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

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.

Papilledema and hypervitaminosis A after elexacaftor/tezacaftor/ivacaftor for cystic fibrosis

“…Although such work has not been done on elexacaftor/tezacaftor/ivacaftor, evidence indicates that monotherapy with ivacaftor substantially improves intestinal absorption in CF patients through a variety of means, including reversal of pancreatic insufficiency, 2 increased intestinal pH, 5 and decreased inflammation. 6 Recently, Sommerburg et al 7 found that therapy with lumacaftor/ivacaftor significantly increased patients' serum vitamin A levels, indicating that improved intestinal function includes increased absorption of vitamin A.…”

Update on the management of vitamins and minerals in cystic fibrosis

“…In the current era, frank micronutrient deficiencies of vitamin A and vitamin E are rarely encountered in patients with CF, presumably owing to early diagnosis and initiation of pancreatic enzymes, CF‐specific vitamin supplementation, and possibly improved absorption with HEMs. On the contrary, instances of elevated vitamin levels are now seen 12–17 . Also, once solely considered as micronutrients, our latest understanding of the role of fat‐soluble vitamins and trace minerals has evolved.…”

Cystic fibrosis year in review 2021

“…For example, changes in fat soluble vitamins. In 45 patients, over age 2 years who had treatment with LUM/IVA for one year, the following was seen, no changes in Vitamin D levels or Retinol, an increase in international normalized ratio (INR), and a decrease in Vitamin E 16 . By two years of treatment, there were no additional changes in Vitamin D or INR, yet retinol increased, and Vitamin E decreased 16 .…”