(225) Essential Fatty Acid and Lipoprotein Status in Pediatric CF: Impact of CFTR Modulators

Background: Dyslipidemias and essential fatty acid deficiencies (EFAD) are well established complications of cystic fibrosis. In the general population, a high saturated fat diet is associated with hyperlipidemia and an increased risk of cardiovascular disease and type 2 diabetes. With improving life expectancy in CF concerns exist about the risks of the “legacy” high fat CF diet. The impact of CFTR modulators on CF-related dyslipidemia and EFAD is not known yet. Previous studies reported dyslipidemia in people with CF (pwCF) using traditional lipid measures. This study aimed to evaluate the lipoprotein and fatty acid (FA) profiles in children and adolescents with CF and to correlate biochemical results with clinical and molecular findings. Both plasma and RBC samples were studied to compare feasibilities of both methods in identifying EFAD markers.

Methods: Blood samples (n=171) were obtained from 142 (78 female) pediatric CF patients aged 9.8±4.7 years (range 4 mo – 18 yr) during routine laboratory draws at pediatric CF center clinic visit. Pancreatic insufficiency was present in 92% and glucose intolerance or diabetes in 14%. BMI%ile for age Z score was 0.23±0.89 (range: -2.4 – 2.6). F508del mutation was homozygous for 56% and heterozygous for 41%. CFTR modulator therapy had been in place for ≥ 3 mo for 62% of samples. Sample collection began September 2019, paused during the COVID 19 pandemic, then resumed July 2021. All samples were processed by an accredited, regional laboratory with expertise in FA analysis. Serum was separated and refrigerated for lipoprotein analysis. Plasma was separated and frozen, RBCs were washed and frozen for FA analysis. NMR lipoprotein assays (Regensburg, Germany) were conducted to determine particle number and size of lipoprotein classes. Triglyceride, total and HDL-cholesterol were measured directly (Roche). LDL- and VLDL-cholesterol were calculated. To correlate laboratory results with clinical findings, medical records were reviewed, and 24-hour dietary recalls were conducted by a CF clinic dietitian concurrent with study labs.

Results: For pwCF homozygous F508del/F508del, 43% tested positive for EFAD biomarkers (RBC linoleic acid, RBC Mead acid, and RBC Triene/Tetraene or T/T ratio) compared to only 13%of pwCF heterozygous F508del (p≤ 0.01). There was no significant difference in the concentrations of FA and EFAD biomarkers between those with or without CFTR modulator therapy. Lipoprotein abnormalities were identified with 69% and 39% of samples with low HDL and large-HDL, 87% and 52% with increased VLDL particle size and large-VLDL particle number, while only 5% had elevated LDL and/or Small LDL particle numbers. High total cholesterol and high triglycerides were found in 15% and 17%. HDL cholesterol was low in 24%, but only 3% had high LDL cholesterol.

Conclusions: Despite clinical advances and the use of CFTR modulator therapy, EFAD remains prevalent and under-recognized in the pediatric CF population. Among pwCF, those homozygous for f508del may have a higher risk of EFAD. Limitations of this study (4 different CFTR modulator therapies and small sample sizes in each group) may have precluded significant findings for EFAD and lipid profiles, but pwCF receiving modulator therapy appear to have healthier lipid profiles than those without. Evaluation of lipids and FA is not routinely done in pwCF but is should be included in the standard of care for timely dietary interventions.

Acknowledgements: This work was support by the William L. Roberts Memorial Fund.

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