Characterization of Metabolomic Fingerprints in Patients With Hepatic Encephalopathy and Fulminant Hepatitis or Acute Decompensation of Cirrhosis, Before and After Liver Transplantation

Background: Hepatic encephalopathy (HE) is a pattern of neurological and neuropsychiatric symptoms caused by a liver disease, whether acute (acute liver failure [ALF]) or chronic (acute-on-chronic liver failure [ACLF]) and/or a portosystemic shunt. To date, the only final curative treatment of HE remains liver transplantation (LT). Unfortunately, differences in the pathophysiological mechanisms that underlie HE in ACLF and ALF remain partially unknown, as does the evolution of these metabolic pathways after LT. Therefore, we aimed to analyze and compare the plasmatic metabolome in patients with overt HE in the context of ACLF or ALF, and to study the kinetics of resolution after LT. Methods: We performed untargeted metabolomics method with liquid phase chromatography coupled with high resolution mass spectrometry in plasma from 40 patients presenting with overt HE and ACLF (n = 34) or ALF (n = 6). Among the ACLF group, 12 patients underwent LT during the follow-up, and the same analyses were performed on D1, D7 and D30 after LT. Results: We did not demonstrate any difference in HE specific plasmatic metabolomic fingerprints between ACLF and ALF except for N-Acetyl-L-Cysteine (ratio of 0,10, p 0,0165) which was administrate in every ALF patient and for taurine (ratio of 0,36, p 0,0332) which has already been linked to ALF. Among the 12 ACLF patients that underwent LT, we have shown the temporal resolution of symptoms and metabolic disturbances related to HE in immediate and delayed post-LT on several metabolic pathways that has been previously linked to HE (Figure 1) such as glutamine and α-kétoglutarate (glutamate pathway), phosphorylcholine (choline pathway), taurodeoxycholic acid and glycodeoxycholic acid (bile acids pathway). A total of 28 metabolites have been identified and we have shown a resolution kinetic during the 30 first days after LT. Conclusion: We were not able to demonstrate any metabolic difference regarding HE between patients in ALF and ACLF. To our knowledge, we characterized for the first time the resolution of plasma metabolome abnormalities of HE in patients after LT.Figure 1.: Comparison with a mixed model analysis of variance in Hydrophilic Interaction Liquid Chromatography method: A and B: relative abundances (areas under the curve) of glutamine and α-ketoglutarate (glutamate pathway) in ACLF and transplanted patients (n = 12) over time (D0, D1, D7 and D30 after LT). C: relative abundance (area under the curve) of phosphorylcholine (choline pathway) in ACLF and transplanted patients (n = 12) over time (D0, D1, D7 and D30 after LT). D and E: relative abundances (areas under the curve) of taurodeoxycholic acid and glycodeoxycholic acid (bile acids pathway) in ACLF and transplanted patients (n = 12) over time (D0, D1, D7 and D30 after LT). ACLF: acute-on-chronic liver failure, LT: liver transplantation.