Seasonal variation of plasma free normetanephrine concentrations: implications for biochemical diagnosis of pheochromocytoma

Abstract

Background: Higher plasma concentrations of catecholamines in winter than in summer are established; whether this impacts plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown. Objective: In this study, we examined seasonal variations in plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming (‘arterialization’ of venous blood) on blood flow and measured concentrations. Methods: Measurements of plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for measurements of plasma metanephrines and forearm blood flow before and after forearm warming. Results: There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, plasma concentrations of normetanephrine were higher (P!0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P!0.0001). These differences resulted in a twofold higher (PZ0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (PZ0.0010). Forearm warming increased blood flow and lowered (PZ0.0020) plasma normetanephrine concentrations. Conclusions: Plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.