Docahexaenoic Acid (DHA)
DESCRIPTION
Docahexaenoic acid, or DHA, It is a long-chain polyunsaturated fatty acid (LCPUFA) of the n-3 or omega-3 type. DHA is an all cis polyunsaturated fatty acid containing 22 carbon atoms and 6 double bonds.
DHA (cis-4,7,10,13,16,19-Docosahexaenoic Acid)
DHA is also known as DHA; C22: 6n-3 and cis-4, 7, 10, 13, 16, 19-docosahexaenoic acid. DHA is a vital component of the phospholipids of human cellular membranes, especially those in the brain and retina. It is necessary for optimal neural development and visual acuity. DHA is the most abundant omega-3 fatty acid in human breast milk. DHA occurs naturally in the form of triacylglycerols (TAGs).
ACTIONS AND PHARMACOLOGY
ACTIONS
Supplemental DHA may lower triglyceride levels and in some, may elevate HDL-cholesterol levels. DHA is vital for normal brain development for the fetus and infant and for the maintenance of normal brain function throughout life. Supplemental DHA may have anti-inflammatory and immune-modulating activities.
MECHANISM OF ACTION
DHA's triglyceride-lowering property results from the combined effects of inhibition of lipogenesis and stimulation of fatty acid oxidation. Fatty acid oxidation of eicosapentaenoic (EPA) acid occurs mainly in the mitochondria, while DHA undergoes fatty acid oxidation in the peroxisomes.
DHA is taken up by the brain in preference to other fatty acids and is incorporated into the phospholipids of the cell membranes of brain cells and the retina. DHA-containing phospholipids in the cell membranes of the neurons appear to be necessary for neurite elongation and formation of synapses. DHA-containing phospholipids in these cells are believed to be vital for cell signaling. DHA is the prominent structural fatty acid in the gray matter of the brain and retinal tissues of humans, as well as other animals.
PHARMACOKINETICS
DHA-laden TAGs, following ingestion, undergo hydrolysis via lipases to form monoglycerides (MG) and free fatty acids (FFA). Once formed, the MG and the FFA are absorbed by the enterocytes. In the enterocytes, reacylation takes place reforming TAGs, which are then assembled with phospholipids, cholesterol and apoproteins into chylomicrons. The chylomicrons are released into the lymphatics and from there transported to the systemic circulation. In the circulation, the chylomicrons are degraded by lipoprotein lipase, and the fatty acids, including DHA, are taken up in part by the endothelial tissues. DHA is transported via the circulation to various tissues in the body, where it is used for the synthesis of phospholipids. These phospholipids are incorporated into the cell membranes of red blood cells, platelet cells and cells of the brain and retina. DHA is taken up by the brain in preference to other fatty acids. During fetal development, DHA is preferentially transported across the placenta into the fetal circulation. About 10% of DHA is retroconverted to eicosapentaenoic acid (EPA).
INDICATIONS AND USAGE
DHA is indicated to lower triglycerides in some hypertriglyceridemic individuals. It may also be indicated for pregnant women and nursing mothers, for those with peroxisomal disorders (such as Zellweger's syndrome), for cystic fibrosis sufferers, for those with attention deficit disorder, dyslexia and, possibly, those with cognitive impairment and dementia (including Alzheimer's disease).
RESEARCH SUMMARY
A double-blind placebo-controlled study was performed to determine the triglyceride-lowering effect of DHA compared with EPA. In this seven-week study, 234 healthy men were randomly given: DHA in the ethyl ester form at a dose of 3.6 grams daily, the ethyl ester of EPA at 3.l8 grams daily or corn oil at 4 grams daily. Triglycerides decreased by 26% in the DHA group and 21% in the EPA group compared with placebo. Some retroconversion of DHA to EPA was noted, but no significant conversion of EPA to DHA was observed. A slight, but significant, increase in HDL-cholesterol was seen in the DHA group.
In another study on the effect of DHA on serum triglycerides, 27 hypertriglyceridemic subjects were randomized to receive either 1.25 grams of DHA daily, 2.5 grams of DHA daily or a vegetable oil placebo. The DHA was in the natural form derived from triglycerol microalgae, and the study lasted six weeks. Serum triglycerides decreased 17 to 21% and were of similar magnitude in both DHA groups. HDL-cholesterol increased by 6% and again were of similar magnitude in both DHA groups. LDL-cholesterol increased by 9.3% in the 1.25 gram DHA group. This was not significant. An increase of LDL-cholesterol of 13.6% was noted in the 2.5-gram DHA group, which was statistically significant.
DHA is essential for the growth and functional development of the fetal and infant brain and visual system. Human breast milk contains DHA but, unless supplemented with DHA, infant formulas in the U.S. do not contain any significant amounts. (The DHA level in the breast milk of the average American woman is among the lowest in he world.) In Europe and Japan, by contrast, infant formulas are routinely supplemented with DHA.
Whether to supplement these formulas in the U.S. continues to be a matter of considerable controversy. A recent double-blind, randomized, controlled efficacy and safety trial of infant formulas with and without DHA failed to resolve the controversy. No beneficial effects were noted, but more long-term studies are needed to settle the issue. No adverse safety outcomes, measured by growth, infection, atopy and gastrointestinal tolerance, were noted.
The data for supplementation of DHA in infant-formula milk for pre-term infants are more compelling. One study compared pre-term infants on formula without supplemental DHA with infants getting breast milk. The breast-fed infants had an IQ 8.3 points higher at 71/2 to 8 years of age.
Another study comparing pre-term infants receiving formula supplemented with DHA with those receiving formula unsupplemented with DHA demonstrated a significantly higher Bayley Mental Development Index at 12 months in the infants receiving the DHA-supplemented formula. Large scale retrospective studies have shown that pre-term breast-fed infants have an average 5- to 12-point higher IQ later in life than babies fed formula milk without supplemental DHA. The difference in term infants is 2 to 5 IQ points.
Preliminary research suggests that some other therapeutic roles might emerge for DHA. There is some indication that, in both humans suffering from cystic fibrosis and in the cystic fibrosis mouse model, in cell membranes of the lung, pancreas and intestine (the organs most affected by this disease) there are abnormally elevated levels of arachidonic acid and abnormally diminished levels of DHA. In a pilot animal study, daily supplementation of the mouse diet with DHA corrected the lipid imbalance and reversed the progression of the disease after one week. These results have prompted a human clinical trial, the results of which are not yet available.
DHA is similarly deficient, this time in the brain, as well as in the blood and all body tissues, in those suffering from congenital peroxisomal disorders. This includes those with Zellweger cerebro-hepato-renal syndrome, neonatal adrenoleukodystrophy (made famous by the film Lorenzo's Oil) and infantile Refsum disease, characterized by severe psychomotor retardation, retinopathy, liver disease and early death.
In one very encouraging early study of Zellweger Syndrome patients, the ethyl ester of DHA in daily doses of 100 to 500 milligrams was given to 13 patients. Blood DHA levels became normal within a few weeks, liver enzymes returned nearly to normal, and most of the patients showed improvement in vision, liver function, muscle tone and social skill. Normalization of brain myelin was confirmed by MRI in three patients.
DHA deficiencies have been established in the plasma phospholipids of those with attention deficit disorder, and it has been suggested that such deficiencies may be a risk factor in those with Alzheimer's disease. Nutritional intervention trials are indicated.
A small study suggests that DHA might prove beneficial in the treament of dyslexia. Dark adaptation was found to be impaired in 10 dyslexic subjects¡ªcompared with a non-dyslexic control group. A fish oil high in DHA improved dark adaptation in five subjects after one month of supplementation.
CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS
CONTRAINDICATIONS
At present, DHA is contraindicated for hemophiliacs and those taking warfarin, since fish oils themselves are known to increase bleeding time and have anticoagulant properties.
PRECAUTIONS
Infants, pregnant women or nursing mothers should use DHA only if recommended and monitored by a physician.
Because DHA may have antithrombotic activity, those taking warfarin (Coumadin) and those with hemophilia should exercise caution in its use. Similarly, DHA supplementation should be stopped before any surgery.
ADVERSE REACTIONS
There have been no reports of serious adverse events in those taking DHA supplements. Those side effects that have been reported include mild gastrointestinal upsets such as nausea and diarrhea, eructation and "fishy" smelling breath. To date, there have been no significant reports of nosebleeds and easy bruising. One study performed in healthy adult male volunteers found no observable physiological changes in blood coagulation, platelet function or thrombotic tendencies in those consuming 6 grams daily of supplemental DHA for 90 days. Studies have not yet been done on those with hemophilia or those taking warfarin (Coumadin).
INTERACTIONS
No interactions between DHA and aspirin, other NSAIDs or herbs, such as Allium sativum (garlic) and Ginkgo biloba (ginkgo), have been reported. Such interactions, if they were to occur, might be manifested by nosebleeds and increased susceptibility to bruising.
OVERDOSAGE
None reported.
DOSAGE AND ADMINISTRATION
There are several forms of DHA supplements. These include DHA as the triacylglycerol ester derived from fish or from phytoplankton and DHA as the ethyl ester. Infant formulas containing DHA are available in Europe and Japan, but not yet approved in the U.S. Functional foods high in DHA, such as eggs, are now available.
Recommended DHA products should contain antioxidants, such as tocopherol, to protect against their oxidation.
Usual doses consumed by pregnant and nursing women are 100 to 200 milligrams daily. Doses of DHA for hypertriglyceridemics range from 1 to 4 grams. The dose needs to be determined by optimization of triglyceride levels. In those with elevated triglycerides and elevated cholesterol, doses of 1 to 2 grams daily may lower triglyceride levels and increase HDL-cholesterol levels in some. DHA is best tolerated with meals.
LITERATURE
Davidson MH, Maki KC, Kalkowski J, et al. Effects of docosahexaenoic acid on the serum lipoproteins with combined hyperlipidemia: a randomized, double-blind, placebo-controlled trial. J Am Coll Nutr. 1997; 16:236-243.
Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998; 4:1313-1317.
Freedman SD, Katz MH, Parker EM, et al. A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in aftr -/-mice. Proc Natl Acad Sci USA. 1999; 96:13995-14000.
Grimsgaard S, Bonaa KH, Hansen J-B, Nordoy A. Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol- lowering effects but divergent effects on serum fatty acids. Am J Clin Nutr. 1997; 66:649-959.
Horrocks LA, Yeo YK. Health benefits of docosahexaenoic acid. Pharma Res. 1999; 40:211-225.
Lucas A, Stafford M, Morley R, et al. Efficacy and safety of long-chain polyunsaturated fatty acid supplementation of infant-formula milk: a randomized trial. Lancet. 1999; 354:1948-1954
Madsen L, Rustan AC, Vaagenes H, et al. Eicosapentaenoic and docosahexaenoic acid affect mitochondrial and peroxisomal fatty acid oxidation in relation to substrate preference. Lipids. 1999; 34:951-963..
Martinez M, Vazquez E, Garcia-Silva MT, et al. Therapeutic effects of docosahexaenoic acid ethyl ester in patients with generalized peroxisomal disorders. Am J Clin Nutr. 2000; 71:376S-385S.
Nelson GJ, Schmidt PS, Bartolini GL, et al. The effect of dietary docosahexaenoic acid on platelet function, platelet fatty acid composition, and blood coagulation in humans. Lipids. 1997; 32:1129-1136.
Soderberg M, Edlund C, Kristennson K, et al. Fatty acid composition of brain phospholipids in aging and Alzheimer's disease. Lipids. 1991; 26:421-415.
Stordy BJ. Dark adaptation, motor skills, docosahexaenoic acid, and dyslexia. Am J Clin Nutr. 2000; 71:323S-326S.
