Fontan-associated Liver Disease

Fontan associated liver disease is a spectrum of hepatic injury, from sinusoidal congestion and fibrosis to cirrhosis, portal hypertension and hepatocellular carcinoma, caused by chronic venous hypertension and low cardiac output in a patient with a Fontan circulation.

Some degree of hepatic fibrosis is present in nearly all patients by 10 to 20 years after the operation. Cirrhosis is reported in roughly 10 to 40% by 20 to 30 years, and hepatocellular carcinoma in about 1 to 5% in long term series.

Risk rises with time since Fontan, higher central venous pressure, lower cardiac output, older atriopulmonary connections, and associated factors such as protein losing enteropathy. It is usually silent until late, and liver tests are poor markers of severity.

Other contributors are hypoxia, thromboembolic injury to small hepatic veins, hepatotoxic drugs (amiodarone, bosentan), previous transfusion related viral hepatitis, alcohol and metabolic fatty liver disease.

Pathophysiology.

Raised hepatic venous pressure transmits to the sinusoids, causing sinusoidal dilatation, hepatocyte atrophy, perisinusoidal fibrosis and regenerative nodules, mostly around the central veins at first.

Reduced hepatic arterial and portal flow adds ischaemic injury. Fibrosis progresses to bridging fibrosis and cirrhosis, with portal hypertension from both the congestive and the structural components.

Regenerative nodules are often hypervascular and are hard to distinguish from hepatocellular carcinoma. Carcinoma can arise in cirrhotic and non-cirrhotic Fontan livers.

Portal hypertension produces splenomegaly, thrombocytopenia, varices, ascites and encephalopathy. Reduced liver synthetic function appears late.

Most patients have no liver symptoms. Later features are fatigue, abdominal distension, ascites, splenomegaly, spider naevi, jaundice, easy bruising, haematemesis from varices and confusion. Hepatocellular carcinoma may present with weight loss, abdominal pain, or incidental imaging findings. Signs of Fontan failure usually coexist.

• Blood tests: GGT and ALP (often raised first), ALT and AST (usually near normal or mildly raised), bilirubin, albumin, INR, platelet count (under 150 x 10^9/L suggests portal hypertension), creatinine, AFP, ferritin, viral hepatitis B and C serology, autoimmune markers, and metabolic screen. Compute the Child-Pugh class and MELD-XI score (which excludes INR-dependent bias from anticoagulation).
• Ultrasound with Doppler: nodular surface, heterogeneous echotexture, splenomegaly, portal vein flow, ascites, hepatic vein flow.
• Elastography: stiffness is raised by congestion alone, so values overestimate fibrosis. Use it to follow trends, not to stage.
• Multiphasic MRI or CT: reticular enhancement, nodularity, hypervascular nodules (many benign), and washout nodules that need specialist review for carcinoma.
• Liver biopsy (transjugular route preferred, with hepatic venous pressure measurement) when staging changes transplant decisions. Sampling error is common.
• Upper endoscopy when platelets are under 150 x 10^9/L or imaging shows portal hypertension.
• Catheterisation data: Fontan pressure and cardiac index, which set the cause and the surgical options.

Differential diagnosis.

• Viral, autoimmune, alcohol related, metabolic and drug induced liver disease.
• Hepatic venous outflow obstruction (Budd-Chiari), portal vein thrombosis and constrictive pericarditis.
• Iron overload, Wilson disease and haemochromatosis.
• Hepatocellular carcinoma versus regenerative nodule, and cholangiocarcinoma.

There is no drug that reverses Fontan associated liver disease. Treatment is to improve Fontan haemodynamics, prevent and treat complications, and plan transplantation.

Optimise the circulation. Treat obstruction, collaterals, arrhythmia and ventricular dysfunction by catheter intervention, rhythm control, diuretics and, when appropriate, pulmonary vasodilators. A fenestration or surgical conversion may lower venous pressure in selected patients.

Protect the liver.

• Avoid alcohol. Limit paracetamol to 2 g daily. Avoid NSAIDs and unnecessary hepatotoxic drugs. Monitor liver tests monthly on bosentan and every 6 months on amiodarone.
• Vaccinate against hepatitis A and hepatitis B if not immune.
• Treat obesity and diabetes, and maintain nutrition with adequate protein.

Hepatocellular carcinoma surveillance. Ultrasound with AFP every 6 months, and multiphasic MRI or CT every 12 months, from 10 years after Fontan completion (earlier with cirrhosis or nodularity). AFP is insensitive. A new or washout nodule needs a specialist hepatobiliary and transplant review.

• Treatment of carcinoma in Child-Pugh A disease: resection or ablation for small tumours, transarterial chemoembolisation for multifocal disease, and systemic therapy: atezolizumab 1200 mg with bevacizumab 15 mg/kg intravenously every 3 weeks (screen and treat varices first; avoid with uncontrolled bleeding risk or untreated varices), or lenvatinib 8 mg daily (under 60 kg) or 12 mg daily (60 kg or over), or sorafenib 400 mg twice daily. Check blood pressure, proteinuria, thyroid function and liver tests with each cycle.
• Transplantation is considered for early stage disease within accepted criteria, and requires combined heart and liver assessment.

Varices and portal hypertension.

• Band ligation is the preferred prevention of first and recurrent bleeding. Non-selective beta blockers can reduce cardiac output and heart rate in the Fontan circulation, so use only with specialist agreement (carvedilol 6.25 mg daily, increased to 12.5 mg daily).
• Acute variceal bleeding: octreotide 50 microgram intravenous bolus then 50 microgram/h for 2 to 5 days, ceftriaxone 1 g intravenously daily for up to 7 days, endoscopy within 12 hours, and transfusion to a haemoglobin of 7 to 8 g/dL. Avoid terlipressin, which reduces cardiac output through vasoconstriction. Avoid fluid overload.

Ascites. Spironolactone 100 mg and furosemide 40 mg orally each morning, titrated every 3 to 5 days to a maximum of 400 mg and 160 mg, with sodium restriction to about 2 g daily. Large volume paracentesis with 6 to 8 g of albumin for each litre removed. Avoid over diuresis, hyponatraemia and renal injury.

Hepatic encephalopathy. Lactulose 15 to 30 mL orally twice daily, titrated to 2 to 3 soft stools daily, with rifaximin 550 mg twice daily added for recurrence.

Transplantation. Heart transplantation alone for fibrosis without advanced portal hypertension. Combined heart and liver transplantation for cirrhosis with portal hypertension, refractory ascites, variceal bleeding, or carcinoma within criteria, when the Fontan circulation is also failing. Refer early.

Monitoring. Liver tests, platelets, INR, albumin and creatinine every 6 months. Ultrasound every 6 months with AFP. Multiphasic imaging yearly. Endoscopy every 1 to 3 years with portal hypertension. Review of Fontan haemodynamics every 3 to 5 years.

Referral and escalation. Refer every patient from adolescence to a joint adult congenital heart disease and hepatology service. Urgent referral for haematemesis, ascites, jaundice, encephalopathy, a new liver nodule or rising AFP.

Special groups.

• Pregnancy: cirrhosis with portal hypertension carries high risk of variceal bleeding and failure, so counsel against pregnancy; avoid warfarin from 6 to 12 weeks and endothelin receptor antagonists.
• Children and adolescents: baseline liver imaging from about 10 years after Fontan, with growth and nutritional review.
• Kidney impairment: avoid NSAIDs and large volume diuresis, and adjust drug doses by eGFR.
• Region specific: viral hepatitis B and C and schistosomiasis are frequent coexisting causes of liver disease in sub-Saharan Africa and should be tested for.