The abnormal hemodynamics in Fontan circulation due to persistently increased systemic venous pressure results in hepatic venous congestion and Fontan-associated liver disease. Combined assessment of cardiac and liver fibrosis and cardiac remodeling using multiparametric MRI in this context have not been fully explored. To evaluate cardiac and liver fibrosis and cardiac remodeling using multiparametric MRI in patients who have undergone Fontan procedures. Thirty-eight patients and 23 controls underwent cardiac and liver MRI examinations in a 3.0-T scanner. Mann-Whitney, Fisher exact test, and Spearman's correlation were applied to evaluate myocardial volumes, function, native cardiac and liver T1 mapping, ECVs and liver stiffness. The mean native cardiac T1 value (p = 0.018), cardiac ECV (p < 0.001), liver native T1 (p < 0.001), liver ECV (p < 0.001), and liver stiffness (p < 0.001) were higher in patients than controls. The indexed end-diastolic volume (EDVi) correlated with the myocardial ECV (r = 0.356; p = 0.033), native liver T1 (r = 0.571; p < 0.001), and with liver stiffness (r = 0.391; p = 0.015). In addition, liver stiffness correlated with liver ECV (r = 0.361; p = 0.031) and native liver T1 (r = 0.458; p = 0.004). An association between cardiac remodeling and cardiac and liver fibrosis were found in this population. The usefulness of MRI to follow cardiac and liver involvement in these patients is critical to improve treatment strategies and to prevent the need for combined liver and heart transplantation.

Fontan circulation (FC) in complex congenital heart disease is characterized by altered hemodynamics and associated with Fontan-associated liver disease. Patients with FC may exhibit abnormalities in cholate clearance due to abnormal perfusion. We aimed to compare cholate clearance in adults with FC to healthy controls and explore associations between cholate clearance and clinical features.

This is a prospective cohort study of patients with FC ≥18 years of age between 2019 and 2022. Systemic and portal hepatic clearance of cholate was assessed using a dual cholate clearance assay (HepQuant Shunt), measuring systemic and portal hepatic filtration rates (HFRs). Systemic HFR/portal HFR ratio (SHUNT%) was calculated. Participants with FC and healthy controls were compared using the Fisher exact test and Wilcoxon test. Univariable regression and multivariable analyses determined associations with clinical variables. There were 35 participants with FC (54% women; median age 29.0 years [interquartile range, 24.0-36.0], 91% White) and 26 controls. In addition to lower platelet counts and higher aspartate aminotransferase to platelet ratio index, and Fibrosis-4 indices, FC participants had lower systemic HFR and portal HFR. SHUNT% was comparable with controls but ranged from 8% to 76%, with 8 (23%) having SHUNT% >30%. In those with FC, increase in SHUNT% was associated with elevated Fontan pressure, higher aortopulmonary collateral flow, decreased oxygen saturation, elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, thrombocytopenia, and Fibrosis-4 ≥1.45.

Cholate clearance, as defined by systemic and portal HFR, is impaired in those with FC. Features of worse Fontan physiology correlate with higher SHUNT%, supporting the hypothesis that hemodynamic derangements play a role in progression of Fontan-associated liver disease.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03726229.

Fontan-associated liver disease (FALD) often occurs in patients with single-ventricle physiology following Fontan surgery, and ranges from liver congestion to cirrhosis. The assessment of the severity of FALD using noninvasive methods is challenging. However, transient elastography (TE) may be useful for the noninvasive evaluation of FALD and prediction of clinical outcomes.

To evaluate the role of TE in the diagnosis of FALD and its association with clinically relevant events.

This retrospective single-center study (Hospital Universitario La Paz, Madrid), including 91 post-Fontan patients aged > 18 years old. Laboratory and ultrasound findings, and liver stiffness measurements (LSM) by TE (FibroScan®) were assessed. FALD was defined using ultrasound criteria (hepatomegaly, liver surface nodularity, parenchymal heterogeneity, hyperechoic lesions, splenomegaly, collaterals) and advanced FALD was defined according to the European Association for the Study of the Liver-European Reference Network statement (esophageal varices, portosystemic shunts, ascites, splenomegaly). Clinically relevant events included heart or heart-liver transplantation indication, hepatocellular carcinoma, and all-cause mortality.

Patient characteristics were: 60.4% male; Mean age, 33.3 ± 8.2 years; Mean elapsed time since surgery, 24.3 ± 7.7 years; 89% with FALD; 73% with advanced FALD. LSM by TE was associated with FALD [odds ratio (OR) = 1.34; 95% confidence interval (95%CI): 1.10-1.64; P = 0.003] and advanced FALD (OR = 1.10; 95%CI: 1.01-1.19; P = 0.023). Areas under the curve (AUC) were 0.905 and 0.764 for FALD and advanced FALD, respectively. FALD cut-off values comprised: Optimal, 20 kPa (sensitivity: 92.3%; specificity: 80.0%); Rule-out, 15 kPa (sensitivity: 96.9%); Rule-in, 25 kPa (specificity: 100%). A FALD algorithm was proposed based on LSM by TE and elapsed time since surgery (AUC: 0.877; sensitivity, 95.4%; specificity, 80.0%; positive predictive value, 96.9%; negative predictive value, 72.7%). LSM by TE was associated with clinically relevant events (OR = 1.07; 95%CI: 1.01-1.13; P = 0.021) and all-cause mortality (OR = 1.23; 95%CI: 1.02-1.47; P = 0.026).

In adult patients post-Fontan surgery, TE is a useful noninvasive method for FALD diagnosis. The association between LSM by TE and clinically relevant events suggests a role in prognosis.

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Almost all patients with Fontan operation develop liver fibrosis at a young age, known as Fontan-associated liver disease (FALD). The pathogenesis and mechanisms underlying FALD remain little understood, and there are no effective therapies. We aimed to present a comprehensive multiomic analysis of human FALD, revealing the fundamental biology and pathogenesis of FALD.

We recently generated a single-cell transcriptomic and epigenomic atlas of human FALD using single-nucleus multiomic RNA sequencing and assay for transposase-accessible chromatin using sequencing, which uncovered substantial metabolic reprogramming. Here, we applied liquid chromatography-mass spectrometry-based untargeted metabolomics to unveil the metabolomic landscape of human FALD, using liver samples/biopsies from age- and sex-matched donors and patients with FALD (n=12 per group). Results were integrated with liver single-nucleus multiomic RNA sequencing and assay for transposase-accessible chromatin using sequencing and serum metabolomics data to present a comprehensive multiomic atlas of FALD.We discovered significant metabolic abnormalities in livers of adolescent patients with Fontan circulation, particularly amino acid metabolism, peroxisomal fatty acid oxidation, cytochrome P450 system, glycolysis, tricarboxylic acid cycle, ketone body metabolism, and bile acid metabolism. Integrated analyses with liver single-nucleus multiomic RNA sequencing and assay for transposase-accessible chromatin using sequencing results unveiled potential underlying mechanisms of these metabolic changes. Comparison with serum metabolomics data indicate that liver metabolic reprogramming contributes to circulatory metabolomic changes in FALD. Furthermore, comparison with metabolomics data of human metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis highlighted dysregulated amino acid metabolism as a common metabolic abnormality.

Our comprehensive multiomic analyses reveal new insights into the fundamental biology and pathogenesis mechanisms of human FALD.

Fontan-Associated Liver Disease (FALD) is a dramatically emerging problem even if not precisely defined in term of debated diagnosis and surveillance protocols. We analyze FALD prevalence, clinical impact and implications in a European cohort of patients. It's a retrospective observational multicenter study including Fontan patients operated between 1990 and 2022. Anatomical, clinical, surgical and liver-related data were collected, defining FALD as a spectrum of time-related structural-functional liver modifications due to congestive hepatopathy (from mild liver fibrosis to liver cirrhosis and hepatocellular carcinoma) diagnosed through multiparametric evaluations. 14 centers routinely conducted liver assessment after Fontan completion. Out of 2141 patients, 343 (16%) were diagnosed with FALD (M/F = 198/145; median age 18 years, IQR 15-26) with a median follow-up time of 14 years (IQR 9-20) from Fontan surgery. Among these, there were 19 (5.5%) deaths, 5 (26.3%) of whom related to advanced liver disease/cancer. FALD showed no significant association with gender (p = 0.4, adjusted p-value = 0.5), dominant ventricular morphology (p = 0.060, adjusted p-value = 0.086) nor surgery type (p = 0.3, adjusted p-value = 0.4). Significant association emerged between FALD and fenestration absence (p < 0.001, adjusted p-value < 0.001), systemic ventricular (p < 0.001, adjusted p-value < 0.001) and atrio-ventricular valve (p < 0.001) dysfunction, III-IV NYHA classes (p < 0.001, adjusted p-value < 0.001), tachyarrhythmias (p < 0.001) and liver stiffness ≥ 22 kPa on transient elastography (p < 0.001, adjusted p-value < 0.001). The analysis demonstrated no significant association between FALD and abnormal liver function tests (p = 0.2), heart transplantation (p = 0.6, adjusted p-value = 0.6), worse survival (p = 0.38). This study shows significant mortality related to FALD, which is also associated to clinical signs of failing Fontan circulation, stressing the pressing need of universally shared diagnostic criteria and surveillance protocols, to prevent and/or early-identify FALD and its more lethal complications.

Fontan-type surgery is a palliative procedure for congenital heart disease with univentricular physiology that may, in the long term, lead to advanced chronic liver disease. Herein, we assessed the accuracy of conventional non-invasive models for assessing liver fibrosis in the context of Fontan circulation and developed a new risk score employing non-invasive tools.

A prospective, cross-sectional, observational study was conducted across five European centers and encompassing all consecutive adult patients with Fontan circulation, liver biopsy and non-invasive tests (e.g. elastography, APRI, and FIB-4). The primary outcome was the identification of severe liver fibrosis on biopsy. Multivariable logistic regression identified non-invasive predictors of severe fibrosis, leading to the development and internal validation of a new scoring model named the FonLiver risk score.

In total, 217 patients (mean [SD] age, 27.9 [8.9] years; 50.7% males) were included. Severe liver fibrosis was present in 47.9% (95% CI 41.2%-54.5%) and correlated with a lower functional class, protein-losing enteropathy, and compromised cardiopulmonary and systemic hemodynamics. The final FonLiver risk score incorporated liver stiffness measurement using transient elastography and platelet count, and demonstrated strong discrimination and calibration (AUROC of 0.81). The FonLiver risk score outperformed conventional prediction models (e.g. APRI and FIB-4), which all exhibited worse performance in our cohort (AUROC <0.70 for all).

Severe liver fibrosis is prevalent in adults following Fontan-type surgery and can be effectively estimated using the novel FonLiver risk score. This scoring system can be easily incorporated into the routine assessment of patients with Fontan circulation.

Fontan-type surgery is used as a palliative procedure for congenital heart disease with univentricular physiology that may, in the long term, lead to advanced chronic liver disease. The severity of liver fibrosis progression has been proposed as a surrogate for failing Fontan hemodynamics as well as worse outcomes after heart transplantation. The development of FALD screening protocols would facilitate the early detection of advanced fibrosis and anticipate interventions to optimize the Fontan circulation, thereby improving outcomes. In our international series, we have developed the FonLiver risk score to predict severe fibrosis, that can be easily incorporated into the routine assessment of patients with Fontan circulation.

Fontan-associated liver disease (FALD) is a significant complication in patients with Fontan palliation. The improved longevity following Fontan palliation has led to wider recognition of FALD and its association with hepatocellular carcinoma (HCC). This review examines the intricate link between FALD and HCC development, emphasizing the unique hemodynamic changes in Fontan circulation that promote hepatic congestion, fibrosis and cirrhosis, thereby facilitating carcinogenesis. The review comprehensively analyzes the existing literature, highlighting key risk factors, pathophysiological mechanisms, and diagnostic challenges in FALD-related HCC. While HCC incidence in FALD remains relatively low (1.5-5.0%), its higher mortality rate of 29.4% necessitates a thorough understanding of contributing factors and screening requirements. The management of FALD involves multidisciplinary approaches, addressing cardiac and hepatic aspects, with regular surveillance for liver disease progression and HCC using advanced imaging and biomarkers. Therapeutic considerations include interventions to manage hepatic congestion and fibrosis, although balancing these with the unique cardiac needs of Fontan circulation remains challenging. Interestingly, FALD management often mirrors that of other liver diseases, underscoring the need for tailored approaches. In severe cases, combined heart-liver transplantation offers a comprehensive solution for FALD-HCC. This review consolidates current knowledge on the epidemiology, pathogenesis and comprehensive management of HCC in the specific context of FALD, ultimately improving outcomes for this unique patient population.

Fontan-associated liver disease (FALD) occurs in all patients who have undergone Fontan palliation for functional single ventricle congenital heart defects. While liver fibrosis is universal in patients who have undergone Fontan palliation, FALD may lead to more serious consequences including portal hypertension, cirrhosis, and hepatocellular carcinoma. Scientific studies of the pathophysiology and clinical management of FALD have been limited to date by the heterogeneous nature of the disease, relatively small population of patients with Fontan physiology, and inaccuracy of noninvasive staging tests. As survival after the Fontan procedure improves, the population of adults with Fontan physiology is growing, leading to more severe extracardiac complications related to the Fontan circulation and growing demand for heart and liver transplantation. The accurate evaluation, staging, and management of FALD comprises a clinical challenge which requires expert multidisciplinary input.

Background: The Fontan procedure has provided pediatric patients suffering from severe congenital heart disease the opportunity to reach adulthood. Increasingly, we encounter the liver repercussions of Fontan circulation, alongside a decline in heart function and exercise performance. This study aims to identify the univentricular heart malformations that are most susceptible to liver dysfunction; assess which markers of liver injury are essential for multidisciplinary clinical follow-up of Fontan patients; determine the optimal approach for evaluating liver function in Fontan patients; and explore how a congenital cardiology team can interpret the data and respond effectively to signs of organ failure. Methods: Cross-sectional clinical study including patients who underwent a Fontan procedure at the University Hospital of Padua between 1982 and 2017. Patients were admitted for elective hospitalization between June 2021 and June 2022 and underwent clinical assessment, laboratory tests, and instrumental examinations. Results: Seventy patients were included in the study. On admission, 48 patients (72%) were in New York Heart Association (NYHA) functional class I, and the cardiopulmonary exercise test was normal for age and gender. At laboratory tests, 56% of patients showed changes in NTproBNP values, most of whom had right-sided ventricular morphology. Liver function tests showed abnormal Gamma-Glutamyl Transferase (GGT) blood levels in 68%. On cardiac imaging, at least moderate atrioventricular valve insufficiency was found in 9% of cases. Fibroscan showed altered hepatic stiffness values in 25% of cases. Statistical analysis showed that systemic atrioventricular valve (SAVV) dysfunction was significantly associated with a reduction of maximum oxygen consumption (VO2 max) and hepatic stiffness. Conclusions: SAVV dysfunction is significantly responsible for worse functional outcomes and the development of hepatic fibrosis due to an increase in venous congestion. Setting up a careful multidisciplinary follow-up in these patients is mandatory for early detection of complications, prompt treatment, and better outcomes.

T1 relaxation time quantification on parametric maps is routinely used in cardiac imaging and may serve as a non-invasive biomarker for diffuse liver disease. In this study, we aimed to investigate the relationship between liver T1 values and cardiac function in patients with congenital heart disease (CHD) and compared patients with a biventricular circulation (BVC) to those with a Fontan circulation (FC). Magnetic resonance images from patients with CHD, obtained between June and December 2023 on a 1.5 T machine, were retrospectively reviewed. The examinations included cardiac cine sequences to assess ventricular mass and volumes, along with liver T1 mapping. T1 values were measured in eight liver segments and were compared with ventricular mass and volumes in patients with BVC and FC. In total, 104 patients (75 with BVC and 29 with FC) were included. T1 values varied significantly among the eight liver segments in both patient groups. In an age-matched comparison, patients with FC had significantly higher T1 values in all liver segments. In patients with BVC and right ventricular (RV) enlargement, a positive correlation between RV volume and T1 values in the right liver lobe was found (R > 0.504, p < 0.033). In patients with FC, the T1 values did not differ between patients with an extracardiac conduit or a lateral tunnel. Liver T1 mapping suggests more severe liver affection in patients with FC compared to those with BVC. It seems a valuable addition to cardiovascular magnetic resonance for patients who are at risk of systemic venous congestion.

The Fontan operation is associated with chronic venous hypertension, liver and renal disease, and several other sequelae. The alterative surgical approach, when feasible, a biventricular conversion (BiV), may diminish some of these long-term risks.

The aim of this study was to compare long-term outcomes of patients undergoing BiV with those undergoing a destination Fontan operation.

We identified all patients with univentricular physiology cared for at Boston Children's Hospital between 2007 and 2022 and divided them into those who received BiV or Fontan operations. Outcomes included 10-year incidences of modified major adverse cardiovascular events (MACE), liver dysfunction, renal dysfunction, and transplant-free survival. Outcomes in the 2 groups were compared using propensity matching.

A total of 927 patients were evaluated, 341 BiV and 586 Fontan. Following propensity matching, 258 patients from each group were compared. There were no differences between groups in estimated 10-year freedom from MACE (P = 0.70), transplant-free survival (P = 0.70), or freedom from renal disease (P = 0.60). However, estimated 10-year freedom from liver disease was greater in BiV patients (82% BiV vs 71% Fontan, P = 0.02). Incidence rate per 100 person-years follow-up of surgical interventions and readmissions was higher among BiV patients (10.11 vs 1.85, P < 0.001 and 13.09 vs 9.6, P = 0.002), while catheter-based interventions were higher among Fontan patients (8.41 vs 4.63, P < 0.001).

Among a contemporary cohort of patients with single ventricle anatomy, BiV provide comparable long-term survival and lower risk of liver disease when compared to patients who have undergoing Fontan operations.

Knowledge about health-related quality of life (HRQoL) over time in Fontan patients is sparse. We aimed to describe HRQoL over a ten-year period in a population-based Fontan cohort. Further, we compared HRQoL in Fontan patients with the general population. In 2011, Danish Fontan patients were invited to participate in a nationwide study assessing HRQoL. Depending on age, 152 participants filled out either the Pediatric Quality of Life Inventory or the 36-Item Short Form Health Survey. After a decade, patients from the initial study were invited to participate in a follow-up study. All were given the same questionnaire as in the first study, plus the 12-Item Short Form Health Survey (SF-12) as part of the Danish National Health Survey. HRQoL over time was described, and SF-12 scores were compared with the general population. A total of 109 Fontan patients completed the questionnaires in both studies. The mean patient age was 14.9 ± 6.6 years and 25.6 ± 6.5 years respectively. Despite an increase in complications, HRQoL did not decrease during the study period. Physical HRQoL scores were lower than mental HRQoL scores at both time points. The SF-12 physical component score was significantly lower in Fontan patients than in the general population (median score 52 vs. 56, p < 0.001), while the SF-12 mental component score was comparable (median score 51 vs. 50, p = 0.019). HRQoL remained stable over a ten-year period in a contemporary Danish Fontan cohort. Still, the physical HRQoL remained significantly lower than that of the general population.

Despite the development of several imaging modalities for diagnosing Fontan-associated liver disease (FALD), there is no optimal protocol for the follow-up of FALD. We conducted a systematic review and meta-analysis to identify factors related to liver fibrosis using biopsy reports and to identify alternative noninvasive modalities that could better reflect liver histological changes in FALD.

A systematic review and meta-analysis were conducted following the PRISMA guidelines Table S2. We searched Embase, PubMed, and Cochrane databases for studies on FALD, focusing on those assessing clinical factors associated with liver fibrosis severity through liver biopsy and noninvasive imaging techniques.

A total of 42 studies were identified, of which 12 conducted meta-analyses and subgroup analyses of the severity of liver fibrosis using liver biopsies. Liver biopsy results showed a weak positive correlation between Fontan duration and fibrosis severity (R = 0.36). Subgroup analyses revealed significant differences in hemodynamic parameters, such as Fontan pressure, between patients with mild and severe fibrosis. Platelet count, aspartate aminotransferase to platelet ratio index, and fibrosis-4 index were significantly associated with fibrosis severity, with severe fibrosis showing lower platelet counts and higher aspartate aminotransferase to platelet ratio index and fibrosis-4 index levels. Noninvasive imaging modalities, particularly magnetic resonance elastography and shear wave elastography, demonstrated strong correlations with biopsy-confirmed fibrosis severity.

This study identifies key clinical factors, and noninvasive modalities accurately reflect liver fibrosis severity in patients with FALD. Clinical factors such as platelet count, aspartate aminotransferase to platelet ratio index, and fibrosis-4 index may aid in identifying patients at risk for severe fibrosis. In addition, magnetic resonance elastography and shear wave elastography are promising tools for noninvasive assessment in our study. Further research is needed to refine these diagnostic approaches and improve patient management.

The Fontan operation, which directly connects the superior and inferior vena cava to the pulmonary artery, is a palliative surgery for children with a functional or anatomic single ventricle. This procedure leads to hemodynamic changes (Fontan circulation) in patients, who tend to develop congestive hepatic fibrosis characterized by sinusoidal fibrosis and dilatation beginning approximately 10 years after the procedure. In addition, in the context of severe fibrosis and cirrhosis, hepato-gastrointestinal complications including hepatocellular carcinoma, focal nodular hyperplasia, and portal hypertension can arise. Fontan-associated liver disease (FALD) encompasses the broad spectrum of liver alterations secondary to postoperative hemodynamic changes, and the effective management of FALD requires contributions from specialists in hepatology, gastroenterology, surgery, radiology, histopathology, and pediatric and adult cardiology. In this article, we outline the pathogenesis of FALD and discuss the importance of a multidisciplinary collaborative approach to its management.

Elevated spleen stiffness may be seen in patients with portal hypertension due to cirrhosis. In patients with Fontan physiology, elevated liver stiffness has been shown to correlate poorly with liver fibrosis. It is unknown whether spleen stiffness may instead serve as a surrogate marker of liver fibrosis in these patients.

To compare spleen stiffness determined by shear wave elastography (SWE) with histological findings of an ultrasound-guided liver biopsy in patients who had undergone Fontan palliation as a potential surrogate for Fontan-associated liver disease.

This was an IRB-approved single-center, retrospective study. Patients with Fontan palliation who had undergone both a spleen SWE study and a percutaneous liver biopsy between 2016 and 2020 were included. Biopsy, performed during cardiac catheterization, within 3 months of the SWE was required for inclusion. Using Kruskal-Wallis tests, spleen stiffness was compared with three liver biopsy scoring methods: Ishak, METAVIR, and congestive hepatic fibrosis score (CHFS). When available, Pearson's correlation was also used to compare collagen deposition determined using Sirius Red stain (%SR) with SWE values. A P-value < 0.05 was considered statistically significant.

Twenty-two patients (15 males) were included in the study, with a median age of 17 years (IQR is 14.8-20.5 years; age range: 7 years to 30.2 years). The median spleen stiffness was 2.94 m/s (IQR: 2.57-3.61 m/s; range: 1.48-4.27 m/s). The median Fontan pressure was 11 mm Hg (IQR: 10-13.3 mm Hg; range: 7-19 mm Hg) obtained within a median of 10 days (IQR: 1-41 days) of SWE. Splenic stiffness did not correlate with the extent of fibrosis determined by histology (all P > 0.05). There was also no statistically significant correlation between the %SR staining and SWE-determined spleen stiffness (Pearson's correlation of 0.165, P = 0.59, n = 13).

In this preliminary study, SWE spleen stiffness values did not correlate with biopsy-determined scoring of liver fibrosis in patients with Fontan physiology.

Liver fibrosis has been recognized as a long-term morbidity associated with Fontan circulation (Fontan-associated liver disease, FALD). The pathophysiology of FALD is not completely understood and abnormal flow dynamics may be associated with this condition. Liver hemodynamics can be quantitatively evaluated with four-dimensional phase-contrast flow magnetic resonance imaging (4D PC flow MRI). The study aimed to evaluate suitability of liver 4D PC flow MRI in Fontan patients and relate flow measurements to normal values and FALD severity.

Twenty-two Fontan patients were examined by 4D PC flow MRI at 1.5 Tesla to assess mesenteric, portal, splenic, and hepatic venous blood flow. Severity of FALD was graded based on routine screening, including abdominal ultrasound and laboratory tests.

Median age was 18.5 (interquartile range, IQR 15.5-20.2) years. FALD was graded as "none or mild" in 16 and as "moderate to severe" in six cases. Ten patients presented at least one feature of portal hypertension (ascites, splenomegaly, or thrombocytopenia). For the entire cohort, blood flow in the superior mesenteric, splenic, and portal vein was lower than reported in the literature. No significant differences were observed in relation to FALD severity. Features of portal hypertension were associated with a higher splenic vein blood flow (0.34 ± 0.17 vs. 0.20 ± 0.07 l/min, p = 0.046). Splenic vein blood flow was negatively correlated to platelet count (r = -0.590, p = 0.005).

4D PC flow MRI appears suitable to assess liver hemodynamics in Fontan patients and integration into clinical follow-up might help to improve our understanding of FALD.

The "International Society for Heart and Lung Transplantation Guidelines for the Evaluation and Care of Cardiac Transplant Candidates-2024" updates and replaces the "Listing Criteria for Heart Transplantation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates-2006" and the "2016 International Society for Heart Lung Transplantation Listing Criteria for Heart Transplantation: A 10-year Update." The document aims to provide tools to help integrate the numerous variables involved in evaluating patients for transplantation, emphasizing updating the collaborative treatment while waiting for a transplant. There have been significant practice-changing developments in the care of heart transplant recipients since the publication of the International Society for Heart and Lung Transplantation (ISHLT) guidelines in 2006 and the 10-year update in 2016. The changes pertain to 3 aspects of heart transplantation: (1) patient selection criteria, (2) care of selected patient populations, and (3) durable mechanical support. To address these issues, 3 task forces were assembled. Each task force was cochaired by a pediatric heart transplant physician with the specific mandate to highlight issues unique to the pediatric heart transplant population and ensure their adequate representation. This guideline was harmonized with other ISHLT guidelines published through November 2023. The 2024 ISHLT guidelines for the evaluation and care of cardiac transplant candidates provide recommendations based on contemporary scientific evidence and patient management flow diagrams. The American College of Cardiology and American Heart Association modular knowledge chunk format has been implemented, allowing guideline information to be grouped into discrete packages (or modules) of information on a disease-specific topic or management issue. Aiming to improve the quality of care for heart transplant candidates, the recommendations present an evidence-based approach.

To determine the effect of stress maneuvers/interventions on ultrasound liver stiffness measurements (LSMs) in patients with Fontan circulation and healthy controls.

In this prospective, IRB-approved study of 10 patients after Fontan palliation and 10 healthy controls, ultrasound 2D shear-wave elastography LSMs were acquired at baseline and after maximum inspiration, expiration, standing, handgrip, aerobic exercise, i.v. fluid (500 mL normal saline) administration, and i.v. furosemide (20 mg) administration. Absolute and percent change in LSM were compared between baseline and each maneuver, and then from fluid infusion to after diuresis.

Median ages were 25.5 and 26 years in the post-Fontan and control groups (p = 0.796). LSMs after Fontan were higher at baseline (2.6 vs. 1.3 m/s) and with all maneuvers compared to controls (all p < 0.001). Changes in LSM with maneuvers, exercise, fluid, or diuresis were not significant when compared to baseline in post-Fontan patients. LSM in controls increased with inspiration (+0.02 m/s, 1.6%, p = 0.03), standing (+0.07 m/s, 5.5%, p = 0.03), and fluid administration (+0.10 m/s, 7.8%, p = 0.002), and decreased 60 minutes after diuretic administration (-0.05 m/s, -3.9%, p = 0.01) compared to baseline. LSM after diuretic administration significantly decreased when compared to after i.v. fluid administration at 30 minutes (-0.79 m/s, -26.5%, p = 0.004) and 60 minutes (-0.78 m/s, -26.2%, p = 0.017) for patients after Fontan and controls at 15 minutes (-0.12 m/s, -8.70%, p = 0.002), 30 minutes (-0.15 m/s, -10.9%, p = 0.003), and 60 minutes (-0.1 m/s, -10.9%, p = 0.005).

LSM after Fontan is higher with more variability compared to controls. Diuresis is associated with significantly decreased liver stiffness in both patients after Fontan and controls, with the suggestion of a greater effect in Fontan patients.

Although the Fontan procedure has improved the survival of patients with single-ventricle heart disease, the long-term consequences of the procedure have been a concern. This study aimed to explore the patients' postoperative clinical characteristics, including a diagnosis of Fontan-associated liver disease (FALD).

A nationwide Japanese epidemiological survey of post-Fontan patients was undertaken in 2021. The survey targets were selected from all departments of pediatrics, pediatric surgery, cardiology, cardiovascular surgery, and gastroenterology using stratified random sampling by the number of beds. Each department was asked to complete a mail-back questionnaire on the numbers of patients and their clinical characteristics. The diagnosis of FALD was made by each attending physician.

The estimated number of post-Fontan patients was 7810 (95% confidence interval, 5430-10 200) in 2020, with a period prevalence of 61.9 per million. During the follow-up of 13.8 years after the Fontan procedure, 40% of patients were diagnosed with FALD. An elevated γ-glutamyl transpeptidase level was the most common finding leading to the FALD diagnosis (41%), and 45% of the patients also showed liver fibrosis. Compared with non-FALD patients, FALD patients were older, had longer duration since the Fontan procedure, and had more severe cardiac or liver conditions. However, more than half of the non-FALD patients had elevated liver enzyme levels, suggesting underestimation of the number of FALD patients.

In 2020, approximately 40% of post-Fontan patients underwent follow-up with a diagnosis of FALD, although the lack of established diagnostic criteria for FALD could affect the reported prevalence of FALD.

Congenitally corrected transposition of the great arteries (ccTGA) is an infrequent and complex congenital malformation, which accounts for approximately 0.5% of all congenital heart defects. This defect is characterized by both atrioventricular and ventriculoarterial discordance, with the right atrium connected to the morphological left ventricle (LV), ejecting blood into the pulmonary artery, while the left atrium is connected to the morphological right ventricle (RV), ejecting blood into the aorta. Due to this double discordance, the blood flow is physiologically normal. Most patients have coexisting cardiac abnormalities that require further treatment. Untreated natural course is often associated with progressive failure of the systemic right ventricle (RV), tricuspid valve (TV) regurgitation, arrhythmia, and sudden cardiac death, which occurs in approximately 50% of patients below the age of 40. Some patients do not require surgical intervention, but most undergo physiological repair leaving the right ventricle in the systemic position, anatomical surgery which restores the left ventricle as the systemic ventricle, or univentricular palliation. Various types of anatomic repair have been proposed for the correction of double discordance. They combine an atrial switch (Senning or Mustard procedure) with either an arterial switch operation (ASO) as a double-switch operation or, in the cases of relevant left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), intra-ventricular rerouting by a Rastelli procedure. More recently implemented procedures, variations of aortic root translocations such as the Nikaidoh or the half-turned truncal switch/en bloc rotation, improve left ventricular outflow tract (LVOT) geometry and supposedly prevent the recurrence of LVOTO. Anatomic repair for congenitally corrected ccTGA has been shown to enable patients to survive into adulthood.

The Fontan procedure is used to palliate complex forms of congenital heart disease. This results in adverse hepatic sequelae now known as Fontan-associated liver disease (FALD). Conventional laboratory measures of liver disease do not correlate well with FALD severity. Cytokeratin-18 (CK-18) is a measure of cell death and is sensitive in detecting other causes of liver disease. Our aim was to assess the use of a novel measure of liver disease, CK-18, in Fontan patients. This is a single-center, prospective, cross-sectional study of Fontan patients aged 8-21 years old. We performed ultrasound elastography, echocardiography, magnetic resonance imaging, and serum laboratory testing. Novel laboratory test CK-18 levels in Fontan subjects were compared to healthy age-matched controls. Thirteen Fontan patients were evaluated with a median age 15 years (10, 14), 4 Hypoplastic left heart syndrome, 11 were male, and 5 were symptomatic. Fontan patients had normal AST/ALT, but a significantly elevated liver stiffness by elastography (median 13.4 kPa). Hepatic stiffness by elastography was associated with diastolic-indexed (rho = 0.58, p = 0.04) ventricular volumes. Compared to 10 aged-matched controls, CK-18 was higher in the Fontan group-cleaved CK-18 protein (p < 0.01) and full CK-18 protein, (p = 0.02). CK-18 was positively associated with AST and ALT. Elevated CK-18 levels were found in Fontan patients compared to controls suggesting hepatic cell death even in these relatively healthy Fontan patients. CK-18 was elevated prior to changes in traditional testing. CK-18 may be a useful sensitive marker of liver disease in FALD.

Fontan-associated liver disease (FALD) refers to structural and functional changes of the liver caused by the physiology of the Fontan palliation. Currently, liver biopsy is the gold standard to assess liver fibrosis of FALD.

Investigate biomarkers correlating with severity of liver biopsy fibrosis in FALD.

A retrospective study of post-Fontan patients ≥ 10 years of age who underwent liver biopsy was conducted. Advanced liver disease (ALD) was defined as bridging fibrosis and/or cirrhosis on liver biopsy. AST-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4) and Liver Stiffness Measurement (LSM) from FibroScan were used as non-invasive fibrosis scores.

Sixty-six patients (26/47; 55.3% adults and 13/19 children; 68.4%) had ALD on biopsy. ALD was associated with lower platelet count (151 vs. 198 K/uL, p = 0.003), higher APRI (0.64 vs. 0.32, p = 0.01), higher FIB-4 (0.64 vs. 0.32, p = 0.02). Liver fibrosis score correlated with APRI (0.34, p = 0.02) and FIB-4 (0.47, p = 0.001) in adults. LSM had a high sensitivity at 81.3% with 45.5% specificity at a cut-off 18.5 kPa.

APRI and FIB-4 had modest discrimination to identify adults with advanced liver disease, but not children, indicating that these values may be followed as a marker of FALD progression in older patients.

The World Federation for Ultrasound in Medicine and Biology (WFUMB) endorsed the development of this document on multiparametric ultrasound. Part 1 is an update to the WFUMB Liver Elastography Guidelines Update released in 2018 and provides new evidence on the role of ultrasound elastography in chronic liver disease. The recommendations in this update were made and graded using the Oxford classification, including level of evidence (LoE), grade of recommendation (GoR) and proportion of agreement (Oxford Centre for Evidence-Based Medicine [OCEBM] 2009). The guidelines are clinically oriented, and the role of shear wave elastography in both fibrosis staging and prognostication in different etiologies of liver disease is discussed, highlighting advantages and limitations. A comprehensive section is devoted to the assessment of portal hypertension, with specific recommendations for the interpretation of liver and spleen stiffness measurements in this setting.

The evaluation of Fontan-associated liver disease is often challenging. Diffusion-weighted magnetic resonance imaging can detect hepatic fibrosis from capillary perfusion and diffusion abnormalities from extracellular matrix accumulation. This study investigated its role in the evaluation of liver disease in Fontan patients and explored possible diagnostic methods for early detection of advanced liver fibrosis.

Stable adult Fontan patients who could safely be examined with magnetic resonance imaging were enrolled, and blood biomarkers, transient elastography were also examined.

Forty-six patients received diffusion-weighted imaging; and 58.7% were diagnosed with advanced liver fibrosis (severe liver fibrosis, 37.0%, and cirrhosis 21.7%). Two parameters of hepatic dysfunction, platelet counts (Spearman's ρ: -0.456, P = 0.001) and cholesterol levels (Spearman's ρ: -0.383, P = 0.009), decreased with increasing severity of fibrosis. Using transient elastography, a cut-off value of 14.2 kPa predicted the presence of advanced liver fibrosis, but with a low positive predictive value. When we included platelet count, cholesterol, post-Fontan years and transient elastography values as a composite, the capability of predicting advanced liver fibrosis was the most satisfactory (C statistic 0.817 ± 0.071, P < 0.001). A cut-off value of 5.0 revealed a sensitivity of 78% and a specificity of 82%.

In Fontan patients, diffusion-weighted imaging was helpful in detecting liver fibrosis that was correlated with hepatic dysfunction. A simple score was proposed for long-term surveillance and early detection of advanced liver disease in adult Fontan patients. For adult Fontan patients with a calculated score > 5.0, we may consider timely diffusion-weight imaging and early management for liver complications.

To describe our experience in performing transfemoral-transcaval liver biopsy (TFTC) and transjugular liver biopsy (TJLB) in patients with Fontan-associated liver disease (FALD).

A single-center, retrospective review of 23 TFTC and seven TJLB performed between August 2011 and May 2023 on patients who previously underwent the Fontan procedure (median age 23.1 years, ranging 11-43 years, 48% female). Patient demographics, laboratory values, pathology, radiology, and cardiology reports were reviewed. Liver explants were correlated with histopathological evaluation to determine sampling accuracy when available.

All biopsies achieved technical success (accurate targeting and safe tissue sample extraction) and histopathological success (yielding sufficient tissue for accurate diagnosis). Liver biopsies were performed during simultaneous cardiac catheterization in 28 of 30 (93%) procedures. There was no statistically significant change in hemoglobin, hematocrit, platelet count post-procedure, and fluoroscopy times. There was one major complication within the TJLB group and one minor complication within the TFTC group.

Transvenous liver biopsies, whether via transfemoral or transjugular route, may be safely performed in FALD patients while yielding samples with technical and histopathological success. The transfemoral approach, which is our preferred method; its compatibility with simultaneous cardiac catheterization and its potentially increased safety profile stemming from the avoidance of transversing the Fontan shunt-makes it a particular advantageous option in the management of FALD.

We performed a single-centre retrospective study comparing the accuracy of non-invasive elastography with liver biopsy in accurate assessment of Fontan-associated liver disease.

Fontan patients who underwent combined assessment with a percutaneous liver biopsy and non-invasive elastography between January 2015 and December 2023 at our Children's hospital were included. Liver biopsies were classified using the Congestive Hepatic Fibrosis Score as early Fontan-associated liver disease (scores 1, 2) and advanced Fontan-associated liver disease (score 3/bridging fibrosis and score 4/cirrhosis). Elastography values were categorised as advanced Fontan-associated liver disease for liver elasticity >2.1 m/s by ultrasound and liver stiffness >5 KPa on magnetic resonance elastography.

We included 130 patients (116 children, 89%, mean age at biopsy: 14.6 years ± 3.6) who underwent liver biopsy at a mean duration of 11.1 years (±0.3) following Fontan surgery. Advanced Fontan-associated liver disease was noted in 41 (31.5%) patients with 13 (10%) showing frank cirrhosis. Pre-biopsy ultrasound showed advanced liver fibrosis in 18/125 (14%), with low sensitivity (23%), high specificity (90%), and low accuracy (68%, k = 0.1) in diagnosing advanced Fontan-associated liver disease. Similarly, pre-biopsy magnetic resonance elastography showed advanced fibrosis in 23/86 (27%) of patients, with low sensitivity (30%), fair specificity (75%), and low accuracy (63%, k = 0.1). Interestingly, advanced Fontan-associated liver disease was missed by ultrasound in 29% and by magnetic resonance elastography in 25% of patients. Advanced Fontan-associated liver disease was associated with lower platelet count (p = 0.02) and higher Gamma-glutamyl Transferase levels (p = 0.02).

Advanced hepatic fibrosis is common among paediatric Fontan patients. Non-invasive elastography may overestimate and underestimate the degree of liver fibrosis, and therefore, liver biopsy may be required for confirming disease severity.

The Fontan palliation is the final stage of surgery for many children born with univentricular physiology. Almost all Fontan patients develop liver fibrosis which may eventually lead to cirrhosis and hepatocellular carcinoma (HCC). These are important causes of morbidity and mortality in these patients. We performed a systematic review and meta-analysis to assess the incidence of cirrhosis and HCC in Fontan patients and stratify it based on time since surgery.

A literature search of seven databases identified 1158 records. Studies reporting the number of cirrhosis and HCC cases in Fontan patients and time since Fontan surgery were included. In the cirrhosis cohort, we included only those studies where all patients underwent liver biopsy.

A total of 23 studies were included: 12 and 13 studies in the cirrhosis and HCC cohorts, respectively, with two studies included in both cohorts. The incidence of cirrhosis was 0.97 per 100 patient-years (95% CI 0.57-1.63), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 1.61 per 100 patient-years (95% CI 1.24-2.08) and 32.2% (95% CI 25.8%-39.4%), respectively. The incidence of HCC was 0.12 per 100 patient-years (95% CI 0.07-0.21), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 0.20 per 100 patient-years (95% CI 0.12-0.35) and 3.9% (95% CI 2.2%-6.8%), respectively. Only about 70% of patients with HCC (20/28) had underlying cirrhosis.

The incidence of cirrhosis and HCC increases over time, especially at ≥20 years post Fontan surgery. Studies are needed to further identify at-risk patients in order to streamline surveillance for these highly morbid conditions.

There are no consensus guidelines defining optimal timing for the Fontan operation, the last planned surgery in staged palliation for single-ventricle heart disease.

Identify patient-level characteristics, center-level variation, and secular trends driving Fontan timing.

A retrospective observational study of subjects who underwent Fontan from 2007 to 2021 at centers in the Pediatric Health Information Systems database was performed using linear mixed-effects modeling in which age at Fontan was regressed on patient characteristics and date of operation with center as random effect.

We included 10,305 subjects (40.4% female, 44% non-white) at 47 centers. Median age at Fontan was 3.4 years (IQR 2.6-4.4). Hypoplastic left heart syndrome (-4.4 months, 95%CI -5.5 to -3.3) and concomitant conditions (-2.6 months, 95%CI -4.1 to -1.1) were associated with younger age at Fontan. Subjects with technology-dependence (+4.6 months, 95%CI 3.1-6.1) were older at Fontan. Black (+4.1 months, 95%CI 2.5-5.7) and Asian (+8.3 months, 95%CI 5.4-11.2) race were associated with older age at Fontan. There was significant variation in Fontan timing between centers. Center accounted for 10% of variation (ICC 0.10, 95%CI 0.07-0.14). Center surgical volume was not associated with Fontan timing (P = .21). Operation year was associated with age at Fontan, with a 3.1 month increase in age for every 5 years (+0.61 months, 95%CI 0.48-0.75).

After adjusting for patient-level characteristics there remains significant inter-center variation in Fontan timing. Age at Fontan has increased. Future studies addressing optimal Fontan timing are warranted.

Liver congestion is increasingly encountered in clinical practice and presents diagnostic pitfalls of which radiologists must be aware. The complex altered hemodynamics associated with liver congestion leads to diffuse parenchymal changes and the development of benign and malignant nodules. Distinguishing commonly encountered benign hypervascular lesions, such as focal nodular hyperplasia (FNH)-like nodules, from hepatocellular carcinoma (HCC) can be challenging due to overlapping imaging features. FNH-like lesions enhance during the hepatic arterial phase and remain isoenhancing relative to the background liver parenchyma but infrequently appear to wash out at delayed phase imaging, similar to what might be seen with HCC. Heterogeneity, presence of an enhancing capsule, washout during the portal venous phase, intermediate signal intensity at T2-weighted imaging, restricted diffusion, and lack of uptake at hepatobiliary phase imaging point toward the diagnosis of HCC, although these features are not sensitive individually. It is important to emphasize that the Liver Imaging Reporting and Data System (LI-RADS) algorithm cannot be applied in congested livers since major LI-RADS features lack specificity in distinguishing HCC from benign hypervascular lesions in this population. Also, the morphologic changes and increased liver stiffness caused by congestion make the imaging diagnosis of cirrhosis difficult. The authors discuss the complex liver macro- and microhemodynamics underlying liver congestion; propose a more inclusive approach to and conceptualization of liver congestion; describe the pathophysiology of liver congestion, hepatocellular injury, and the development of benign and malignant nodules; review the imaging findings and mimics of liver congestion and hypervascular lesions; and present a diagnostic algorithm for approaching hypervascular liver lesions. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first "responder" in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A's transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.