Metabolomic profiling of pheochromocytomas in dogs: Catecholamine phenotype and tricarboxylic acid cycle metabolites

Background: In humans with pheochromocytomas (PCCs), targeted metabolomics is used to determine the catecholamine phenotype or to uncover underlying pathogenic variants in tricarboxylic acid (TCA) cycle genes such as succinate dehydrogenase subunits (SDHx). Hypothesis/Objectives: To analyze catecholamine contents and TCA cycle metabolites of PCCs and normal adrenals (NAs). Animals: Ten healthy dogs, 21 dogs with PCC. Methods: Prospective observational study. Dogs diagnosed with PCC based on histopathological and immunohistochemical confirmation were included. Tissue catecholamine contents and TCA metabolites in PCCs and NAs were measured by liquid chromatography with mass spectrometry or electrochemical detection. Results: Compared to NAs, PCCs had significantly higher tissue proportion of norepinephrine (88% [median: range, 38%-98%] vs 14% [11%-26%]; P <.001), and significantly lower tissue proportion of epinephrine (12% [1%-62%] vs 86% [74%-89%]; P <.001). Pheochromocytomas exhibited significantly lower fumarate (0.4-fold; P <.001), and malate (0.5-fold; P =.008) contents than NAs. Citrate was significantly higher in PCCs than in NAs (1.6-fold; P =.015). One dog in the PCC group had an aberrant succinate : fumarate ratio that was 25-fold higher than in the other PCCs, suggesting an SDHx mutation. Conclusions and Clinical Importance: This study reveals a distinct catecholamine content and TCA cycle metabolite profile in PCCs. Metabolite profiling might be used to uncover underlying pathogenic variants in TCA cycle genes in dogs.