Establishment of reference intervals for plasma metanephrines in seated position measured by LC-MS/MS and assessment of diagnostic performance in pheochromocytoma/paraganglioma

Abstract

Background: The use of supine reference intervals instead of the corresponding seated reference intervals for seated plasma-free metanephrines (MNs) in pheochromocytoma /paraganglioma (PPGL) screening has been controversial in recent years. Each clinical laboratory should choose the optimal sampling posture and diagnostic strategy according to local conditions. 
 Methods: The reference population consisted of 736 cases aged 14 to 92 years old and the validation population consisted of 1068 patients aged 8 to 87 years old. Seated MNs were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the reference intervals and diagnostic cut-off values were established and the diagnostic performance compared with reference intervals established in a supine position.
 Results: There was no correlation between seated plasma MNs and age (P>0.05) and there were differences in MNs among the various disease groups (P<0.05). MNs were different in gender (P<0.0001). The upper reference limit (URL) established in this study had the same sensitivity (100%) and better specificity (94.6% vs 83.5%) compared with the published age-adjusted supine reference intervals. The proportion of suspected patients with MNs within the URL-2×URL range was lower using seated reference intervals compared to supine intervals (5.3% vs 15.7%).
 Conclusion: Using the corresponding seated reference intervals for seated plasma MNs can reduce the unnecessary re-examinations of suspected patients with slightly elevated MNs. The cut-off value established by seated plasma MNs has good diagnostic performance in PPGL. Use of seated sampling is an acceptable practice and is more convenient and economical than supine sampling.

A Laboratory Medicine Perspective on the Investigation of Phaeochromocytoma and Paraganglioma

“…There has been some debate over whether supine sampling is necessary in all patients under investigation for PPGL [ 72 , 73 ], as although this is ideal, some diagnostic centres may find it difficult to provide the resources necessary for supine sampling in all patients. Some researchers have published data suggesting that seated sampling offers a high degree of diagnostic sensitivity and so have argued that seated sampling is acceptable [ 74 , 75 ]. A large study of the diagnostic performance of plasma and urine metanephrines in different patient groups by Eisenhofer at al [ 44 ] found that false negatives were more likely in patients undergoing surveillance due to an increased risk of PPGL (due to a genetic predisposition or history of treated PPGL) as minor elevations in plasma and urine metanephrines were more common (these patients are more likely to be harbouring small, pre-symptomatic PPGL).…”

“…Posture during sample collection for the reference population also has a significant effect on plasma metanephrine reference ranges [ 56 ], with seated healthy individuals having significantly higher normetanephrine than supine individuals. The application of higher, seated reference ranges or lower supine ranges may have a significant effect on diagnostic sensitivity and specificity, although this will also depend on the posture used for collection of samples in clinical practice [ 56 , 74 , 75 ]. For example, applying lower supine ranges while collecting samples in a seated position will likely lead to a high false-positive rate, while applying higher seated ranges while collecting samples in a supine posture may lead to impaired diagnostic sensitivity [ 56 ].…”