Prevalence, Risk Factors, and Prognosis for Fontan-Associated Liver Disease: A Systematic Review and Exploratory Meta-Analysis

Abstract

BACKGROUND: Patients with Fontan circulation are at risk of progressive liver disease, but the prevalence and risk factors for Fontan-associated liver disease (FALD) remain unclear. OBJECTIVES: The aim of the study was to review unbiased data on FALD prevalence, diagnostic methods, risk factors, and prognostic significance, and to undertake exploratory meta-analysis on available data. METHODS: This systematic review included studies with unselected FALD screening. Outcomes were imaging or biopsy-proven cirrhosis, advanced fibrosis, portal hypertension, and hepatocellular carcinoma. Exploratory meta-analysis was performed, as well as subgroup analyses and meta-regression to explore contributors towards outcome heterogeneity. RESULTS: Thirty-seven studies comprising 5,701 patients were included, with a median of 17 years of follow-up post-Fontan completion. All estimates of FALD were highly heterogeneous, reflecting variable patient factors and institutional practices. Cirrhosis was diagnosed in 21% of patients, but ranged from 0% to 76%. Advanced fibrosis without cirrhosis was noted in 30%, portal hypertension in 17%, and hepatocellular carcinoma in 2%, also with significant heterogeneity. Subgroup analysis and meta-regression highlighted several factors that contributed to such heterogeneity. It was found that cirrhosis was less commonly diagnosed by biopsy than by imaging (10% vs 26%). Other risk factors for cirrhosis included years post-Fontan completion, atriopulmonary Fontan, moderate or greater ventricular dysfunction, and higher pulmonary capillary wedge pressure. Qualitative synthesis noted FALD to be associated with elevated risk of cardiovascular and all-cause mortality. CONCLUSIONS: Liver disease is common post-Fontan completion, though prevalence varies widely. Several risk factors should guide patient screening. A universal, prognostically meaningful FALD definition is needed to advance research and clinical care