Reply: Unifying FALD assessment—A call to arms

We appreciate the thoughtful comments by Dr Cao and colleagues on our recent systematic review and meta-analysis of Fontan-associated liver disease (FALD). Their observations highlight key issues in refining FALD diagnostic strategies.1 First, we agree that the lack of a universally accepted diagnostic standard for FALD presents inherent challenges. While liver biopsy remains the current gold standard, we noted in our introduction that its use is limited by invasiveness, bleeding risk, and sampling error. Furthermore, variability in histological scoring systems across centers may contribute to heterogeneity in fibrosis assessment.2,3 Nevertheless, in the absence of a validated, quantifiable alternative, liver biopsy remains the most reliable and widely used method in both clinical and research settings. Despite its limitations, our study used biopsy-confirmed fibrosis to anchor the evaluation of clinical and noninvasive markers, reflecting current multicenter practice. As randomized controlled trials are not feasible in this context, we sought to integrate the best available evidence to identify practical and reproducible predictors of fibrosis. Second, we concur that liver stiffness measurements via elastography may be influenced by hepatic congestion, potentially leading to overestimation of fibrosis. We explicitly noted this in our discussion and emphasized the need to interpret elastography findings alongside clinical, hemodynamic, and biochemical data. Nonetheless, our findings suggest that magnetic resonance elastography (MRE) and shear wave elastography (SWE) correlate more strongly with biopsy-proven fibrosis than transient elastography, supporting their clinical utility.4 We agree that further research incorporating congestion markers is warranted to refine these tools. Third, we acknowledge the potential for selection bias, as liver biopsies were often performed in patients with suspected liver disease. We addressed this limitation in the manuscript and assessed study quality using the RoBANS tool. Our review included both retrospective and protocol-based prospective cohorts to mitigate this concern. Broader and standardized biopsy criteria are essential for future studies. Lastly, although reference ranges for laboratory and hemodynamic parameters differ between pediatric and adult populations, these differences are further complicated in Fontan physiology by chronic hemodynamic changes and progressive hepatic congestion. These factors, and age-related physiology, contribute to patient-specific baselines. Nevertheless, major Fontan-related complications such as hepatic dysfunction arise through shared pathophysiologic mechanisms regardless of age.5 Accordingly, in prognostic and complication-focused research, it is more meaningful to focus on the direction of change rather than age-specific cutoffs.3,6 Our analysis focused on relative differences between patients with mild and severe fibrosis, rather than static norms. Markers like platelet count, Fontan pressure, GGT, and bilirubin reflect common Fontan-associated mechanisms with consistent patterns across age groups. This allowed us to identify fibrosis-related trends while preserving analytic rigor. Study heterogeneity reflects real-world variation in FALD care. Despite limitations, our review provides relevant insights and highlights the need for standardized prospective studies to guide future FALD surveillance. We hope it contributes to future multicenter studies and the development of FALD guidelines.