Liver biochemical indexes and cholesterol metabolism in cystic fibrosis patients with F508del/CFTR variant genotype after elexacaftor/tezacaftor/ivacaftor treatment.

ABSTRACT

Modulators of cystic fibrosis transmembrane conductance regulator (CFTR) improved cystic fibrosis (CF) patients' outcome. The elexacaftor/tezacaftor/ivacaftor (ETI) combination was safe and effective improving lung function in patients with different CFTR genotypes, including at least one F508del mutation. However, cases with liver damage were reported. We describe 105 CF patients heterozygous for F508del in trans with another CFTR mutation, treated for 1 year with ETI. We analyzed liver biochemical parameters and cholesterol metabolism, including lathosterol and phytosterols, surrogate markers of cholesterol de-novo synthesis and absorption, respectively. The treatment significantly improved sweat chloride, body mass index and forced expiratory volume in 1 s, whereas it caused a significant increase of total and conjugated bilirubin, ALT and GGT, even if no patients developed CF liver disease. Such alterations were less relevant than those previously observed in ETI-treated F508del homozygous patients. Furthermore, ETI treatment significantly increased serum cholesterol by enhancing its absorption (correlation between serum cholesterol and phytosterols). Whereas, we observed a normalization of de-novo biosynthesis (lathosterol reduction) that was not observed in homozygous patients. These data suggest that the second mutation in trans with the F508del contributes to reduce the liver cholesterol accumulation and thus, the triggering of liver inflammation. However, no differences in the alteration of biochemical indexes were observed between CF patients with and without liver steatosis, and between patients with different mutations in trans with the F508del. Such data suggest to further investigate the effects of ETI therapy on liver function indexes and new predictive biomarkers.