False-positive results for pheochromocytoma associated with norepinephrine reuptake blockade

Abstract

Measurements of plasma metanephrines and methoxytyramine provide a sensitive test for diagnosis of pheochromocytoma/paraganglioma. False-positive results remain a problem, particularly in patients taking norepinephrine reuptake-blocking drugs. Therefore, in this retrospective observational study, we measured plasma metanephrines and methoxytyramine in 61 patients taking norepinephrine reuptake blockers (tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors) and 17 others taking selective serotonin reuptake inhibitors, all without pheochromocytoma/paraganglioma. We highlight a singular case with strongly elevated plasma normetanephrine and methoxytyramine concentrations associated with norepinephrine reuptake blockade. Data were compared to results from 252 and 1804 respective patients with and without tumors. Plasma normetanephrine was 40% higher (P < 0.0001) in patients on norepinephrine reuptake blockers and methoxytyramine was 127% higher (P = 0.0062) in patients taking tricyclic antidepressants compared to patients not taking uptake blockers and without tumors. The corresponding false-positive rates rose (P < 0.0001) from 4.8% to 23.0% for normetanephrine and from 0.9% to 28.6% for methoxytyramine. Selective serotonin reuptake inhibitors did not increase plasma concentrations of metabolites. In the highlighted case, plasma normetanephrine and methoxytyramine were elevated more than six times above upper reference limits. A pheochromocytoma/paraganglioma, however, was excluded by functional imaging. All biochemical test results normalized after discontinuation of norepinephrine reuptake blockers. These findings clarify that norepinephrine reuptake blockers usually result in mild elevations of normetanephrine and methoxytyramine that, nevertheless, significantly increase the number of false-positive results. There can, however, be exceptions where increases in normetanephrine and methoxytyramine reach pathological levels. Such exceptions may reflect failure of centrally mediated sympathoinhibition that normally occurs with the norepinephrine reuptake blockade.

Keywords: clonidine; doxepin; duloxetine; false-positive; metanephrine; metanephrines; methoxytyramine; normetanephrine; pheochromocytoma; serotonin–norepinephrine reuptake inhibitor; tricyclic antidepressant.

Figure 1

Dot plot display of plasma normetanephrine (A), metanephrine (B) and methoxytyramine (C) concentrations for patients taking tricyclic antidepressants (TCAs), mixed serotonin norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) compared to patients without and with pheochromocytoma or paraganglioma (PPGL). There were missing data for methoxytyramine in 24 patients without PPGL, in 11 patients without PPGL taking NRIs and in one patient with PPGL. For metanephrine, there were missing data in one patient taking SNRI. The black highlighted diamond indicates the patient for the case presentation who was taking both a TCA and an SNRI. Dashed horizontal lines with the gray area in panel A1 illustrate age-specific upper cutoffs for plasma normetanephrine with highest cutoff value of 1.04 nmol/L for patients >60 years. Figure A2 shows the plasma normetanephrine concentration in relation to the age-specifics upper cutoffs, (i.e. values above 1 indicate elevated normetanephrine levels). Dashed horizontal lines in B and C show upper cutoff limits for plasma metanephrine or methoxytyramine. Horizontal black lines show medians for each group. Differences between groups are shown as P-values by the Steel–Dwass nonparametric method for multiple comparisons. Y-axes are shown as logarithmic scales.

Figure 2

Box plot display of plasma norepinephrine (A) and DHPG (B) and relationships of plasma DHPG with norepinephrine (C) in patients with and without norepinephrine reuptake inhibition (NRI). In panel C, data for patients without NRI (gray dots) show a positive relationship (r_s = 0.515, P < 0.0001), whereas data for patients in whom norepinephrine reuptake was blocked (black dots) show a relationship (r_s = 0.284, P = 0.048) with an 87% decrease in the slope compared to patients with intact norepinephrine transporter function. Data are also shown for the three sampling time points (S1, S2, S3) in the patient of the case presentation (diamonds), the first two sampling points (S1 and S2) with and the third without the norepinephrine reuptake blockade. Box plots show medians and interquartile ranges.

Figure 3

Timeline of medical history, including symptoms, relevant medications and measurements of metanephrines (t₁, t₂, t₃, t₄), for the patient chosen for the case presentation. The blue bar indicates time of artificial ventilation. Bars without coloring indicate times of medication administration.

Figure 4

Concept of central and peripheral actions of norepinephrine reuptake inhibitors (NRIs) and relevant monoamine pathways. (A: Noradrenergic axonal terminal with postsynaptic α₂-adrenoreceptors in the rostral ventrolateral medulla (RVLM). NRIs block the norepinephrine transporter, increasing local concentrations of catecholamines which then activate central α₂-adrenoreceptors to increase sympathoinhibitory signals to postganglionic sympathetic neurons (C) in arterioles (B). (C) Enlarged view of a single sympathetic varicosity. Released norepinephrine is recaptured via norepinephrine transporters or metabolized extraneuronally to normetanephrine (NMN) by catechol-O-methyltransferase (COMT). Reuptake into the varicosity can sequester norepinephrine back into vesicles or deaminate it to dihydroxyphenylglycol (DHPG) via monoamine oxidase A (MAO). (D1–3) Zoom-in on sympathetic noradrenergic varicosities, illustrating norepinephrine levels in the bloodstream depending on NRI presence, central sympathoinhibition efficacy (and resulting postganglionic sympathetic nerve activity) and norepinephrine reuptake transporter functionality. In the presence of NRIs, central sympathoinhibition increases, leading to decreased postganglionic sympathetic nerve activity and norepinephrine release, but on the other hand, norepinephrine reuptake decreases, hence resulting in similar or slightly higher bloodstream norepinephrine levels (D2). With the norepinephrine reuptake blockade, but no increased sympathoinhibition during the presence of NRI, large proportions of norepinephrine escape to the bloodstream (D3). D3 represents the pathophysiology in the presented index patient. Created with BioRender.com