The FUEL FALD Study: Effects of Udenafil on Liver Stiffness and Fibrosis after Fontan

Fontan-associated liver disease (FALD) is a fibrotic liver disease in individuals with Fontan physiology. This study sought to determine the efficacy of treatment with udenafil, a phosphodiesterase type 5 inhibitor, for reducing liver congestion leading to a decreased liver stiffness and reduction in serologic biomarkers of liver fibrosis. In patients enrolling in the FUEL trial open label extension, liver stiffness measurements were obtained by ultrasound shear wave elastography (SWE) and magnetic resonance elastography (MRE); serum markers of liver fibrosis were measured by the Enhanced Liver Fibrosis (ELF) score. Change in liver stiffness and ELF score after 12 months of udenafil treatment were analyzed. In 88 subjects, 36 were previously treated with udenafil and 52 were udenafil-naïve. The cohort's baseline liver stiffness was elevated by SWE, mean 2.0 ± 0.4 m/sec (adult upper limit normal 1.5 m/sec), and MRE, mean 5.3 ± 1.2 kPa (adult upper limit normal 2.8 kPa). After 12 months of udenafil treatment, there was no change in SWE (post-treatment mean 1.9 ± 0.3 m/sec, p = 0.28) nor change in MRE (post-treatment mean 5.2 ± 0.97 kPa, p = 0.68). The cohort's baseline ELF score was elevated at 10.4 ± 1.0 according to values correlating with liver fibrosis in other diseases. ELF score decreased at 12 months to 9.8 ± 0.8 (p < 0.0001). Liver stiffness did not change following 12 months of udenafil treatment, but ELF scores significantly decreased. Further study is needed to understand the relationship of ELF score to age, but these results suggest the possibility that udenafil may alter the overall Fontan fibrotic milieu.