Fontan Associated Liver Disease and the Evaluation of Biomarkers for Disease Severity Assessment

Study Description: Up to 100 subjects who completed the Fontan procedure for severe Congenital Heart Disease (CHD) and are at risk for congestive hepatopathy or Fontan Associated Liver Disease (FALD) will be offered inclusion in the study. During the study we will pursue novel biomarkers for disease severity. Objectives: Primary Objective: The goal of this study is to globally investigate a large cohort of FALD subjects to generate an understanding of how congestive hepatopathy drives the pathogenesis of cirrhosis in FALD. We will use our findings to generate novel biomarkers that will enable improved follow-up of subjects and enhance transplant decision making. Secondary Objectives: 1. Measurement of TGF-beta serum levels in Fontan subjects and comparing them to liver tissue biopsies in hope of pursuing a novel biomarker for the development of advanced FALD. 2. Evaluation of FALD subjects coagulation profile including von Willebrand factor assessment and correlating it to disease severity by liver biopsy. 3. Comparison of PAR-1 and PAR-2 receptor staining from liver tissue biopsies of Fontan subjects and corelate their presence to the severity of the subjects FALD. 4. Identification of genetic modifiers of FALD 5. Evaluation of hepatic transcriptome in various stages of FALD. 6. Characterization of microbiome signatures in FALD Endpoints: Primary Endpoints: 1. Identification of novel biomarkers correlating with disease progression markers in Fontan Associated Liver Disease. 2. Develop an understanding of the biological mechanisms and the genetic modifiers of the progression of Fontan Associated Liver Disease. Secondary Endpoints: 1. TGF-beta superfamily measurement in serum and establishment of a cut-off level correlating with FALD severity. 2. Complete coagulation profile measurement and vWF-Ag quantification with establishment of cut- offs correlating with FALD severity. 3. PAR-1 and PAR-2 immuno-staining in Fontan subjects liver tissue biopsies. 4. Establishment of positive or negative correlation between candidate susceptible genes and disease phenotype. 5. Identification of novel markers of fibrosis or the development of hepatic neoplasia from transcriptome analysis. 6. Characterization of microbiome signatures (taxonomic and functional), as well as identification of specific species.