Predictive biomarkers to inform transplant candidacy in Fontan-associated liver disease

Juliet Emamaullee, MD, PhD

University of Southern California (USC), Children’s Hospital Los Angeles

2023

This project was funded in part by the Cortney Gives BAK Foundation.

Summary: Children born with single ventricle physiology congenital heart disease undergo a series of operations, including the Fontan procedure, to restore adequate heart function and allow normal growth and development. A new form of chronic liver disease, which has been named ‘Fontan-associated liver disease’ (FALD), has been observed in patients with Fontan physiology, and it has become evident that nearly all patients have evidence of FALD on liver biopsy by young adulthood. Heart transplant (HT) continues to offer the best and only option for long-term survival in patients with a failing Fontan. However, transplant decision making with regards to HT alone versus combined-heart liver transplantation (CHLT), recognizing that virtually all patients have FALD, is complicated by the lack of non-invasive tests to establish and monitor severity of FALD. Thus, determining and monitoring the severity of fibrosis FALD has emerged as critically important aspect of clinical management and transplant stratification in the Fontan population. In this proposal, our overall objectives are to determine transient elastography parameters and plasma protein markers that strongly correlate with severity of FALD on liver biopsy to identify additional biomarkers and therapeutic targets that could stabilize or even reverse FALD, which would reduce the need for CHLT. Our central hypothesis is that non-invasive tests can be developed that accurately reflect FALD severity on liver biopsy, thereby removing the need for liver biopsy and enabling longitudinal surveillance in patients being considered for HT alone versus CHLT. The scientific premise for this project is that establishing clinically relevant non-invasive testing strategies and biomarkers associated with FALD severity will inform decisions regarding transplant candidacy and reduce unnecessary CHLT in this population. The overall objectives will be pursued in two aims. In Aim 1, we will establish Fibroscan transient elastography parameters that correlate with severity of FALD on biopsy and differentiate bridging fibrosis, the branching point that currently drives decision making for CHLT in this population. In Aim 2, we will develop a panel of blood-based biomarkers that accurately predicts FALD severity using plasma proteomics to identify patients with bridging fibrosis. Our expected outcomes are to have identified the transient elastography parameters, a widely available clinical test, and a focused panel of blood-based biomarkers that accurately reflect FALD severity. This will directly impact clinical management of all patients post-Fontan, including those being considered for CHLT. The long-term goal of this project is to develop reliable non-invasive testing strategies that accurately reflect histological severity of FALD to guide transplant teams regarding CHLT candidacy.