A high rate of modestly elevated plasma normetanephrine in a population referred for suspected PPGL when measured in a seated position

in European Journal of Endocrinology
Correspondence should be addressed to G A Kline; Email: Gregory.kline@ahs.ca
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Objective

Determine rate of high plasma normetanephrine or metanephrine (PNM-PMN) in a large sample of patients according to PNM-PMN posture and age-adjusted references.

Design

Retrospective re-analysis of PNM-PMN from a Canadian reference laboratory (n = 5452), 2011–2015; most were in seated position (n = 5112) rather than supine (n = 340). An international PPGL database demonstrated expected distribution of supine PNM-PMN in PPGL patients.

Methods

All PNM-PMN from a tertiary referral laboratory were reviewed. Any PNM-PMN result greater than 2× upper reference limit (URL) was considered likely true PPGL. Results 1–2× URL were uncertain, requiring additional testing/follow-up despite most being false positive given the rarity of PPGL. The rate of results in the 1–2× URL category were calculated for each group according to collection posture and differing published URL: seated, supine or supine age adjusted.

Results

When collected and interpreted by seated URL, 19.6% of PNM required additional testing; only 4.6% being >2× URL. For patients over age 50 years, the abnormal rate was 24.9%. When collected supine, interpreted by supine age-adjusted URL, only 5.3% of PNM were mildly elevated. Possible false positives may be even lower when considering PMN or plasma methoxytyramine which were commonly high in true PPGL despite mild PNM elevations.

Conclusions

In a general medical population, seated PNM has a high rate of abnormal results, far exceeding expected prevalence. Supine measurement with supine, age-adjusted interpretation is strongly preferred prior to costly or invasive PPGL investigations.

Summary

Review of 5452 plasma normetanephrine measurements showed 20% to be high, likely false positives for most. Supine, age-adjusted measures were half as likely to be elevated.

 

     European Society of Endocrinology

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Figures

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    (A) Median and distribution of PNM in patients suspected of PPGL, referred for seated, outpatient commercial lab sample collection. (B) Distribution of PNM in patients with suspected PPGL referred for resting, supine sample collection. (C) distribution of PNM results in 686 confirmed PPGL cases with samples collected resting, supine. Upper reference limits shown represent commonly used upper reference limits for seated collection samples. PNM, plasma normetanephrine; PPGL, pheochromocytoma/paraganglioma; URL, upper reference limit; 2× URL, twice the upper reference limit. P < 0.001 Mann–Whitney U test. A full colour version of this figure is available at https://doi.org/10.1530/EJE-19-0176.

  • View in gallery

    (A) Distribution of seated PNM results in 5112 patients suspected of PPGL according to patient age and with reference to the standard, seated upper reference limit as well as supine, age-adjusted upper reference limit. (B) Distribution of supine, resting PNM in 340 patients suspected of PPGL, according to patient age and with reference to the standard seated upper reference limit as well as supine, age-adjusted upper reference limit. (C) Distribution of supine, resting PNM in patients with confirmed PPGL according to fixed upper reference limits and age adjusted. Note that 462 subjects with much higher PNM are not shown, in order to focus on patients with PNM near the reference limits. Colored triangles in (C) represent patients with normal PNM but high PMN or PMTY. PMN, plasma metanephrine; PMTY, plasma methoxytyramine; PNM, plasma normetanephrine; PPGL, pheochromocytoma/paraganglioma; URL, upper reference limit. A full colour version of this figure is available at https://doi.org/10.1530/EJE-19-0176.

  • View in gallery

    Plasma metanephrine results according to three levels of plasma normetanephrine in a general PPGL screening population (A), a supine endocrine testing population (B) and a cohort of confirmed PPGL (C). PMN, plasma metanephrine; PNM, plasma normetanephrine; PPGL, pheochromocytoma/paraganglioma, URL, upper reference limit of a (seated) reference range.

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