Patients with Fontan-associated liver disease (FALD) and advanced fibrosis or a composite clinical outcome expressed upregulated genes related to inflammation, congestion and angiogenesis, a new study shows. Katia Bravo-Jaimes, MD, of the Mayo Clinic, Jacksonville, Florida, and colleagues reported these findings in a manuscript published Monday online and in the Feb. 20 issue of the Journal of the American College of Cardiology. Despite several advances in the Fontan operation since it was first described in 1971, complications, including FALD, still occur after the procedure. More than 70,000 post-Fontan patients worldwide are now adults, so there is a need to better understand FALD’s molecular pathways. Study setup The authors compared intrahepatic gene expression profiles in adults with Fontan circulation to donor controls to test three hypotheses: Fontan circulation and advanced fibrosis yields a distinct gene transcriptome that is in contrast to that of early fibrosis and control patients; The differences involve enriched pathways related to angiogenesis; and Fontan subgroups that show distinct clinical features and prognosis can be identified using molecular phenotyping. Fontan patients included in the study were adults 18 years or older who had at least two visits to the Ahmanson/UCLA Adult Congenital Heart Disease Center between January 2005 and November 2021 and had tissue available from at least one liver biopsy. The study assessed patient profiles and composite clinical outcomes, which were extracted from medical records. The composite clinical outcome, which reflected end-organ dysfunction outside the heart since the date of the Fontan procedure, included decompensated cirrhosis (defined as ascites requiring paracentesis, esophageal variceal bleeding or hepatic encephalopathy), hepatocellular carcinoma, chronic kidney disease stage 4 or higher, or death. The results were stratified by early vs. advanced fibrosis. Results The study included 106 patients with 112 RNA samples of adequate quality. Fourteen samples were used as controls – five from normal lives and nine from biopsies post-transplantation. Of these 106 patients, 51.8% were women, 66.9% were white, and 27.4% were Hispanic. A total of 15 patients (14.2%) had no fibrosis, 50 (47.1%) had early fibrosis, and 41 (38.7%) had advanced fibrosis. Patients without fibrosis were more likely to have aortopulmonary collaterals (46.7% without fibrosis, 10% with early fibrosis, 26.8% with advanced fibrosis, p=0.03). Patients with advanced fibrosis had higher B-type natriuretic peptide levels and higher Fontan, mean pulmonary artery and capillary wedge pressures. A total of 23 patients (22%) experienced the composite clinical outcome, and this was not predicted by the presence of advanced liver fibrosis, right ventricular morphology, presence of aortopulmonary collaterals, or level of Fontan pressure. Tissue samples with the composite clinical outcome had upregulated genes as compared with samples without the composite outcome. A total of 136 upregulated genes were identified in samples both with and without the composite outcome and were enriched in cellular response to cytokine stimulus or oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-β signaling pathway and vascular development. The authors wrote that confirming the gatekeeping pathways involved in FALD could help clinicians better risk-stratify patients they select for heart transplantation vs. combined heart and liver transplantation, and that this will help strategies to prevent advanced hepatic fibrosis be further developed. ‘Critical first step’ In an accompanying editorial, Yuli Y. Kim, of the Hospital of the University of Pennsylvania and Childrens Hospital of Philadelphia, and Maarouf A. Hoteit, MD, of the Hospital of the University of Pennsylvania, called the study’s finding of a relationship between FALD and inflammatory pathways “fascinating” and one that “challenges the previous characterization of FALD as a noninflammatory condition.” Kim and Hoteit pointed out that the lack of a control group with non-FALD chronic liver disease means it cannot be determined whether FALD specifically or advanced fibrosis generally causes this inflammation. “This study, and particularly the data source itself, therefore serves a critical first step that is needed to set the stage for further inquiry,” the editorialists wrote. After listing limitations to tissue-based transcriptomic analyses, the expert commenters said the study investigators “are to be congratulated by this effort, a welcome foray into ‘-omics’ science in congenital heart disease.” “Their work opens the door to a new line of investigation in FALD,” the editorialists concluded. “In addition to disease profiling, future investigation could hopefully yield transcriptome biomarkers for FALD and potential therapeutic targets that will ultimately guide clinicians in managing and treating this end-organ complication of functional single-ventricle disease.” Sources: Bravo-Jaimes K, Wu X, Reardon LC, et al. Intrahepatic Transcriptomics Differentiate Advanced Fibrosis and Clinical Outcomes in Adults With Fontan Circulation. J Am Coll Cardiol. 2024;83:726–738. Kim YY, Hoteit MA. Turning to “Omics” in Understanding Fontan-Associated Liver Disease. J Am Coll Cardiol. 2024;83:739–740. Image Credit: Rasi – stock.adobe.com