Impact of ursodeoxycholic acid treatment on Fontan-associated liver disease

Abstract

Background: Fontan-associated liver disease (FALD) is a type of progressive liver fibrosis that occurs following Fontan surgery and can be complicated by hepatocellular carcinoma (HCC). Established treatments for FALD are lacking. Therefore, we investigated the efficacy of ursodeoxycholic acid (UDCA) in patients with FALD.

Methods: This single-center retrospective study was conducted from 2003 to 2024 and involved 220 patients (103 men, 46.8%) who had been diagnosed with FALD. UDCA was administered to 113 patients presenting with liver or biliary enzyme abnormalities. We evaluated the patients' liver enzyme levels 3, 6, and 12 months after treatment. HCC developed in 10.5% and the mortality rate was 4.5%. Survival and cumulative incidence of HCC were compared between patients with and without UDCA treatment using Kaplan-Meier curves and propensity-matched analysis (n = 68 per group).

Results: UDCA treatment significantly reduced the aspartate aminotransferase (AST), alanine transaminase (ALT), and gamma-glutamyl transferase (GGT) levels at 3 months. The mean pretreatment AST/ALT/GGT levels were 26/22/323 U/L, respectively, and decreased to 19/15/102 U/L at 3 months, 18/12/88 U/L at 6 months, and 16/19/64 U/L at 12 months. However, the total bilirubin level and platelet count did not show significant differences. The survival rate was higher and the HCC rate was lower in patients with than without UDCA treatment. The 5-year incidence rate of HCC was 5.6% in the UDCA group and 24.2% in the untreated group.

Conclusions: UDCA treatment significantly reduced liver enzyme levels, including GGT, and mitigated the progression of HCC. UDCA may be beneficial for patients with FALD.

Keywords: Fontan procedure; Fontan-associated liver disease; Hepatocellular carcinoma; Ursodeoxycholic acid.

Fig. 1

Flowchart of UDCA-treated and untreated patients with FALD and their outcomes. a Flowchart of the total cohort of 220 patients with FALD referred to our department. UDCA treatment was administered to 113 patients. HCC was observed in 17 untreated patients and in 6 UDCA-treated patients. b Flowchart of patients with FALD after propensity matching. HCC was observed in 15 untreated patients and in 4 UDCA-treated patients. c Flowchart of patients with FALD with ≥6 months of follow-up. HCC was observed in 6 untreated patients and in 4 UDCA-treated patients. FALD Fontan-associated liver disease, GGT gamma-glutamyl transferase, HCC hepatocellular carcinoma, MELD-XI model for end-stage liver disease excluding the international normalized ratio, UDCA ursodeoxycholic acid

Fig. 1

Flowchart of UDCA-treated and untreated patients with FALD and their outcomes. a Flowchart of the total cohort of 220 patients with FALD referred to our department. UDCA treatment was administered to 113 patients. HCC was observed in 17 untreated patients and in 6 UDCA-treated patients. b Flowchart of patients with FALD after propensity matching. HCC was observed in 15 untreated patients and in 4 UDCA-treated patients. c Flowchart of patients with FALD with ≥6 months of follow-up. HCC was observed in 6 untreated patients and in 4 UDCA-treated patients. FALD Fontan-associated liver disease, GGT gamma-glutamyl transferase, HCC hepatocellular carcinoma, MELD-XI model for end-stage liver disease excluding the international normalized ratio, UDCA ursodeoxycholic acid

Fig. 2

Changes in liver and biliary enzyme levels and platelet count following UDCA treatment. a Mean T-BIL levels were slightly decreased at 6 and 12 months after UDCA treatment; however, the change was not statistically significant. There were significant decreases in (b) AST levels, c ALT levels, and d GGT levels following UDCA treatment. e Platelet counts slightly increased 12 months after treatment but the change was not statistically significant. Data are presented as means with standard deviations. ALT alanine transaminase, AST aspartate aminotransferase, GGT gamma-glutamyl transferase, M months, T-BIL total bilirubin, PLT platelet count, UDCA ursodeoxycholic acid, Y year

Fig. 3

Comparison of liver and biliary enzyme levels between UDCA-treated and untreated patients with ≥6 months of follow-up. There were no significant differences in (a) T-BIL levels or (b) AST levels between UDCA-treated and untreated patients. There were significant reductions in (c) ALT levels and d GGT levels in treated patients vs. untreated patients. e Platelet counts did not significantly differ between the groups. Data are presented as means with standard deviations. ALT alanine transaminase, AST aspartate aminotransferase, GGT gamma-glutamyl transferase, T-BIL total bilirubin, PLT platelet count, UDCA ursodeoxycholic acid

Fig. 4.

Survival and HCC incidence rates in patients with FALD stratified by UDCA treatment. a Kaplan–Meier survival curve for the total cohort. The 5-year survival rates were significantly higher in UDCA-treated patients than in untreated patients. b Kaplan–Meier curve showing the incidence of HCC in the total cohort. The incidence was significantly lower in treated patients. c Kaplan–Meier curve for the incidence of HCC in patients with ≥6 months of follow-up. The difference in HCC incidence between the groups was not statistically significant. d Kaplan–Meier curve for the time to HCC occurrence following Fontan surgery. The occurrence of HCC was significantly delayed in treated patients relative to untreated ones. FALD Fontan-associated liver disease, HCC hepatocellular carcinoma, UDCA ursodeoxycholic acid