Lumacaftor-ivacaftor effects on cystic fibrosis-related liver involvement in adolescents with homozygous F508 del-CFTR.

Adolescent Aminophenols / adverse effects Aminopyridines Benzodioxoles / adverse effects Biomarkers Cystic Fibrosis / complications Cystic Fibrosis Transmembrane Conductance Regulator / genetics Drug Combinations Humans Liver / diagnostic imaging Mutation Prospective Studies Quinolones
CFTR modulator Cystic-fibrosis liver disease cirrhosis hepatobiliary liver enzymes pediatrics

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:
03 2022
Historique:
received: 05 12 2020
revised: 24 07 2021
accepted: 28 07 2021
pubmed: 30 8 2021
medline: 14 4 2022
entrez: 29 8 2021
Statut: ppublish

Résumé

The effects of lumacaftor-ivacaftor on cystic fibrosis transmembrane conductance regulator (CFTR)-associated liver disease remain unclear. The objective of the study was to describe the effect of this treatment on features of liver involvement in a cystic fibrosis (CF) adolescent population homozygous for F508del. Clinical characteristics, liver blood tests, abdominal ultrasonography (US), and pancreas and liver proton density fat fraction (PDFF) by magnetic resonance imaging, were obtained at treatment initiation and at 12 months for all patients. Biomarkers of CFTR activity (sweat chloride test, nasal potential difference, and intestinal current measurement) were assessed at initiation and at 6 months therapy. Of the 37 patients who started ivacaftor/lumacaftor treatment, 28 were eligible for analysis. In this group, before treatment initiation, 4 patients were diagnosed with multinodular liver and portal hypertension, 19 with other forms of CF liver involvement, and 5 with no signs of liver involvement. During treatment, no hepatic adverse reactions were documented, and no patient developed liver failure. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyl transferase (GGT) decreased significantly following initiation of lumacaftor-ivacaftor, and remained so after 12 months treatment. This was not correlated with changes in clinical status, liver and pancreas US and PDFF, fecal elastase, or lumacaftor-ivacaftor serum levels. The most "responsive" patients demonstrated a significant increase in biomarkers of CFTR activity. These results may suggest a potential beneficial effect of CFTR modulators on CF liver disease and warrant further investigation in larger, prospective studies.

Sections du résumé

BACKGROUND
The effects of lumacaftor-ivacaftor on cystic fibrosis transmembrane conductance regulator (CFTR)-associated liver disease remain unclear. The objective of the study was to describe the effect of this treatment on features of liver involvement in a cystic fibrosis (CF) adolescent population homozygous for F508del.
METHODS
Clinical characteristics, liver blood tests, abdominal ultrasonography (US), and pancreas and liver proton density fat fraction (PDFF) by magnetic resonance imaging, were obtained at treatment initiation and at 12 months for all patients. Biomarkers of CFTR activity (sweat chloride test, nasal potential difference, and intestinal current measurement) were assessed at initiation and at 6 months therapy.
RESULTS
Of the 37 patients who started ivacaftor/lumacaftor treatment, 28 were eligible for analysis. In this group, before treatment initiation, 4 patients were diagnosed with multinodular liver and portal hypertension, 19 with other forms of CF liver involvement, and 5 with no signs of liver involvement. During treatment, no hepatic adverse reactions were documented, and no patient developed liver failure. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyl transferase (GGT) decreased significantly following initiation of lumacaftor-ivacaftor, and remained so after 12 months treatment. This was not correlated with changes in clinical status, liver and pancreas US and PDFF, fecal elastase, or lumacaftor-ivacaftor serum levels. The most "responsive" patients demonstrated a significant increase in biomarkers of CFTR activity.
CONCLUSIONS
These results may suggest a potential beneficial effect of CFTR modulators on CF liver disease and warrant further investigation in larger, prospective studies.

Identifiants

DOI: 10.1016/j.jcf.2021.07.018 PMID: 34454846
pubmed: 34454846
pii: S1569-1993(21)01337-0
doi: 10.1016/j.jcf.2021.07.018
pii:
doi:

Substances chimiques

Aminophenols 0
Aminopyridines 0
Benzodioxoles 0
Biomarkers 0
CFTR protein, human 0
Drug Combinations 0
Quinolones 0
Cystic Fibrosis Transmembrane Conductance Regulator 126880-72-6
ivacaftor 1Y740ILL1Z
lumacaftor EGP8L81APK

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

212-219

Informations de copyright

Copyright © 2021. Published by Elsevier B.V.

Auteurs

David Drummond (D)

Service de Pneumologie et Allergologie Pédiatriques, Centre de Référence Maladies Rares Mucoviscidose et Maladies apparentées, Centre de Ressources et de Compétences pour la Mucoviscidose, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France; Université de Paris, Paris, France.

Jérémy Dana (J)

Université de Paris, Paris, France; Service d'Imagerie pédiatrique, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France; Université de Strasbourg, Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Institut Hospitalo-Universitaire, Strasbourg, France.

Laureline Berteloot (L)

Service d'Imagerie pédiatrique, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France.

Elena K Schneider-Futschik (EK)

Department of Pharmacology & Therapeutics, Lung Health Research Centre, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia; Laboratoire de Biochimie, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France.

Frédérique Chedevergne (F)

Service de Pneumologie et Allergologie Pédiatriques, Centre de Référence Maladies Rares Mucoviscidose et Maladies apparentées, Centre de Ressources et de Compétences pour la Mucoviscidose, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France.

Céline Bailly-Botuha (C)

Service de Pneumologie et Allergologie Pédiatriques, Centre de Référence Maladies Rares Mucoviscidose et Maladies apparentées, Centre de Ressources et de Compétences pour la Mucoviscidose, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France.

Thao Nguyen-Khoa (T)

Service de Pneumologie et Allergologie Pédiatriques, Centre de Référence Maladies Rares Mucoviscidose et Maladies apparentées, Centre de Ressources et de Compétences pour la Mucoviscidose, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France; Laboratoire de Biochimie, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France.

Mathieu Cornet (M)

Service de Pneumologie et Allergologie Pédiatriques, Centre de Référence Maladies Rares Mucoviscidose et Maladies apparentées, Centre de Ressources et de Compétences pour la Mucoviscidose, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France; Université de Paris, Paris, France; INSERM U1151, Institut Necker Enfants Malades, Paris, France.

Muriel Le Bourgeois (M)

Service de Pneumologie et Allergologie Pédiatriques, Centre de Référence Maladies Rares Mucoviscidose et Maladies apparentées, Centre de Ressources et de Compétences pour la Mucoviscidose, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France.

Dominique Debray (D)

Université de Paris, Paris, France; Unité d'Hépatologie pédiatrique, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France.

Muriel Girard (M)

Université de Paris, Paris, France; Department of Pharmacology & Therapeutics, Lung Health Research Centre, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia; Unité d'Hépatologie pédiatrique, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France.

Isabelle Sermet-Gaudelus (I)

Service de Pneumologie et Allergologie Pédiatriques, Centre de Référence Maladies Rares Mucoviscidose et Maladies apparentées, Centre de Ressources et de Compétences pour la Mucoviscidose, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France; Université de Paris, Paris, France; Department of Pharmacology & Therapeutics, Lung Health Research Centre, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Paris, France. Electronic address: isabelle.sermet@aphp.fr.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Phénols › Aminophénols › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Aminopyridines › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzodioxoles › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies néonatales › Mucoviscidose › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Pompes ioniques › Transporteurs d'anions › Transporteurs d'anions organiques › Transporteurs d'anions organiques ATP-dépendants › Protéines associées à la multirésistance aux médicaments › Protéine CFTR › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Préparations pharmaceutiques › Association médicamenteuse › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Système digestif › Foie › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études prospectives › Lumacaftor-ivacaftor effects on cystic...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Quinoléines › Quinolinone › Lumacaftor-ivacaftor effects on cystic...