Plasma methoxytyramine: clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma

Abstract

Context: Measurements of plasma methoxytyramine, the O-methylated dopamine metabolite, are useful for detecting rare dopamine-producing pheochromocytomas and paragangliomas (PPGLs) and head and neck paragangliomas (HNPGLs), but utility for screening beyond that achieved using standard measurements of normetanephrine and metanephrine is unclear.

Objective: Evaluation of the additional utility of methoxytyramine compared to plasma normetanephrine and metanephrine for diagnosis of PPGLs and HNPGLs.

Design: Comparative prospective study.

Methods: Comparison of mass spectrometric-based measurements of plasma methoxytyramine, normetanephrine and metanephrine in 1963 patients tested for PPGLs at six tertiary medical centers according to reference intervals verified in 423 normotensive and hypertensive volunteers.

Results: Of the screened patients, 213 had PPGLs and 38 HNPGLs. Using an upper cut-off of 0.10 nmol/L for methoxytyramine, 0.45 nmol/L for metanephrine and age-specific upper cut-offs for normetanephrine, diagnostic sensitivity with the addition of methoxytyramine increased from 97.2% to 98.6% for patients with PPGLs and from 22.1% to 50.0% for patients with HNPGLs, with a small decrease in specificity from 95.9% to 95.1%. Addition of methoxytyramine did not significantly alter areas under receiver operating characteristic curves for patients with PPGLs (0.984 vs 0.991), but did increase (P < 0.05) areas for patients with HNPGLs (0.627 vs 0.801). Addition of methoxytyramine also increased the proportion of patients with PPGLs who showed highly positive predictive elevations of multiple metabolites (70.9% vs 49.3%).

Conclusions: While the benefit of additional measurements of plasma methoxytyramine for the detection of PPGLs is modest, the measurements do assist with positive confirmation of disease and are useful for the detection of HNPGLs.

Figure 1

Relationships of age with plasma concentrations of normetanephrine. Panel A illustrates age relationships for subjects of the reference population (solid black dots) and patients tested for PPGLs without evidence of tumors (solid gray dots). Panel B illustrates age relationships with normetanephrine on a logarithmic scale for patients with PPGLs and positive results for normetanephrine alone (solid black square), methoxytramine or methoxytyramine and normetanephrine (solid black upward triangle), metanephrine or metanephrine and normetanephrine (solid black downward triangle), all three metabolites (solid black diamond) or no metabolites (solid gray dot) compared with patients without tumors (solid black dot). The dashed lines indicate age-specific UCs of reference intervals derived from the formula (UC nmol/L = 0.000002074 × age³ + 0.54) for patients 5 years to a maximum of 65 years.

Figure 2

Dot plots for plasma concentrations of methoxytyramine (A), normetanephrine (B) and methanephrine (C) for the reference population (REF), patients tested for PPGLs with no evidence of tumors (NO TUM) compared to patients with PPGLs and HNPGLs. Dashed horizontal lines designate upper cut-off values of reference intervals, which for normetanephrine range from 0.55 nmol/L (100 pg/mL) in 5 -year-olds to 1.09 nmol/L (200 pg/mL) in 65 –year-olds as illustrated in Fig. 1. Median values are shown for each metabolite. Different symbols serve to illustrate subjects of the reference population or patients without tumors (solid gray dot) compared to patients with tumors and positive results for normetanephrine alone (solid black square), methoxytramine or methoxytyramine and normetanephrine (solid black upward triangle), metanephrine or metanephrine and normetanephrine (solid black downward triangle), all three metabolites (solid black diamond) or no metabolites (solid black dot).

Figure 3

Receiver operating characteristic curves for diagnosis of PPGLs (A) and HNPGLs (B). Curves are shown for combinations of normetanephrine and metanephrine (lower curve) vs normetanephrine, metanephrine and methoxytyramine (upper curve). A full color version of this figure is available at http://dx.doi.org/10.1530/EJE-17-0077.

Figure 4

Relationships of fold increases of plasma normetanephrine above upper cut-offs vs fold increases above upper cut-offs for methoxytyramine (A) and metanephrine (B) for patient populations with and without PPGLs. Dashed vertical and horizontal lines to illustrate fold increases of 1.0 at upper cut-offs. Different symbols serve to illustrate patients without tumors (solid gray dot), patients with tumors and positive results for normetanephrine alone (solid black square), for methoxytramine or methoxytyramine and normetanephrine (solid black upward triangle), metanephrine or metanephrine and normetanephrine (solid black downward triangle), all three metabolites (solid black diamond) or no metabolites (solid black dot).

Figure 5

Relationships of pretest prevalence of PPGLs vs posttest probability of the tumors. Posttest probabilities are shown according to positive results for normetanephrine or metanephrine (97.2% of all patients) vs positive results for both normetanephrine and metanephrine (49.3% of all patients) in panel A. In panel B, posttest probabilities are shown according to positive results for normetanephrine or metanephrine or methoxytyramine (98.6% of all patients) vs positive results for all three metabolites (23.0% of all patients) vs positive results for both normetanephrine and metanephrine (26.3% of all patients) and vs positive results for both normetanephrine and methoxytyramine (21.6% of all patients). Shaded areas serve to illustrate posttest probabilities at common pretest prevalence of 0.5% for patients tested because of signs and symptoms to 5% in patients with incidentalomas.