NETwork of Linoleic Acid Supplementation in Cystic Fibrosis (NETLACF)

Double-blind Randomized Controlled Study of Linoleic Acid Supplementation for 1 Year in Patients With Cystic Fibrosis - Influence on Clinical Status and Metabolism

Undernutrition is a common problem in patients with cystic fibrosis (CF) despite international consensus that the patients shall be given 120-200% of energy recommendations. Studies imply that one problem might be that the patients are not compensated for the essential fatty acid deficiency (linoleic acid, LA), which is well known in these patients. This deficiency is shown not to be due to fat malabsorption, but related to an increased turnover of arachidonic acid, a transformation product of LA. This abnormality is related to mutations associated with a more severe clinical phenotype. The most common and typical symptom of LA deficiency is poor growth. Studies in animals have further indicated that many of the symptoms in CF are related to the deficiency. A series of recent prospective studies from Wisconsin corroborate the importance of LA for growth. In Sweden LA has been supplemented to most patients since the late 70´, and the condition of patients have been among the leading in the world regarding growth, pulmonary function and survival. Short-term studies have shown better effect of LA supplementation compared to similar supply of energy without including extra LA. There are few long-term studies, performed before the gene was identified, giving very heterogeneous patient groups in regard to genotype, but with some positive results on growth and physiology. It´s of interest that modern personalized extremely expensive therapy with correctors and potentiators for Cystic Fibrosis Transmembrane Conductance Regulator may influence lipid metabolism. LA might thus tentatively be a cheap adjuvant to this modern therapy, but this has to be specially studied. The aim of the study is to find if there are differences in clinical and metabolic outcome between two groups, blindly given similar amount of extra calories, in one group consisting of linoleic acid.The benefit for the patients would be great if the expected positive effect can be proved in the planned study. The treatment will be cheap and without adverse effects. From socioeconomic point of view is would be a great advantage.

Two group of matched children with CF were randomized to two type of oils given 20 g oil and 600 mg DHA daily for one year and anthropometry, pulmonary function, biochemistry, resting energy expenditure, lipid mediators, inflammatory and intestinal markers were studied at start and at 6 months and 1 year. Dietary intake was controlled and life quality recording at start and end of study.

arachidonic acid,, lipid mediators, cytokines, growth, pulmonary function, IGF-1, resting energy expenditure, docosahexaenoic acid

Questionaire about health, physical activity, well being (8 items), CFQ-child + CFQ- parents (higher rates are better) The score changes are analysed.The CFQ considers the physical, image, digestive, respiratory, emotional, social, food, treatment, vitality, health, social role and weight domains. Each domain has a score and its sum generates the total score, whose values can vary from 0 to 100 The scores will also be related to measurements.

change in lipid mediators in blood and urine, ion trap- Mass Spectrometry, picoMol (> 150 products of both the n-6 and n-3 series)

Inclusion Criteria: Two mutations related to severe clinical status such as dF508, or other stop mutations or class II mutations. Severe status includes pancreatic insufficiency Exclusion Criteria: Liver cirrhosis and/or portal hypertension, transplantation or on transplantation list, intake of lipid supplements the latest 2 months

The results will be anonymous and reported to peer review journals for publication. Beside the local PIs there will be other local staff involved and for the analyses also co-workers as shown in the study protocol which will be attached for review.

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Wheelock CE, Strandvik B. Abnormal n-6 fatty acid metabolism in cystic fibrosis contributes to pulmonary symptoms. Prostaglandins Leukot Essent Fatty Acids. 2020 Sep;160:102156. doi: 10.1016/j.plefa.2020.102156. Epub 2020 Jun 26.

Strandvik B. Is the ENaC Dysregulation in CF an Effect of Protein-Lipid Interaction in the Membranes? Int J Mol Sci. 2021 Mar 8;22(5):2739. doi: 10.3390/ijms22052739.

Strandvik B. Nutrition in Cystic Fibrosis-Some Notes on the Fat Recommendations. Nutrients. 2022 Feb 18;14(4):853. doi: 10.3390/nu14040853.