{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:10:09Z","timestamp":1789193409145,"version":"build-2803163510"},"reference-count":31,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL130307"],"award-info":[{"award-number":["R01HL130307"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL130209"],"award-info":[{"award-number":["R01HL130209"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Comprehensive Physiology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background\/Objectives<\/jats:title>\n                    <jats:p>The cirrhotic liver's metabolic capacity remains incompletely characterized, particularly its role in shaping portal metabolite signals that reach the systemic circulation. Transjugular intrahepatic portosystemic shunt (TIPS) placement allows paired portal and right atrial sampling to estimate transhepatic gradients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed global metabolomic profiling on paired portal vein and right atrial samples from 11 patients with cirrhosis during TIPS placement, with right atrial sampling repeated immediately after shunt creation. Pre\u2010TIPS right atrial profiles were compared with peripheral venous samples from 15 healthy controls. For each metabolite, we calculated a transhepatic gradient (portal to pre\u2010TIPS right atrial relative abundance) and a post\u2010TIPS change, and used directional concordance between the two as indirect evidence of hepatic processing. Of 676 metabolites, 612 had sufficient paired data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 676 metabolites, 305 (45.1%) differed between cirrhotic patients and controls at\n                      <jats:italic>q<\/jats:italic>\n                      \u2009&lt;\u20090.1, with 170 elevated and 135 depleted. Among 612 metabolites with paired data, 124 changed after TIPS at\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05, and 113 (91.1%) were directionally concordant with their pre\u2010TIPS transhepatic gradients. Fifty of these showed impaired hepatic extraction and 63 showed a hepatic dilution pattern.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The cirrhotic liver retains measurable but selective metabolite processing, with disruption that may carry consequences beyond the liver itself. Cirrhosis is better understood as a disorder of hepatic signaling with systemic consequences than as uniform hepatic failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cph4.70255","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:32:43Z","timestamp":1789191163000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transhepatic Gradients Reveal Selective Hepatic Processing Defects With Systemic Consequences in Cirrhosis"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9871-8904","authenticated-orcid":false,"given":"Graham","family":"Stockdale","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine Integrated Hospital Care Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Fawaz","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine, Allergy and Critical Care, Department of Medicine Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marla","family":"Bashour","sequence":"additional","affiliation":[{"name":"Medical Education and Simulation Northeast Ohio Medical University  Rootstown Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2169-7727","authenticated-orcid":false,"given":"Kulwant S.","family":"Aulak","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity Cleveland Clinic Research, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5308-5082","authenticated-orcid":false,"given":"Maria Del Pilar Bayona","family":"Molano","sequence":"additional","affiliation":[{"name":"Department of Interventional Radiology University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baljendra","family":"Kapoor","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4425-1288","authenticated-orcid":false,"given":"Raed A.","family":"Dweik","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine Integrated Hospital Care Institute, Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Inflammation and Immunity Cleveland Clinic Research, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2321-9545","authenticated-orcid":false,"given":"Adriano R.","family":"Tonelli","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine Integrated Hospital Care Institute, Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Inflammation and Immunity Cleveland Clinic Research, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41575-021-00520-7","article-title":"Cirrhosis\u2010Associated Immune Dysfunction","volume":"19","author":"Albillos A.","year":"2022","journal-title":"Nature Reviews. Gastroenterology & Hepatology"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1161\/ATVBAHA.114.304398","article-title":"Homoarginine and Cardiovascular Outcome in the Population\u2010Based Dallas Heart Study","volume":"34","author":"Atzler D.","year":"2014","journal-title":"Arteriosclerosis, Thrombosis, and Vascular Biology"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1053\/j.gastro.2020.07.019","article-title":"Serum Levels of Metabolites Produced by Intestinal Microbes and Lipid Moieties Independently Associated With Acute\u2010on\u2010Chronic Liver Failure and Death in Patients With Cirrhosis","volume":"159","author":"Bajaj J. S.","year":"2020","journal-title":"Gastroenterology"},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"2853","DOI":"10.1093\/hmg\/9.19.2853","article-title":"Hyperammonemia With Reduced Ornithine, Citrulline, Arginine and Proline: A New Inborn Error Caused by a Mutation in the Gene Encoding Delta(1)\u2010Pyrroline\u20105\u2010Carboxylate Synthase","volume":"9","author":"Baumgartner M. R.","year":"2000","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1080\/07853890500472151","article-title":"Asymmetric Dimethylarginine (ADMA): A Novel Risk Marker in Cardiovascular Medicine and Beyond","volume":"38","author":"Boger R. 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Urea Synthesis\u2014The Liver Workhorse of Nitrogen Metabolism","volume":"40","author":"Vilstrup H.","year":"2025","journal-title":"Metabolic Brain Disease"},{"key":"e_1_2_11_32_1","doi-asserted-by":"crossref","DOI":"10.1080\/07853890.2024.2328521","article-title":"Global Burden of Liver Cirrhosis 1990\u20102019 and 20\u2009Years Forecast: Results From the Global Burden of Disease Study 2019","volume":"56","author":"Wang Y.","year":"2024","journal-title":"Annals of Medicine"}],"container-title":["Comprehensive Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cph4.70255","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cph4.70255","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cph4.70255","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:32:47Z","timestamp":1789191167000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cph4.70255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,11]]},"references-count":31,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/cph4.70255"],"URL":"https:\/\/doi.org\/10.1002\/cph4.70255","archive":["Portico"],"relation":{},"ISSN":["2040-4603","2040-4603"],"issn-type":[{"value":"2040-4603","type":"print"},{"value":"2040-4603","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,11]]},"assertion":[{"value":"2026-04-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70255"}}