Global Plasma Metabolomic Profiling Reveals Dysregulated Lipid Metabolism in Patients with Hepatic Sinusoidal Obstruction Syndrome - a Pilot Biomarker Study

Hepatic sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication after Allogeneic hematopoietic stem cell transplantation (allo-HCT) attributed to the toxic effects of the conditioning regimen on endothelial cells. Although the Treosulfan-based toxicity-reduced regimen has significantly improved transplant outcomes, especially in patients with class III high-risk β-Thalassemia major, the incidence of hepatic SOS following Treo-based conditioning is still around 25%. There are no reports on the mechanism of pathogenesis of SOS associated with Treo-based conditioning in high-risk TM so far. In this pilot study, we performed Global plasma metabolomics (GPM) to identify potential predictive biomarkers for SOS.Paired plasma samples were collected before and at the end of conditioning from patients (n=7) with high-risk β-Thalassemia major receiving the Treo-based regimen (four with very severe SOS and 3 with no hepatotoxicity). GPM was carried out using Liquid Chromatography coupled with Tandem Mass Spectrometry (LC-MS/MS). MS data analysis and statistics were performed using MetaboAnalyst 5.0.Metabolomic profiles in pre-conditioning plasma samples identified 476 dysregulated metabolites in patients with SOS. Further fold-change analysis [cut-off >1.3 and <0.76 for up and downregulated, respectively; p-value ≤ 0.05)] revealed 86 upregulated and 65 downregulated metabolites. Some upregulated metabolites of biological relevance included Purine nucleosides (Succinyl adenosine), Glycerolipids (Diacylglycerols), Glycerophospholipids (Phosphatidic acid, Lysophosphatidic acid), while Glycerophospholipids (Phosphatidylglycerol, Phosphatidylcholine) and Fatty Acyls (Leukotriene D4) were downregulated. Pathway enrichment analysis showed Glycerolipid metabolism and phospholipid biosynthesis as top dysregulated pathways in patients with SOS.At the end of conditioning, we identified 528 dysregulated metabolites in patients with SOS, of which 27 were upregulated, and 32 were downregulated upon further fold-change analysis. Some of the upregulated metabolites of biological relevance identified included Fatty acyls (13-Hydroxyoctadecadienoic acid (13-HODE); alpha-Dimorphecolic acid (9-HODE); 9,10-Epoxyoctadecenoic acid (EpOME); 12,13-EpOME) in patients with SOS at the end of Treo-based conditioning.Using an untargeted metabolomics approach, we identified a set of plausible biomarkers primarily related to lipid metabolism to predict SOS both at the pre-conditioning stage and the end of conditioning. Targeted metabolomics for validating these biomarkers is ongoing in the laboratory. Once validated, these biomarkers could help predict patients at risk of developing SOS and help design therapeutic interventions to initiate prophylactic measures for patients at increased risk of developing SOS.