Fontan circulation is rooted in the concept of perpetual fluid motion described in the mid-17th century. However, after half a century of experience, the reality is markedly different; it represents a state of “chronic heart failure” created by surgical intervention. This failure is rarely attributable to the heart itself but rather to an insufficient circulation.
One of the organs profoundly affected by this circulatory insufficiency is the liver. Elevated central venous pressure and impaired hepatic lymphatic drainage contribute to liver fibrosis, which becomes severe in over 65% of patients. Fontan-associated liver disease (FALD) encompasses a wide spectrum of hepatic conditions ranging from mild biochemical alterations indicative of cytolytic and/or cholestatic liver injury to advanced fibrosis, compensated or decompensated cirrhosis, focal nodular hyperplasia, and even hepatocellular neoplasms.
The study under review investigates the correlation of liver fibrosis scores with haemodynamic status, degree of liver cirrhosis, and prognosis in adults with Fontan circulation. Two non-invasive scores were assessed: the APRI ratio [AST/platelet count] and FIB-4 [(age x AST)/(platelet count x √ALT)]. The study included 159 adults with Fontan circulation who underwent catheterisation at Mayo Clinic between 1999 and 2017. Haemodynamic, laboratory, imaging, and pathological data were collected.
Both scores showed weak correlations with Fontan circulation resistances and pulmonary capillary wedge pressure. No correlations were found between liver fibrosis indices and ventricular end-diastolic pressure, arterial oxygen saturation, cardiac index, or pulmonary vascular resistance. Among 31 patients who underwent liver biopsy, no correlations were observed between the degree of fibrosis and liver fibrosis scores. In fact, most liver fibrosis markers failed to correlate with the indices studied. However, a significant association was found with prognosis: over a mean follow-up of 9 years, 64 patients (40.8%) died. Multivariable analysis, which incorporated prognostic factors described in the literature, revealed that each unit increase in the APRI score was associated with a hazard ratio (HR) for mortality of 1.31, and each unit increase in the FIB-4 score was associated with an HR of 2.15 (p=.003 for both).
The authors concluded that APRI and FIB-4 scores were associated with long-term mortality in adults with Fontan circulation. However, these scores were not useful for determining haemodynamic status or the degree of liver fibrosis.
COMMENTARY
Cirrhosis, a key feature of FALD, represents a late-stage consequence of Fontan circulation. Progressive liver fibrosis caused by congestion disrupts hepatic architecture, leading to hepatocyte regeneration and nodule formation. Metabolic liver function typically declines in advanced stages. However, there is limited correlation between the degree of liver fibrosis and the clinical manifestations or non-invasive diagnostic tests. Currently, there are more adults than children living with Fontan circulation worldwide, bringing FALD into sharper focus as a disease that takes decades to develop.
Liver biopsy remains the gold standard for diagnosis. However, the heterogeneous nature of hepatic involvement in FALD means that significant lesions can be missed. APRI and FIB-4 are inexpensive, easy-to-calculate indices derived from laboratory tests originally designed for viral hepatitis. Their non-invasive nature makes them attractive for studying Fontan patients. This study is the first to evaluate the correlation between these indices, clinical outcomes, and haemodynamic status in adult Fontan patients. The lack of correlation with haemodynamic status suggests that the pathophysiology of FALD is more complex than sustained elevated central venous pressure alone.
Regarding the study’s limitations, it is important to note that the Mayo Clinic is a quaternary center for congenital heart disease, introducing selection bias as the most complex cases are referred there. Furthermore, nearly two-thirds of the cohort had an atriopulmonary connection, a technique now largely abandoned due to its high rate of long-term complications. Currently, extracardiac conduit Fontan circulation is the most commonly employed technique, yet it represented less than 10% of the study cohort, affecting the external validity of the findings.
In conclusion, FALD, particularly cirrhosis, will become increasingly prevalent among Fontan patients simply due to the growing number of adults with this circulation type and the decades-long course of the disease. The complex pathophysiology underlying FALD cannot be adequately assessed using scores designed for other diseases, even those affecting the same organ. Non-invasive alternatives and multidisciplinary teams are essential for studying and managing this unique aspect of Fontan circulation.
REFERENCE:
Martin de Miguel I, Kamath PS, Egbe AC, Jain CC, Cetta F, Connolly HM, et al. Haemodynamic and prognostic associations of liver fibrosis scores in Fontan-associated liver disease. Heart. 2022:heartjnl-2022-321435. doi: 10.1136/heartjnl-2022-321435.
