Detection of pheochromocytoma by enzyme immunoassay measurements of plasma metanephrines requires appropriately established upper cut-offs of reference intervals

Dirk Weismann; Anna Raida; Timo Deutschbein; Aleksander Prejbisz; Andrzej Januszewicz; Holger S. Willenberg; Mirko Peitzsch; Roland Darr; Reiner Klemm; Georg Manz; Martin Bidlingmaier; Graeme Eisenhofer; Martin Fassnacht

doi:10.1530/endoabs.35.OC2.4

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Endocrine Abstracts (2014) 35 OC2.4 | DOI: 10.1530/endoabs.35.OC2.4

ECE2014 Oral Communications Adrenal clinical (5 abstracts)

Detection of pheochromocytoma by enzyme immunoassay measurements of plasma metanephrines requires appropriately established upper cut-offs of reference intervals

Dirk Weismann ¹ , Anna Raida ¹ , Timo Deutschbein ¹ , Aleksander Prejbisz ² , Andrzej Januszewicz ² , Holger S. Willenberg ³ , Mirko Peitzsch ⁴ , Roland Därr ⁴ , Reiner Klemm ⁵ , Georg Manz ⁵ , Martin Bidlingmaier ⁶ , Graeme Eisenhofer ⁴ & Martin Fassnacht ⁶

Err

Author affiliations

¹Endocrine and Diabetes Unit, University Hospital Wuerzburg, Wuerzburg, Germany; ²Department of Hypertension, Institute of Cardiology, Warsaw, Warsaw, Poland; ³Dept. Endocrinology and Diabetes, University of Duesseldorf, Duesseldorf, Germany; ⁴Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Dresden, Dresden, Germany; ⁵LDN Labor Diagnostika Nord GmbH, Nordhorn, Germany; ⁶Endocrine Research Unit, Medical Clinic Innenstadt – LMU Munic, Munic, Germany.

Aim: To determine diagnostic performance of normetanephrine (NMN) and metanephrine (MN) measured by an enzyme immunoassay (EIA) compared with liquid chromatographic–tandem mass spectrometry (LC-MS/MS).

Methods: Subjects included 341 patients (174 males) with a mean age of 52 year (range 13–86) tested for PHEO, which was confirmed in 54 patients. Samples where collected from fasting patients after 30 min of supine rest and analyzed for NMN, MN and methoxytyramine (MTY) by LC-MS/MS at Dresden and for NMN and MN by immunoassay at Nordhorn.

Results: Areas under ROC curves for the EIA (0.993) were similar to those for LC-MS/MS, with and without MTY (0.999 and 0.985), indicating excellent diagnostic performance of both methods. However, upper cutoffs (UC) stipulated by the manufacturers for the EIA (180 pg/ml for NMN and 90 pg/ml for MN) are too high to reliably identify patients with PHEO under any condition of blood sampling (26.3% patients with PHEO missed due to false negatives). Using age-adjusted UC for NMN and a static UC for MN,¹ LC-MS/MS measurements returned a diagnostic sensitivity of 98.1% with a specificity of 99.7%; sensitivity increased to 100% upon inclusion of MTY with minimal loss of specificity (99.3%). Plasma concentrations of NMN and MN were measured 44% and 26% lower by the EIA than by LC-MS/MS. Correction of UCs for that difference (UC_NMN=0.0002169×(age³)+56.5 and UC_MN=65 pg/m) increased diagnostic sensitivity for the EIA from 73.6% to 96.2% with a minimal loss in specificity (98.9% to 97.2%).

Conclusions: With the EIA, PHEOs can be diagnosed with high sensitivity and specificity, but UCs must be established for supine and fasting sampling conditions. Additionally, the assay needs recalibration to avoid underestimation of plasma metanephrines.

Reference

1 Eisenhofer G. et al. Annals of Clinical Biochemistry 50, 62–69 (2013).