Portal de Periódicos da CAPES

Effects of CFTR modulator therapies on liver stiffness and bile flow: A single-centre experience

2023; Elsevier BV; Volume: 79; Issue: 2 Linguagem: Inglês

10.1016/j.jhep.2023.02.006

1600-0641

Pier Luigi Calvo, Laura Giugliano, Andrea Evangelista, Elisabetta Bignamini, Michele Pinon,

Infant Nutrition and Health

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 Reply to: "The effects of CFTR modulator therapies on liver stiffness and bile flow: A single-centre experience"Journal of HepatologyVol. 79Issue 2PreviewWe would like to thank Calvo et al.1 for their interest in our recently published review on cystic fibrosis-related liver disease (CFLD).2 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. Full-Text PDF We found the review by Jérémy Dana, Dominique Debray et al.[1]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. 2022 Feb; 76: 420-434https://doi:10.1016/j.jhep.2021.09.042. Epub 2021 Oct 2034678405Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar 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. Liver enzyme tests (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) are poorly sensitive markers of liver disease in CFLD and only persistently elevated gamma-glutamyltransferase (GGT)[2]Bodewes F.A.J.A. van der Doef H.P.J. Houwen R.H.J. Verkade H.J. Increase of serum c-glutamyltransferase associated with development of cirrhotic cystic fibrosis liver disease.J Pediatr Gastroenterol Nutr. 2015; 61: 113-118https://doi.org/10.1097/MPG.0000000000000758Crossref PubMed Scopus (27) Google Scholar is associated with the development of cirrhosis. Liver steatosis, a frequent and less aggressive liver disease in patients with cystic fibrosis (CF), may be a cofounding factor in determining GGT alterations.[3]Colombo C. Battezzati P.M. Liver involvement in cystic fibrosis: primary organ damage or innocent bystander?.J Hepatol. 2004 Dec; 41 (15582140): 1041-1044https://doi.org/10.1016/j.jhep.2004.10.002Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Due to the focal nature of the fibrosis and the impossibility of obtaining multiple samples, liver biopsy is rarely performed in patients with CF. Liver stiffness (LS), which is generally evaluated by vibration-controlled transient elastography (VCTE) using Fibroscan,[4]Klotter V. Gunchick C. Siemers E. Rath T. Hudel H. Naehrlich L. et al.Assessment of pathologic increase in liver stiffness enables earlier diagnosis of CFLD: results from a prospective longitudinal cohort study.PLoS One. 2017 Jun 2; 12 (28575039 PMCID: PMC5456384)e0178784https://doi.org/10.1371/journal.pone.0178784Crossref PubMed Scopus (26) Google Scholar could be useful, as it assesses a tissue volume that is about 100-fold larger than that of a standard biopsy specimen. Moreover, VCTE has not only been used for the assessment of classical hepatic damage, but also for biliary damage, such as in primary biliary cholangitis[5]Corpechot C. Carrat F. Gaouar F. Chau F. Hirschfield G. Gulamhusein A. et al.Global & ERN Rare-Liver PBC Study Groups. Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis.J Hepatol. 2022 Dec; 77 (Epub 2022 Jun 28 35777587): 1545-1553https://doi.org/10.1016/j.jhep.2022.06.017Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar and sclerosing cholangitis.[6]Cazzagon N. Lemoinne S. El Mouhadi S. Trivedi P.J. Gaouar F. Kemgang A. et al.The complementary value of magnetic resonance imaging and vibration-controlled transient elastography for risk stratification in primary sclerosing cholangitis.Am J Gastroenterol. 2019 Dec; 114 (31738286): 1878-1885https://doi.org/10.14309/ajg.0000000000000461Crossref PubMed Scopus (20) Google Scholar It has also recently been described as a predictor of clinical outcomes and a useful surrogate endpoint in therapeutic trials. However, VCTE may be influenced by vascular or lymphatic stasis.[7]Jalal Z. Iriart X. De Lédinghen V. Barnetche T. Hiriart J.B. Vergniol J. et al.Liver stiffness measurements for evaluation of central venous pressure in congenital heart diseases.Heart. 2015 Sep; 101 (Epub 2015 Jun 17 26085526): 1499-1504https://doi.org/10.1136/heartjnl-2014-307385Crossref PubMed Scopus (49) Google Scholar CFTR modulator therapies are expected to either prevent or improve CFLD by correcting CFTR defects in cholangiocytes and enhancing HCO3- secretion, as the "bicarbonate umbrella" protects cholangiocytes against hydrophilic bile acids.[8]Beuers U. Hohenester S. de Buy Wenniger L.J.M. Kremer A.E. Jansen P.L.M. Elferink R.P.J.O. The biliary HCO(3)(-) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies.Hepatology. 2010; 52: 1489-1496https://doi.org/10.1002/hep.23810Crossref PubMed Scopus (278) Google Scholar Moreover, increasing HCO3− coupled water in bile may stimulate bile flow and contribute to a reduction in viscosity and biliary obstruction. However, this mechanism has not yet been fully supported by the relatively rare findings of inspissated bile secretion, hence other mechanisms, e.g. involving intestinal inflammation or dysbiosis, are still under investigation.[1]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. 2022 Feb; 76: 420-434https://doi:10.1016/j.jhep.2021.09.042. Epub 2021 Oct 2034678405Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Data regarding the efficacy of CFTR modulators on CFLD are scarce.[9]Drummond D. Dana J. Berteloot L. Schneider-Futschik E.K. Chedevergne F. Nguyen-Khoa T. et al.Lumacaftor-ivacaftor effects on cystic fibrosis-related liver involvement in adolescents with homozygous F508 del-CFTR.J Cyst Fibros. 2022 Mar; 21 (Epub 2021 Aug 26 34454846): 212-219https://doi.org/10.1016/j.jcf.2021.07.018Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Moreover, liver enzyme alterations are often observed in treated patients with CFLD and, if consistent (5-10x), therapy must be discontinued.[10]Wainwright C.E. Elborn J.S. Ramsey B.W. Marigowda G. Huang X. Cipolli M. et al.Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.N Engl J Med. 2015; 373: 220-231https://doi.org/10.1056/NEJMoa1409547Crossref PubMed Scopus (1034) Google Scholar This prospective single-centre cohort study was carried out to evaluate liver function in patients treated with CFTR modulators over time. All patients with CF who were eligible to start ivacaftor/tezacaftor/elexacaftor in the Cystic Fibrosis Centre of the Città della Salute e della Scienza della Città of Torino, Italy were enrolled (Jan 2021-Aug 2022). All patients were evaluated before starting treatment and at 1, 3 and 6 months with haematological examinations and LS measurement obtained by VCTE. Fifty-five patients were enrolled: mean age 17.7 years (SD 4.9), 49% males. Pre-treatment, the mean VCTE was 5.1 kPa (SD 1.8). At baseline, mean AST/ALT/GGT levels were 24.4 (SD 9.8), 26 (SD 17) and 14.5 IU/L (SD 9.1), respectively. The patients were classified by VCTE into: normal ( 7 kPa: n = 11, 20%). Two patients (1 male, 1 female) (3.6%) discontinued treatment at 3 and 6 months. One had a worsening of spirometry (FEV1 reduction) and the other had a worsening of LS with a significant rise (>5x the upper limit of normal) in liver enzyme levels. A significant mean LS reduction (mean difference [MD] -0.46, p = 0.046) was observed at month 6 (Fig. 1A). Patients with normal LS had no significant change in LS over time. In the 5-7 kPa group, a reduction of mean LS was observed at month 6 (MD -0.69, p = 0.059; adjMD -0.70, p = 0.058), although the biggest reduction had been observed at month 1 (MD -0.98, p = 0.003, adjMD -0.98, p = 0.04). The same type of reduction was observed in patients with a LS of >7 kPa who had a reduction in mean LS at month 1 (MD -1.22, p = 0.077, adjMD -1.58, p = 0.018) and at month 6 (MD -2.08, p = 0.001, adjMD-2.07, p <0.001) (Fig 1D). Overall, ALT levels increased at month 1 (MD +13.22, p = 0.005) and remained almost stable at the 6-month follow-up (MD +10.45, p = 0.029) (Fig 1B), with similar patterns in all stiffness groups (Fig. 1E). The same trend was also observed for GGT levels, which were increased at month 1 (MD+ 4.6, p = 0.001) but were almost stable at the 6-month follow-up (MD +3.3, p = 0.019) (Fig 1C). A similar trend in GGT was observed in all stiffness groups (Fig 1F). A significant reduction in LS was present in all patients with CFLD, especially during the first month of treatment, which was associated with a mild rise in ALT and GGT. The speed of this reduction suggests a rapid improvement in biliary excretion with a lower viscosity that might lead to amelioration of bile duct damage. These data imply that, together with, or rather than, liver tests, LS may be monitored during CFTR modulator therapy to improve early detection of a therapeutic response or progression. The authors received no financial support to produce this manuscript. Calvo PL is consultant for Albireo, Mirum and Nestlè. Giugliano L, Evangelista A, Bignamini E and Pinon M have no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. PLC participated in the research design, data collection, data analysis, writing of the article, and approval of the article. L.G. participated in the research design, data collection, statistics and data analysis writing of the article, and approval of the article. A:E. participated in the research design, statistics and data analysis and approval of the article. BE participated in the research design and approval of the article. MP participated in the research design, data collection, writing of the article, and approval of the article. The following are the supplementary data to this article: Download .pdf (3.69 MB) Help with pdf files Multimedia component 1