The Fontan operation is a palliative procedure which results in single ventricle physiology(1). Wedged between two capillary beds, with the pulmonary venous bed downstream, which has no pulsatile energy added in the absence of a functional subpulmonary ventricle, and the splachnic bed upstream, which may have compromised inflow due to inherent cardiac output restriction characteristic of the Fontan circulation (FC), the liver exists in a precarious state(1).

This almost inevitably leads to Fontan-associated liver disease (FALD),(2) marked by fibrosis, cirrhosis, and occasionally hepatocellular carcinoma (HCC)(3). The first case of HCC in a Fontan patient was reported in 2005, and subsequent studies have described varied presentations, diagnoses, treatments, and outcomes(4). A retrospective, multicenter case series indicated a 1-year survival rate of only 50% (5), stressing the importance of meticulous liver surveillance.  

Advanced FALD with cirrhosis, portal hypertension, and specific risk factors such as lower oxygen saturation, older style Fontan connections or prior surgeries increases the likelihood of HCC development. The annual incidence of HCC in the Fontan population is estimated at 1.5–5%, with poor survival rates(6-11). Risk factors for carcinogenesis and natural history of disease remain incompletely understood. 
Rosenthal et al. aimed to further characterize HCC in Fontan patients and examine their diagnostic, treatment, and survival pathways. This was a multicenter, retrospective case-control study analyzed adult patients (>18 years old) with FC between 2005 and 2021 to investigate HCC. Cases were identified through histological or imaging criteria. Imaging diagnosis was defined as focal liver lesion(s) plus one of the following: alpha-fetoprotein (AFP) >20 ng/mL or evidence of lesion growth >50% in a period of 6 months or less or growth >100% in a period of over 6 months on serial imaging studies. Controls were selected in a 3:1 ratio based on strict inclusion and exclusion criteria, and all data were centralized using a secure database system.

The main findings of the study were: 

• HCC was more prevalent in the latter years with 7% diagnosed in first half of the study period (2005-2012) and 93% in the second half (2013-2021). Screening will likely lead to an increase in diagnoses of HCC.
• Although there was no significant difference between cases and controls regarding age, time since Fontan, age at Fontan, race, or primary cardiac diagnosis, patients with HCC had undergone more frequently right atrium to pulmonary artery or right atrium to right ventricle Fontan repair, had a higher frequency of prior Fontan revisions and cardiac comorbidities, such as arrhythmias, desaturation, and heart failure. FC patients with more cardiac comorbidities and evidence of more advanced FALD (blood work, imaging, biopsy) deserve particular attention.
• Patients under active HCC surveillance were almost 5 times more likely to be diagnosed at an early stages (16% and 52%, respectively), compared to those not under active surveillance. Over the entire study period, survival was 83% in those who received curative therapy (89% for transplant, 78% for resection, and 88% for ablation),  compared to 59% in those who received non-ablation liver-directed therapy (LDT) and 33 % in those who after systemic and symptomatic/ palliative therapy. Though unadjusted 1-year survival was similar between curative therapy and other LDT (90.4% vs 90.9%,respectively), 3-year survival was higher in those who underwent curative therapy (80.4% vs 64%,P= 0.049). Patients with intermediate-stage HCC (BCLC B) faced a fivefold increased risk of death, while those with advanced or end-stage HCC (BCLC C or D) had nearly 20 times the risk compared to early-stage cases. Considering the increased likelihood of curative therapies and better outcomes in those diagnosed early, this study confirms the importance of HCC screening.
• Median AFP levels were 77 ng/mL, although 29% of cases had AFP <10 ng/mL at diagnosis. The practice to have a baseline MRI with AFP and liver ultrasound every 6 months seems reasonable as a screening practice. 

The study of Rosenthal et al. presents a updated and comprehensive analysis of diagnosis, treatment, and outcomes in a large Fontan patient cohort including 58 adults with FC with HCC between 2005 and 2021. Individuals with FC diagnosed with HCC exhibit distinctive features, including significant cardiac comorbidities, advanced FALD with a high prevalence of cirrhotic morphology, all at a relatively young age at diagnosis. Abdominal imaging by ultrasound, MRI, or CT along with AFP levels can be used to screen for HCC. Early-stage diagnosis and curative treatments improved survival, with active surveillance showing a potential, though nonsignificant, survival benefit. Rosethal et al. emphasizes the importance of routine screening for early detection and calls for collaboration among specialists to establish a universal HCC screening protocol for Fontan patients.