List of metabolites measured with the AbsoluteIDQ ® p 180 Kit included in statistical analyses ( 127 of 188 ) * *

Objective: Excess catecholamine release by pheochromocytomas and paragangliomas (PPGL) leads to characteristic clinical features and increased morbidity and mortality. The influence of PPGLs on metabolism is ill described but may impact diagnosis and management. The objective of this study was to systematically and quantitatively study PPGL induced metabolic changes at a systems level. Design: Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens in a clinically well characterized prospective cohort study. Methods: Analyses of metabolic profiles of plasma specimens from 56 prospectively enrolled and clinically well characterized patients (23 males, 33 females) with catecholamine-producing PPGL before and after surgery, as well as measurement of 24h-urinary catecholamine using LC-MS/MS. Results: From 127 analyzed metabolites, 15 were identified with significant changes before and after surgery: 5 amino acids/biogenic amines (creatinine, histidine, ornithine, sarcosine, tyrosine) and 1 glycerophospholipid (PCaeC34:2) with increased concentrations and 6 glycerophospholipids (PCaaC38:1, PCaaC42:0, PCaeC40:2, PCaeC42:5, PCaeC44:5, PCaeC44:6), 2 sphingomyelins (SMC24:1, SMC26:1) and hexose with decreased levels after surgery. Patients with a noradrenergic tumor phenotype had more pronounced alterations compared to those with an adrenergic tumor phenotype. Weak, but significant correlations for 8 of these 15 metabolites with total urine catecholamine levels were identified. Conclusions: This first large prospective metabolomics analysis of PPGL patients demonstrates broad metabolic consequences of catecholamine excess. Robust impact on lipid and amino acid metabolism may contribute to increased morbidity of PPGL patients. DOI: https://doi.org/10.1530/EJE-19-0589 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-169736 Journal Article Supplemental Material Originally published at: Erlic, Zoran; Kurlbaum, Max; Deutschbein, Timo; Nölting, Svenja; Prejbisz, Aleksander; Timmers, Henri J; Richter, Susan; Prehn, Cornelia; Weismann, Dirk; Adamski, Jerzy; Januszewicz, Andrzej; Reincke, Martin; Fassnacht, Martin; Robledo, Mercedes; Eisenhofer, Graeme; Beuschlein, Felix; Kroiss, Matthias (2019). Metabolic impact of pheochromocytoma/paraganglioma: Targeted metabolomics in patients before and after tumor removal. European Journal of Endocrinology, 181(6):647-657. DOI: https://doi.org/10.1530/EJE-19-0589 1 Supplemental Material Erlic Z. et al. Metabolic impact of pheochromocytoma/paraganglioma: Targeted metabolomics in patients before and after tumor removal. INDEX page nr Table 1a. List of metabolites measured with the AbsoluteIDQ® p180 Kit included in statistical analyses 2 Table 1b: List of metabolites measured with the AbsoluteIDQ® p180 Kit excluded from the statistical analyses 4 2. Statistical analyses results 2.1 Targeted metabolomics prior surgery 2.1 a) Statistical analyses for sex comparison (female/male) in PPGL patients prior surgery 6 2.1 b) Statistical analyses for tumor localization (adrenal/extraadrenal) in PPGL patients prior surgery 9 2.1 c) Statistical analyses for catecholamine phenotype (adrenergic/noradrenergic) in PPGL patients prior surgery 12 2.1 d) Statistical analyses stratified by BMI (threshold 25kg/m2) in PPGL patients prior surgery 15 2.1 e) Statistical analyses stratified by arterial hypertension (present/absent) in PPGL patients prior surgery 18 2.1 f) Statistical analyses stratified by diabetes mellitus (present/absent) in PPGL patients prior surgery 21 2.1 g) Statistical analyses stratified by age (threshold 45 years) in PPGL patients prior surgery 24 2.2 Changes of targeted metabolomics following surgery 2.2 a) Statistical analyses for comparison before and after surgery in all patients with biochemical remission 27 2.2 b) Statistical analyses for comparison before and after surgery in female patients with biochemical remission 30 2.2 c) Statistical analyses for comparison before and after surgery in male patients with biochemical remission 33 2.2 d) Statistical analyses for comparison before and after surgery in adrenergic tumor patients with biochemical remission 36 2.2 e) Statistical analyses for comparison before and after surgery in noradrenergic patients with biochemical remission 39 2.2 f) Statistical analysis for comparison before and after surgery in patients with preoperative BMI <25 and postoperative biochemical remission 42 2.2 g) Statistical analysis for comparison before and after surgery in patients with preoperative BMI ≥25 and postoperative biochemical remission 45 2.2 h) Statistical analysis for comparison before and after surgery in patients with preoperative age <45 and postoperative biochemical remission 48 2.2 i) Statistical analysis for comparison before and after surgery in patients with preoperative age ≥45 and postoperative biochemical remission 51