Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma - PubMed (original) (raw)

. 2013 Jan;50(Pt 1):62-9.

doi: 10.1258/acb.2012.012066. Epub 2012 Oct 12.

Peter Lattke, Maria Herberg, Gabriele Siegert, Nan Qin, Roland Därr, Jana Hoyer, Arno Villringer, Aleksander Prejbisz, Andrzej Januszewicz, Alan Remaley, Victoria Martucci, Karel Pacak, H Alec Ross, Fred C G J Sweep, Jacques W M Lenders

Affiliations

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

Graeme Eisenhofer et al. Ann Clin Biochem. 2013 Jan.

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: None.

Figures

Figure 1

Figure 1

Scatter plots showing relationships of age with plasma concentrations of normetanephrine (a) and metanephrine (b) for subjects of the reference population (n = 1226)

Figure 2

Figure 2

Box plots showing distributions of plasma concentrations of normetanephrine (a) and metanephrine (b) among the five subgroups of the reference population. CV, child volunteers; NV, normotensive heathy volunteers; HS, hypertensive subjects; P1, patient group 1 (tested for phaeochromocytoma because of an incidental mass found on imaging, an underlying germline mutation or a previous history of the tumour); P2, patient group 2 (tested for phaeochromocytoma because of signs and symptoms of catecholamine excess). *†Indicates groups with higher* and lower† concentrations than other connected groups at the indicated levels of significance

Figure 3

Figure 3

Scatter plots showing relationships of age with plasma concentrations of normetanephrine for patients of the validation population without (a) and with (b) phaeochromocytoma. The dashed horizontal lines serve to illustrate the static age-unadjusted upper cut-off for plasma normetanephrine (0.706 nmol/L) determined from the 97.5 percentiles of the combined reference population (Table 2). The curved line serves to illustrate age-adjusted cut-offs for plasma normetanephrine (UCNMN) according to the equation, UCNMN = 2.074 × 10−6age3 + 0.540, established for the curvilinear model. Note that for patients with phaeochromocytoma (b), data for plasma normetanephrine are plotted using a logarithmic scale

Similar articles

Cited by

References

    1. Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. Nat Clin Pract Endocrinol Metab. 2007;3:92–102. - PubMed
    1. Peaston RT, Ball S. Biochemical detection of phaeochromocytoma: why are we continuing to ignore the evidence? Ann Clin Biochem. 2008;45:6–10. - PubMed
    1. Whiting MJ, Doogue MP. Advances in biochemical screening for phaeochromocytoma using biogenic amines. Clin Biochem Rev. 2009;30:3–17. - PMC - PubMed
    1. Eisenhofer G. Screening for pheochromocytomas and paragangliomas. Curr Hypertens Rep. 2012;14:130–7. - PubMed
    1. Eisenhofer G, Keiser H, Friberg P, et al. Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors. J Clin Endocrinol Metab. 1998;83:2175–85. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources