Risk factors for Fontan-associated hepatocellular carcinoma

Abstract

Aims The incidence of hepatocellular carcinoma (HCC) in patients with Fontan-associated liver disease (i.e., FALD-HCC) has increased over time. However, the risk factors for HCC development remain unclear. Here, we compared the levels of non-invasive markers to the survival rate of FALD-HCC patients. Methods From 2003 to 2021, 154 patients (66 men, 42.9%) developed liver disease after undergoing Fontan procedures. HCC was diagnosed in 15 (9.7%) (8 men, 53.3%) at a median age of 34 years (range, 21–45 years). We compared FALD-HCC and non-HCC cases; we generated marker level cutoffs using receiver operating characteristic curves. We sought to identify risk factors for HCC and mortality. Results The incidence of HCC was 4.9% in FALD patients within 20 years after the Fontan procedure. Compared with non-HCC patients, FALD-HCC patients exhibited higher incidences of polysplenia and esophageal varices. At the time of HCC development, the hyaluronic acid (HA) level (p = 0.04) and the fibrosis-4 index (p = 0.02) were significantly higher in FALD-HCC patients than in non-HCC patients; the total bilirubin (T-BIL) level (p = 0.07) and the model for end-stage liver disease score [excluding the international normalized ratio (MELD-XI)] (p = 0.06) tended to be higher in FALD-HCC patients. Within approximately 20 years of the Fontan procedure, 10 patients died (survival rate, 96.9%). Kaplan–Meier curve analysis indicated that patients with T-BIL levels ≥ 2.2 mg/dL, HA levels ≥ 55.5 ng/mL, and MELD-XI scores ≥ 18.7 were at high risk of HCC, a generally poor prognosis, and both polysplenia and esophageal varices. Multivariate Cox regression analyses indicated that the complication of polysplenia [Hazard ratio (HR): 10.915] and a higher MELD-XI score (HR: 1.148, both p < 0.01) were independent risk factors for FALD-HCC. Conclusions The complication of polysplenia and a MELD-XI score may predict HCC development and mortality in FALD patients.

Meta‐analysis: Incidence of cirrhosis and hepatocellular carcinoma in patients with Fontan palliation

“…23 In another study from Japan, the cumulative incidence of HCC at 10, 20, and 30 years post Fontan was 0.8%, 2.9%, and 13.3%, respectively. 7 When compared to other liver diseases, the 20-year cumulative incidence of HCC in Fontan patients is higher than in those with autoimmune hepatitis (2.7%) but lower than in those with alcohol-induced cirrhosis without decompensation (24.8%). 54,55 On the other hand, the incidence of HCC in Fontan is similar to or higher than those with inactive chronic Hepatitis B (0.02-0.2 per 100 person-years) but lower than those with chronic HBV and cirrhosis (2.2-3.7 per 100 person-years) and chronic HCV (1%-8%).…”

“…[22][23][24][25] Of the remaining 23 studies, 12 and 13 studies were included in the cirrhosis and HCC cohorts, respectively, with two studies, Wu 2017 and Munsterman 2019, common to both cohorts. 4,[6][7][8][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] The included studies in cirrhosis and HCC cohorts are reported in Tables 1 and 2, respectively. No randomised control trials were identified in the literature search.…”

“…A total of 2467 patients from 13 studies were included, with mean patient age of 23.7 ± 4.2 years and mean follow-up of 18.2 ± 3.9 years. 4,[6][7][8][9]26,[32][33][34][39][40][41][43][44][45][46] Of these, 1347 (54.6%) were males. Seven patients had history of HBV, 13 of HCV, two of excessive alcohol use, and two of metabolic dysfunction-associated steatohepatitis (previously non-alcoholic steatohepatitis).…”

“…5 The risk of progression of FALD to cirrhosis and subsequent risk of hepatocellular carcinoma (HCC) increases over time, regardless of type of Fontan surgery or age at Fontan. [6][7][8][9] Studies across the globe have reported variable rates of cirrhosis and HCC development, which may be secondary to multiple factors related to patient characteristics and underlying comorbidities. Given the significant morbidity and mortality associated with cirrhosis and HCC, several institutes have adopted their own protocol of routinely screening Fontan patients, often based on past experiences with other chronic liver diseases such as hepatitis C (HCV).…”

Imaging of Fontan-Associated Liver Disease

“…Retrospective studies have shown a prevalence of HCC of 0.18% to 1.3%. 20,21 In recent single-center study by Kogiso et al, 22 9.7% developed HCC within 20 years after the Fontan procedure. In a larger retrospective review of 1117 Fontan patients, Inuzuka et al 9 found that the incidence of liver fibrosis, FNH-like lesions, liver cirrhosis, and HCC started to increase at 5, 5, 10, and 15 years and reached a cumulative incidence of 27.3%, 8.7%, 13.0%, and 1.0%, respectively, at 20 years after Fontan operation.…”