CFTR Modulator Therapy with Lumacaftor/Ivacaftor Alters Plasma Concentrations of Lipid-Soluble Vitamins A and E in Patients with Cystic Fibrosis.

Olaf Sommerburg,Jürgen Okun,Mirjam Stahl,Simon Y Gräber,Mark O Wielpütz,Patricia Leutz-Schmidt,S Philipp Schneider,Susanne Hämmerling,Marcus A Mall,Werner Siems,Claus-Dieter Langhans

doi:10.3390/antiox10030483

Abstract

Rationale: Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leads to impaired pancreatic function and therefore reduced intestinal absorption of lipids and fat-soluble vitamins especially in patients with CF developing pancreatic insufficiency (PI). Previous studies showed that CFTR modulator therapy with lumacaftor-ivacaftor (LUM/IVA) in Phe508del-homozygous patients with CF results in improvement of pulmonary disease and thriving. However, the effects of LUM/IVA on plasma concentration of the lipid soluble vitamins A and E remain unknown. Objectives: To investigate the course of plasma vitamin A and E in patients with CF under LUM/IVA therapy. Methods: Data from annual follow-up examinations of patients with CF were obtained to assess clinical outcomes including pulmonary function status, body mass index (BMI), and clinical chemistry as well as fat-soluble vitamins in Phe508del-homozygous CF patients before initiation and during LUM/IVA therapy. Results: Patients with CF receiving LUM/IVA improved substantially, including improvement in pulmonary inflammation, associated with a decrease in blood immunoglobulin G (IgG) from 9.4 to 8.2 g/L after two years (p < 0.001). During the same time, plasma vitamin A increased significantly from 1.2 to 1.6 µmol/L (p < 0.05), however, levels above the upper limit of normal were not detected in any of the patients. In contrast, plasma vitamin E as vitamin E/cholesterol ratio decreased moderately over the same time from 6.2 to 5.5 µmol/L (p < 0.01). Conclusions: CFTR modulator therapy with LUM/IVA alters concentrations of vitamins A and vitamin E in plasma. The increase of vitamin A must be monitored critically to avoid hypervitaminosis A in patients with CF.

Highlights

Cystic fibrosis (CF) is a complex multi-organ disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR gene) [1,2]
45 patients with CF were homozygous for the Phe508del CFTR mutation, at least two years old and treated with
Mutation-specific CFTR modulator therapy led to significant clinical improvements in patients with CF

Summary

Introduction

Cystic fibrosis (CF) is a complex multi-organ disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR gene) [1,2]. The CFTR protein forms a cAMP-regulated ion channel responsible for chloride and bicarbonate secretion in epithelial cells. Since CFTR regulates the epithelial Na+ channel (ENaC), it plays a central role in the adequate humidification of epithelial surfaces [3]. The CFTR defect in the lungs leads to chronic airway mucus obstruction, infection, and inflammation. The resulting progressive lung damage remains with about 80% the leading cause of morbidity and mortality in CF [4]. Of the about 2100 CFTR mutations known today, the Phe508del mutation is present in about 90% of cases on at least one allele, and nearly half of all CF patients are homozygous for Phe508del [5]

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