Transhepatic Gradients Reveal Selective Hepatic Processing Defects With Systemic Consequences in Cirrhosis

ABSTRACT Background/Objectives 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. Methods 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‐TIPS right atrial profiles were compared with peripheral venous samples from 15 healthy controls. For each metabolite, we calculated a transhepatic gradient (portal to pre‐TIPS right atrial relative abundance) and a post‐TIPS change, and used directional concordance between the two as indirect evidence of hepatic processing. Of 676 metabolites, 612 had sufficient paired data. Results Of 676 metabolites, 305 (45.1%) differed between cirrhotic patients and controls at q < 0.1, with 170 elevated and 135 depleted. Among 612 metabolites with paired data, 124 changed after TIPS at p < 0.05, and 113 (91.1%) were directionally concordant with their pre‐TIPS transhepatic gradients. Fifty of these showed impaired hepatic extraction and 63 showed a hepatic dilution pattern. Conclusions 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.