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.

Fig 1. ROC curve data and FALD-HCC development.

T-BIL level; b) HA level; and c) MELD-XI score. The T-BIL cutoff for HCC diagnosis based on the ROC curves was ≥ 2.2 mg/dL (sensitivity, 0.500; specificity, 0.849; AUROC, 0.691; a); for HA, the cutoff was ≥ 55.5 ng/ mL (sensitivity, 0.778; specificity, 0.612; AUROC, 0.781; b); for the MELD-XI score, the cutoff was ≥ 18.7 (sensitivity, 0.400; specificity, 0.871; AUROC, 0.663; c). AUROC, area under the ROC curve; HA, hyaluronic acid; HCC, hepatocellular carcinoma; MELD-XI, model for end-stage liver disease excluding the international normalized ratio; ROC, receiver operating characteristic; T-BIL, total bilirubin.

Fig 2

HCC incidences after the Fontan procedure in subgroups divided according to a) Polysplenia status, b) esophageal varices status, c) T-BIL level, d) HA level, and e) MELD-XI score. HCC incidences were calculated using the Kaplan–Meier method. Subgroup analyses showed that polysplenia and esophageal varices significantly increased the risk of HCC (both p = 0.01, panels a and b). Furthermore, in patients with T-BIL levels ≥ 2.2 mg/dL (p = 0.02, c), HA levels ≥ 55.5 ng/mL (p = 0.04, d), and MELD-XI scores ≥ 18.7 (p = 0.02, e), the HCC risk was significantly increased. HA, hyaluronic acid; HCC, hepatocellular carcinoma; MELD-XI, model for end-stage liver disease excluding the international normalized ratio; T-BIL, total bilirubin.

Fig 3. Survival rates after the fontan procedure stratified according to subgroup.

a) Overall survival, and survival stratified according to b) polysplenia status; c) esophageal varices status; d) T-BIL level; e) HA level; and f) MELD-XI score at the time of HCC diagnosis. Survival rates were estimated using the Kaplan–Meier method. The survival rate was 96.9% at 20 years after surgery (a). Survival was poor in patients with polysplenia (p = 0.04, b) and esophageal varices (p < 0.01, c). Patients with T-BIL levels ≥ 2.2 mg/dL (p < 0.01, d), HA levels ≥ 55.5 ng/mL (p < 0.01, e), and MELD-XI scores ≥18.7 (p < 0.01, f) exhibited worse outcomes than did other patients. HA, hyaluronic acid; MELD-XI, model for end-stage liver disease excluding the international normalized ratio; T-BIL, total bilirubin.