Fontan-associated liver disease (FALD) is an increasingly recognized long-term complication of the Fontan circulation, associated with elevated risks of hepatocellular carcinoma, cardiovascular morbidity, and all-cause mortality. As this population grows, so too does the need for effective risk stratification strategies that balance diagnostic yield with resource utilization. In this context, Seol et al1 should be commended for their timely and comprehensive synthesis of the current evidence on FALD. Their systematic review highlights several noninvasive factors associated with biopsy-proven severe fibrosis, including time since Fontan completion, platelet count, the aspartate aminotransferase to platelet ratio index, Fibrosis-4 index, and Fontan pressure. However, we have concerns regarding the validity of these conclusions due to 3 methodological limitations. Firstly, there is currently no universally accepted or validated diagnostic modality for FALD. While the authors used liver biopsy as the reference standard, fibrosis in FALD is patchy and heterogeneous. Biopsy may underestimate fibrosis severity by up to 40% when compared with explanted livers at combined heart–liver transplantation.2 Moreover, FALD-related fibrosis often involves perisinusoidal extending to periportal regions in the absence of significant inflammation,3 whereas histological scoring systems such as METAVIR and Batts-Ludwig, which were included in this systematic review, primarily assess portal fibrosis and inflammatory activity. As a result, some patients with severe fibrosis may have been misclassified into the mild fibrosis group, potentially diluting observed differences in noninvasive markers and reducing the apparent discriminative value of these tools. Secondly, while elastography measured by ultrasound or magnetic resonance imaging is appealing, it can be confounded by hepatic congestion, potentially leading to overestimation of fibrosis in the absence of true architectural changes.4 As highlighted in our recent review, the prevalence of cirrhosis diagnosed on imaging was more than double that diagnosed on biopsy,5 further underscoring the limitations of current diagnostic approaches when used in isolation. Thirdly, while the review sought to minimize selection bias, many of the included studies performed liver biopsy only in patients with a clinical suspicion of liver disease. In some cohorts, biopsy was undertaken in fewer than 25% of participants, introducing a risk of ascertainment bias. Moreover, the pooling of both pediatric and adult studies may further complicate interpretation, particularly as advanced fibrosis was diagnosed at a younger age in children, raising questions about the comparability of these populations. Ultimately, while we agree that risk stratification is an essential step forward in the diagnosis and management of FALD, we are concerned that the conclusions of this systematic review may be premature and limited by the methodological variations of the included studies. In our view, the more pertinent message from this work is the considerable heterogeneity in how fibrosis is defined and assessed across studies. To address this, a more uniform evaluation of diagnostic approaches is urgently needed, not only to improve consistency but to identify methods that are prognostically meaningful and to pave the way for targeted therapies.
Cao et al. (Tue,) studied this question.