Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis.
Adult
Aminophenols
/ therapeutic use
Aminopyridines
/ therapeutic use
Benzodioxoles
/ therapeutic use
Cholesterol
/ blood
Cystic Fibrosis
/ complications
Cystic Fibrosis Transmembrane Conductance Regulator
/ genetics
Drug Combinations
Female
Humans
Liver
/ drug effects
Male
Mutation
Quinolones
/ therapeutic use
Treatment Outcome
Young Adult
Cholesterol homeostasis
Cystic fibrosis
Gas chromatography
Lumacaftor/ivacaftor
Pancreatic insufficiency
Journal
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
ISSN: 1873-5010
Titre abrégé: J Cyst Fibros
Pays: Netherlands
ID NLM: 101128966
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
26
11
2019
revised:
17
06
2020
accepted:
17
06
2020
pubmed:
27
6
2020
medline:
15
12
2021
entrez:
27
6
2020
Statut:
ppublish
Résumé
Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508). Aim of the study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508). Cholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin. Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced. These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.
Sections du résumé
BACKGROUND
Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508). Aim of the study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508).
METHODS
Cholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin.
RESULTS
Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced.
CONCLUSIONS
These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.
Identifiants
pubmed: 32586737
pii: S1569-1993(20)30779-7
doi: 10.1016/j.jcf.2020.06.015
pii:
doi:
Substances chimiques
Aminophenols
0
Aminopyridines
0
Benzodioxoles
0
Drug Combinations
0
Quinolones
0
cystic fibrosis transmembrane conductance regulator delta F508
0
lumacaftor, ivacaftor drug combination
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1-e6Informations de copyright
Copyright © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest None of the authors have any relevant conflicts of interest to disclose.