Anatomy of Fontan Circulation
Patients born with complex congenital heart defects that are not amenable to a two-ventricle repair are offered Fontan palliation. Multiple variations in the configuration of the Fontan pathway exist based on era of surgery and individual patient anatomy. In general, in this form of circulation, blood is pumped from the single ventricular heart to the body and venous drainage flows directly to the lungs.¹ There is no pumping chamber immediately prior to the pulmonary circulation. The systemic venous pressure is the driving pressure through the lungs. Even under ideal Fontan circumstances, it is higher than normal and can affect other organs, particularly the liver. In addition, since the entire circulation is supported by one ventricle, the overall cardiac output is lower, which also affects organ function.

Anatomy and Physiology of the Liver
The liver is divided into two lobes (left and right) and 8 anatomic segments. It receives blood from the hepatic artery and portal vein.¹ The portal vein contributes 70-80% of the blood supply but only 50% of the oxygen. Blood drains from the liver into the hepatic veins, which empty into the inferior vena cava. Similar to most filter systems, the liver needs adequate flow entering it, low resistance through it, and a low pressure system to drain into to function optimally. In Fontan associated liver disease (FALD), all three aspects are altered.

Etiology of Liver Disease
There are many causes of liver disease in patients with and without Fontan circulation. In the general population, liver disease is often caused by alcoholic liver disease (18.3% of adult liver transplant waitlist registrants) and non-alcoholic steatohepatitis (15.8%).² These factors can also affect patients with Fontan circulation, although not necessarily more common in this population, and should be addressed appropriately. Infections, such as hepatitis C, may be more common in Fontan patients from multiple blood transfusions prior to adequate screening programs.¹ Hepatitis C is the leading etiology of chronic liver disease among adult liver transplant waitlist registrants, comprising 35.2% of the general population and another 9.7% when there is co-morbid alcoholic liver disease.² Medications, such as amiodarone, are also often used in patients with Fontan circulation and can contribute to liver disease.³ Finally, there are factors that are specific to patients with Fontan circulation, including an acute increase in central venous pressure following Fontan completion. The venous pressure, and subsequently liver stiffness, rise post-operatively.⁴ In addition, the chronic systemic venous elevations are not pulsatile.¹ There is some evidence that pulsatile elevations, like those seen with tricuspid regurgitation, are better tolerated. Patients with Fontan circulation also have impaired lymphatic drainage. The lymphatic system can act as a pressure pop-off when functioning normally.

Epidemiology of Fontan Associated Liver Disease
The Fontan operation was first performed in 1968, with improved techniques and survival in subsequent decades. Although we have learned a lot about the sequelae of Fontan circulation, there is still a lot to be learned, and outcomes will continue to evolve. Most studies have found a steady increase in the prevalence of liver disease as time since Fontan surgery increases, regardless of liver disease assessment.⁵ Small studies have shown progressive hepatic enlargement and congestion.⁶ In a recent study, the majority of patients had advanced liver disease 21 years post Fontan.⁷ However, large, prospective longitudinal studies are lacking.

Methods of Assessing Liver Disease
There are multiple methods of assessing liver disease in patients with and without Fontan circulation. Gross imaging, with ultrasound, CT scan, or MRI, will document liver size and contour and identify specific masses or lesions. It should be noted many suspicious lesions can be mistaken for hepatocellular carcinoma by standard imaging criteria.⁸ Elastography is a measure of stiffness and can be done with either ultrasound or MRI. Although small studies have shown correlation with fibrosis on biopsy as well as progression of liver disease,^{9, 10} elastography may overestimate fibrosis due to congestion.¹¹ Lab values, including a calculated MELD-XI score, assess liver function and ongoing damage. Liver biopsy evaluates for microscopic abnormalities including fibrosis and evaluates suspicious lesions for malignancy. A transhepatic gradient is an invasive test that measures the resistance within the liver. There are limitations with available screening tools. Recent literature suggests that our current serum biomarkers and imaging modalities are unable to accurately assess liver fibrosis in this population.⁷

Initial Evaluation
There is no consensus on timing or type of liver evaluation in patients with Fontan circulation. The goal of screening is to assess the following: liver function, effects of liver dysfunction/cirrhosis, and presence of hepatocellular carcinoma. It should likely start in childhood and increase in frequency as patients get older. Initial evaluation can include lab work (GGT, bilirubin, alkaline phosphatase, albumin, total protein, INR, CBC with platelets), calculation of MELD-XI score (uses creatinine and bilirubin), and liver imaging (ultrasound, CT, or MRI). Elastography, hepatitis C antibodies, and hepatitis A and B IgG titers can also be considered. Other possible labs include alpha-fetoprotein, hyaluronic acid, alpha 2 macroglobulin, and type IV collagen.^{5, 12} Liver biopsy can be considered and is often done at the time of diagnostic cardiac catheterization performed for other indications.

Management of FALD
Like many diseases, prevention is preferred to treating the disease. Preventing liver injury begins prior to the Fontan surgery. Prenatal diagnosis of complex congenital heart disease can prevent patients from presenting in extremis and help avoid initial liver insult.¹³ Hepatitis vaccines are also recommended.¹ Post-Fontan, it is important to avoid hepatotoxins as much as possible, including alcohol, obesity/steatosis and amiodarone. Optimizing the Fontan circulation is crucial to preventing acute injuries, as well slowing progression of FALD. Anatomically, baffle stenosis and arch obstruction should be treated aggressively. Physiologically, improving systolic function and forward flow, and decreasing pulmonary vascular resistance, which is the "afterload" of the liver, should improve liver function. High quality data are lacking on outcomes of specific interventions on progression of liver disease.

Heart/Liver Transplant
Little is known about combined heart and liver transplant in patients with FALD. Although very few centers offer it, initial outcomes have been promising.¹⁴ Indications for combined organ transplant include synthetic liver dysfunction, clinical cirrhosis, and hepatocellular carcinoma. Fibrosis is common among patients with failing Fontan circulation, but does not independently require combined heart and liver transplant.¹⁵ Coordination with a knowledgeable hepatologist is crucial.

Future Directions
We are in an exciting time for understanding the long-term complications and co-morbidities among patients with Fontan circulation. Our realization of the importance of liver function in these patients has led to the development of interdisciplinary collaborations to improve the diagnosis, prevention, and treatment strategies for patients with FALD.

References

1. Daniels CJ, Bradley EA, Landzberg MJ, et al. Fontan-associated liver disease: proceedings from the American College of Cardiology Stakeholders Meeting, October 1 to 2, 2015, Washington DC. J Am Coll Cardiol 2017;70:3173-94.
2. Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015;148:547-55.
3. Schumacher JD, Guo GL. Mechanistic review of drug-induced steatohepatitis. Toxicol Appl Pharmacol 2015;289:40-7.
4. Deorsola L, Aidala E, Cascarano MT, Valori A, Agnoletti G, Pace Napoleone C. Liver stiffness modifications shortly after total cavopulmonary connection. Interact Cardiovasc Thorac Surg 2016;23:513-8.
5. Bradley E, Hendrickson B, Daniels C. Fontan liver disease: review of an emerging epidemic and management options. Curr Treat Options Cardiovasc Med 2015;17:51.
6. Lewis MJ, Hecht E, Ginns J, Benton J, Prince M, Rosenbaum MS. Serial cardiac MRIs in adult Fontan patients detect progressive hepatic enlargement and congestion. Congenit Heart Dis 2017;12:153-8.
7. Munsterman ID, Duijnhouwer AL, Kendall TJ, et al. The clinical spectrum of Fontan-associated liver disease: results from a prospective multimodality screening cohort. Eur Heart J 2018. [Epub ahead of print]
8. Wells ML, Hough DM, Fidler JL, Kamath PS, Poterucha JT, Venkatesh SK. Benign nodules in post-Fontan livers can show imaging features considered diagnostic for hepatocellular carcinoma. Abdom Radiol 2017;42:2623-31.
9. Evans WN, Acherman RJ, Ciccolo ML, et al. A composite noninvasive index correlates with liver fibrosis scores in post-Fontan patients: preliminary findings. Congenit Heart Dis 2018;13:38-45.
10. Egbe A, Miranda WR, Connolly HM, et al. Temporal changes in liver stiffness after Fontan operation: results of serial magnetic resonance elastography. Int J Cardiol 2018;258:299-304.
11. Ackerman T, GEerts A, Van Vlierberghe H, De Backer J, Francois K. Hepatic changes in the Fontan circulation: identification of liver dysfunction and an attempt to streamline follow-up screening. Pediatr Cardiol 2018;39:1604-13.
12. Shimizu M, Miyamoto K, Nishihara Y, et al. Risk factors and serological markers of liver cirrhosis after Fontan procedure. Heart Vessels 2016;31:1514-21.
13. Sivarajan V, Penny DJ, Filan P, Brizard C, Shekerdemian LS. Impact of antenatal diagnosis of hypoplastic left heart syndrome on the clinical presentation and surgical outcomes: the Australian experience. J Paediatr Child Health 2009;45:112-7.
14. D'Souza BA, Fuller S, Gleason LP, et al. Single-center outcomes of combined heart and liver transplantation in the failing Fontan. Clin Transplant 2017;31.
15. Simpson KE, Esmaeeli A, Khanna G, et al. Liver cirrhosis in Fontan patients does not affect 1-year post-heart transplant mortality or markers of liver function. J Heart Lung Transplant 2014;33:170-7.

Clinical Topics: Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and Heart Failure, Congenital Heart Disease, CHD and Pediatrics and Imaging, CHD and Pediatrics and Interventions, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Interventions and Imaging, Interventions and Structural Heart Disease, Computed Tomography, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Nuclear Imaging

Keywords: Heart Defects, Congenital, Hepatitis C Antibodies, Fontan Procedure, Elasticity Imaging Techniques, Alkaline Phosphatase, Collagen Type IV, Creatinine, Hyaluronic Acid, Carcinoma, Hepatocellular, Amiodarone, Hepatic Veins, Pulmonary Circulation, Liver Transplantation, Hepatitis A, Portal Vein, Hepatic Artery, Central Venous Pressure, Vena Cava, Inferior, Tricuspid Valve Insufficiency, Constriction, Pathologic, Blood Platelets, Liver Neoplasms, Liver Cirrhosis, Liver Diseases, Alcoholic, Tomography, X-Ray Computed, Hepatitis C, Cardiac Output, Magnetic Resonance Imaging, Cardiac Catheterization, Vascular Resistance, Prenatal Diagnosis, Lymphatic System, Longitudinal Studies, Albumins, Vaccines, Immunoglobulin G, Oxygen

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