Ultrasound Evaluation of Fontan-Associated Liver Disease: A State-of-The-Art Review

1. Introduction

The Fontan procedure is a surgical intervention used to treat congenital heart defects resulting in a single functional ventricle, such as hypoplastic left heart syndrome or tricuspid atresia. This procedure diverts systemic venous return directly to the pulmonary arteries, bypassing the heart. The initial version of the Fontan procedure, known as the atrio-pulmonary connection or classical Fontan, was originally developed for patients with tricuspid atresia. This approach involved closing the atrial septal defect and directly linking the right atrium to the right pulmonary artery. Over time, several modifications were introduced (Figure 1), including the revised atrio-pulmonary technique by Kreutzer and the right atrial-to-pulmonary artery connection described by Björk et al. [1,2]. A significant evolution came in 1988 with the introduction of the total cavopulmonary connection, or lateral tunnel, by De Leval. In this method, the superior vena cava is connected to the right pulmonary artery (classical Glenn shunt), while the inferior vena cava is routed to the right atrium through an intracardiac tunnel. The most recent development is the extracardiac cavopulmonary connection, which involves a direct anastomosis between the superior vena cava and the right pulmonary artery. A vascular conduit is placed externally to link the inferior vena cava to the right pulmonary artery. This technique offers advantages such as avoiding myocardial ischemia, reducing the number of suture lines, and eliminating the use of foreign material within the right atrium.

The Fontan circulation, characterized by the absence of a subpulmonary ventricle, fundamentally alters cardiovascular dynamics. In this configuration, systemic venous blood is directed passively into the pulmonary arteries, relying on elevated central venous pressure (CVP) to drive pulmonary perfusion. This passive flow results in a reduced preload to the systemic ventricle, limiting stroke volume and cardiac output. Concurrently, the systemic ventricle faces increased afterload, as it must overcome both systemic and pulmonary vascular resistances without the assistance of a sub-pulmonary pump. Three main mechanisms facilitate the passage of blood from the systemic venous system to the left atrium in the Fontan circulation [3]:

• The suction effect generated by left atrial relaxation during diastole.
• The action of the respiratory and muscular pumps, driven by the negative intrathoracic pressure during inspiration, which enhances inferior vena cava return and promotes pulmonary vessel recruitment.
• The maintenance of low pulmonary vascular resistance, provided there is no mechanical obstruction within the Fontan conduit, the main pulmonary arteries, or the pulmonary veins.

These hemodynamic changes can lead to ventricular dysfunction over time, manifesting as decreased ejection fraction and diastolic impairment. Additionally, the elevated CVP inherent in the Fontan circulation contributes to complications such as hepatic congestion, protein-losing enteropathy, and decreased exercise tolerance. Understanding these alterations is crucial for optimizing long-term management and improving outcomes in patients with Fontan physiology.

These hemodynamic challenges predispose patients to long-term complications, including liver and kidney diseases. The Fontan physiology is characterized by chronically elevated CVP and reduced cardiac output, significantly altering normal organ perfusion and function[3]. These changes can progressively impair the liver and kidneys, organs highly sensitive to hemodynamic stress [3].

Fontan circulation can fail due to systolic or diastolic ventricular dysfunction, atrioventricular valve disease, elevated pulmonary vascular resistance, recurrent arrhythmias, lymphatic insufficiency, or end-organ complications [4]. Accordingly, symptoms may be related to heart failure and hypoxemia or end-organ complications, resulting in different clinical and hemodynamic Fontan failure phenotypes [4] (Table 1).

• Systolic Failure Phenotype (SFP): the single ventricle’s pumping ability deteriorates, leading to a reduced ejection fraction. Clinically, patients may experience fatigue, ascites and exercise intolerance. Hemodynamically, this group is characterized by a low cardiac index, often less than 2,2 L/min/m², and variable Fontan pressures. These patients are typically the most ill and often require early evaluation for transplant due to poor outcomes with medical therapy alone.
• Preserved Systolic Function with Elevated Pressure (PFP): In this phenotype, the ventricle itself is functioning normally in terms of contractility, but the Fontan circuit develops resistance. Elevated pressures within the Fontan pathway—often due to increased pulmonary vascular resistance, conduit stenosis, or lack of compliance—lead to systemic venous congestion. Patients may present with peripheral edema, liver congestion, and ascites. Despite a preserved cardiac output, end-organ dysfunction progresses, and clinical management often focuses on relieving congestion or improving Fontan flow dynamics.
• Lymphatic Failure Phenotype (LFP): Some patients with Fontan circulation develop complications related to abnormal lymphatic flow, even in the absence of severe hemodynamic derangements. These patients may present with protein-losing enteropathy, plastic bronchitis, or chylous effusions. This phenotype is increasingly recognized because of chronic central venous hypertension impairing lymphatic drainage, especially from the gut and lungs. Management often requires targeted lymphatic interventions, such as lymphangiography-guided embolization or specialized dietary and pharmacologic therapies.
• Normal Hemodynamics Phenotype (NHP): A subset of patients may exhibit clinical symptoms of Fontan failure despite having normal cardiac function and pressures. These cases can be particularly challenging to diagnose and manage, as standard hemodynamic evaluations appear normal. The underlying mechanisms are not fully understood but may involve diastolic dysfunction, subtle microvascular issues, or autonomic imbalance. Despite “normal” measurements, these patients may have reduced exercise tolerance or quality of life and require a multidisciplinary approach to evaluation.

Fontan-associated liver disease (FALD) encompasses a broad spectrum of structural, functional, and clinical liver alterations secondary to Fontan hemodynamic changes [3,5] (Table 2). These changes are due to the pathological hemodynamic state that exists in any type of Fontan circulation from the first day of the surgical procedure, meaning that FALD can also occur in patients without Fontan circulatory failure [3,4]. Liver damage can start even before the Fontan procedure and is present in patients without Fontan circulatory failure [3,4] (Table 3). This review aims to provide an updated overview of FALD and to summarize current knowledge on the role of imaging modalities in the evaluation of liver disease in this population, with a particular focus on ultrasound-based techniques.

2. Fald Epidemiology

The number of individuals living with Fontan-type surgery in 2020 was estimated to be 66 per million, expected to rise to 79 per million by 2030 [6,7]. In 2020, this population comprised 55% adults, 17% adolescents, and 28% children. These proportions are projected to shift to 64%, 13% and 23% respectively, by 2030 [6]. The true incidence of FALD is not known and likely underrecognized since there is no consensus on a uniformly accepted definition of the disease. The reported prevalence of FALD is 13-86% [6]. However, the actual prevalence of some of these conditions could be higher due to subclinical disease presentation and the lack of a universal definition. Hispanic ethnicity was associated with increased all-cause mortality [6]. Furthermore, the prevalence of FALD is underrecognized, but there is evidence that its incidence increases with age [4]. FALD is associated with late mortality but excellent post-transplant survival [4]. This underscores the need for FALD-specific liver surveillance strategies in patients post-Fontan.

3. Pathophysiology

The mechanisms underlying the pathophysiology of FALD are multifactorial (Table 4). Different mechanisms related to the vascular supply and drainage of the liver have been linked to the development of hepatic damage in Fontan patients [7].

The hepatic veins transmit systemic venous hypertension to the sinusoid, leading to sinusoidal dilatation, hyperfiltration, and perisinusoidal edema [8,9]. In turn, sinusoidal shear stress promotes sinusoidal endothelial cell capillarization, decreases intrahepatic nitric oxide concentration, and facilitates the mechanical activation of mechanosensitive cell signaling pathways in hepatic stellate cells, resulting in liver fibrosis [10,11,12]. These changes also hamper the diffusion of oxygen and nutrients and promote centrilobular hepatocellular dropout and atrophy [13].

Elevated CVP may reduce the effectiveness of the hepatic arterial buffering response [5,14]. These changes put the liver at risk for hypoxic injury during an acute event (cardiac surgeries or cardiopulmonary collapse) [15,16]. Moreover, in the long term, chronic reduced cardiac output and the development of aberrant intrapulmonary shunts would perpetuate liver hypoxia [15,16].

The anatomical and functional characteristics of the Fontan circulation and the acquired thrombophilic state (low serum levels of antithrombin III, thrombomodulin, alpha-2-antiplasmin, and C and S proteins and high levels of thrombin-antithrombin complex) may facilitate intrahepatic microthrombosis [17,18,19].

Increased hepatic lymphangiogenesis and lymphatic stasis contribute to significant dilatation of hepatic sinusoids, the space of Disse, and channels passing through the limiting plate, potentially leading to collagen fiber deposition [20,21]. A state of latent microinflammation may promote end-organ fibrogenesis. Increased intestinal permeability secondary to venous and lymphatic congestion and chronic ischemia may play a central role in the inflammatory state.

Additional risk factors include an increased prevalence of hepatitis C and B virus infection and risk of hepatotoxic injury due to medications (i.e. amiodarone) [22].

4. Clinical Presentation

FALD most often develops subclinically during the early phases. Due to the distension of the Glisson capsule, some patients report discomfort in the upper right quadrant of the abdomen [7,23]. The liver edge is easily palpable, firm, smooth, and tender in these cases. Hepatojugular reflux may also be easily identified after applying compression over the liver [24]. Mild jaundice is common, yet severe jaundice is rare; however, it may occur at the end of an episode of hypoxic hepatitis [7,24]. Even in the advanced stages of FALD, with established but compensated cirrhosis, clinical symptoms may be absent or present with more nonspecific symptoms, such as anorexia, fatigue, and weight loss [24]. In late-stage and decompensated liver disease, ascites, jaundice, variceal bleeding, and hepatic encephalopathy may occur, suggesting the presence of portal hypertension (PHTN), which is associated with adverse outcomes in patients with a Fontan circulation [7,23]. Variceal bleeding has been reported after the Fontan procedure, with a variable incidence ranging from 9.3-38% [23]. In children, the prevalence of varices is even lower (about 9%), suggesting that their development is a late complication [25]. Given the high mortality risk associated with this complication (15%–20%), upper gastrointestinal endoscopy is commonly recommended for adult patients with cirrhosis or signs of PHTN [26].

5. Diagnosis

The diagnosis of FALD requires a comprehensive and integrated approach, as no single test can definitively identify or stage the condition. Evaluation typically begins with a thorough clinical assessment, including history and physical examination [27]. Clinicians look for signs of chronic liver disease such as hepatomegaly, ascites, jaundice, spider angiomas, and splenomegaly [27]. Symptoms may be subtle in early stages and include fatigue, abdominal discomfort, or evidence of portal hypertension, like gastrointestinal bleeding [27]. Laboratory testing plays a central role in the diagnostic process (Table 5). Liver enzymes such as ALT and AST may be normal or only mildly elevated, while markers of cholestasis (such as alkaline phosphatase and GGT) and bilirubin levels can provide additional insight [28]. Tests of synthetic liver function, including serum albumin and the international normalized ratio (INR), are useful for assessing disease severity [28]. A complete blood count may reveal thrombocytopenia, often a sign of portal hypertension, and serologic testing helps to exclude other causes of liver disease, such as viral hepatitis or autoimmune hepatitis [28]. Common fibrosis scores like APRI and FIB-4 are frequently used in other chronic liver diseases but have limited accuracy in FALD due to the unique hemodynamics of the Fontan circulation [28].

Imaging is a cornerstone of noninvasive evaluation. Abdominal ultrasound is often the first-line modality, allowing for assessment of liver size, texture, nodularity, and signs of portal hypertension such as splenomegaly or ascites [29,30]. Doppler ultrasound adds valuable information by evaluating hepatic and portal venous waveforms, which can reflect changes in venous congestion or progression toward cirrhosis [30,31]. Liver elastography, through either transient elastography or shear wave techniques, provides an estimate of liver stiffness [31]. However, stiffness values may be confounded by hepatic congestion and must be interpreted cautiously. Cross-sectional imaging with contrast-enhanced computed tomography (CT) or magnetic resonance (MR) offers detailed structural information and helps detect liver nodules, vascular changes, or collateral circulation [32]. MR with hepatobiliary contrast agents and MR elastography can offer superior tissue characterization, though their availability may be limited in some centers [32].

Endoscopic evaluation is recommended in patients at risk of portal hypertension [33]. Upper gastrointestinal endoscopy allows for direct visualization of esophageal and gastric varices, which may be asymptomatic until bleeding occurs [33]. In select cases, invasive testing is necessary [34]. Liver biopsy remains the gold standard for assessing fibrosis and confirming cirrhosis [34,35]. Histological findings in FALD typically include sinusoidal dilation, perivenular and perisinusoidal fibrosis, and in advanced stages, nodular regenerative hyperplasia [36]. However, in the case of FALD, this procedure is more challenging due to the potential for sampling errors caused by the heterogeneous nature and patchy distribution of fibrosis [36]. Additionally, because it is an invasive procedure, liver biopsy carries an increased risk of bleeding due to anticoagulant therapy and high CVP, making it unsuitable for routine longitudinal follow-up. In the pediatric population, sedation and general anesthesia are often required. Consequently, noninvasive diagnosis and staging could be an attractive alternative [37]. While hepatic venous pressure gradient (HVPG) is a standard tool in other liver diseases, it is less useful in the Fontan population due to altered vascular anatomy and hemodynamics. Conversely, cardiac catheterization remains an important tool to assess Fontan pressures and exclude hemodynamic contributors to liver congestion. Finally, in patients with advanced disease or cirrhosis, surveillance for hepatocellular carcinoma is crucial [38,39]. This typically involves regular imaging—such as ultrasound or MRI—every 6 to 12 months, sometimes paired with serum alpha-fetoprotein (AFP), although AFP alone has limited sensitivity and specificity [38,39].

7. Imaging

Imaging plays a valuable role in the diagnosis and surveillance of FALD [3]. Common imaging findings in patients with FALD include a heterogeneous liver texture. Initially, hepatomegaly is likely to develop because of venous congestion. With the development of advanced cirrhosis, atrophy of the right lobe with hypertrophy of the caudate lobe are seen, together with dilation of hepatic veins, IVC, and signs of PHTN, such as ascites, splenomegaly, and varices [3,7]. The specific atrophy of the right hepatic lobe in advanced cirrhosis can be explained by a combination of decreased portal and arterial inflow, intrahepatic anatomical changes and compensatory hypertrophy of the left lobe.

In advanced cirrhosis, there is significant disruption of hepatic blood flow, particularly a reduction in portal vein inflow to the right lobe. With the development of portal hypertension and portosystemic shunting, the right lobe becomes more susceptible to hypoperfusion, leading to chronic ischemia and atrophy. Structural changes in the liver (fibrosis, regenerative nodules, intrahepatic shunts) can compress portal branches supplying the right lobe. In some cases, a selective thrombosis of the right portal vein branch can be observed. As chronic liver disease progresses, the left lobe may become hypertrophic and more metabolically active, compensating for the reduced function of the right lobe. This is part of the compensatory atrophy-hypertrophy complex, where the right lobes shrink, and the left lobe enlarges.

Patients with imaging findings consistent with PHTN have a ninefold increased risk of HCC, liver transplantation, and death. While hepatomegaly can easily be seen on imaging methods, fibrosis remains undetectable until advanced stages. Typical manifestations of cirrhosis (fibrosis), such as regional atrophy, caudate lobe hypertrophy, and increased nodularity, are often masked in earlier stages due to liver swelling caused by congestion, which can obscure fibrotic shrinkage. The heterogeneous distribution of fibrosis is also characterized by multiple peripheral nodules of varying sizes in both early and late disease stages [3,7]. Over time, as cirrhosis progresses, right lobe atrophy and a nodular liver surface may become evident [3,7]. Typically, a patchy and uneven distribution of fibrosis or cirrhosis is seen [3,7]. Additionally, venovenous shunts, a dilated inferior vena cava, and engorged hepatic veins are frequently observed due to elevated CVP [3,7]. The combination of elevated CVP and low cardiac output leads to hepatic ischemia.

8. B-Mode Findings

Ultrasound can be used to detect heterogeneous echogenicity and hepatomegaly, which are early signs of congestive hepatopathy [40]. Several studies reported correlations between the severity of ultrasound features and the degree of hepatic fibrosis or cirrhosis (30, 41, 42). The most common ultrasound findings include a nodular liver surface, atrophy of the right lobe, rounded margins, and irregular profiles [43,44,45] (Figure 2). The echotexture appears granular and markedly heterogeneous, with hyperechogenic nodules of varying sizes [43,44,45] (Figure 3, Figure 4, Figure 5, Figure 6, Figure 7 and Figure 8).

In a study of 55 patients who had undergone the Fontan procedure, 67% exhibited heterogeneous hepatic echotexture or nodularity on the liver surface, findings that correlated with the time elapsed since the procedure. Severe congestion with PHTN may present with dilated portal veins (diameter >13 mm), enlarged paraumbilical veins, collateral circulation, splenomegaly (Figure 9), ascites, and reversal of portal vein flow [44,46,47].

Compared to liver cirrhosis secondary to hepatitis, extrahepatic portosystemic shunts in FALD are either uncommon or small, even in decompensated states. This is likely due to the high systemic venous pressure in Fontan circulation and the relatively low-pressure gradient between the portal and systemic veins, which limits the formation of large portosystemic collaterals [48]. Doppler ultrasonography is currently the most useful radiological tool for assessing liver disease. It provides useful information on blood flow and allows conclusions to be drawn about portal hypertension and thus about the cause of splenomegaly, hepatomegaly, ascites and liver nodules.

Doppler patterns in Fontan patients resemble those observed in chronic liver disease, including reduced portal flow velocity (mean flow velocity < 14 cm/sec) [49]. The Fontan procedure inevitably alters hepatic venous waveforms on Doppler US (Figure 10, Figure 11, Figure 12 and Figure 13). Inverted portal flow has a specificity of 100% for diagnosing PHTN [50] (Figure 12). The hepatopetal phase pattern in the hepatic vein differs between patients with total cavo-pulmonary anastomosis (including both lateral tunnels and extracardiac conduits) and those with atrio-pulmonary connection [51,52,53]. In atrio-pulmonary connection, hepatopetal flow is preserved (Figure 10), reflecting the exclusion of atrial contribution to venous circulation, whereas in total cavo-pulmonary anastomosis, flow reversal (Figure 11) occurs only during early expiration. Similar to congestive heart failure, hepatic veins and the IVC are dilated, with abnormally increased hepatic vein pulsatility, regardless of the anastomosis technique [48,54,55]. The loss of the normal three-phase Doppler pattern in hepatic veins is universal following bi-cavopulmonary surgery due to the absence of atrial contraction. The presence of a monophasic pattern indicates advanced liver injury [56].

In patients with Fontan circulation, the hepatic veins invariably demonstrate a blunted, hepatopetal monophasic flow pattern, consistent with chronic hepatic congestion. However, the flow velocity is lower than in the general population [56,57]. In contrast, in later stages characterized by cirrhosis and increased hepatic stiffness, further dampening or paradoxical changes in the venous flow pattern may be observed.

In particular, the hepatic venous Doppler waveform offers valuable insight into hemodynamic changes over time. In the early post-Fontan period, in the absence of atrial contraction and before structural liver damage is evident, the hepatic venous flow may display a relatively blunted monophasic or biphasic waveform with reduced phasicity, reflecting the lack of pulsatility and elevated central venous pressure.

As FALD progresses, and especially in the setting of developing cirrhosis, the Doppler waveform may become more dampened or even flat, corresponding to the increasing stiffness of the hepatic parenchyma, reduced compliance of the vascular bed, and worsening portal hypertension. Simultaneously, the hepatic veins may appear dilated in the early and mid-stages of disease due to chronic venous congestion but may show reduced caliber in later stages as fibrosis progresses and vascular remodeling occurs.

Tracking these Doppler changes, from waveform morphology to vein diameter, could provide a non-invasive, dynamic marker of FALD evolution. Including representative Doppler images at different timepoints post-Fontan would help clinicians recognize these transitions and potentially stratify risk or guide surveillance intensity.

Interestingly, hepatic vein waveform analysis can also serve as a surrogate marker for cardiac index, providing indirect insight into the hemodynamic status of Fontan circulation. Post-Fontan, IVC and hepatic vein dilation is common, but the main and intrahepatic portal veins tend to be small, likely due to reduced portal perfusion secondary to increased sinusoidal pressure and venous stasis [58]. The lumen width depends on the severity of the liver cirrhosis and, presumably, the duration of the disease. In FALD, the chronic elevation of central venous pressure leads to venous congestion and dilation of the hepatic veins and IVC due to the following reasons: the Fontan circulation results in chronically elevated systemic venous pressure, which is transmitted directly to the hepatic veins via the IVC. Over time, this causes passive venous dilatation, which can persist or even worsen despite progression to fibrosis and cirrhosis. Thus, even in advanced congestive cirrhosis from FALD, the hepatic veins and IVC often remain dilated. This is in contrast to classic cirrhosis from other etiologies, where fibrotic contraction can narrow venous structures.

A controlled study of 106 individuals by Kutty et al. found higher resistance and pulsatility indices in the celiac trunk and mesenteric artery, along with a significant decrease in portal velocity in Fontan patients [57]. These changes can be observed in cirrhosis of any etiology as they reflect hemodynamic consequences of cirrhosis in general. In advanced cirrhosis, increased intrahepatic vascular resistance leads to reduced portal inflow, which causes a compensatory increase in arterial inflow. Over time, changes in downstream compliance and resistance cause elevated RI and PI in splanchnic arteries. In FALD, the portal flow is often lower than in other cirrhosis types, and hepatic artery compensation may be more marked. Tellez et al. [59,60] describe that the portal hypertension model in FALD is characteristically hypodynamic and arterial splanchnic perfusion may also be impaired, as shown in Doppler studies. Indeed, this is what makes FALD a unique entity.

8.1. Ultrasound Differentiation of Liver Nodules

In FALD patients, these are typically multiple, hypervascular, hyperechoic nodules, smaller than 3 cm, and located at the liver’s outer margins. Hypervascular liver nodules are common in Fontan patients, with the vast majority representing benign regenerative nodules or focal nodular hyperplasia (FNH) [59] (Table 6). The exact pathophysiology underlying nodule formation remains unclear, but their peripheral location and radiological characteristics suggest a vascular origin. It has been hypothesized that central venous hypertension, transmitted directly to hepatic perivenular areas, reduces portal blood flow and promotes arterialization [61]. The prevalence of these nodules in adult Fontan patients ranges from 20% to 30% [59]. These nodules, often termed large regenerative nodules or FNH-like nodules, have also been identified in other conditions involving hepatic venous outflow obstruction, such as Budd-Chiari syndrome and right heart failure [59].

FNH-like nodules in FALD tend to be small, multiple, and predominantly located in the right lobe near the liver surface and within 2 cm (Figure 14 and Figure 15) [62]. On B-mode evaluation, FNH-like nodules often appear as small, hyperechoic, and sometimes multiple lesions, mostly located in the right hepatic lobe [61]. In contrast-enhanced ultrasound (CEUS), FNH-like nodules in FALD exhibit enhancement patterns similar to FNH, including hyperenhancement in the arterial phase, centrifugal enhancement, central stellate vasculature, and sustained enhancement without washout [61]. These nodules may demonstrate central hypoenhancement in the portal and late phase, corresponding to a central scar [61]. On CT, arterial phase nodules appear hyperenhancing compared to the surrounding liver parenchyma. In portal and delayed phases, they generally remain iso- or hyperattenuating, but occasional washout may be seen, due to background parenchymal congestion. On MRI T1- and T2-weighted sequences, the nodules are isointense or mildly hypointense on T1 and isointense or mildly hyperintense on T2 [63]. A central scar, hypointense on T1 and hyperintense on T2, may be present [63]. In the hepatobiliary phase, FNH-like nodules retain contrast and appear hyperintense [63]. This helps differentiate them from HCC, which usually appears hypointense in this phase. On DWI (Diffusion-weighted imaging), these nodules do not restrict diffusion, in contrast to HCC, which often shows diffusion restriction [63].

9. Hepatocellular Carcinoma (Hcc) in Fald

HCC can develop in adult patients with FALD [64]. Routine HCC surveillance in FALD has been recommended, but there is no consensus on surveillance frequency, imaging modalities, or the optimal timing after the Fontan procedure [3,59]. The progression from a dysplastic nodule to HCC is a potential stepwise pathway in Fontan-associated cirrhosis. Interval size increase, washout in the portal venous phase, mosaic architecture, and elevated alpha-fetoprotein levels may indicate malignancy [30,48].

HCC typically presents with arterial-phase hyperenhancement followed by mild late washout on dynamic contrast-enhanced imaging [23,65,66,67,68]. Suspicion of HCC increases with large nodule size, interval growth, echogenicity changes, a mass-like appearance, or nodules causing contour abnormalities on the liver surface. FNH-like nodules often show arterial hyperenhancement and no washout on CEUS, mimicking classic FNH. However, some may exhibit delayed washout, raising suspicion for HCC. Therefore, correlation with MRI and clinical context is essential to avoid misdiagnosis and unnecessary interventions [61,69]. Wells et al. argued that washout might not indicate an intrinsic abnormality of the nodule itself but rather reflect the background parenchymal contrast retention due to hepatic congestion and fibrosis [70]. Screening every 4–12 months using radiological techniques is cost-effective and improves survival in cirrhotic patients. Most experts recommend periodic surveillance, though the optimal imaging method and interval remain undetermined [71,72]. HCC treatment should follow standard clinical guidelines used for other cirrhosis etiologies [73].

10. Contrast-Enhanced Ultrasound (Ceus) in Fald

CEUS is valuable for characterizing the contrast enhancement patterns of liver nodules [74,75,76]. In Europe, the US contrast agent SonoVue® (sulfur hexafluoride; Bracco, Milan, Italy) is approved only for intravenous applications in patients over 18 years of age. CEUS use in Fontan patients remains limited due to their frequent collateral circulation with right-to-left shunts, which is considered a contraindication in Europe but not in the United States. Beyond structural liver changes, CEUS reveals markedly heterogeneous hepatic enhancement with mosaic or reticular patterns, mainly due to slow and reduced enhancement near congested hepatic veins—one of the most common imaging features of FALD [48,77]. Anecdotal experience suggests that CEUS demonstrates heterogeneous and decreased liver enhancement in the portal venous phase, similar to cirrhosis of other etiologies (Figure 16, Figure 17 and Figure 18). Abnormal enhancement is more prominent at the liver periphery than centrally, while the hypertrophic caudate lobe often shows more homogeneous enhancement. In patients with FALD, the altered hemodynamics resulting from chronic hepatic venous congestion and low cardiac output can significantly influence CEUS dynamics. Despite these circulatory changes, CEUS in FALD generally preserves the standard temporal enhancement pattern. The hepatic veins, although congested, do not typically show early enhancement, as microbubble distribution primarily reflects arterial input. The systemic hypokinetic circulation characteristic of FALD may lead to delayed arterial arrival times and a prolonged transit of contrast, especially in the background of the liver. Nonetheless, FNH-like nodules frequently exhibit intense and early arterial-phase hyperenhancement, suggesting preserved or increased arterial supply in these lesions. This contrast behavior is essential for lesion characterization.

CEUS plays a crucial role in evaluating hepatic nodules in FALD (Figure 19). In non-cardiac cirrhosis, contrast washout in the late phase is highly indicative of HCC. However, in FALD and other congestive hepatopathies like Budd-Chiari syndrome, FNH-like nodules can also exhibit delayed washout, leading to false positives if the LI-RADS system is strictly applied [78]. Washout in the portal venous phase, in contrast, is uncommon in FNH-like nodules and more specific for HCC [69]. Despite limitations, ancillary LI-RADS criteria and portal venous phase washout remain useful for identifying potentially malignant lesions [79,80].

Therefore, CEUS in FALD must be interpreted with awareness of the altered vascular physiology, and ideally integrated with MR findings and clinical context for accurate diagnosis and longitudinal monitoring.

11. Liver & Spleen Stiffness

Different elastography techniques have been investigated for liver stiffness measurement (LSM) in Fontan patients, including point shear-wave elastography (also known as point radiation force impulse), two-dimensional shear-wave elastography imaging, transient elastography (TE) (Fibroscan®), and MR elastography (MRE) [81,82,83,84,85,86,87]. However, their application in Fontan patients remains challenging because systemic venous congestion can lead to an overestimation of LSM (Table 7). Fontan surgery results in an immediate increase in liver stiffness (LS) due solely to hepatic congestion [88] (Figure 20). Over time, signs of Fontan failure typically emerge, leading to further increases in LS values, which may exceed 15 kPa levels indicative of advanced disease stages in non-congestive liver diseases. In these cases, fibrosis progression may play a role [25,71]. Real-time tissue elastography (RTE) has been shown to reflect liver fibrosis in FALD from the early stages. When combined with hepatic vein waveform analysis, RTE has proven to be a valuable non-invasive tool for evaluating clinical conditions in FALD patients [31].

US elastography, particularly shear-wave techniques, is increasingly being used for serial follow-up in these patients [89,90,91,92,93,94,95,96,97,98,99,100]. Longitudinal LSM assessment during follow-up could help monitor disease progression and predict clinical outcomes. However, elastography results must be interpreted with caution in the Fontan population, as no validated cut-off values for severe liver fibrosis exist for this specific group, unlike in other forms of chronic liver disease [89,90,91,92,93,94,95,96,97,98,99,100,101].

A few small studies have been published correlating spleen stiffness measurement (SSM) with liver fibrosis, but no firm conclusions can be drawn [100,104,105,106]. One prospective study reported that SSM was higher in children with Fontan circulation than in healthy controls [107].On the other hand, a retrospective study found SWE-SSM to be comparable to that of healthy controls [106]. Thus, more studies are needed to evaluate the role of spleen stiffness measurement in staging FALD.

12. Liver Ultrasound-Guided Biopsy

Liver biopsy is the gold standard diagnostic procedure and is still necessary to determine the extent of liver damage [42,108,109]. Typical histological features of FALD include sinusoidal dilation, centrilobular hemorrhagic necrosis, perisinusoidal fibrosis, ductular reaction, perivenular fibrous septa, central fibrous bridges, and nodular regenerative hyperplasia. Sinusoidal dilation is present in 90-97% of Fontan patients and is the earliest parenchymal change. Typically, it is more pronounced than in other causes of cardiogenic hepatopathy. The distribution of fibrosis in the early stages is typically perisinusoidal (in the space of Disse), which is not the case in other forms of cardiac-derived liver disease. Extensive bridges of centrilobular fibrosis associated with regenerative nodules are a late finding in patients with advanced liver disease. Periportal inflammation is usually minimal or absent, which helps differentiate FALD from other liver disease etiologies [110]. Some authors recommend a liver biopsy for all patients 10 years after Fontan surgery [71]. In a cohort of 67 patients, this strategy revealed that all patients developed hepatic fibrosis, and its extent increased over time. However, the authors found no correlation between the degree of fibrosis and clinically relevant events, hemodynamic, or analytical parameters [111], thereby questioning its utility in clinical practice. Liver biopsy is currently recommended when the etiology of liver disease is unclear or in candidates for heart and/or liver transplantation [57,112,113].

13. Ultrasound Follow-Up

In 2019, a statement from the American Heart Association acknowledged that there is insufficient evidence to develop clear recommendations, but that cardiac and end-organ surveillance in children and adults is warranted and clinically important [114] (Table 8). Monitoring should be performed by multidisciplinary Fontan/single-ventricle care clinics with healthcare personnel familiar with and experienced in managing Fontan circulation and complications. Cardiovascular imaging assessments are already common at many institutions and should be performed at regular intervals across all age groups. Cardiac MR, including anatomical and functional investigations, should be performed every 2–3 years, and CT angiography should be done when clinically indicated [115].Cardiac catheterization is recommended once every 10 years or when clinically indicated [116].End-organ status assessment is a newer concept, with imaging and frequency tailored to patient age: every 3–4 years for children under 12 years, and every 1–3 years for adolescents aged 12–18 years [116]. Findings at any test may alter the follow-up interval or trigger additional investigations. The general imaging strategy should be as follows [116]:

• Lymphatic and endocrine system: MR lymphography with T2-weighted MR imaging. Bone-age estimation and bone mineral density assessment are also recommended.

• Brain and neurocognitive function: Neurodevelopmental/cognitive testing and brain MRI can provide important information.

• Lungs: Chest radiography is recommended.

• Liver: Abdominal/liver ultrasound is recommended, including elastography if possible. MR, including liver biopsy, might be considered. Annual ultrasound imaging with elastography has been proposed, with more frequent controls if radiologic signs of fibrosis or nodules are found [116].

Some centers advocate annual liver MRI from adolescence onwards, later combined with ultrasound elastography when routine biopsy is proposed [116]. The risk of HCC in FALD should not be underestimated. Estimates of the cumulative incidence of HCC within 20 years after the Fontan procedure range from 0.6% to 4.9% and may be increasing over time [62,117,118]. HCC in this population also carries a poor prognosis, with less than 50% survival at 1 year, which is comparable to HCC secondary to other causes [119]. There is broad agreement on the need for liver imaging follow-up to detect possible malignancy. HCC is very unlikely within the first 10 years after Fontan-type surgery, with an exponential increase in risk over time [23]. However, according to LI-RADS criteria, imaging alone cannot accurately distinguish between malignant and benign nodules in the context of congestive hepatopathy, and biopsy is required for a definitive diagnosis [5]. Predictive factors for new-onset HCC include higher body mass index, worse NYHA functional class, poorer results on serological biomarkers of liver fibrosis (FIB-4 and APRI score), early Fontan circulatory failure, MELD score >19, and high levels of serum AFP [117]. Active HCC surveillance might be initiated at least 10 years after completion of the Fontan procedure and should be strongly considered earlier in the case of Fontan circulatory failure, even in the absence of cirrhosis. A practical approach could involve combining serial ultrasound (every 6 months) by experienced personnel with contrast-enhanced imaging at baseline (10 years after surgery) and periodically during follow-up to identify the full spectrum of liver nodules [120,121]. MR is generally preferred over CT, as hepatobiliary contrast agents offer advantages in diagnostic accuracy, and it is non-irradiating. However, a significant drawback is that MRI is contraindicated in many Fontan patients with older cardiac devices [121]. Although robust evidence is lacking, performing an MR at least every 1–2 years could be a practical and reasonable approach [122].

Serum AFP is a valuable complementary biomarker for diagnosing HCC in FALD, as it is elevated above the standard upper limit in 74–80% of patients diagnosed with HCC [122]. In a large prospective series with a high prevalence of non-neoplastic nodules (48%), no patient with Fontan-type surgery without HCC showed elevated AFP (defined as >7 ng/dl) [39]. Results from a large cohort of stable Fontan patients found that the likelihood of HCC was 26 times higher in patients with AFP levels > 10 ng/dl [36]. Interestingly, patients who did not develop HCC had a substantially lower AFP value (median: 2.9 ng/dl), supporting its role in predicting new-onset HCC in this population [36]. Consequently, elevated AFP levels in patients with FALD should always raise suspicion of HCC.

A 2023 EASL-ERN position paper emphasized the need for follow-up to be conducted within specialized multidisciplinary Fontan clinics [3] (figle 8). These teams should include hepatologists, cardiologists, and radiologists familiar with the unique pathophysiology of Fontan circulation and its complications. Cardiac MR is recommended every 2 to 3 years to evaluate ventricular function, flow dynamics, and Fontan pathway anatomy [3]. In patients with contraindications to MRI or when detailed hemodynamic data are required, cardiac catheterization is considered appropriate [3]. Annual liver ultrasound combined with elastography is advised as the first-line imaging modality [3]. At 10 years post-Fontan, a baseline liver MRI with hepatobiliary contrast is recommended to characterize hepatic architecture and detect potential nodules [3]. This should be repeated every 1 to 2 years, particularly in high-risk patients or when sonographic abnormalities are detected. In the event of suspicious lesions or inconclusive findings, contrast-enhanced CT or additional MR is warranted [3]. Given the limitations of standard LI-RADS criteria in the context of congestive hepatopathy, histological confirmation via liver biopsy is often necessary to distinguish benign nodules from HCC [3].

Serial AFP measurement should be incorporated into routine follow-up. An AFP value above 10 ng/mL has been identified as a strong predictor of HCC, and should prompt more aggressive diagnostic work-up, including advanced imaging or biopsy [3]. The timing of active HCC surveillance is typically initiated at least 10 years after Fontan completion, though earlier monitoring may be warranted in patients exhibiting Fontan circulatory failure or elevated non-invasive fibrosis scores such as FIB-4, APRI, or MELD >19 [3]. Surveillance intervals should remain flexible, with the frequency of imaging and biomarker assessment tailored to the patient's evolving risk profile and clinical findings.

14. Conclusion

Although the Fontan procedure has extended patients' lifespan, there remains a significant risk of morbidity and mortality. Patients undergoing the Fontan procedure at birth require lifelong follow-up with medical care, which has a considerable financial and societal impact. However, much remains unknown about how Fontan palliation affects patients differently. End-organ effects are increasingly recognized, with particular attention to cardiac, lymphatic, and liver changes, which require monitoring through radiological techniques to ensure optimal timing for treatment and, eventually, cardiac transplantation or combined liver-heart transplantation. FALD is an emerging liver disease that poses a significant clinical challenge. A FALD surveillance program should be recommended to detect liver disease progression at an early stage, allowing for interventions that optimize Fontan circulation and prevent advanced liver fibrosis. The lack of funding for research is a clear obstacle to expanding knowledge of FALD. Therefore, multi-institutional collaborative registries and prospective studies are essential.