. C. G. J., & Lenders, J. W. M.
Affiliations
  • Institute of Clinical Chemistry and Laboratory Medicine;
  • University Hospital Carl Gustav Carus (DE)
  • Department of Medicine III;
  • Max Planck Institute for Human Cognitive and Brain Sciences (DE)
  • Institute of Cardiology (PL)
  • Department of Laboratory Medicine;
  • National Institutes of Health (US)
  • Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA;
  • Radboud University Nijmegen (NL)
Corresponding author
Eisenhofer, Graeme
ORCID
Venue
Annals of Clinical Biochemistry International Journal of Laboratory Medicine
Publisher
SAGE Publications
Published
2012-10-12
Volume
50
Issue
1
Pages
62-69
ISSN
  • 0004-5632 (ISSN-L)
  • 1758-1001
DOI
10.1258/acb.2012.012066
PMC
PMC4714582
OpenAlex
W2018647473
Cited by
113
References
38
Citations by year
2026: 6 · 2025: 3 · 2024: 6 · 2023: 9 · 2022: 8 · 2021: 6 · 2020: 9 · 2019: 12 · 2018: 4 · 2017: 13 · 2016: 9 · 2015: 5 · 2014: 16 · 2013: 7
FWCI
9.14
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Annals of Clinical Biochemistry International Journal of Laboratory Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
Funders
  • National Institutes of Health
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (Z01HD008735)
Topics
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Health Professions › Medical Laboratory Technology › Clinical Laboratory Practices and Quality Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
pheochromocytoma, plasma metanephrines, reference values, upper reference limit, sensitivity and specificity, false positives
MeSH terms
Adolescent, Adrenal Gland Neoplasms, Adult, Age Factors, Aged, Aged, 80 and over, Child, Child, Preschool, False Positive Reactions, Female, Humans, Hypertension, Male, Metanephrine, Middle Aged, Normetanephrine, Pheochromocytoma, Reference Values, Sensitivity and Specificity, Sex Factors, Case-Control Studies

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