EXPLANATION


Advancements in the management of univentricular heart disease and the success of the Fontan procedure has resulted in improved survival rates and an increasing population of patients with this unique physiology. In 2020, the number of patients who are living with the Fontan circulation in a total of eleven countries including the United States, Australia, New Zealand and Europe, was estimated to be 66 per one million. Despite its success, the Fontan circulation is associated with many chronic complications, including Fontan associated liver disease (FALD), which significantly impacts morbidity and mortality.


Alsaied et al proposed a consensus definition of FALD as, “the broad spectrum of liver disease and its consequences, attributable to Fontan hemodynamics. FALD includes varying degrees of hepatic fibrosis, compensated and decompensated cirrhosis, focal nodular hyperplasia, laboratory evidence of hepatic injury or impaired synthetic function, and hepatocellular neoplastic lesions.” One of the most serious complications of FALD is hepatocellular carcinoma, with an estimated prevalence of 0.18 to 1.3% in patients palliated with the Fontan procedure. Several factors are believed to play a role in the development of FALD including increased hepatic venous pressure, chronic hypoxia, diminished cardiac output, malfunction of liver sinusoidal endothelial cells resulting in decreased nitric oxide production and increased cytokine and complement secretion, increased inflammatory biomarkers, alterations in the flow of lymphatic fluid, and abnormal neurohormonal activation. It has also been speculated that patient factors predisposing to portal fibrosis before the Fontan operation may also contribute to the development of FALD. Currently, there is no consensus on the best surveillance strategy and diagnostic testing for and clinical management of FALD. The diagnosis relies on clinical history and physical examination, serum tests of liver function, various imaging modalities (magnetic resonance imaging (MRI) elastography and contrast imaging, computerized tomography, and liver ultrasound), and histological diagnosis via liver biopsy.


Hepatic fibrosis has almost been universally demonstrated in this patient population, predominantly through surveillance liver biopsies. However, a healthy clinical appearance, normal laboratory studies and acceptable Fontan hemodynamics do not correlate with the absence of fibrotic changes on surveillance liver biopsies. In 2020, a multi-disciplinary group from the American Society of Transplantation proposed an algorithm to guide the screening and management of FALD in patients palliated with the Fontan procedure. The time which has elapsed following the Fontan procedure is an important risk factor for the development of FALD. Therefore, the algorithm recommends that patients with no clinical evidence of chronic liver disease have a surveillance liver biopsy at ten years post-Fontan procedure. This is ideally performed concurrently with a cardiac catheterization to assess Fontan hemodynamics. Further management recommendations are based on liver biopsy results, which are the following: 1) No hepatic fibrosis: MRI elastography, annual liver laboratory studies, annual liver ultrasound, repeat liver biopsy or imaging based on clinical changes; 2) Mild/moderate hepatic fibrosis: hepatology referral, liver laboratory studies every six months, address modifiable risk factors such as obesity and alcohol use; 3) Bridging hepatic fibrosis/cirrhosis: hepatology referral, MRI elastography at least annually, liver laboratory studies every three months, esophagogastroduodenoscopy to evaluate for esophageal varices, consider early referral for combined heart and liver transplantation.


In patients who are more than three years post-Fontan but who have clinical evidence of chronic liver disease, such as ascites, splenomegaly, thrombocytopenia, gastrointestinal bleeding, and jaundice, early referral to hepatology for diagnostic work-up and consideration for combined heart and liver transplantation is recommended. Although liver biopsy is regarded as the gold standard for the diagnosis of FALD, it is an invasive procedure associated with an increased risk of bleeding, particularly in Fontan patients with elevated central venous pressures. In addition, liver biopsy is susceptible to sampling error due to a patchy distribution of liver fibrosis. Treatment of advanced FALD includes lifestyle modifications, optimization of the Fontan circulation (through treatment of elevated pulmonary vascular resistance and/or Fontan pathway obstruction and creation/enlargement of a Fontan fenestration), and management of veno-venous collaterals.


The patient in the stem has good functional status with no clinical evidence of liver disease and no echocardiographic evidence of Fontan pathway obstruction. For this patient, recent recommendations suggest routine surveillance of FALD with liver biopsy at ten years post- Fontan operation, ideally performed at the same time as a cardiac catheterization. Liver biopsy at five years post-Fontan is not recommended in a patient without evidence of chronic liver disease. Liver biopsy at fifteen years post-Fontan is longer than the published recommendations for patients without evidence of liver disease.


REFERENCES


Emamaullee J, Zaidi AN, Schiano T, et al. Fontan-Associated Liver Disease: Screening, Management, and Transplant Considerations. Circulation. 2020;142(6):591-604.


de Lange C, Möller T, Hebelka H. Fontan-associated liver disease: Diagnosis, surveillance, and management. Front Pediatr. 2023;11:1100514. Published 2023 Mar 3. doi:10.3389/fped.2023.1100514


Alsaied T, Rathod RH, Aboulhosn JA, et al. Reaching consensus for unified medical language in Fontan care. ESC Heart Fail. 2021;8(5):3894-3905. doi:10.1002/ehf2.13294