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by the Advisory Committee on Child Health and Nutrition, International Food Manufacturers (IFM)
Summary
Recent research indicates that providing supplements of specific fatty acids, namely docosahexaenoic acid (DHA) and arachidonic acid (AA), to infants, pregnant women and individuals with certain metabolic disorders may offer preventive and therapeutic benefits, especially in relation to brain development. In addition, supplementing both fatty acids together in prescribed amounts may augment their effects on neurotransmission and membrane maturation. Recently, a small group of experts has concluded that “infant formulas for term infants should contain at least 0.2% of total fatty acids as DHA and 0.35% as AA, while formulas for preterm infants should include at least 0.35% DHA and 0.4% AA.” All recent reviews and recommendations have underlined the lack of adverse effects from these supplementations. In addition, providing supplements of DHA to pregnant women was recently shown to be associated with improved early developmental outcome of the offspring.
Signs of low levels of DHA and AA in infants and young children with such pediatric conditions as foetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis, phenylketonuria, unipolar depression, aggressive hostility, and congenital metabolic disorders, particularly adrenoleukodystrophy, suggest that supplements may effect positive changes in their symptoms. However, few studies have addressed the effects of DHA on these conditions and, at least for now, it is difficult to justify supplementation of DHA in patients with most of these disorders.
Certain of the conditions have been studied enough to consider supplementation. Infants and children with phenylketonuria may benefit from diets supplemented with long-chain fatty acids, especially DHA, AA and eicosapentaenoic acid (EPA.) Providing these supplements to pregnant women and to patients who are not in good compliance with a PKU diet may also have some benefit. In cystic fibrosis, supplementing long-chain fatty acids through the addition of fish oil to the diet (effective doses of fish oil range from 4.5-5.3 grams per day) may provide therapeutic effects and, in studies, no adverse effects of such supplementation have been reported. There has been much interest in the relationship between attention-deficit/hyperactivity disorder (ADHD) and diets supplemented with long-chain fatty acids, but not enough studies on this subject have been done for any conclusions to be made at present. As for peroxisomal (metabolic) disorders, no recommendations for routine clinical use of DHA have been issued to date.
Caution is urged in the use of these highly bioactive fatty acids on a purely deductive basis until further studies can substantiate their effects.
Background
Fatty acids occur in two forms:
- Saturated, found in solid form at room temperature and predominantly in animal products
- Unsaturated, found in liquid (oil) form at room temperature and predominantly in plants and fish
Unsaturated fatty acids can also be classified into two types, n-6 (omega 6) or n-3 (omega 3) fatty acids based on their molecular structure.
One of the n-3 unsaturated fatty acids, docosahexaenoic acid (DHA), may play a role in the functional development of the brain during pregnancy and early childhood, and it has been shown to exhibit anti-inflammatory properties. For these reasons, it has received much attention and some experts now suggest that DHA should be used as a supplement for preventive and therapeutic purposes.
DHA is thought to be “conditionally” essential for the early growth and functional development of the brain(1), but this theory remains unproven except in a few fish species(2.) When plasma and red blood cells from infants who receive supplemental DHA are compared to those who have not, the unsupplemented infants appear to be capable of producing only about 70 percent of the DHA they require. Currently, no one knows whether this 30 percent deficit of DHA results in developmental impairment but various studies have suggested that it does.
DHA is the predominant n-3 fatty acid found in the brain. Its turnover rate in the brain is very fast, even faster than has been generally realized in the past. Arachidonic acid (AA) is the predominant n-6 fatty acid in the brain, but its levels seem to be more stable, perhaps because of the relatively high levels of its precursor, linoleic acid (LA), in typical Western diets. Recent studies of these two fatty acids suggest that supplementing AA and DHA together may exert additional positive effects on neurotransmission and membrane maturation.
Preterm infants and, to a lesser extent, term infants supplied with both DHA and AA in amounts and ratios close to those found in mature human milk have been shown to have better neurofunctional outcomes, particularly over the short term. The persistence of benefits over medium and long terms requires further study(3,4.) The findings in term infants are more controversial perhaps due, in part, to variations in study designs leading to different conclusions and recommendations. The last version of the Cochrane Library concludes that, “…there is little evidence from randomized trials of LCP (long-chain polyunsaturated fatty acid) supplementation (in term infants) to support the hypothesis that LCPs confer any benefit on visual or cognitive development”(5.) A slightly more recent meta-analysis of some of the same data(6) showed short-term benefits of DHA supplementation on the visual function of term infants. After considering all available data, a small group of experts(7) recently concluded that “infant formulas for term infants should contain at least 0.2% of total fatty acids as DHA and 0.35% as AA, while formulas for preterm infants should include at least 0.35% DHA and 0.4% AA.” All recent reviews and recommendations have underlined the lack of adverse effects from LCP supplementations.
Providing supplements of DHA to pregnant women were recently shown to be associated with improved early developmental outcome of the offspring suggesting that supplementation during pregnancy may be important(8.)
DHA in chronic pediatric disorders
Low plasma and/or red blood cell DHA content has been documented in infants and children with foetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis, phenylketonuria, unipolar depression, aggressive hostility, and congenital metabolic disorders, particularly adrenoleukodystrophy(9.) These observations suggest a relationship between low DHA status and symptoms of these disorders, but few studies have addressed the effects of DHA on these symptoms. At least for now, it is difficult to justify supplementation of DHA in patients with most of these disorders. The following disorders represent those in which the effects of dietary supplementation with DHA, alone or together with other LCPs, have been investigated.
Phenylketonuria
The dietary treatment of patients affected by deficiencies of phenylalanine-hydroxylase includes the use of vegetables and manufactured products with no- or low-phenylalanine content. Phenylketonuria, the most well known of these syndromes, occurs in about 1 out of 8-10,000 newborns in the Western World. It is well known that high levels of phenylalanine are toxic to brain cells. In accepted dietary treatments, animal foods are not consumed so preformed LCPs are excluded from the diet. Consequently, treated patients must rely on their own internal synthesis of LCP from ALA and LA, the amounts of which are also typically sub-optimal in dietary products for patients with phenylketonuria. In other words, patients who are compliant with the recommended diet may develop a treatment-related decrease of circulating DHA.
In fact, well-treated hyperphenylalaninemics (HPA) have low levels of LCP, particularly DHA, in plasma and red blood cells(10, 11.) The addition of LCP to the diet of older children with phenylketonuria, through supplementation with fish oil for three months(12) or with specific preparations containing AA, EPA (eicosapentaenoic acid), and DHA for one year(13), raises plasma levels of these fatty acids and improves visual response. However, three years after ending the supplementation, no biochemical or functional differences between supplemented and unsupplemented HPA children are apparent(14.) Incidentally, the specific AA/EPA/DHA capsule did enrich the diet of treated HPA children with 0.2-0.3 percent of their daily energy intake as n-6 and n-3 LCP as recommended by some expert panels(15.)
Since the first months of life are the most vulnerable period for brain development, LCP could play a relevant role in the nutrition of PKU infants. Early breastfeeding appears to be associated with a better developmental outcome of older HPA children(16) and since human milk is a rich source of preformed LCPs, it is tempting to suggest that this is the reason for the better outcome. In fact, blood AA levels, along with blood phenylalanine(17), appear to be predictors of the neural performance of children with HPA at 12 months of age. Along with HPA infants and children, pregnant women with HPA and HPA adults who are not compliant with their diet treatments might benefit from LCP supplementation. Providing LCP supplements to pregnant women should help assure maximal placental transfer of LCPs during the last three months of pregnancy. The provision of DHA supplements to poorly compliant patients should increase levels of neuroprotection and lessen the theoretical risk of inhibiting their own LCP synthesis with toxic phenylalanine byproducts.
Cystic fibrosis
Cystic fibrosis (CF) is the most common autosomal recessive genetic disease among Caucasians, affecting approximately 1 in 2500 newborns worldwide. Patients with the disease tend to suffer with chronic pulmonary infections, often with obstruction, and with pancreatic insufficiency. Recently, a reversible fatty acid imbalance that may underlie the chronic lung and pancreatic lesions of CF(18) was demonstrated in a mouse model that mimicked the human disease. The mice had elevated lung and pancreatic membrane levels of AA and low levels of DHA. Oral administration of high doses of DHA not only corrected the membrane fatty acid imbalance but also reversed the signs of CF in the affected organs of the mice. The knowledge of the membrane-bound ratios of AA to DHA now provides a new basis for possible therapeutic diets. In fact, a recent Cochrane review concluded, “Regular n-3 supplements may provide some benefits for people with CF with relatively few adverse effects, although the evidence is insufficient to draw firm conclusions”(19.)
As a matter of interest, other Cochrane reviews of dietary interventions in CF (for example, energy and protein supplements) conclude that no evidence supports their use(20,21.) Positive effects, including improvement of pulmonary function, have been observed with fish oil supplementation (both DHA and EPA) for periods of 6 weeks to 8 months(22,23.) The extent to which improvements are associated with the combination of EPA and DHA versus EPA alone requires further clarification but recent observations suggest an independent effect of DHA alone(24.) Effective doses of fish oil range from 4.5-5.3 grams per day, which provides 2.7-3.2 grams per day of EPA and 1.8-2.1 grams per day of DHA.
All studies have shown the absorption and incorporation of n-3 LCP into circulating phospholipids of patients with CF but some have not shown significant clinical effects(25.) In any case, no adverse effects of such supplementation have been reported. Mizejewski et al(26) suggested recently, “DHA dietary supplementation may provide a valuable adjunct therapeutic modality for CF, especially regarding nutrition and inflammation.” They further suggested that DHA dietary supplementation might have a therapeutic potential for CF approaching that of supplemental folic acid around the time of conception for prevention of neural tube defects and low phenylalanine diets for infants with PKU.
Attention-deficit/hyperactivity (ADHD) disorders
The cause of attention-deficit/hyperactivity disorder (ADHD) is poorly understood. Treatment options include amphetamines, psychiatric counseling, a combination of the two or nothing. The desire for an alternative to long-term treatment with amphetamines along with discoveries about the positive role of DHA in brain function(27) have led to increased interest in the effect of DHA supplementation on this condition.
The introductory paragraph of a recently published study concerning the role of DHA in patients with ADHD(28) summarizes most of what is known about the subject:
Currently, there is considerable interest in the possibility that dietary supplementation with the long-chain polyunsaturated fatty acid, DHA, will decrease the symptoms of ADHD. Indeed, children with ADHD have low plasma and erythrocyte phospholipid levels of DHA(29,30.) Assuming that brain levels also are low, it has been argued that DHA supplementation will increase levels and that the resulting alterations in synaptic transmission will decrease the symptoms of ADHD. Despite a lack of data to support either efficacy or safety, DHA supplements are readily available and are being marketed for the treatment of children with ADHD(31.)”
This double blind, placebo controlled study showed that DHA supplementation for four months dramatically increased plasma phospholipid DHA but had no effect on symptoms of ADHD. The investigators suggested that a longer period of supplementation and/or a larger dose might be required to alter the fatty acid content of the central nervous system. They also suggested that future studies test the hypothesis that AA should be supplemented together with DHA, in a combination similar to that supplied to formula-fed infants and to those with phenylketonuria. No conclusions on this issue can be made at present.
Peroxisomal (metabolic) disorders
Patients with generalized peroxisomal disorders (Zellweger syndrome and adrenoleukodystrophy, for examples) show a profound brain deficiency of DHA and low DHA concentrations in all tissues(32.) DHA supplementation in patients with these disorders has been proposed and various studies have demonstrated that blood levels of DHA increase substantially with treatment resulting in clinical improvement. It has been further suggested that DHA improves myelination in peroxisomal disorders; however, since DHA is not a component of myelin, the mechanism is unclear(33,34.) The authors of these uncontrolled studies speculate that DHA’s action may be at the level of the cellular membrane of the oligodendrocyte or neuron. Despite the enthusiasm for the use of DHA in peroxisomal disorders, Noetzel recommends that DHA supplementation be undertaken only as a part of a controlled trial(35.) No recommendations for routine clinical use of DHA in peroxisomal disorders have been issued to date.
Conclusions
LCPs may have advantageous effects in some chronic childhood disorders including those involving the brain (PKU, for example) and disorders in which inflammation plays a primary role (CF, for example.) DHA may play a neuroprotective role in brain disorders and its administration along with AA (as occurs in human milk and in infant formulas) may augment the effects, at least during the period of supplementation. Specific disorders involving the brain in which this combination may play a role include inborn errors of amino acid and organic acid metabolism as well as the rare peroxisomal disorders. At present, phenylketonuria is the only one of these disorders for which data from a randomized controlled trial are available.
CF is the best example of an inflammatory disorder that may benefit from n-3 LCP supplementation. Positive functional effects of supplementation in patients with CF have been observed in randomized controlled trials. It has also been suggested that n-3 LCP supplementation may be beneficial in intestinal inflammatory disorders(36.) Although further information is necessary, it is likely that a combination of EPA and DHA (as found in fish oil, for example) is necessary for optimal anti-inflammatory effects.
Caution is urged in the use of these highly bioactive fatty acids on a purely deductive basis. Such a practice, even if not harmful, may raise false expectations.
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April 2003
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