Effect of Cystic Fibrosis Transmembrane Conductance Regulator Modulators on Liver Enzymes among Patients with Cystic Fibrosis: A Systematic Review and Meta-Analysis

Introduction: Cystic fibrosis (CF) is a genetic disorder that affects the cystic fibrosis transmembrane conductance regulator (CFTR) channels and leads to multi-organ damage including the lungs, pancreas, and liver. CF is the most common in the Caucasian individuals with an incidence of 1:3500 births in the United States (US), and a prevalence of 100,000 patients worldwide. Novel CFTR modulator medications have improved pulmonary outcomes in CF. Lumacaftor/Ivacaftor and Elexacaftor/Tezacaftor/Ivacaftor are the CFTR modulators approved in the US. The impact of these medications on the liver is not well established. We performed the first systematic review and meta-analysis to evaluate the effect of CFTR modulators on liver enzymes. Methods: A comprehensive literature search of major databases was conducted from inception to March 2023. The primary outcomes were changes in the serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (T.bili), and gamma-glutamyl transferase (GGT). The secondary outcomes were changes in the same serum biomarkers in patients with CF-related liver disease (CFLD), without CFLD, and based on the type of CFTR modulator used. Means and standard deviations of the serum biomarkers both before and after starting CFTR modulators were pooled using random-effects model with a 95% confidence interval (CI), and standardized-group mean differences were analyzed with R software (version 4.3.0). Results: Six studies (3 retrospective and 3 prospective cohort studies) with a total of 1135 patients were included. Three studies were conducted in Europe, 2 in the US, and 1 in Asia. The mean age in this cohort was 18.44 ± 6.42 years, and 53% were males. There were 83 patients on Lumacaftor/Ivacaftor, 69 patients on Elexacaftor/Tezacaftor/Ivacaftor, and 21 patients on Ivacaftor. The remaining patients were not stratified by the type of CFTR by the studies. Mean follow-up period was 15 months. ALT was the most likely to improve while receiving therapy with CFTR modulators (-0.90 (95% CI:-1.71,-0.08; P=0.037)) (Figure 1). T.bili and GGT levels also improved in patients taking Lumacaftor/Ivacaftor, with P-values 0.033 and 0.012, respectively (Table 1). A decrease in fibrosis scores was observed but could not be pooled as different scores were used. Conclusion: CFTR modulators appear to improve the levels of liver enzymes in CF patients. Larger multi-center randomized controlled trials are needed to validate the findings in our analysis.Figure 1.: Forest plot for the change in ALT in cystic fibrosis (CF) patients on CFTR modulator therapy. CI, confidence interval. Table 1. - Change in serum biomarkers with 95% confidence intervals in CF patients after starting CFTR modulator therapy Change in serum biomarkers Overall CF patients on lumacaftor/ivacaftor CF patients with liver involvement CF patients without liver involvement AST -0.56 (-1.54, 0.41); P=0.20 -0.17 (-2.35, 2.01); P=0.767 -0.87 (-6.00, 4.26); P=0.276 -0.15 (-6.24, 5.93); P=0.800 ALT -0.90 (-1.71, -0.08); P=0.037 -0.65 (-2.43, 1.13); P=0.256 -0.99 (-12.50, 10.50); P=0.468 0.01 (-2.09, 2.12); P=0.943 T.bili -0.32 (-0.89, 0.25); P=0.211 -0.70 (-1.26, -0.14); P=0.033 N/A N/A GGT -0.57 (-1.19, 0.05); P=0.065 -0.98 (-1.45, -0.51); P=0.012 N/A N/A