Effects of CFTR modulators on serum biomarkers of liver fibrosis in children with cystic fibrosis

Abstract

The cystic fibrosis (CF) transmembrane conductance regulator corrector/potentiator combinations lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor improve sweat chloride, pulmonary function, and nutrition. Yet it is unclear whether they may also impact the progression of liver fibrosis, which is a substantial source of morbidity and mortality for patients with CF. We conducted a retrospective, single-center analysis of children and adolescents with CF treated with lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor therapy, focusing on alterations in liver function tests and fibrosis indices using previously-established thresholds that corresponded with increased liver elastography. In pairwise comparisons of before and during treatment timepoints, we found that those with CF-associated liver involvement experienced significant decreases in gamma-glutamyl transferase, aspartate aminotransferase-to-platelet index, and gamma-glutamyl transferase-to-platelet ratio while on lumacaftor/ivacaftor. These differences were not observed in patients treated with elexacaftor/tezacaftor/ivacaftor, nor were they observed in patients without underlying CF-associated liver disease. These results provide the first evidence that lumacaftor/ivacaftor may improve liver fibrosis in children and adolescents with CF and suggest it may be beneficial in the treatment of CF-associated liver disease.

Evolving nutritional needs, obesity, and overweight status in cystic fibrosis

“…Levitte recently undertook evaluation of multiple modulator therapies on biomarkers of liver fibrosis in children with CF, finding significant decreases in multiple markers while on lumacaftor/ivacaftor but not ETI. BMI and FEV1 improvements were noted in the ETI treatment group without benefit to liver fibrosis markers [35 ▪▪ ]. Larger scale analysis of these findings is needed.…”

Risk factors for more rapid progression of severe liver fibrosis in children with cystic fibrosis‐related liver disease: A multi‐center study validated by liver biopsy

“…In summary, this study provides a unique assessment of the clinical and biochemical variables over time that are associated with the development of liver biopsy‐validated severe paediatric CFLD, including moderate pulmonary dysfunction defined as FEV 1 % <64%. For patients identified early as more rapid progressors, there is emerging evidence from retrospective studies of the potential benefit of CFTR modulators to improve liver biomarkers or even reduce the incidence of cirrhosis in those with CFLD 41,42 . In the future, targeted gene therapy or other proposed medications that promote bile flow or reduce portal pressures could also be considered 43 .…”

“…For patients identified early as more rapid progressors, there is emerging evidence from retrospective studies of the potential benefit of CFTR modulators to improve liver biomarkers or even reduce the incidence of cirrhosis in those with CFLD. 41,42 In the future, targeted gene therapy or other proposed medications that promote bile flow or reduce portal pressures could also be considered. 43 We also found a negative association between severe liver-biopsy proven fibrosis with pancreatic insufficiency and F508del homozygosity which merits further study and validation by others.…”

Cystic fibrosis liver disease in the post-modulator era

“…In participants with prior liver involvement, there was an increase in ALT and a decrease in platelets but no change in APRI. In those without prior liver involvement, there was an increase in ALT, APRI, GPR, and platelets suggesting some progression/development of liver fibrosis [27 ▪ ].…”