Pre- and Post-Portosystemic Shunt Placement Metabolomics Reveal Molecular Signatures for the Development of Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a common complication of advanced liver disease causing brain dysfunction. This is likely due to the accumulation of unfiltered toxins within the bloodstream. A known risk factor for developing or worsening HE is the placement of a transjugular intrahepatic portosystemic shunt (TIPS), which connects the pre-hepatic and post-hepatic circulation allowing some blood to bypass the dysfunctional liver and decreases portal hypertension. To better understand the pathophysiology of post-TIPS HE, we conducted a multi-center prospective cohort study employing metabolomic analyses on hepatic vein and peripheral vein blood samples from participants with cirrhosis undergoing elective TIPS placement, measuring chemical modifications and changes in concentrations of metabolites resulting from TIPS placement. In doing so, we identified numerous alterations in metabolites, including bile acids, glycerophosphocholines, and bilirubins possibly implicated in the development and severity of HE. ### Competing Interest Statement AmZ is a co-founder and equity-holder in Endure Biotherapeutics. ### Funding Statement Initial funds for the studies were provided by a pilot and feasibility grant from UL1 TR001442. ACDM is supported by R01 HL148801-02S1. SF was supported by the PD Soros Foundation. AlZ is supported by NIH K08 DK113244 and the UF Foundation-Robert Duggan Fund. AmZ is supported by Kavli Institute for Brain and Mind at UC San Diego, AASLD Liver Scholar Award, VA Merit BLR&D Award I01 BX005707, and NIH K08 DK102902, R03 DK114536, R21 MH117780, R01 HL148801, R01 EB030134, and U01 CA265719. All UC San Diego authors receive institutional support from NIH P30 DK120515, P30 DK063491, P30 CA014195, P50 AA011999, and UL1 TR001442. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Boards of University of California, San Diego, and University of Florida gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced are available online at https://gnps.ucsd.edu/