The prolonged survival of children with previously fatal diseases is affecting adult medicine. There are an estimated 650,000 to 1.3 million adults with congenital heart disease, and this number is expected to increase 5% annually. The delivery of health care to children transitioning to young adulthood with some of the severest forms of congenital heart disease clearly merits careful consideration.
Originally used for tricuspid atresia, the Fontan operation is a surgical treatment for single-ventricle physiology. It is the most common congenital heart disease procedure performed after 2 years of age. As many as 1200 Fontan procedures are performed annually in the United States with a 20-year survival rate of 70% to 85%.
The procedure establishes independent pulmonary and systemic circulations in patients with a single functional ventricle (Fig. 1). Postoperatively, systemic venous blood returns directly to the pulmonary arteries and bypasses the atrioventricular pumps. Improved oxygen saturation results, but this causes chronic elevation of the central venous pressure, absent pulsatile pulmonary flow, and decreased cardiac output. The consequences of long-term central venous and systemic arterial hemodynamic impairment are key mediators in organ dysfunction in Fontan patients.[4-7]
Characteristics and Evaluation of Fontan Hepatopathy
The exact evolution of Fontan hepatopathy is unclear, but it becomes more pronounced with time after the Fontan surgery. Early liver dysfunction is frequently underrecognized because abnormalities in routine serum biochemical testing are relatively mild. Hepatomegaly may be interpreted as consistent with the cardiac condition. Clinically recognizable features of liver disease are late findings. Patients, families, and health care providers are frequently ill-prepared for the discovery of severe liver dysfunction. Screening for Fontan-associated liver disease is evolving, is multimodal, and is nonuniform across centers.
Because of the unreliability of clinical examinations and routine serum biochemistry in identifying liver disease in Fontan patients, alternative strategies have been explored. Virtually all current methods reported for screening Fontan hepatopathy suffer methodological deficiencies that limit widespread recommendation: selection bias and small sample sizes; limited power for correlating findings between hemodynamic, histological, and functional parameters; and/or retrospective analyses with heterogeneous patient populations, multiple underlying congenital heart lesions, and variant Fontan operations.
Liver Biopsy in Fontan Patients
The traditional assessment tool for liver disease and fibrosis is percutaneous liver biopsy. Passive congestion of the liver results in centrilobular hepatocellular injury, sinusoidal dilatation, and the late evolution of centrilobular to centrilobular fibrosis. In Fontan livers, fibrosis is predominantly sinusoidal, but portal fibrosis has also been described.[4-6, 8-10] Whether the portal fibrosis reflects pre-Fontan liver injury or is a result of chronic venous outflow obstruction is debated.[6, 9, 10] There is a paucity of portal or lobular inflammation, and this suggests that hemodynamic factors influence disease progression. Elevated systemic venous pressures, decreased heart rate and the interval in years since the Fontan procedure correlate with progression of liver fibrosis. The safety of percutaneous liver biopsy in this population is not known. Additionally, liver pathology is not uniformly distributed in the livers of Fontan patients and is subject to sampling error.[9-12] Screening with liver biopsy and its timing are problematic (Figs. 2 and 3).
Noninvasive Markers of Liver Function and Fibrosis in Fontan Patients
Noninvasive indicators of the hepatic status have been investigated. Narkewicz et al. studied 11 children after the Fontan procedure and correlated indices of cardiac and hepatic function, including the galactose elimination capacity. They found a trend in the impairment of coagulation parameters and significant decreases in the galactose elimination capacity related to the length of time after the Fontan procedure. Additionally, serum markers of fibrosis correlated with fibrosis assessed by dual phase computed tomograpy or transient elastography. In a study of 16 patients, Ginde et al. identified 75% as having abnormal serum markers, with 44% predictive of F2 stage fibrosis, and one patient with cirrhosis. Friedrich-Rust et al. reported that 28 of 39 children had significant fibrosis according to serum markers. A positive correlation between serum markers and the age of the patient at the time of the Fontan procedure (but not the number of years after Fontan surgery) was found in that study. The use of transient elastography in Friedrich-Rust et al.'s study suggested that an even higher proportion of advanced disease (41%) was correlated with the patient age at evaluation and the time since surgery. Because venous congestion adds to liver stiffness, the amount of fibrosis is overestimated with this technique.
Liver Imaging in Fontan Patients
A paradigm for liver disease progression in Fontan patients involves increased central venous pressure, which results in liver congestion and dilation of sinusoids, atrophy of hepatocytes, and progressive fibrosis. In this scenario, the liver becomes increasingly dependent on the hepatic artery blood supply, and this leads to abnormal regional blood flow and regenerative nodules. Using both dual-phase computed tomography and magnetic resonance imaging, several studies support this view of the evolution of liver dysfunction in Fontan patients.[4, 5, 11, 12, 14, 16, 17] Virtually all patients show abnormal parenchymal perfusion reminiscent of Budd-Chiari syndrome imaging, and this suggests a common pathophysiology of postsinusoidal portal hypertension. Imaging series consistently report that approximately 30% of older children and young adults who have undergone the Fontan operation have hypervascular lesions with radiological characteristics of nodular regenerative hyperplasia, as would be expected in a portal vein flow–impaired, arterially dependent liver (Fig. 4). Importantly, hepatocellular carcinoma has been reported in post-Fontan patients. Vascular lesions could indicate more advanced disease or identify higher risk patients who warrant closer monitoring.
Potential Heart-Liver and Liver-Heart Interactions in Fontan Patients
Imaging has demonstrated portal hypertension in post-Fontan patients, but there are no systematic reports of portal pressures in Fontan patients.[4, 11, 18] Wedged hepatic vein pressure gradient measurements may not be an accurate reflection of portal pressures in this group of patients. Direct portal vein pressure measurement has been reported in one case report. Bleeding from gastroesophageal varices can complicate the care of Fontan patients and may not be amenable to beta-blockade or transjugular shunts.[4, 18]
Just as the liver is affected by the abnormal Fontan circulation, portal hypertension may affect the progression of cardiopulmonary dysfunction. Some Fontan patients develop progressive hypoxia. Large-vessel, pulmonary-to-systemic venous communications, putatively formed as decompressive phenomena from elevated pulmonary vascular pressures, or, alternatively, diffuse peripheral pulmonary capillary vasodilation may develop. Are these findings type 2 hepatopulmonary syndrome and type 1 hepatopulmonary syndrome, respectively? Additionally, a failing Fontan circulation decreases the cardiac response to stress, decreases chronotropic responses, and elevates diastolic ventricular pressures. Some patients who have undergone the Fontan operation suffer from increased pulmonary vascular resistance.[6, 7] Are these findings influenced by evolving cirrhotic cardiomyopathy or portopulmonary hypertension?
Fontan Procedure and Transplantation
Adults with congenital heart disease account for 3% of heart recipients and 40% of heart-lung recipients worldwide, many of whom have undergone the Fontan procedure.[20, 21] Underappreciated or poorly identified liver dysfunction may add significantly to the morbidity and mortality associated with these interventions.[22, 23] The involvement of liver disease specialists in the assessment of Fontan patients earlier in their clinical course and during heart transplant evaluations for these patients may improve patient and operation selection and posttransplant outcomes.
Although firm recommendations regarding liver disease screening cannot be made, clearly Fontan recipients are at risk for the development of significant liver disease. One empirically based approach uses clinical and laboratory assessment and magnetic resonance imaging–based screening.[4, 6, 12, 17] Because of the lower sedation requirement, initial magnetic resonance imaging screening can be performed after 8 years of age and at least 5 to 7 years after the Fontan procedure. Yearly alpha-fetoprotein measurements beginning 5 to 7 years after the Fontan procedure are reasonable because of the frequency of hypervascular nodules in older patients. Serial imaging and alpha-fetoprotein measurements are warranted for patients who are identified with hypervascular nodules.
A spectrum of liver dysfunction likely occurs over the course of a patient's life after the Fontan procedure, and this evolves through the dynamic interaction of the portal and cardiopulmonary vasculatures in this anatomically challenged setting. Centers need to develop multidisciplinary clinical protocols for the lifelong management of Fontan patients. The task at hand for pediatric and adult liver specialists is to accurately delineate the natural history and develop appropriate diagnostic and staging algorithms for hepatic disease. A careful study of hemodynamic changes and hepatic responses involved in the Fontan liver could lead to the development of interventional strategies that decrease morbidity and mortality in long-term survivors. “Kicking the can down the road,” or delaying acknowledgment of the issue until adulthood, does not help patients and likely leads to missed opportunities for learning and developing potential interventions. The establishment of a prospective, multicenter research network with multispecialty representation focusing on this growing population will help to answer these vexing issues.
I would like to thank Eric Jablonowski for his Fontan illustration, and all of my colleagues who help care for these children and young adults: Carlos Abramowsky, Adina Alazraki, Kiery Braithwaite, Wendy Book, Nitika Gupta, Saul Karpen, William Mahle, Michael McConnell, and Bahig Shehata.