But what is Fontan Physiology and how does it impact the Liver?
The Fontan operation is the third step in a series of surgeries to palliate single ventricle congenital heart disease (such as tricuspid atresia, mitral atresia, hypoplastic left heart syndrome). The first and second steps are the Norwood and bidirectional Glenn operations respectively, which serve to make a superior cavopulmonary connection. The Fontan operation then creates a surgical shunt to divert blood from the IVC and SVC to the pulmonary arteries (see Figure below). This operation is typically performed in children aged 2-5 years. In the US currently > 900 Fontan operations are performed each year, with 97% early survival rate!
Figure 1 – Diagram of Fontan circulation
How is the liver affected during this process?
Fontan associated liver disease (FALD) is multifactorial- stemming from issues preoperatively, intraoperatively, and postoperatively. Prior to Fontan correction, single ventricle physiology may cause hepatic insults from hypotensive crises and relative ischemia. The series of stages cardiac surgeries can lead to additional ischemic insults to the liver. After completion of the surgeries, Fontan physiology leads to chronically elevated central venous pressure, decreased pulsatility in the hepatic veins, and frequently decreased cardiac output, and passive hepatic venous congestion. As a result of decreased cardiac output and hypoxemia, there is decreased oxygen delivery to centrilobular hepatocytes (zone 3). Hepatic venous congestion leads to reactive fibrogenesis – centrilobular hepatocyte atrophy, sinusoidal fibrosis, bridging fibrosis and ultimately cardiac cirrhosis.
Figure 2 – Mechanisms of liver injury in FALD,
Liver fibrosis on biopsy is nearly universal in Fontan patients at 10 years or more postoperatively.5 The remaining challenge is determining how to screen for liver disease in these patients, as it is often clinically silent. FALD also increases the chances of developing liver lesions, from focal nodular hyperplasia, adenomas, to even hepatocellular carcinoma, which can unfortunately be seen in pediatric patients.
Back to the case
How would you screen this young man for FALD?
FALD screening may vary based on institution. A recent review published by a working group of experts provides an excellent summary of the literature with suggestions for management. We’ll summarize modalities of screening below:
— Biochemical studies – Transaminases, bilirubin, and alkaline phosphatase are often normal in patients with FALD, and do not correlate with degree of fibrosis. The most common lab abnormality is GGT elevation in approximately 40-60% of patients with FALD; however, this does not correlate with fibrosis.INR has been correlated with degree of fibrosis in FALD in a single-center series. Since INR is likely to be elevated in Fontan patients from anticoagulation therapy, the MELD-XI (MELD without INR) has been used to risk stratify patients on anticoagulation and has been shown to correlate with degree of FALD.
–Imaging – The American Heart Association and American College of Cardiology FALD stakeholders group suggest screening with ultrasound doppler of liver and spleen should be performed every 1-3 years at minimum. However, ultrasound is not a particularly sensitive screening tool for fibrosis. A majority of patients in a ultrasound screening study were found to have heterogenous echotexture or nodularity of the liver surface which correlated with time since Fontan. There has been growing interest in the use of US elastography and MR elastography as screening tools for FALD. A challenge with elastography in FALD is the difficulty in distinguishing fibrosis from passive congestion. The authors of this FALD imaging review describe how imaging screening can be utilized for monitoring fibrosis and focal lesions in FALD, acknowledging that this may vary at different institutions. For example, at Cincinnati Children’s, Fontan patients undergo contrast enhanced MRI and MR elastography every other year starting at 13 years of age or at initial presentation. An algorithm for the follow up of detected focal lesions is shown below (Figure 3).
–Biopsy – Liver biopsy remains the gold standard for detection of fibrosis and for characterization of focal liver lesions in FALD. Bleeding after liver biopsy is a particular concern in this population due to anticoagulative therapy, and elevated CVP. Transjugular liver biopsy during cardiac catheterization allows for simultaneous cardiac assessment during one procedure, and may be a safer option with limited postprocedural complications. Of note, progression of FALD has not been shown to correlate with cardiac status, and the only factor that has been significantly and reliably associated with fibrosis is time from Fontan. The METAVIR scoring system for fibrosis may underestimate reflect the degree of injury in FALD due to the focus on portal fibrosis, whereas the venous outflow obstruction in FALD presents as centrilobular and sinusoidal fibrosis.The Congestive Hepatic Fibrosis Score (CHFS) takes into account centrilobular and sinusoidal fibrosis, and may be a better overall scoring system for FALD.
Figure 3 -Algorithm for monitoring detecting focal lesions in FALD
Recommendations for Transplantation: Heart Alone vs Heart-Liver
In patients who have a failing Fontan, we are faced with the question of heart transplant alone vs a combined heart and liver transplant (CHLT). This is obviously a complicated topic that we will only touch on briefly in this post. There is some evidence to suggest that FALD may stabilize after heart transplant alone; however, the risk of HCC remains. Data from Stanford, UCLA, Mayo Clinic, and the University of Pennsylvania support decreased rates of acute cellular rejection following as compared to episodes of acute cellular rejection in patients who received isolated heart transplants. The degree of immune allosensitization in Fontan patients may also make the immune benefits of CHLT appealing. CHLT may also be considered in patients who have developed HCC from FALD but may not have failing Fontan physiology.
Figure 4 -Considerations for CHLT vs Heart Transplant Alone