Fontan‐associated liver disease
Authors: Moira B. Hilscher, Michael L. Wells, Sudhakar K. Venkatesh, Frank Cetta, Patrick S. Kamath
Journal: Hepatology (2022)

Hilscher MB, Wells ML, Venkatesh SK, Cetta F, Kamath PS. Fontan‐associated liver disease. Hepatology. 2022;75:1300–1321. https://doi.org/10.1002/hep.32406HilscherMB, WellsML, VenkateshSK, CettaF, KamathPS. Fontan‐associated liver disease. Hepatology. 2022;75:1300–1321. https://doi.org/10.1002/hep.32406 INTRODUCTION Fontan‐associated liver disease (FALD) is a form of congestive hepatopathy that is universal among patients who have undergone Fontan palliation for functional single ventricle congenital heart disease (CHD).[1–6] In the United States, more than 900 Fontan operations are performed in children annually.[7] Advances in surgical techniques have led to improvements in postoperative mortality rates, and survival of patients with Fontan physiology into adulthood is the rule rather the exception.[8,9] As a result, the population of adult patients with Fontan physiology is expected to grow over the coming years. In 2018, estimates of the global population of patients with Fontan physiology ranged from 50,000 to 70,000, and studies suggest that this number may double over the next decade.[10] This population growth will have significant implications for health care utilization, particularly in the setting of organ transplantation and existing shortages in organ supply. Liver fibrosis following the Fontan procedure was first recognized in a patient in 1981.[2] Sinusoidal fibrosis is now thought to be universal within a few years of the Fontan surgery.[11] Several studies have since corroborated a spectrum of liver pathology in patients after Fontan ranging from hepatic fibrosis to cardiac cirrhosis and portal hypertension (PHTN).[12–15] HCC is an additional feared manifestation of FALD that may portend a poor prognosis.[16,17] The accurate diagnosis and optimal management of FALD, including criteria to implement screening for HCC, remain areas of controversy, highlighting the need for prospective, multicenter studies and more in‐depth investigations of the pathophysiology of FALD. BACKGROUND Functional single ventricle physiology and the Fontan operation In 1971, Francis Fontan reported the first successful total right heart bypass that separated the pulmonary and systemic circulations and relieved ventricular volume overload in patients with tricuspid valve atresia.[18] Since then, many technical modifications of the Fontan operation have been used for patients with a variety of forms of functional single ventricle.[19] The terms "single ventricle," "common ventricle," or "univentricular heart" are used in a sporadic and nonexact fashion in the literature, but all share one anatomic feature[20]: the atrioventricular connection(s) is/are completely or predominantly committed to a single systemic ventricular chamber. As a result, there is nearly complete mixing of the systemic and pulmonary venous returns such that oxygen saturation in the aorta and the pulmonary artery (PA) are typically equal. The proportion of ventricular output to either the pulmonary or systemic vascular bed is determined by the resistance to flow in each circuit. The best descriptive term for these patients, who comprise less than 10% of all patients with CHD, is "functional single ventricle physiology." The Fontan operation is definitive palliation for patients with functional single ventricle physiology. In the current era, most Fontan operations are performed between 2 and 4 years of age. In the 1950s, a connection between the superior vena cava (SVC) and the right PA was investigated simultaneously in Hungary, Russia, and the United States.[21] It was later ascribed to William Glenn's name. This anastomosis was eventually modified to permit flow toward both PAs and is currently referred to as a "bidirectional cavopulmonary connection" or "bidirectional Glenn operation." The Glenn procedure became a standard interim staging procedure for many patients with functional single ventricle physiology after the 1980s and is now usually performed between 3 and 8 months of age. The anastomosis between the SVC and PA is in an end‐to‐side fashion enabling flow toward both lungs. Bypass of the right side of the heart is completed when flow from the IVC is directed to the PAs through a tunnel that may be intracardiac or extracardiac (Figure 1). Over the years, these tubes have been constructed of a variety of materials. Unfortunately, progressive narrowing has been the natural history of many of these conduits. This causes elevation of pressure in the IVC, impeding egress of blood flow from the liver. This is likely a major contributor to FALD.FIGURE 1: Diagram demonstrating an extracardiac Fontan connection constructed with a Goretex tube. The superior vena cava to pulmonary artery anastomosis is also demonstrated. In this manner, a total right heart bypass is accomplished. RA (right atrium), SVC (superior vena cava), IVC (inferior vena cava), RPA (right pulmonary artery)Because there is no pump to drive blood flow into the lungs, one would question how the fluid dynamics of a patient with Fontan physiology work. Penny and Redington demonstrated that the act of spontaneous breathing, which generates negative intrathoracic pressure, is vital to propel blood flow into the lungs in patients with Fontan physiology.[22] The act of spontaneous breathing draws blood into the chest and through the Fontan circuit. Equally vital is low downstream pressure. Obstruction to flow at the pulmonary vein or atrioventricular valve levels is poorly tolerated in patients with Fontan physiology. It is also important to ensure that the Fontan conduit is patent to keep IVC pressures low.[23,24] In addition, the diastolic pressure in the systemic ventricle needs to be as low as possible because ventricular noncompliance will cause a backup of pressure throughout the Fontan circuit. In the current era, operative mortality for the Fontan operation is relatively low (<3%). However, these patients face many challenges during their lifetimes. Estimated 10, 20, and 30‐ year survival based on a cohort of patients originally operated in the 1970s and 1980s was only 74%, 61%, and 43%, respectively. However, for those operated after 2001, 10‐year survival was 95%.[25] Most patients after Fontan have problems with arrhythmias as they enter their second and third decades. The overall outlook for most patients after Fontan operation should be "guarded optimism," as there are patients after Fontan taking no cardiac medications who have near normal functional capacity. Some are even termed "super‐Fontans."[26] Fontan failure "Fontan failure" (FF) describes dysfunction of the Fontan circulation, which may lead to both cardiac and noncardiac complications.[27] Failure of the Fontan circulation is associated with impaired quality of life and a high incidence of mortality.[28,29] FF is a heterogenous condition and warrants investigation of the liver, including physical examination, laboratory evaluation, and imaging of the liver. PATHOPHYSIOLOGY OF LIVER DYSFUNCTION IN PATIENTS WITH FONTAN PHYSIOLOGY Fontan physiology is characterized by chronic, sustained elevation in central venous pressure (CVP), which is largely due to lack of a subpulmonic ventricle and an obligatory passive pulmonary circulation. The absence of a subpulmonic ventricle additionally limits preload to the systemic ventricle, stroke volume, and, thereby, cardiac output.[28] Cardiac output may be further compromised during periods of high demand, such as exercise.[30] This sustained chronic central venous hypertension predisposes to a variety of physiologic disturbances and multiorgan dysfunction. The vascular anatomy of the liver renders it particularly susceptible to the altered hemodynamics of Fontan physiology. The Fontan surgery creates a total cavopulmonary anastomosis, which induces nonpulsatile flow and increased pressure in the IVC. This nonpulsatile pressure transmits directly from the IVC to the hepatic veins (HVs) and hepatic sinusoids. Portal venous inflow is regulated by mesenteric venous inflow and the pressure gradient between the portal vein and HVs. In the Fontan circulation, elevated pressure within the HVs and sinusoids minimizes this gradient and therefore compromises portal venous inflow.[31] Furthermore, portal inflow from the splanchnic circulation may be reduced in the setting of depressed cardiac output.[1,11] The liver in the Fontan physiology is therefore more reliant on hepatic arterial inflow and is susceptible to changes in the arterial circulation as a result. Relative hypoxia and mild low arterial blood oxygenation impair oxygen delivery to zone 3 hepatocytes, which exacerbates the fibrogenic response.[32] In contrast to the pulsatile back‐pressure associated with passive venous congestion of the liver due to other cardiac defects, the passive venous congestion associated with Fontan physiology is continuous and nonpulsatile. Such sustained alterations in hemodynamics and the mechanical milieu are central to the pathophysiology of FALD. Pathologic changes in shear stress and cyclic stretch imposed by congestion instigate mechanosensitive cell signaling pathways in HSCs and LSECs, which contribute to the fibrogenic response.[33,34] HSCs subjected to pathologic mechanical forces secrete fibronectin, which instigates assembly of provisional extracellular matrix, a critical step in early fibrogenesis.[33] Cyclic stretch additionally enhances the engagement of fibronectin with fibrin to facilitate fibrogenesis. LSECs are early sentinels of disturbances in the hepatic circulation, and studies suggest that their response to aberrant mechanical forces is critical in the pathophysiology of PHTN in the setting of FALD. Pathologic levels of cyclic stretch induce transcriptional upregulation and secretion of cytokines by LSECs, including the neutrophil chemotactic chemokine (C‐X‐C motif) ligand (CXCL) 1.[34] CXCL1 induces sinusoidal recruitment of neutrophils, which aggregate with platelets within liver sinusoids to generate neutrophil extracellular traps (NETs). NETs instigate formation of sinusoidal microvascular thromboses, which increase portal pressure through pressure and volume effects within liver sinusoids. Microvascular thromboses additionally contribute to congestion‐related fibrosis.[33] In addition to the liver, fibrosis has been observed in other organs after the Fontan procedure, including the kidneys and myocardium, leading to the hypothesis that the Fontan circulation creates a systemic profibrogenic state.[32] A recent study revealed that liver stiffness quantified by magnetic resonance elastography (MRE) correlates with myocardial fibrosis, diastolic dysfunction, and circulating levels of fibrosis biomarkers, including matrix metalloproteinases and tissue inhibitors of metalloproteinases.[35] The authors suggest from these data that the Fontan physiology induces a profibrotic milieu, which exacerbates end‐organ dysfunction. Although complement and cytokine activation have been well‐described early after the Fontan operation, clinically stable patients with Fontan physiology additionally have elevated serum cytokines and biomarkers of inflammation, including TNF‐α, growth‐derived factor‐15 (GDF‐15), β2‐macroglobulin, and IL‐6.[36] Such subclinical, chronic inflammation could conceivably enhance a profibrotic milieu and contribute to progressive multiorgan fibrosis. GDF‐15 in particular has been correlated with fibrosis in patients with heart failure.[37] Imbalances in neurohormonal activation may also contribute to FALD. Circulating levels of renin,[36] angiotensin, and aldosterone[38] are increased in patients with Fontan physiology.[32,36] Angiotensin II promotes secretion of collagen I by activated HSCs,[39–42] and angiotensin blockade demonstrates antifibrotic effects in experimental models of chronic liver disease.[43–47] However, to date, the impact of angiotensin‐converting enzyme inhibition on fibrosis burden in patients after Fontan has not been studied.[32] The role of the microbiome in the pathophysiology of congestive hepatopathy in addition to other liver diseases is an active area of interest.[48] Hemodynamic changes imposed by heart failure alter intestinal perfusion and predispose to intestinal ischemia, enhance intestinal permeability, and augment bacterial translocation events and systemic inflammation. Higher concentrations of adherent bacteria have been observed in the intestinal mucosal biofilm of patients with heart failure compared with healthy controls,[49] and several studies confirm elevated circulating levels of proinflammatory cytokines in patients with heart failure, including TNF‐α, IL‐6, and C‐reactive protein.[50–55] Although formal analysis of the microbiome in patients after Fontan has not yet been completed, this remains an area of interest in the pathophysiology of FALD. FALD may be accelerated by coincident liver diseases, such as nonalcoholic fatty liver disease, alcohol‐associated liver disease, and other autoimmune and metabolic liver diseases. All patients with FALD should be counseled regarding mitigation of modifiable risk factors to prevent progression of liver disease, including minimization of alcohol, avoidance of hepatotoxic medications, and maintenance of normal weight.[56] Weight control is of particular importance given recent evidence linking adult weight gain with development of FF.[57] The cohort of patients with CHD who underwent surgical repair before the implementation of routine hepatitis C screening in 1992 additionally have a 5‐fold increased prevalence of hepatitis C infection compared with the age‐matched general population.[58–60] FACTORS ASSOCIATED WITH FALD The optimal criteria to diagnose FALD remains a clinical challenge, which also hampers our ability to accurately determine its prevalence among patients with Fontan physiology. The reported prevalence of FALD accordingly varies with the diagnostic criteria applied. A study of 60 adult survivors of the Fontan procedure reported an incidence of cirrhosis of 55%.[6] In this study, cirrhosis was diagnosed based on suggestive imaging or biopsy findings, and the median interval between the Fontan surgery and the diagnosis of cirrhosis was 18.4 years. A single‐center retrospective study conducted at a tertiary care center used a combination of radiologic, laboratory, and clinical characteristics to diagnose cirrhosis and reported 10, 20, and 30‐year freedom from cirrhosis of 99%, 94%, and 57%, respectively.[61] However, liver fibrosis is believed to be widely prevalent in patients with Fontan physiology, with a recent biopsy series reporting the universal prevalence of hepatic fibrosis 10 years after the Fontan procedure.[11] Several studies have attempted to identify factors predictive of liver fibrosis in patients after Fontan. Duration of the Fontan circulation has consistently been associated with incidence of fibrosis and cirrhosis.[11,12,61–64] However, liver fibrosis may predate creation of the Fontan circulation in patients with functional single ventricle physiology.[65] Both portal and sinusoidal fibrosis have been detected in patients who died shortly after the Fontan procedure, suggesting that hepatic damage existed at the time of Fontan creation due to pre‐Fontan insults.[2,66] The severity of fibrosis in these studies was attributed in part to pre‐Fontan elevations in right atrial pressure. Sinusoidal fibrosis correlated with older age at the time of Fontan surgery, suggesting that prolonged duration of single ventricle physiology instigates fibrogenesis.[2] As a result, initiation of noninvasive screening for hepatic complications before the Fontan procedure has been proposed.[67] The hemodynamics and mechanical features of the Fontan circulation also impact the progression of fibrosis. Elevated right heart pressure has been associated with cirrhosis in patients after Fontan.[12,62] A retrospective study of hemodynamic assessments found significant elevations in PA pressure, end‐diastolic ventricular pressure, and wedge pressure among patients with Fontan physiology who had evidence of cirrhosis on noninvasive imaging.[63] CLINICAL MANIFESTATIONS OF FALD FALD is often clinically indolent, thereby highlighting the need for accurate screening guidelines and diagnostic modalities. The clinical and laboratory manifestations of FALD vary according to the stage of disease and presence of passive hepatic congestion versus low cardiac output, although both congestion and low cardiac output may exist in patients with Fontan physiology.[67] Hepatic congestion may lead to ascites, hepatomegaly, and jaundice in the absence of advanced fibrosis. Hepato‐jugular reflux may be detected on physical examination in patients with hepatic congestion. However, its presence is variable in patients after Fontan due to their unique anatomy and presence of caval‐pulmonary anastomoses. Common laboratory manifestations of hepatic congestion include predominantly indirect hyperbilirubinemia and prolongation of the prothrombin time out of proportion to other coagulation indices.[68] Decreased serum albumin is noted in 30%–50% of patients with chronic heart failure.[69] Mild aminotransferase elevation occurs in approximately one‐third of patients with hepatic congestion and may be accompanied by moderate elevations in alkaline phosphatase and gamma‐glutamyl transpeptidase (GGT).[70] On the other hand, chronic ischemia in the setting of reduced cardiac output may induce a cholestatic pattern of liver test abnormalities, with bilirubin levels as high as 10–15 mg/dl or more, and elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase to three to five times the upper limit of normal. It is important to note that hyperbilirubinemia may also herald the onset of late‐stage liver disease.[31] As liver test abnormalities may only occur in advanced FALD, other strategies, such as early noninvasive imaging, are important in the diagnosis of FALD. Clinical signs and symptoms of cirrhosis may be observed in late, advanced FALD. Similar to other etiologies of liver disease, patients with compensated cirrhosis may be asymptomatic or may present with nonspecific symptoms such as anorexia, fatigue, or weight loss. Ascites, hepatic encephalopathy, jaundice, or variceal bleeding herald decompensated disease, although it is important to recognize that ascites may be of cardiac etiology and may occur in the absence of cirrhosis in patients after Fontan. Manifestations of PHTN including ascites, variceal bleeding, and hepatic encephalopathy are important to note given their association with adverse outcomes in the population after Fontan.[71] If ascites develops, measurement of the serum albumin ascites gradient, ascites total protein, and serum brain natriuretic peptide (BNP) may help to differentiate ascites or cardiac or hepatic origin.[72] A serum BNP >364 pg/ml has a sensitivity of 98% and specificity of 99% in the diagnosis of cardiac ascites, whereas a serum BNP <182 pg/ml has been proposed as a cutoff to exclude the possibility of a cardiac etiology.[73] However, in patients after Fontan who have both cardiac and hepatic dysfunction, these levels of plasma BNP may be unreliable in differentiating ascites of hepatic origin from ascites of cardiac origin. The incidence of varices in patients who have undergone the Fontan procedure ranges from 9.3% to 38%,[62,74,75] although variceal bleeding is uncommon. A prospective study identified esophageal varices in 27% (6/26) of patients with Fontan physiology who had radiologic evidence of cirrhosis or a liver stiffness of >13 kPa on transient elastography.[76] Because mortality associated with an episode of variceal bleeding in patients with cirrhosis and without underlying cardiac disease is as high as 15%–20%,[77] endoscopy is recommended in patients with cirrhosis or evidence of PHTN but may require appropriate anesthesia support. Although varices may be incidentally noted on cross‐sectional imaging, upper gastrointestinal endoscopy is the only modality recommended for screening. HCC is an uncommon but feared complication of the Fontan procedure with an estimated prevalence of 0.18%–1.3% among patients with Fontan physiology.[78,79] Two recent retrospective multicenter studies report the incidence, presentation, treatment modalities, and outcomes of HCC among patients with Fontan physiology.[16,78] In these studies, the mean age at the time of HCC diagnosis was 30 years, and the youngest patient diagnosed was 12 years of age. The median duration from Fontan operation to HCC diagnosis was approximately 22 years. Approximately half of the patients with HCC were symptomatic at the time of diagnosis, and presenting symptoms included jaundice, abdominal pain, dyspnea, ascites, hematemesis, and fever. Both studies reported a cumulative survival of approximately 50% at 12 months. Survival was poorer for patients who had symptoms at the time of diagnosis, a tumor size of >4 cm, or metastatic disease. Interestingly, case series report that cirrhosis is present in only 50% of patients with Fontan physiology with HCC,[16,78] suggesting that cirrhosis is not prerequisite for the development of HCC in the setting of Fontan physiology. This highlights the need for further studies to stratify risk and to implement standardized surveillance for patients after Fontan to diagnose HCC in its early stages. DIAGNOSIS OF FALD The optimal strategy to diagnose and stage FALD remain a clinical challenge. Liver biopsy is the gold standard to diagnose and stage most adult liver pathologies. However, biopsy has several limitations in the setting of FALD,[80] including sampling error, risk of bleeding and infection, and need for procedural sedation. Furthermore, due to its invasive nature, liver biopsy is not suitable for longitudinal monitoring of liver disease. Transjugular liver biopsies are challenging given the Fontan venous anatomy. As a result, noninvasive diagnostic and staging methods are attractive in this patient population but also have limitations. For example, the congested liver can have a grossly nodular appearance suggestive of cirrhosis on imaging even in the absence of advanced fibrosis, and the presence of hepatic congestion can confound noninvasive assessments of liver fibrosis such as elastography. Furthermore, serum markers of liver function do not correlate with the stage of liver fibrosis.[11] The diagnosis of cirrhosis in patients with FALD should therefore incorporate a combination of supportive clinical, laboratory, and imaging parameters.[67] Laboratory‐based screening methods and scores Laboratory scoring systems have not yet been validated in the Fontan population but can supplement radiologic studies and clinical assessment in the diagnosis of cirrhosis. Among these is the AST‐to‐platelet ratio index (APRI), which was originally created to stage fibrosis among patients with chronic hepatitis C infection.[81] The Fibrosis‐4 (FIB‐4) model incorporates age, AST elevation, ALT elevation, and platelet count and has demonstrated predictive accuracy in patients with chronic hepatitis C and nonalcoholic fatty liver disease.[82] Both the APRI and the FIB‐4 scores are readily obtained from routine laboratory studies and thus constitute cost‐ and time‐effective means to assess for advanced fibrosis. Noninvasive hepatic fibrosis markers were compared in a cross‐sectional study of 204 patients who had undergone the Fontan procedure, 25.9% of whom had hepatic complications as defined by evidence of cirrhosis on CT scan, liver nodules, thrombocytopenia, or hyperbilirubinemia.[64] The authors compared the Forns index, APRI score, AST/ALT ratio, cirrhosis discriminant score, and Pohl score (see Table 1). Of these scores, the Forns index, which incorporates platelet count, GGT, age, and cholesterol, performed best with an area under the receiver operating characteristic curve (AUROC) of 0.786. TABLE 1 - Noninvasive scoring systems that can be used to estimate fibrosis stage APRI score AST, platelet count FIB‐4 score Platelet count, AST, ALT, age Forns index Age, GGT, cholesterol, platelet count AST/ALT ratio AST, ALT Cirrhosis discriminant score Age, platelet count, ALT, AST, upper limit of normal of AST, INR Pohl score AST, ALT, platelet count MELD score Creatinine, bilirubin, INR, sodium MELD‐XI score Bilirubin, creatinine The Model for End‐Stage Liver Disease (MELD) Excluding INR (MELD‐XI) score was devised to predict short‐term survival in patients with cirrhosis on anticoagulation and appears to correlate with severity of liver disease.[83] Given the frequent need for anticoagulation among patients with Fontan physiology, there has been much interest in the use of MELD‐XI as a screening or stratification tool in the setting of FALD. Retrospective studies suggest that the MELD‐XI score correlates with systolic ventricular dysfunction, decreased oxygen saturation,[84] and hepatic fibrosis scores on pathology among patients after Fontan (correlation coefficient = 0.4; p = 0.003).[85] The MELD‐XI score may additionally have a role in predicting transplant outcomes among patients with Fontan physiology and in determining need for isolated heart transplantation (IHT) versus simultaneous heart and liver transplantation (SHLT).[7,86] A recent retrospective study analyzed 596 patients with Fontan physiology who underwent IHT through a review of the Pediatric Heart Transplant database.[87] Multivariate analysis revealed increased posttransplant mortality for every unit increase in the MELD‐XI score. The authors of this study then divided this patient population into two cohorts: those with a high MELD‐XI score (defined as a MELD‐XI score of 11.5 or higher) and those with a low MELD‐XI score (MELD‐XI score of 11.5 or lower). Patients in the high MELD‐XI cohort had inferior postheart transplant survival at 1 (84.4% vs. 88.7%) and 5 years (71.7% vs. 80.9%) (p = 0.02).[87] Although specific cutoffs to screen for FALD or stratify risk of transplantation remain to be defined in this patient population, these studies suggest that a high MELD‐XI score may suggest suboptimal functioning of the Fontan circulation and increased risk of liver disease and poorer outcomes after IHT. Imaging in FALD The Fontan circulation causes several radiologic changes in the liver due to passive venous congestion resulting from elevated CVP and hepatic ischemia from low cardiac output. Elevated CVP causes hepatomegaly, dilation of the IVC, and dilation of the HVs (Figure 2), which are easily observed on ultrasound (US), CT, and MRI.[88,89] These findings are most commonly seen immediately following Fontan surgery. Veno‐venous shunts between HVs may be seen in severe congestion. In advanced fibrosis and cirrhosis, the liver becomes less compliant and dilated HVs within the liver may not be observed. When cirrhosis develops, atrophy of the right lobe of the liver and a nodular outline may be seen.FIGURE 2: A 26‐year‐old female with a history of tricuspid atresia and hypoplastic right ventricle who underwent Fontan surgery at age three presented with upper abdominal discomfort. Contrast enhanced MRI images in coronal plane (A) and axial planes (B,C) demonstrating hepatomegaly (liver span of 17 cm), dilated inferior vena cava (white arrow) and hepatic veins (arrow heads) and veno‐venous collaterals (black arrows). All features are consistent with congestive hepatopathy. Liver biopsy showed congestive changes with mild perisinusoidal fibrosisChronic congestion leads to dilated hepatic sinusoids, perivenous hemorrhage, and accompanying perisinusoidal fibrosis manifest as heterogeneous liver parenchymal texture on imaging. Heterogeneous parenchymal echogenicity may be seen on US. However, this is not specific for congestion because increased echogenicity can also be seen in hepatic steatosis and fibrosis that may be present in patients after Fontan. Careful interpretation of increased liver echogenicity is therefore required in patients after Fontan. On noncontrast‐enhanced CT, reticular regions of low attenuation correspond to areas of edema and/or fibrosis (Figure 3). On MRI, patchy regions of hyperintensity on T2 weighted images and diffusion weighted imaging may be seen in the periphery and most often in the right lobe (Figure 4). Heterogeneous enhancement of the liver parenchyma is most prominent during portal venous phase.[89] The heterogeneous enhancement is due to slow portal venous circulation secondary to increased hepatic venous pressure and may equilibrate in the equilibrium or delayed phase. The heterogeneous texture and enhancement, however, is not uniform throughout the liver but patchy. This correlates with the patchy distribution of congestive changes. Two patterns of parenchymal heterogeneous enhancement that are associated with severity of congestion have been described: (a) reticular pattern‐diffuse patchy or mosaic enhancement of the entire liver parenchyma with predominant changes in the peripheral liver, and (b) zonal pattern‐heterogeneous enhancement in the periphery with sparing of the central or perihilar zone[62] (Figure 3). The reticular pattern is seen with severe congestion and correlates with time from Fontan procedure (Figures 3–5). Patchy late arterial phase parenchymal enhancement occurs typically in the periphery and severely congested regions and represents increased arterial blood flow (arterial buffer) in these regions. Imaging with hepatobiliary contrast agents such as gadoxetate demonstrate the heterogeneous uptake of contrast and peripheral reticular areas of poor uptake (Figures 4 and 6).FIGURE 3: Heterogeneous texture of liver parenchyma in different patients after the Fontan procedure. (A) Ultrasound showing heterogeneous echogenicity of the liver. (B) Contrast‐enhanced CT in portal ve