Severe hepatotoxicity is uncommon following the introduction of Elexacaftor/Tezacaftor/Ivacaftor: A real-world two-years follow-up study of the Danish cystic fibrosis cohort.

BACKGROUND

Elexacaftor/Tezacaftor/Ivacaftor (ETI) has raised concerns about liver-related side effects. This study evaluated changes in liver function tests (LFTs) and the prevalence of hepatotoxicity over two years of ETI treatment in a nationwide cohort of Danish people with cystic fibrosis (pwCF)

METHODS

Changes in LFTs were assessed in pwCF aged ≥12 years, including those with pre-existing hepatic impairment, using data from the Danish CF Registry (2016-2025). Statistical analyses included piecewise linear mixed models for long-term changes and descriptive analysis of abnormal LFTs to assess hepatotoxicity.

RESULTS

A total of 331 pwCF were included. Compared to pre-ETI levels, alanine aminotransferase (ALT) levels were significantly elevated at six months post-ETI but stabilized and approached pre-ETI levels by 24 months. Alkaline phosphatase (ALP) levels were lower at all timepoints, with a statistically significant decrease at 24 months. Gamma-glutamyl transferase (GGT) levels were consistently lower post-ETI. The prevalence of abnormal ALT, ALP, and GGT was initially higher post-ETI, peaking at one month, then steadily declining to pre-treatment values within two years. Three individuals (0.9 %) had signs of severe hepatotoxicity with ALT >5x upper limit of normal (ULN) and bilirubin >2xULN post-ETI. Among those with pre-existing hepatic impairment and those with unexpected liver complications post-ETI 5/7 and 5/8, respectively, reached the full ETI dose.

CONCLUSION

ALT levels almost normalized, while GGT and ALP levels declined within two years of ETI treatment. Reassuringly, severe hepatotoxicity was rare, suggesting that close monitoring may suffice for managing mild to moderate hepatotoxicity in pwCF.