Fontan-associated liver disease and hepatocellular carcinoma in adults

Abstract

The Fontan operation creates a unique circulation, and is a palliative therapy for patients with single-ventricle congenital heart disease. Increased venous pressure and decreased cardiac output and hepatic venous drainage result in sinusoidal dilatation around the central veins. This causes congestion and hypoxia in the liver, leading to Fontan-associated liver disease (FALD). Non-invasive and invasive markers enable diagnosis and evaluation of the fibrosis status in chronic liver disease; however, these markers have not been validated in FALD. Additionally, regenerative nodules such as focal nodular hyperplasia (FNH) are frequently found. The severity of fibrosis correlates with the duration of the Fontan procedure and the central venous pressure. Cirrhosis is a risk factor for hepatocellular carcinoma (HCC), the annual risk of which is 1.5-5.0%. HCC is frequently difficult to diagnose and treat because of cardiac complications, coagulopathy, and congenital abnormalities. The mortality rate of FALD with liver cirrhosis and/or FALD-HCC was increased to ~ 29.4% (5/17 cases) in a nationwide survey. Although there is no consensus on the surveillance of patients with FALD, serial monitoring of the alpha fetoprotein level and imaging at 6-month intervals is required in patients with cirrhosis.

Figure 1

Hemodynamic changes after the Fontan procedure and treatment thereof. Central venous pressure frequently increases after Fontan surgery (b) compared to normal (a). ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; AV, atrioventricular; Ca, calcium; CRT, cardiac resynchronization therapy; CVP, central venous pressure; ERA, endothelin receptor blocker; HOT, home oxygen therapy; MP, muscle pump; NO, nitric oxide; PA, pulmonary artery; PV, pulmonary ventricle; PDGE-5, phosphodiesterase 5 inhibitor; PGI2, prostaglandin I2; PTA, percutaneous transluminal angioplasty; RP, PA resistance.

Figure 2

Fontan physiology. Increased venous pressures and decreased cardiac output and hepatic venous drainage result in sinusoidal dilatation around the central veins. This causes congestion and hypoxia in the liver, leading to Fontan-associated liver disease (FALD). Hepatic stellate cells are activated and collagenous fibers are produced. Decreased portal flow induces a hepatic arterial buffer response (HABR) and hypervascular nodules are formed mainly in peripheral areas of the liver.

Figure 3

Liver tumors arising from FALD. A 37-year-old female had a complicated hypervascular tumor periphery on enhanced abdominal CT (a). HCC could not be ruled out. Ultrasound did not detect the nodule and MRI could not be performed because of a pacemaker. Surgically resected specimen revealed FNH (b, left H&E staining). Non-cancerous liver specimen showed sinusoidal dilatation and mild fibrosis (b, right; Victoria blue H&E staining). A 30 year-old male had a hypervascular tumor on enhanced abdominal CT scan (c). The tumor was more enhanced at the late arterial phase. HCC was treated with TACE and PBT; however, it was not completely cured. Finally, surgery was selected and HCC of confluent multinodular type and poorly differentiated was diagnosed (d, left; H&E staining). The tumor was positive by PET-CT (e). A non-cancerous liver specimen showed cirrhosis (d, right; Victoria blue H&E staining). CT, computed tomography; FALD, Fontan-associated liver disease; FNH, focal nodular hyperplasia; H&E, hematoxylin and eosin: HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging; PBT, proton beam therapy; PET, positron emission tomography; TACE, transcatheter arterial chemoembolization: Tc-99m GSA, technetium-99m diethylenetriamine pentaacetic acid galactosyl human serum albumin.

Figure 4

Development of fibrosis after Fontan surgery. Hemodynamic changes, complications of Fontan, viral infection, and metabolic factors are associated with the development of fibrosis. FALD, Fontan-associated liver disease; HCC, hepatocellular carcinoma.

Figure 5

The algorithm for FALD-HCC surveillance. AFP, alpha fetoprotein, APRI, aspartate aminotransferase -to-platelet ratio index; CT, computed tomography; FIB-4, Fibrosis-4; FALD, Fontan-associated liver disease; GI, gastrointestinal; HCC, hepatocellular carcinoma; MELD, model for end-stage liver disease; MRI, magnetic resonance imaging, VAST score, varices, ascites, splenomegaly, thrombocytopenia.