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©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Lumacaftor/ivacaftor therapy is associated with reduced hepatic steatosis in cystic fibrosis patients
Katherine Kutney, Shannon B Donnola, Chris A Flask, Rose Gubitosi-Klug, MaryAnn O’Riordan, Kimberly McBennett, Thomas J Sferra, Beth Kaminski
Katherine Kutney, Rose Gubitosi-Klug, MaryAnn O’Riordan, Kimberly McBennett, Thomas J Sferra, Beth Kaminski, Department of Pediatric Endocrinology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, United States
Katherine Kutney, Chris A Flask, Rose Gubitosi-Klug, MaryAnn O’Riordan, Kimberly McBennett, Thomas J Sferra, Beth Kaminski, Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, United States
Shannon B Donnola, Chris A Flask, Department of Radiology Case Western Reserve University, Cleveland, OH 44106, United States
Chris A Flask, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, United States
Author contributions: Kutney K designed the study, coordinated the research and wrote the manuscript; Donola SB acquired and analyzed MRI images; Flask CA analyzed MRI images and edited the manuscript; Gubitosi-Klug R designed the study and edited the manuscript; O’Riordan M performed statistical analysis; McBennett K designed the study; Sferra TJ designed the study; Kaminski B designed the study and edited the manuscript.
Supported by a grant from the University Hospitals Fellowship Research Award Program (FRAP).
Institutional review board statement: This study was approved by the University Hospitals Cleveland Medical Center Institutional Review Board.
Informed consent statement: All participants gave written informed consent prior to participating in this study.
Conflict-of-interest statement: Flask CA and Kaminski B reports grants from Cystic Fibrosis Foundation, during the conduct of the study. The other authors declare that they have no conflict of interest.
STROBE statement: The authors have read the STROBE statement-checklist of items and the manuscript was prepared and revised according to the strobe guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Katherine Kutney, MD, Assistant Professor, Department of Pediatric Endocrinology, University Hospitals Cleveland Medical Center, 11100 Euclid Ave., Suite 737, Cleveland, OH 44106, United States. katherine.kutney@uhhospitals.org
Telephone: +1-216-8443661 Fax: +1-216-8448900
Received: September 4, 2019
Peer-review started: September 4, 2019
First decision: October 14, 2019
Revised: October 28, 2019
Accepted: November 25, 2019
Article in press: November 25, 2019
Published online: December 27, 2019
ARTICLE HIGHLIGHTS
Research background
Hepatic steatosis is a common form of cystic fibrosis associated liver disease (CFLD). The journal has published previous manuscripts regarding CFLD.
Research motivation
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are a revolutionary therapy which target the underlying cause of CF for the first time. Currently, very little is known about the impact of CFTR modulator therapy on hepatic disease in CF, despite liver failure being the third leading cause of death in CF patients.
Research objectives
The objectives of this study were therefore to determine whether CF related diabetes (CFRD) is associated with hepatic steatosis and to identify predictors of hepatic steatosis in CF.
Research methods
Patients with established CFLD, end stage lung disease, or persistently elevated liver enzymes were excluded. Mean magnetic resonance imaging (MRI) proton density fat fraction (PDFF) was obtained for all participants. Clinical characteristics and blood chemistries were assessed for possible association with hepatic steatosis. Hepatic steatosis was defined as a mean MRI PDFF > 5%. Patients were grouped by diabetes status and CFTR modulator use (lumacaftor/ivacaftor, no lumacaftor/ivacaftor) to determine between group differences. Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher’s exact test.
Research results
Twelve subjects (60%) had CFRD and 8 subjects (40%) had normal glucose tolerance (NGT). The median hepatic fat fraction for all subjects was 3.0% with a range from 0.0%-21.0%. Six subjects (30%) had hepatic steatosis, defined as PDFF > 5%. Hepatic fat fraction was significantly lower in the 9 subjects receiving CFTR modulator therapy (2.0%, 0.0%-6.4%) than in the 11 subjects not receiving CFTR modulators (4.1%, 2.7%-21.0%), P = 0.002. The median hepatic fat fraction was not statistically different between subjects with CFRD (median, range) (2.2%, 0.0-14.5%) and NGT (4.9%, 2.4-21.0%), P = 0.06.
Research conclusions
In the enclosed manuscript, we demonstrate that lumacaftor/ivacaftor therapy is associated with reduced hepatic fat in CF patients. While hepatic steatosis has historically been considered a benign finding in CF, the spreading epidemic of liver failure from non-alcoholic steatohepatitis makes this doubtful.
Research perspectives
It suggests a previously unrecognized effect of CFTR modulators of CFLD. CFTR modulator status should be included in future studies of hepatic steatosis or CFLD.
