Cystic Fibrosis Liver Disease in the era of CFTR Modulator Therapy

Abstract

The multisystem genetic condition cystic fibrosis (CF) has undergone a paradigm shift in therapeutic approaches, thanks to the advent of small molecules that help to correct the underlying defect caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In particular, the licencing of elexacaftor/tezacaftor/ivacaftor (E/T/I) in the United States and Europe in 2020 means that a majority of people with cystic fibrosis (PwCF) in those regions are now eligible for a highly efficacious therapy. However, the effects of E/T/I outside of the lungs are unclear, as trials focussed primarily on pulmonary outcome measures and in particular there have been concerns of hepatotoxicity following case reports. Cystic fibrosis liver disease (CFLD) is the third largest CF-related cause of mortality, and this thesis considers the impact of CFTR modulator therapy on CFLD. Results of work conducted for this thesis were able to demonstrate that E/T/I is generally well tolerated from a hepatic perspective. Those with CFLD had no significant worsening of liver biochemistry or markers of liver fibrosis compared to PwCF without CFLD, and no greater risk of drug-induced liver injury. For some individuals with elevated markers of liver fibrosis prior to starting E/T/I this actually improved following commencement of E/T/I, though the reasons for this are unclear. As PwCF live longer thanks to CFTR modulator therapy, the need for accurate diagnosis and monitoring of significant extrapulmonary disease such as CFLD may become more pressing, however the lack of a clear understanding of the pathogenesis of CFLD can make this challenging, as current diagnostic criteria are broad and heterogenous. Magnetic resonance measurement of extracellular volume in the liver was higher in PwCF with CFLD compared to those without CFLD, suggesting that this could be a useful tool to aid diagnosis and monitoring of CFLD, warranting further evaluation in larger cohorts.

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andrew Jones (Supervisor), Rowland Bright-Thomas (Supervisor), Karen Piper Hanley (Supervisor) & Varinder Athwal (Supervisor)