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Cystic fibrosis-related liver disease: Clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapiesJournal of HepatologyVol. 76Issue 2PreviewCystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. Cystic fibrosis-related liver disease (CFLD) is defined as the pathogenesis related to the underlying CFTR defect in biliary epithelial cells. CFLD needs to be distinguished from other liver manifestations that may not have any pathological significance. The clinical/histological presentation and severity of CFLD vary. The main histological presentation of CFLD is focal biliary fibrosis, which is usually asymptomatic. Full-Text PDF Effects of CFTR modulator therapies on liver stiffness and bile flow: A single-centre experienceJournal of HepatologyVol. 79Issue 2PreviewWe found the review by Jérémy Dana, Dominique Debray et al.1 published in the Journal of Hepatology in October 2021 very interesting. In this review, the authors suggest using liver stiffness rather than liver tests during cystic fibrosis transmembrane regulator (CFTR) modulator therapy to allow for early detection of treatment response or progression of cystic fibrosis-related liver disease (CFLD); however, to date, no data has been published. Full-Text PDF We would like to thank Calvo et al.[1]Calvo PL Giugliano L Evangelista A Bignamini E Pinon M The effects of CFTR modulator therapies on liver stiffness and bile flow: a single centre experience.J Hepatol. 2023; S0168-8278(23)00094-6Google Scholar for their interest in our recently published review on cystic fibrosis-related liver disease (CFLD).[2]Dana J. Debray D. Beaufrère A. Hillaire S. Fabre M. Reinhold C. et al.Cystic fibrosis-related liver disease: clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapies.J Hepatol. 2021; 76: 420-434Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar CFLD includes two main, sometimes co-existing, manifestations: focal biliary fibrosis and portosinusoidal vascular disease. Furthermore, hepatic steatosis, hypothesised to represent liver involvement and not to be part of CFLD, most often co-exists with CFLD. This overlap in liver manifestations may be confusing when monitoring patients under CFTR modulator therapy. Therefore, an accurate phenotypic approach is critical to better understanding clinical outcomes under treatment and should follow a standardised lexicon as described in.[2]Dana J. Debray D. Beaufrère A. Hillaire S. Fabre M. Reinhold C. et al.Cystic fibrosis-related liver disease: clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapies.J Hepatol. 2021; 76: 420-434Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar This requires exhaustive non-invasive liver assessment by imaging (ultrasound or MRI). These imaging modalities offer complete liver parenchyma characterization (normal, abnormal homogeneous or heterogeneous texture, nodular pattern), steatosis quantification (ultrasound-based attenuation or MRI-based proton density fat fraction [PDFF]), liver stiffness quantification (elastography) and portal hypertension assessment. Calvo et al. published a prospective single-centre series of 55 patients starting a triple-combination CFTR modulator regimen (ivacaftor/tezacaftor/elexacaftor) with repeated biochemical (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and gamma glutamyl transferase [GGT]) and liver elastography (vibration-controlled transient elastography) follow-up over 6 months. The results showed a significant mean liver stiffness reduction at 6 months, from 1 month after treatment initiation, but mildly increased ALT and GGT levels. The authors hypothesised a rapid improvement in biliary excretion with a lower bile viscosity. However, this mechanism is not fully supported by relatively rare findings of inspissated bile secretions. Multifactorial uncontrolled biliary inflammation due to the dysregulated Src/NF-κB signalling pathway in CFTR-defective cholangiocytes may be considered.[2]Dana J. Debray D. Beaufrère A. Hillaire S. Fabre M. Reinhold C. et al.Cystic fibrosis-related liver disease: clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapies.J Hepatol. 2021; 76: 420-434Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Indeed, inflammation was demonstrated to result in increased liver stiffness and thus to represent a significant confounder of liver stiffness.[3]Wu M. Wu L. Jin J. Wang J. Li S. Zeng J. et al.Liver stiffness measured with two-dimensional shear-wave elastography is predictive of liver-related events in patients with chronic liver disease due to hepatitis B viral infection.Radiology. 2020; 295: 353-360Crossref PubMed Scopus (14) Google Scholar Improved biliary inflammation by CFTR modulator therapy could participate in the underlying pathophysiology. These biochemical results are consistent with those reported by Levitte et al., who demonstrated no improvement in liver enzymes levels under ivacaftor/tezacaftor/elexacaftor.[4]Levitte S. Fuchs Y. Wise R. Sellers Z.M. Effects of CFTR modulators on serum biomarkers of liver fibrosis in children with cystic fibrosis.Cold Spring Harbor Lab. 2022; 7e0010Google Scholar However, other previously published articles reported a sustained significant decrease in serum levels of ALT, AST and GGT under lumacaftor/ivacaftor.[4]Levitte S. Fuchs Y. Wise R. Sellers Z.M. Effects of CFTR modulators on serum biomarkers of liver fibrosis in children with cystic fibrosis.Cold Spring Harbor Lab. 2022; 7e0010Google Scholar,[5]Drummond D. Dana J. Berteloot L. Schneider-Futschik E.K. Chedevergne F. Bailly-Botuha C. et al.Lumacaftor-ivacaftor effects on cystic fibrosis-related liver involvement in adolescents with homozygous F508 del-CFTR.J Cyst Fibros. 2021; 21: 212-219Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar These equivocal results reinforce the need for exhaustive non-invasive liver assessment based on imaging including steatosis and liver stiffness quantification to monitor liver involvement under CFTR modulator therapy. Moreover, correlation with CFTR activity biomarkers (sweat chloride test, nasal potential difference test and intestinal short-circuit current measurements) is critical. Finally, further studies are required to describe the liver impact of CFTR modulator therapy depending on liver involvement: focal biliary fibrosis, portosinusoidal vascular disease, and/or steatosis. For instance, Drummond et al. reported markedly decreased steatosis (grade 3 to 1 based on PDFF) and normalized GGT and ALT levels after initiation of lumacaftor/ivacaftor in two patients. Liver elastography is a valuable tool to detect early-stage fibrosis and monitor liver involvement under CFTR modulator therapy. Furthermore, it may demonstrate greater capabilities in liver characterization than solely stiffness assessment. Indeed, shear waves disperse as they pass through the liver and such dispersion can be estimated using the dispersion slope in 2D ultrasound-guided shear wave elastography. This mathematical parameter was shown to be indirectly impacted by lobular inflammation in patients with non-alcoholic steatohepatitis,[6]Sugimoto K. Moriyasu F. Oshiro H. Takeuchi H. Abe M. Yoshimasu Y. et al.The role of multiparametric US of the liver for the evaluation of nonalcoholic steatohepatitis.Radiology. 2020; 296: 532-540Crossref PubMed Scopus (102) Google Scholar but could be biased as it was correlated with liver fibrosis.[7]Deffieux T. Gennisson J.L. Bousquet L. Corouge M. Cosconea S. Amroun D. et al.Investigating liver stiffness and viscosity for fibrosis, steatosis and activity staging using shear wave elastography.J Hepatol. 2015; 62: 317-324Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar Multifrequency 3D magnetic resonance elastography has also been shown to discriminate non-alcoholic steatohepatitis using the damping ratio (derived from the complex shear modulus), which may reflect hepatic inflammation.[8]Allen A.M. Shah V.H. Therneau T.M. Venkatesh S.K. Mounajjed T. Larson J.J. et al.The role of three-dimensional magnetic resonance elastography in the diagnosis of nonalcoholic steatohepatitis in obese patients undergoing bariatric surgery.Hepatology. 2020; 71: 510-521Crossref PubMed Scopus (53) Google Scholar This new research avenue may contribute to a better understanding of liver pathophysiology under CFTR modulator therapy. The authors received no financial support to produce this manuscript. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Jérémy Dana wrote the original draft of the article. Valérie Vilgrain and Dominique Debray reviewed, edited and approved the manuscript. The following are the supplementary data to this article: Download .pdf (.52 MB) Help with pdf files Multimedia component 1