Abdominal imaging findings in adult patients with Fontan circulation

The liver may appear normal or slightly hypoechoic on ultrasound (US) at the early stage of congestive hepatopathy. As the fibrosis develops, coarse heterogeneous hyperechoic parenchymal pattern and surface nodularity are visualised [30] (Fig. 1a). The liver is often enlarged with caudate lobe hypertrophy similar to Budd-Chiari syndrome. Correlations have been reported between the severity of US features and the degree of hepatic fibrosis or cirrhosis [20, 36, 37]. Irregular parenchymal fatty infiltration with perivascular distribution can be seen in US and in magnetic resonance imaging (MRI) with in-phase and out-of-phase sequences (Fig. 1b-d) [22, 38]. On MRI, heterogeneous hyperintensity on T2-weighted images and hypointensity on T1-weighted images in the periphery of the liver, which is commonly seen in acute or subacute Budd-Chiari syndrome, is not seen in FALD [39‐41], probably due to chronic gradual congestive changes of the liver over a long period. Diffusion-weighted imaging (DWI) can help estimating the degree of hepatic fibrosis. Wolff et al. [21] reported that low apparent diffusion coefficient values in DWI may reflect progressive liver damage due to chronic congestion and potential hypoperfusion in post-Fontan patients.

In addition to the morphological changes of the liver, markedly heterogeneous hepatic enhancement with mosaic or reticular patterns, resulting from relatively slow and poor enhancement near the congested hepatic veins, is the most common imaging feature in FALD [19, 38]. Contrast-enhanced ultrasound (CEUS) in our anecdotal experience shows heterogeneous and decreased enhancement of the liver in the portal venous phase similar to cirrhotic liver of other common aetiologies (Fig. 1e). The abnormal enhancement is more prominent in the periphery of the liver than the central portion and is most evident in the portal venous phase (Fig. 2a-d). The hypertrophic caudate lobe often shows more homogeneous enhancement compared to the rest of the liver [13] (Fig. 2b). Hepatobiliary phase MRI using a hepatocyte-specific contrast agent (gadoxetate disodium; Primovist; Bayer, Berlin, Germany) often shows heterogeneous hypoenhancement in the hepatobiliary phase, which reflects decreased hepatic function [42] (Fig. 2e). Hepatic fibrosis may be seen as reticular hyperenhancement in the delayed phase of CT or MRI. It has been reported that the degree of hepatic dysfunction is not well correlated with the degree of fibrosis in post-Fontan patients [18, 43]. Therefore, follow-up with clinical and laboratory tests is also essential.

Large regenerative hepatic nodules are commonly seen in adult patients with FALD. The pathophysiology of the development of the nodules is not fully elucidated, although it has been hypothesised that central venous hypertension transmitted directly to the hepatic peri-venular areas diminishes portal blood flow and promotes arterialisation [44‐46]. The prevalence of the nodules in adult patients with Fontan circulation ranges from 20 to 30% [11, 44, 46]. The nodules have been named both large regenerative nodules and focal nodular hyperplasia (FNH)-like nodules in the literature and can be found in patients with other causes of hepatic venous outflow obstruction such as Budd-Chiari syndrome or right heart failure [38, 47‐49]. The nomenclature of “FNH-like nodule” comes from imaging features [38, 46, 50] of hyper-enhancement in the arterial phase and iso-enhancement in the delayed phase (Fig. 3a-c) and from histopathological features [44] of small islands of hepatic parenchyma separated by bands of arterialised vascular fibrous septa with a pseudo-capsule, similar to FNH.

Unfortunately, HCC can develop in adult patients with FALD [25, 26, 32, 46, 51] (Fig. 4) although the incidence of HCC is much lower than that of FNH-like nodules. Routine surveillance in FALD for HCC has been suggested, but there has been no consensus regarding the frequency of surveillance, the type of imaging modalities and the time interval after Fontan procedure. Progression from a dysplastic nodule to HCC is a potential stepwise pathway in liver cirrhosis imposed by Fontan circulation. However, malignant potential of FNH-like nodules is uncertain and has been controversial [18, 24, 44, 46]. Alleged benign large regenerative nodules in the chronic congested liver often mimic HCC radiologically and may render a correct diagnosis difficult [38]. Interval increase in size, washout in the portal venous phase, mosaic architecture, and elevated alpha-fetoprotein may be associated with HCC [22, 38].

FNH-like nodules in FALD are often small and multiple, and show a predilection for the right lobe in the periphery (mostly within 2 cm of the liver surface) [20]. On CEUS, FNH-like nodules in FALD show enhancement features similar to FNH; hyper-enhancement in the arterial phase, centrifugal enhancement, central stellate vasculature and sustained enhancement without washout (Supplementary material 1). MRI using liver-specific contrast agent is useful for characterising FNH-like nodules by demonstrating iso- or hyper-enhancement in the hepatobiliary phase. The FNH-like nodules may show central hypointensity in the hepatobiliary phase representing a central scar (Fig. 3c).

HCC typically shows [25, 32, 51‐57] arterial-phase hyper-enhancement followed by late and mild washout on dynamic contrast-enhanced imaging. CEUS is potentially useful for indeterminate hepatic nodules in FALD on CT or MRI, especially for the patients who are contraindicated for contrast-enhanced CT or MRI. Suspicion of HCC is raised upon large size, interval change in size or echogenicity, mass-like appearance or nodules causing contour abnormality on the liver surface (Fig. 4a). However, it is important to note that the FNH-like nodules can infrequently demonstrate washout in the delayed phase, mimicking HCC [58, 59] (Supplementary material 1). The reported incidence of delayed-phase washout in FNH-like nodules is approximately 10%, in the setting of cardiac cirrhosis secondary to constrictive pericarditis and alcoholic cirrhosis. The pathophysiology for washout of FNH-like nodules is not clear. Wells et al. [22] speculated that the washout may not be related to an abnormality of the nodule itself, but a reflection of the background parenchymal contrast retention due to parenchymal congestion and fibrosis.

MRI using liver-specific contrast agent may be useful for the differentiation between FNH-like nodules and HCC, as HCC mostly show hypointensity in the hepatobiliary phase. DWI may be also useful in differentiating between HCC and FNH-like nodules. In our experience of a single case of HCC in FALD, HCC showed strong restricted diffusion, whereas FNH-like nodules did not show diffusion restriction, compatible with the study by Wells et al. [22] (Figs. 3d and 4d). The authors suggested other ancillary findings favouring benign FNH-like nodules, including hypointensity on T2-weighted images.

On Doppler US, normal hepatic vein shows a triphasic waveform, consisting of a hepatopetal (coming towards the liver) phase occurring during atrial systole and two hepatofugal phases related to atrial and ventricular diastole. Loss of the hepatopetal phase is typically considered to represent increased stiffness of the liver such as in hepatic fibrosis, steatohepatitis and cirrhosis [60‐62].

Fontan operation inevitably alters hepatic venous waveform on Doppler US. The pattern of hepatopetal phase in hepatic vein differs between patients with total cavopulmonary anastomosis (including both lateral tunnels and extracardiac conduits) and with atriopulmonary connection [63‐66] (Fig. 5a–e). Hepatopetal phase is preserved in atriopulmonary connection, which reflects the exclusion of atrial contribution to the venous circulation, whereas flow reversal is only visualised during early expiration in total cavopulmonary anastomosis. Also, similar to congestive heart failure, hepatic veins and IVC are dilated with abnormally increased pulsatility of the hepatic vein regardless of the anastomosis technique [38, 61, 67].

Portal venous waveform on Doppler US normally shows slightly phasic hepatopetal flow with mildly decreased flow during inspiration due to transient compression of the compliant liver parenchyma and easily collapsible portal venules and hepatic sinusoids [61, 68]. In patients with Fontan circulation, the portal veins invariably show hepatopetal flow with variable phasicity, but the flow velocity is lower than in the normal population [69, 70]. While the dilatation of the IVC and hepatic veins is frequently seen in post-Fontan patients, the diameter of the main portal vein and intrahepatic portal veins is usually small, possibly due to reduction of portal perfusion secondary to increased sinusoidal pressure with venous stasis [39] (Fig. 5). Bland portal vein thrombosis seems to be rare in post-Fontan patients with no reported cases compared to Budd-Chiari syndrome, where portal vein thrombosis occurs up to 18% [71, 72]. Hepatofugal flow of the portal vein, which can be found in severe portal hypertension or Budd-Chiari syndrome with large extrahepatic portosystemic collaterals, has not been reported in post-Fontan patients [63, 66, 70, 73‐75] . It can be explained by relatively high systemic venous pressure in Fontan circulation, preventing the development of large extrahepatic portosystemic collaterals.

On the arterial-phase CT with contrast injection through the upper extremity veins, dense opacification in the dependent portion of the IVC and hepatic veins is occasionally seen in post-Fontan patients. This is likely due to passive retrograde flow of the contrast material which is heavier than blood in the absence of effective right heart function (Supplementary material 2). This phenomenon might be different from the opacification of IVC and all hepatic veins in patients with right heart failure [38, 76, 77], which is the result of reflux of contrast media into the inferior vena cava during right atrial contraction or tricuspid regurgitation.

Extrahepatic complications of portal hypertension secondary to liver cirrhosis such as splenomegaly and ascites are commonly seen in adult Fontan patients. Compared to liver cirrhosis secondary to hepatitis, extrahepatic portosystemic shunts are uncommon or small in size in FALD, even in a decompensated state, likely due to the high systemic venous pressure in Fontan circulation and relatively low pressure gradient between the portal and systemic veins to promote the formation of large portosystemic collaterals [38] (Supplementary material 3).

Protein losing enteropathy (PLE) is characterised by enteric loss of proteins including albumin, immunoglobulins and clotting factors. Patients with PLE present with peripheral oedema, ascites, diarrhoea, weight loss and malabsorption. The reported incidence of PLE in Fontan patients ranges from 3 to 18%, with a reported mortality of 50% within 5 years after initial diagnosis [78‐80]. Elevated systemic venous pressure and mesenteric vasoconstriction, which is the natural reaction to decreased cardiac output, might be the cause of PLE. Additionally, lymphatic dilatation, stasis and leakage, and inflammatory reaction secondary to elevated systemic venous pressure, further contribute to the development of PLE [19, 80, 81].

Early clinical diagnosis of PLE is often difficult because the patients may have a long asymptomatic period [80‐82]. As multiple intensive therapeutic approaches enable an improved survival rate of up to 88% at 5 years [83], early recognition of excessive enteric loss of protein is important. Suggestive imaging findings including ascites, diffuse bowel wall thickening, and severe mesenteric oedema along the root of the mesentery on CT or MRI, should prompt a clinical evaluation to rule out PLE [13].

Pheochromocytoma and paraganglioma are neuroendocrine tumours arising from neural crest-derived cells or organs in the adrenal gland and along the central sympathetic and parasympathetic chains, respectively. There have been several anecdotal reports of the development of pheochromocytoma or paraganglioma in patients with congenital cyanotic heart disease after corrective or palliative cardiac surgery, including the Fontan procedure [84‐90]. Suggested pathophysiology is a stimulation of catecholamine overproduction and chronic endocrine hyperactivity resulting from the hypoxic state of congenital heart disease [91]. The tumours may cause palpitations, progressive arrhythmia, fatigue and malaise. Pheochromocytoma or paraganglioma are typically seen as heterogeneously and avidly hyper-enhancing masses with areas of necrosis and cystic component [92, 93] (Fig. 6).