Abstract Rationale Cirrhosis causes profound metabolic alterations linked to diverse complications including hepatic encephalopathy, ascites, and vascular dysfunction. Prior metabolomic studies in patients with cirrhosis have identified biomarkers associated with disease severity and clinical outcomes. However, these studies relied on peripheral venous or single site sampling which fails to capture residual metabolic processing as blood flows across the liver. Direct measurement of transhepatic metabolomic gradients has been exceptionally rare due to the invasive nature of portal vein sampling. Transjugular intrahepatic portosystemic shunt (TIPS) placement provides a unique opportunity to simultaneously access portal and right atrial blood, enabling direct assessment of metabolite processing across the cirrhotic liver. This study aimed to characterize transhepatic metabolomic gradients and identify abnormal patterns of hepatic metabolism in cirrhosis. Methods Metabolomic profiling was performed on paired portal vein and right atrial blood samples from 11 cirrhotic patients during TIPS placement, with additional right atrial sampling immediately post-TIPS. Fifteen healthy controls provided peripheral venous samples for comparison. Of 844 named endogenous metabolites identified, 692 had sufficient paired data for analysis. A three-step framework was employed: baseline comparison between cirrhosis and controls, metabolomic transhepatic gradient calculation (portal/pre-TIPS right atrium), and assessment of post-TIPS changes (post/pre-TIPS right atrium). Statistical significance was assessed using false discovery rate (FDR)-adjusted p-values (q 0.1) for baseline comparisons and standard p-values (p 0.05) for post-TIPS changes. Results Baseline comparison revealed 321/781 (41.1%) of metabolites significantly altered versus controls. Of the 692 metabolites with sufficient paired data, 159 (23.0%) showed significant post-TIPS changes. Among these, 152 (95.6%) demonstrated concordant gradient and post-TIPS directions, suggesting hepatic involvement. Two distinct patterns emerged: 53 metabolites showed reduced hepatic extraction (portal concentration exceeding right atrial, increasing post-TIPS), while 99 showed loss of hepatic enrichment (portal concentration below right atrial, decreasing post-TIPS). S-1-pyrroline-5-carboxylate showed the highest gradient (2.91-fold) with 130% post-TIPS accumulation. Nitric oxide pathway disruption was evident through impaired dimethylarginine clearance (gradient 1.16, +23% post-TIPS). Nucleotide metabolism showed marked disruption with inosine decreasing 67% and 7-methylguanine 48% post-TIPS. Conclusions Transhepatic metabolomic gradient analysis during TIPS placement reveals selective rather than global metabolic dysfunction in cirrhosis, with distinct patterns of reduced extraction and lost hepatic enrichment. S-1-pyrroline-5-carboxylate accumulation may mechanistically drive post-TIPS encephalopathy through urea cycle disruption. Combined dimethylarginine accumulation and homoarginine depletion suggest converging nitric oxide pathway disruption potentially contributing to portopulmonary hypertension. This abstract is funded by: NIH grant R01HL130307 (ART) and R01HL130209 (RAD)
Stockdale et al. (Fri,) studied this question.