Severe Fontan-Associated Liver Disease and Its Association With Mortality

Abstract

Background Data are rare about the incidence of severe Fontan-associated liver disease (FALD) and its association with mortality. We sought to: (1) estimate the probability of developing severe FALD in patients who undergo the Fontan procedure (Fontan patients), compared with severe liver complications in patients with a ventricular septal defect; (2) assess the severe FALD-mortality association; and (3) identify risk factors for developing severe FALD. Methods and Results Using the Quebec Congenital Heart Disease database, a total of 512 Fontan patients and 10 232 patients with a ventricular septal defect were identified. Kaplan-Meier curves demonstrated significantly higher cumulative risk of severe FALD in Fontan patients (11.95% and 52.24% at 10 and 35 years, respectively), than the risk of severe liver complications in patients with a ventricular septal defect (0.50% and 2.75%, respectively). At 5 years, the cumulative risk of death was 12.60% in patients with severe FALD versus 3.70% in Fontan patients without FALD (log-rank P=0.0171). Cox proportional hazard models identified significant associations between the development of severe FALD and congestive heart failure and supraventricular tachycardia, with hazard ratios (HRs) of 2.36 (95% CI, 1.38-4.02) and 2.45 (95% CI, 1.37-4.39), respectively. More recent Fontan completion was related to reduced risks of severe FALD, with an HR of 0.95 (95% CI, 0.93-0.97) for each more recent year. Conclusions This large-scale population-based study documents that severe FALD in Fontan patients was associated with a >3-fold increase in mortality. The risk of FALD is time-dependent and can reach >50% by 35 years after the Fontan operation. Conditions promoting poor Fontan hemodynamics were associated with severe FALD development.

Keywords: Fontan procedure; congenital heart defects; liver diseases; mortality; risk factor.

Figure 1. Population derivation flowchart.

§Propensity score matching (PS) takes sex, age at Fontan, year of Fontan, atrial fibrillation, stroke, congestive heart failure, heart block, ventricular arrhythmia, pulmonary hypertension, and arterial hypertension into account. Fontan‐associated liver disease (FALD) cases and non‐FALD controls were matched at the time of the first FALD diagnosis. CHD indicates congenital heart disease; QC, Quebec; and VSD, ventricular septal defect.

Figure 2. Risk of developing severe Fontan‐associated liver disease (FALD)/severe liver complications (SLCs) in matched Fontan vs ventricular septal defect (VSD) cohorts.

Ten‐year cumulative risk of developing severe FALD/SLCs in patients who undergo the Fontan procedure (Fontan patients) is 11.95%; and in patients with VSD, it is 0.50%. Long‐term (35‐year) cumulative risk of developing severe FALD/SLCs in Fontan patients is 52.24%; and in patients with VSD, it is 2.75%. Log‐rank P<0.0001. FU indicates follow‐up.

Figure 3. Comparison of survival probability in patients with severe Fontan‐associated liver disease (FALD) vs patients without severe FALD.

Cumulative risk of death is 12.62% in patients with severe FALD and 3.75% in patients without severe FALD (non‐FALD). Log‐rank P=0.0171. Non‐FALD indicates without severe FALD; and FU, follow‐up.

Figure 4. Forest plot illustrating the identified risk factors of severe Fontan‐associated liver disease (FALD) in patients who undergo the Fontan procedure.

Results of Cox regression. (Comorbidities act as time‐dependent variables.) CHF indicates congestive heart failure; and CV, cardiovascular.