Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma

Abstract

Phaeochromocytomas and paragangliomas (PPGLs) are highly heterogeneous tumours with variable catecholamine biochemical phenotypes and diverse hereditary backgrounds. This analysis of 18 catecholamine-related plasma and urinary biomarkers in 365 patients with PPGLs and 846 subjects without PPGLs examined how catecholamine metabolomic profiles are impacted by hereditary background and relate to variable hormone secretion. Catecholamine secretion was assessed in a subgroup of 156 patients from whom tumour tissue was available for measurements of catecholamine contents. Among all analytes, the free catecholamine O-methylated metabolites measured in plasma showed the largest tumour-related increases relative to the reference group. Patients with tumours due to multiple endocrine neoplasia type 2 and neurofibromatosis type 1 (NF1) showed similar catecholamine metabolite and secretory profiles to patients with adrenaline-producing tumours and no evident hereditary background. Tumours from these three patient groups contained higher contents of catecholamines, but secreted the hormones at lower rates than tumours that did not contain appreciable adrenaline, the latter including PPGLs due to von Hippel-Lindau (VHL) and succinate dehydrogenase (SDH) gene mutations. Large increases of plasma dopamine and its metabolites additionally characterised patients with PPGLs due to the latter mutations, whereas patients with NF1 were characterised by large increases in plasma dihydroxyphenylglycol and dihydroxyphenylacetic acid, the deaminated metabolites of noradrenaline and dopamine. This analysis establishes the utility of comprehensive catecholamine metabolite profiling for characterising the distinct and highly diverse catecholamine metabolomic and secretory phenotypes among different groups of patients with PPGLs. The data further suggest developmental origins of PPGLs from different populations of chromaffin cell progenitors.

Figure 1

Plasma and urinary catecholamine metabolomic profiles in patients with PPGLs relative to reference. Data are shown as fold-increases (means±SEM) of values in patients with PPGLs above mean values for the reference population. Data for the catecholamines, including noradrenaline (NA), adrenaline (A) and dopamine (DA) are shown by the empty bars (□); for the free O-methylated catecholamine metabolites, including normetanephrine (f-NMN), metanephrine (f-MN) and methoxytyramine (f-MTY), by the black bars (■); for the deconjugated O-methylated catecholamine metabolites, including deconjugated normetanephrine (d-NMN), deconjugated metanephrine (d-MN) and deconjugated methoxytyramine (d-MTY) by the dark grey bars ( ); for the deaminated catecholamine metabolites, including dihydroxyphenylglycol (DHPG), vanillylmandelic acid (VMA) and dihydroxyphenylacetic acid (DOPAC), by the medium grey bars ( ); and for the amino acid precursor of the catecholamines, dihydroxyphenylalanine (DOPA), by the light grey bar ( ).

Figure 2

Bar graphs showing tumour contents of catecholamines (panel A), rates of tumour-derived catecholamine secretion into plasma (panel B) and excretion into urine (panel C), and rate constants for tumour-derived catecholamine secretion into plasma (panel D) and excretion into urine (panel E). Data are shown for tumours from patients with VHL syndrome (n=44), MEN 2 (n=32), NF1 (n=6) and with mutations of SDHB (n=11) and SDHD (n=3) genes. Data are also shown for noradrenergic (NA, n=26) and adrenergic (A, n=34) tumours from patients without evidence of an established hereditary syndrome or gene mutation. Different alphabetic characters indicate significant differences (P<0.05) between groups, while presence of identical characters indicates lack of a significant difference.

Figure 3

Neuronal, extraneuronal and adrenal pathways of metabolism for noradrenaline and adrenaline. Abbreviations: NA, noradrenaline; A, adrenaline; DHPG, dihydroxyphenylglycol; MN, metanephrine; NMN, normetanephrine; MHPG, methoxyhydroxyphenylglycol; VMA, vanillylmandelic acid; MHPG-SO₄, methoxyhydroxyphenylglycol sulphate; NMN-SO₄, normetanephrine sulphate; MN-SO₄ metanephrine sulphate; MAO, monoamine oxidase; COMT, catechol-O-methyltransferase; ADH, alcohol dehydrogenase; SULT1A3, sulfotransferase type 1A3.