Metabolomic profiles differentiate between porto-sinusoidal vascular disorder, cirrhosis, and healthy individuals

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Background & AimsPorto-sinusoidal vascular disorder (PSVD) is a rare and diagnostically challenging vascular liver disease. This study aimed to identify distinct metabolomic signatures in patients with PSVD, cirrhosis, and healthy volunteers (HV) to facilitate non-invasive diagnosis and elucidate perturbed metabolic pathways. MethodsSerum samples from 20 HV and patients with histologically confirmed PSVD or cirrhosis were analyzed. Metabolites were measured using liquid chromatography-mass spectrometry (LC-MS). Differential abundance was evaluated with Limma’s moderated t-statistics. Artificial neural network (ANN) and support vector machine (SVM) models were developed to classify PSVD against cirrhosis or HV metabolomic profiles. An independent cohort was used for validation. ResultsA total of 283 metabolites were included for downstream analysis. Clustering effectively separated PSVD metabolomes from HV, although a subset of PSVD patients (n=5, 25%) overlapped with cirrhosis. Differential testing revealed significant PSVD-linked metabolic perturbations, including taurocholic and adipic acids, distinguishing PSVD from both HV and cirrhosis. Alterations in pyrimidine, glycine, serine, and threonine pathways were exclusively associated with PSVD. Machine learning models utilizing selected metabolic signatures reliably differentiated PSVD from HV or cirrhosis using only 4 to 6 metabolites. Validation in an independent cohort demonstrated the high discriminative ability of taurocholic acid (AUROC 0.899) for PSVD vs HV and the taurocholic acid/aspartic acid ratio (AUROC 0.720) for PSVD vs cirrhosis. ConclusionsHigh-throughput metabolomics enabled the identification of distinct metabolic profiles for differentiating PSVD, cirrhosis, and healthy individuals. Unique alterations in the glycine, serine, and threonine pathways suggest their potential involvement in PSVD pathogenesis. Impact And ImplicationsPorto-sinusoidal vascular disorder (PSVD) is a vascular liver disease that can lead to pre-sinusoidal portal hypertension in the absence of cirrhosis, with poorly understood pathophysiology and no established treatment. Our study demonstrates that analyzing the serum metabolome could reveal distinct metabolic signatures in PSVD patients, including alterations in the pyrimidine, glycine, serine and threonine pathways and potentially shedding light on the disease's underlying pathways. These findings hold potential for earlier and non-invasive diagnosis of PSVD, potentially reducing reliance on invasive procedures like liver biopsy and guiding diagnostic pathways.