Agostoni, C.1; Heird, W.2
Section Editor(s): Finkel, Yigael M.D., Ph.D.; Baker, , Robert D. Jr. M.D., Ph.D.; Rosenthal, Philip M.D.; Sherman, Philip M. M.D., F.R.C.P.C.
1Department of Pediatrics, San Paolo Hospital, University of Milan, Italy
2Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas USA
Long-chain polyunsaturated fatty acids (LCPUFA, or LCP) include the essential fatty acids alpha-linolenic acid (ALA, 18:3 n-3) and linoleic acid (LA, 18:2 n-6) as well as a number of metabolites of both, including eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4 n-6). Of these, DHA has received the greatest attention, primarily because it appears to be necessary for normal growth and development of the infant brain and visual system. Indeed, it is the predominant n-3 fatty acid in the developing brain and the predominant fatty acid in the retinal photoreceptor membrane. AA is the predominant n-6 fatty acid in the developing brain and is a precursor of biologically important eicosanoids.
Although infants can synthesize DHA and AA from ALA and LA, respectively, formula-fed infants who receive no dietary DHA and AA have lower plasma and erythrocyte levels of DHA and AA than do breast-fed infants who presumably receive adequate amounts of these fatty acids or infants fed formulas supplemented with DHA and AA. In addition, breast-fed infants and infants fed formulas supplemented with DHA and AA have better neurofunctional outcomes than do those fed unsupplemented formulas, particularly over the short term (1). Because of this, formulas throughout the world are now fortified with DHA and AA, and these appear to be safe.
More recently, there has been interest in supplementing pregnant women and breastfeeding women with DHA to improve early developmental outcome of the offspring. However, data concerning this issue are scarce.
Infants or children with fetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis (CF), phenylketonuria (PKU), unipolar depression, aggressive hostility, and congenital peroxisomal disorders, particularly adrenoleukodystrophy, also have low plasma or erythrocyte levels of DHA, suggesting a relationship between low DHA status and symptoms of these disorders. In addition, EPA and DHA are thought to be anti-inflammatory, and their use in a variety of such disorders in both adults and children has been proposed. To date, it is difficult to justify supplementation of DHA in patients with most of these disorders. Those in which the effects of DHA alone or together with other LCP have been investigated are considered below.
The dietary treatment of patients with PKU includes use of manufactured products with little or no phenylalanine. Because this largely precludes the major source of DHA and AA, patients with PKU must rely only on the endogenous synthesis of LCP from their precursors, the content of which also is often suboptimal in dietary products for patients with PKU, particularly that of ALA, the precursor of DHA. In other words, “successful” dietary treatment of PKU appears to result in an iatrogenic decrease of the circulating DHA pools. The addition of DHA and AA (2) or DHA and EPA (3) to the diets of older children with PKU raises plasma levels of these fatty acids and improves the visual response of the treated children. However, 3 years after supplementation, no biochemical or functional differences between supplemented and unsupplemented children are apparent (4).
Because the first few months of life represent the most vulnerable period for brain development, early supplementation with preformed LCP could be an important addition to the nutrition of infants with PKU. Early breastfeeding appears to be associated with a better developmental outcome of older children with PKU (5). Because human milk is a rich source of preformed LCP, it is tempting to suggest that this is the reason for the better developmental outcome (6). Pregnant women with PKU and poorly compliant patients with the condition also might benefit from preformed LCP supplementation. Supplementation of pregnant women should help assure maximal placental transfer of these fatty acids during the last 3 months of pregnancy, and supplementation of poorly compliant patients should provide higher levels of neuroprotection and lessen the theoretical risk of inhibition of endogenous LCP synthesis by toxic phenylalanine by-products.
Recently, a reversible fatty acid imbalance, i.e., elevated AA and low DHA that may underlie the chronic lung and pancreatic lesions of CF, was demonstrated in a mouse model of the human disease (7). Oral administration of high doses of DHA not only corrected the membrane lipid imbalance but also reversed the signs of CF in the affected mice. In addition to this theoretical basis for possible dietary therapeutic interventions, a recent Cochrane review concluded that, “Regular n-3 supplements may provide some benefits for CF patients with relatively few adverse effects” but cautioned that “the evidence, so far, is insufficient to draw firm conclusions” (8). Improvement of pulmonary function (e.g., FEV) has been observed in CF patients after 6-week to 8-month treatments with n-3 LCP including both EPA and DHA. The extent to which improvement was related to the combination of EPA and DHA versus DHA alone requires additional clarification, but recent observations suggest an independent effect of DHA. Effective doses of fish oil range from 4.5 to 5.3 g/d, providing 2.7 to 3.2 g/d of EPA and 1.8 to 2.1 g/d of DHA, but few other doses were evaluated.
The etiology of attention-deficit/hyperactivity disorder (ADHD) is poorly understood, but treatment with amphetamines or a combination of amphetamines and psychiatric counseling is reasonably effective. However, the understandable desire for an alternative to long-term amphetamine treatment and the positive role of DHA in brain function have led to interest in the effect of DHA supplementation for this condition. Indeed, children with ADHD have low plasma and erythrocyte phospholipid levels of DHA and, to a lesser extent, AA. If brain levels also are low, supplementation should increase levels and possibly decrease the symptoms of ADHD. In fact, a variety of supplements are readily available and are being marketed for the treatment of children with ADHD. A single double-blind, placebo-controlled study showed that DHA supplementation for 4 months increased plasma phospholipid DHA dramatically but had no effect on symptoms of ADHD (9). The investigators speculated that a longer period of supplementation, a larger dose, or a combination of AA (e.g., plasma phospholipid AA levels decreased further) and DHA might be effective, but no conclusions on these issues can be made at present.
Patients with generalized peroxisomal disorders (e.g., Zellweger syndrome and adrenoleukodystrophy) have profound brain deficiency of DHA. Consequently, the use of DHA in patients with these disorders is common (10). Blood levels of DHA increase substantially with treatment, and clinical improvement has been reported in uncontrolled studies (11). It has been speculated that DHA acts at the level of the cellular membrane of the oligodendrocyte or neuron, but evidence is lacking. Despite the understandable enthusiasm for use of DHA in these devastating disorders, it has been recommended that such use be undertaken only as a part of a controlled trial.
Preformed LCP may have advantageous effects in some chronic childhood disorders involving the brain (e.g., PKU) or generalized inflammatory diseases (e.g., CF). DHA appears to have a specific neuroprotective role in PKU, and its administration with AA (as is done with human milk and infant formulas) may potentiate this role, at least during supplementation. Specific disorders in which this combination may have a role include other inborn errors of amino acid and organic acid metabolism, as well as the rare peroxisomal disorders. Currently, data from a randomized controlled trial are available only for PKU and ADHD.
CF is the best example of an inflammatory disorder that may benefit from preformed n-3 LCP supplementation. It has been suggested that such supplementation also may be beneficial in intestinal inflammatory disorders, but additional information is required. Interestingly, it is likely that a combination of EPA and DHA (e.g., fish oil) provides optimal anti-inflammatory effects, but the potential negative effect of EPA on growth must be resolved before this can be thoroughly evaluated in infants and children.
Although cautious use of these highly bioactive fatty acids on a purely deductive basis appears reasonably safe, caution is urged to prevent false expectations and potential harm.
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2. Agostoni C, Massetto N, Biasucci G, et al. Effects of long-chain polyunsaturated fatty acid supplementation on fatty acid status and visual function in treated children with hyperphenylalaninemia. J Pediatr 2000; 137:504–9.
3. Beblo S, Reinhardt H, Muntau AC, et al. Fish oil supplementation improves visual evoked potentials in children with phenylketonuria. Neurology 2001; 57:1488–91.
4. Agostoni C, Verduci E, Massetto N, et al. Long-term effects of long-chain polyunsaturated fats in hyperphenylalaninemic children. Arch Dis Child 2003; 88:582–3.
5. Riva E, Agostoni C, Biasucci G, et al. Early breastfeeding is linked to higher intelligence quotient scores in dietary treated phenylketonuric children. Acta Paediatr 1996; 85:56–8.
6. Agostoni C, Verduci E, Massetto N, et al. Plasma long-chain polyunsaturated fatty acids at diagnosis and neurodevelopment through the first 12 months of life in phenylketonuric infants. Dev Med Child Neurol 2003; 45:257–61.
7. Freedman SD, Katz MH, Parker EM, et al. A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr-1-mice. Proc Natl Acad Sci USA 1999; 96:13995–4000.
8. Beckles Willson N, Elliott TM, et al. Omega-3 fatty acids (from fish oil) for cystic fibrosis (Cochrane Review). In: The Cochrane Library, issue 1, 2003. Oxford: Update Software.
9. Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr 2001; 139:189–96.
10. Raymond GV. Peroxisomal disorders. Curr Opin Pediatr 1999; 11:572–9.
11. Martinez M, Vazquez E, Garcia-Silva MT, et al. MRI evidence that docosahexaenoic acid ethyl ester improves myelination in generalized peroxisomal disorders. Neurology 1998; 51:26–32.
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