The Effect of Formula Fortified With Docosahexaenoic Acid (DHA) on Infants With Cystic Fibrosis (CF)

This study brings together several areas of CF and non-CF research: the finding that CF knock-out mice exhibit an abnormality in AA/DHA ratio in membrane bound fatty acids from tissue which expresses CFTR; the fact that very high doses of DHA fed to CF knock-out mice can correct many of the abnormalities seen in these animals; research on fatty acid content in human breast milk; the effects of breast feeding in CF; and the fact that newborn screening for CF is becoming more widespread and may allow for therapeutic interventions very early in life. This is the first study of which we are aware to look at a therapeutic intervention in children diagnosed with CF by newborn screening.

Fatty Acid Metabolism in CF It has been recognized for years that patients with CF have abnormalities in their fatty acid profile.(1) Initially, this was felt to be secondary to malabsorption of essential fats. However, in 1986, Strandvik's laboratory proposed that an abnormality in fatty acid turnover (specifically arachidonic acid metabolism) was a primary problem in patients with CF(2). More recently, Freedman et al (3) have shown that CFTR knockout mice have an abnormality in membrane bound long chain polyunsaturated fatty acids in CFTR expressing tissue with an increased ratio of arachidonic acid (AA) to docosahexanoic acid (DHA) compared to control animals. They have also shown that therapy with formula fortified with high doses of DHA reverses the lipid abnormality and ameliorates the pancreatic duct changes seen in these mice and decreases the inflammatory response to inhaled lipopolysaccharide(3,4).

Freedman et al (5) have gone on to show that abnormalities in membrane bound fatty acids in CFTR expressing tissues in humans are similar to that seen in CF knockout mice. They and Strandvik et al(6) have shown that this fatty acid abnormality is dependent on genotype with more severe fatty acid abnormalities found in patients with "severe" mutations (mutations associated with pancreatic insufficiency). That this abnormality is a primary part of the disease and not secondary to malabsorption is supported by the fact that obligate heterozygotes have fatty acid abnormalities intermediate between affected individuals and normal controls(5). In summary, fatty acid abnormalities appear to be a primary defect in CF and are directly related to the patient's genotype. Furthermore, dietary correction of this fatty acid imbalance improves symptoms in mice. Previous human studies looking at correction of fatty acid imbalances in CF patients have focused on the 18 carbon precursors to AA and DHA (reference 7, for example) or have used very brief treatment periods with eicosapentaenoic acid (EPA) (which was not effective in Freedman's mice) in individuals who already have established disease (8).

Human Breast Milk and Breast Feeding in CF Human breast milk contains low levels of DHA but standard infant formula does not (9).

Traditional infant formulas such as Similac and Enfamil have 18 carbon fatty acids as their source of long chain polyunsaturated fatty acids. These include linoleic acid (18 carbons, 2 double bonds, the last double bond 6 carbons from the methyl end; 18:2n-6) and linolenic acid (18:3n-3). Eighteen carbon fatty acids may be desaturated and elongated to make AA (20:4n-6) and DHA (22:6n-3) which are then incorporated into membrane phospholipids (10). Alternately, these 18 carbon fatty acids can be 0-oxidized in mitochondria and used as an energy source. AA and DHA are necessary for brain growth.(11) The most rapid period of brain growth is the third trimester and it seems likely that this is the most important period of time for accumulation of these fatty acids by the fetus. Prematurely born infants miss out on placental transfer of AA and DHA in the last trimester. They are also more likely to need to use long chain polyunsaturated fatty acids as an energy source since they may have limited caloric intake and increased caloric expenditure due to respiratory disease. It is not surprising, therefore, that AA and DHA supplemented formulas would be found to have a more profound effect upon pre-term than term infants. In fact, new formulas containing AA and DHA have been found to improve neurodevelopment in premature infants (12). However, there is controversy as to whether or not there are neurodevelopmental advantages to term infants being fed fatty acid supplemented formula with some authors reporting a benefit (13) and others (including a very large, double blind, randomized study(14) not finding any difference between term infants fed standard formula and those given long chain polyunsaturated fatty acid supplemented formula. Since brain tissue does not express CFTR and brain levels of AA and DHA were not abnormal in Freedman's mouse experiments (3), it seems unlikely that full term humans with CF would have neurodevelopmental problems related to decreased brain DHA levels different from the general population.