UPLC-MS/MS-Based Serum Metabolomics Signature as Biomarkers of Esophagogastric Variceal Bleeding in Patients With Cirrhosis

Background: Esophagogastric variceal bleeding (EVB) is a common and ominous complication of cirrhosis and represents the degree of portal hypertension progression and cirrhosis decompensation, desiderating the investigation into sensitive and specific markers for early detection and prediction. The purpose of this study is to characterize unique metabolites in serum of cirrhotic EVB patients and identify potential noninvasive biomarkers for detecting and assessing risk of variceal bleeding and cirrhosis progression through metabolomics-based approaches and explore possible pathophysiological mechanisms. Methods: We used ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) to profile serum metabolomes. In one discovery cohort (n = 26, 13 cases of EVB), univariate and multivariate statistical analyses were performed to demonstrate separation between the two groups and identify differentially expressed metabolites. Potential biomarkers were screened by Boruta and logistic regression analyses, further evaluated by receiver operating characteristic analysis, and tested in two validation cohorts (n = 34, 17 cases and n = 10, 5 cases). Results: Bioinformatics analyses demonstrated that EVB patients possessed distinct metabolic phenotypes compared with nEVB controls, characterized by seven elevated and six downregulated metabolites, indicating that EVB-related metabolic disturbance might be associated with vitamin metabolism and fatty acid metabolism. Eight potential biomarkers were selected among which citrulline and alpha-aminobutyric acid with moderate AUC values, tested in the validation cohorts, were identified as specific biomarkers of EVB. Conclusion: Our metabolomic study provides an overview of serum metabolic profiles in EVB patients, highlighting the potential utility of UPLC-MS/MS-based serum fingerprint as a feasible avenue for early detection of EVB.