OMEGA-3 FATTY ACIDS
Omega-3 fatty acids are polyunsaturated, meaning they contain more than one double bond. They are called omega-3 fatty acids because the first double bond counting from the methyl end of the fatty acid is located at the third carbon atom (diagram). Scientific abbreviations for fatty acids can tell the reader something about their structure. The scientific abbreviation for alpha-linolenic acid (ALA) is 18:3n-3. The first part (18:3) tells the reader that ALA is an 18-carbon fatty acid with three double bonds, while the second part (n-3) tells the reader that ALA is an omega-3 fatty acid. ALA is considered an essential fatty acid because it is required for health, but cannot be synthesized by humans. Humans can synthesize other omega-3 fatty acids from ALA, including eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). Because EPA and DHA are abundant in certain species of fish, they are often referred to as marine-derived omega-3 fatty acids, while ALA is considered a plant-derived omega-3 fatty acid (1).
Linoleic acid (18:2n-6) is another essential polyunsaturated fatty acid that contains 18 carbon atoms, but it differs from ALA in that it is an omega-6 fatty acid and has only two double bonds (diagram). It has been estimated that the ratio of omega-6 to omega-3 fatty acids in the diet of early humans was 1:1 (2), but the ratio in the typical western diet is now almost 10:1 due to increased use of vegetable oils rich in linoleic acid and declining fish consumption (3). A large body of scientific research suggests that increasing the relative abundance of dietary omega-3 fatty acids may have a number of health benefits (see sections on Disease Prevention and Disease Treatment).
Alpha-linolenic acid (ALA)
Presently, the only known function of ALA in humans is to serve as a precursor for the synthesis of the long-chain omega-3 fatty acids, EPA and DHA (see the section on Sources).
Eicosapentaenoic acid (EPA)
Eicosanoid synthesis: Eicosanoids are chemical messengers derived from 20-carbon polyunsaturated fatty acids that play critical roles in immune and inflammatory responses. Both 20-carbon omega-6 fatty acids (arachidonic acid) and 20-carbon omega-3 fatty acids (EPA) can be found in cell membranes. During an inflammatory response, arachidonic acid and EPA are metabolized by enzymes known as cyclooxygenases and lipoxygenases to form eicosanoids. In those who consume typical western diets, the amount of arachidonic acid in cell membranes is much greater than the amount of EPA, resulting in the formation of more eicosanoids derived from arachidonic acid than EPA. However, increasing omega-3 fatty acid intake increases the EPA content of cell membranes and decreases the arachidonic acid content, resulting in higher proportions of eicosanoids derived from EPA. Physiologic responses to arachidonic acid-derived eicosanoids differ from responses to EPA-derived eicosanoids. In general, eicosanoids derived from EPA are less potent inducers of inflammation, blood vessel constriction, and clotting than eicosanoids derived from arachidonic acid (3, 4).
Docosahexaenoic acid (DHA)
Vision
DHA is found in very high concentrations in the cell membranes of the retina, which conserves and recycles DHA even when omega-3 fatty acid intake is low. Light entering the eye is sensed by the retina, which generates a nerve impulse that is interpreted as vision by the brain. Studies in animals indicate that DHA is required for the normal development and function of the retina. Moreover, these studies suggest that there is a critical period during retinal development when inadequate DHA will result in permanent abnormalities in retinal function. Recent research indicates that DHA plays an important role in the regeneration of the visual pigment rhodopsin, which plays a critical role in the visual transduction system that converts light to vision (diagram) (5).
Nervous system function
Compared to the rest of the body, the DHA content of the human brain and nervous system is quite high (6). Several possible roles for DHA in the nervous system have been proposed. DHA can protect nerve cells (neurons) cultured outside the body from apoptosis (programmed cell death), leading to the hypothesis that high levels of DHA in the brain may serve to enhance the survival of neurons. Increased incorporation of DHA into cell membranes is known to affect membrane physical properties, such as fluidity. Changes in the physical properties of neuronal membranes may affect nerve transmission processes by altering neurotransmitter availability or altering the functions of neuronal membrane receptor proteins (7). Although DHA is thought to be important to neurologic function, the mechanisms of DHA action in the nervous system require further clarification.
Omega-3 fatty acids
Regulation of gene expression
The results of cell culture and animal feeding studies indicate that omega-3 fatty acids can modulate the expression of a number of genes, including those involved with fatty acid metabolism and inflammation. Although the mechanisms require further clarification, omega-3 fatty acids may regulate gene expression through their effects on the activity of transcription factors (proteins that alter gene transcription by binding to specific response elements on target genes). Transcription factors that appear to be modulated by omega-3 fatty acids include NF-kappa B and members of the peroxisome proliferator-activated receptor (PPAR) family (4, 8).
Linoleic acid
ALA and linoleic acid compete for the same elongase and desaturase enzymes in the synthesis of other biologically important polyunsaturated fatty acids, such as arachidonic acid, EPA and DHA (diagram). Consequently, high linoleic acid intakes relative to ALA intakes result in higher levels of arachidonic acid relative to EPA and DHA in cell membranes. Because EPA and DHA from the diet are rapidly incorporated into cell membranes, the interaction between dietary linoleic acid and ALA is probably most important in individuals who have low EPA and DHA intakes (1).
Outside the body, polyunsaturated fats become rancid (oxidized) more easily than saturated fats. Fat-soluble antioxidants, such as vitamin E, play an important role in preventing the oxidation of polyunsaturated fatty acids. Results of animal studies and limited data in humans suggest that the amount of vitamin E required to prevent lipid peroxidation inside the body increases with the amount of polyunsaturated fat consumed (9). One widely used recommendation for vitamin E intake is 0.6 mg of alpha-tocopherol per gram of dietary polyunsaturated fat. This recommendation was based on a small study in men and the ratio of alpha-tocopherol to linoleic acid in the U.S. diet, and has not been verified in more comprehensive studies. It is presently unclear whether EPA and DHA are more susceptible to oxidative damage within the body (10). Although high vitamin E intakes have not been found to decrease biomarkers of oxidative damage when EPA and DHA intakes are increased (11, 12), some experts believe that an increase in omega-3 fatty acid intake should be accompanied by an increase in vitamin E intake (1).
Cases of clinically apparent omega-3 fatty acid deficiency are quite rare, but they provide evidence of the essentiality of omega-3 fatty acids. A young girl receiving intravenous lipid emulsions with very little ALA developed visual problems and sensory neuropathy, which resolved when she was switched to an emulsion containing more ALA (13). Scaly and hemorrhagic skin and scalp inflammations, impaired wound healing and growth retardation were described in a series of nine nursing home patients fed by gastric tube for several years with a diet formula that contained very little ALA (14).
In 2002, the Food and Nutrition Board of the Institute of Medicine established adequate dietary intake levels (AIs) for omega-3 fatty acids, which are listed in the table below (1).
|
Adequate
Intake (AI) for Omega-3 Fatty Acids
|
||||
| Life Stage | Age | Source |
Males
(g/day)
|
Females
(g/day)
|
| Infants | 0-6 months | ALA, EPA, DHA* |
0.5
|
0.5
|
| Infants | 7-12 months | ALA, EPA, DHA |
0.5
|
0.5
|
| Children | 1-3 years | ALA |
0.7
|
0.7
|
| Children | 4-8 years | ALA |
0.9
|
0.9
|
| Children | 9-13 years | ALA |
1.2
|
1.0
|
| Adolescents | 14-18 years | ALA |
1.6
|
1.1
|
| Adults | 19 years and older | ALA |
1.6
|
1.1
|
| Pregnancy | All ages | ALA |
-
|
1.4
|
| Breastfeeding | All ages | ALA |
-
|
1.3
|
*ALA, alpha-linolenic acid; EPA, eicosapentaenoic acid, DHA, docosahexaenoic acid
Infants
DHA was recognized as important for the developing brain, which accumulates large amounts of DHA during the first two years of life. Although infants can synthesize EPA and DHA from ALA, all omega-3 fatty acids present in human milk and some infant formulas (ALA, EPA, and DHA) can contribute to the AI for infants (1).
Children and adults
Since clinically apparent omega-3 fatty acid deficiency is virtually nonexistent in free-living children and adults, the AIs for children and adults were based on the median dietary intakes of ALA in the U.S (1). In contrast to infants, the recommendation addresses only intake of ALA.
Pregnant and breastfeeding women
The AIs for pregnant and lactating women were based on median intakes of ALA in the U.S. because of a lack of evidence for determining the requirements for omega-3 fatty acids during pregnancy and lactation (1). Despite the known need of infants for EPA and DHA, the current recommendation is only for ALA intake.
Impaired visual and neural development
Preterm infants
Because the last trimester of pregnancy is a critical period for the accumulation of DHA in the brain and retina, preterm infants are particularly vulnerable to adverse effects of insufficient DHA on visual and neural development (15). Human milk contains DHA in addition to ALA and EPA, but until recently, ALA was the only omega-3 fatty acid present in conventional infant formulas. Although preterm infants can synthesize DHA from ALA, they cannot synthesize enough to prevent declines in plasma and cellular DHA levels without additional dietary intake. For these reasons, it was proposed that preterm infant formulas be supplemented with enough DHA to bring plasma and cellular DHA levels of formula-fed infants up to those of breast-fed infants (16). Although early studies found evidence that formula supplemented with fish oil containing EPA and DHA improved visual acuity in preterm infants (17), concern was raised by findings of decreased plasma arachidonic acid levels, which were associated with decreased growth in those infants receiving the fish oil-supplemented formula (18). This effect was attributed to high EPA concentrations in the supplemented formula, which could interfere with the synthesis of arachidonic acid. Eliminating EPA and supplementing preterm formulas with DHA and arachidonic acid has been found to normalize plasma DHA levels in preterm infants without adverse effects on growth. Although human milk is still considered the best source of omega-3 fatty acids for infants, there is substantial evidence that adding DHA to the formula of preterm infants improves the early development of the visual system. Preterm infants fed formulas with DHA added had significantly improved measures of visual function compared to preterm infants fed DHA-free formulas in five out of five randomized controlled trials (17,19-22). A meta-analysis that combined the results of four randomized controlled trials found that infants fed formulas with DHA added showed significant improvements in visual acuity at two and four months of age compared to infants fed DHA-free formulas (23). Moreover, in six randomized controlled trials where arachidonic acid was also added to DHA-supplemented formulas, no adverse affects on growth were observed (24).
Term infants
The benefits of adding DHA to the formula of term infants are less clear than those seen in preterm infants. Some controlled trials found that DHA supplementation of healthy term infants improved visual acuity during the first year of life, but others found no effect (16, 24). A systematic review of nine controlled trials found little evidence to support the hypothesis that supplementation of formula with arachidonic acid and DHA improves visual or general development in term infants (25). However, none of the studies found that the addition of DHA to formula for up to one year resulted in adverse effects on growth.
Although infant requirements for DHA have been the subject of a great deal of research, there has been relatively little investigation of maternal requirements for omega-3 fatty acids, despite the fact that the mother is the sole source of omega-3 fatty acids for the fetus and exclusively breast-fed infant (26). The results of randomized controlled trials during pregnancy suggest that omega-3 fatty acid supplementation does not decrease the incidence of pregnancy-induced hypertension or preeclampsia (27, 28) but may result in modest increases in length of pregnancy, especially in women with low omega-3 fatty acid consumption. In women with high risk pregnancies, fish oil supplementation that provided 2.7 g/day of omega-3 fatty acids during the last trimester of pregnancy lowered the risk of premature delivery from 33% to 21% (29). In healthy Danish women, fish oil supplementation that provided 2.7 g/day of omega-3 fatty acids increased the length of pregnancy by an average of four days (27). More recently, consumption of only 0.13 g/day of DHA from enriched eggs during the last trimester of pregnancy increased the length of pregnancy by an average of 6 days in a low-income population in the U.S (30). Although adverse effects of fish oil or DHA supplementation during pregnancy have not been reported, a number of experts feel it is premature to make specific recommendations for EPA or DHA intake during pregnancy based on available research (31).
Evidence is accumulating that increasing omega-3 fatty acid intake can decrease the risk of cardiovascular diseases by 1) preventing arrhythmias that can lead to sudden cardiac death, 2) decreasing the risk of thrombosis (blood clot formation) that can lead to heart attack or stroke, 3) decreasing serum triglyceride levels, 4) slowing the growth of atherosclerotic plaque, 5) improving vascular endothelial function, 6) lowering blood pressure slightly, 7) decreasing inflammation (32). The American Heart Association found the evidence discussed below convincing enough to recommend that all adults eat a variety of fish, particularly oily fish, at least twice weekly, in addition to consuming vegetable oils rich in ALA (see the section on Sources).
Fish consumption and coronary heart disease
Several well-designed prospective studies have found that men who eat fish at least once weekly have lower mortality from coronary heart disease (CHD) than men who do not eat fish (33-35). One such study followed 1822 men for 30 years and found that mortality from CHD was 38% lower in men who consumed an average of at least 35 g (1.2 ounces) of fish daily than in men who did not eat fish, while mortality from myocardial infarction (MI) was 67% lower (36). The cardioprotective effects of fish consumption may not be confined to those consuming the typical western diet. A study in Shanghai, China that followed more than 18,000 men for 10 years found that men who consumed more than 200 g (7 ounces) of fish or shellfish weekly had a risk of fatal acute MI that was 59% lower than men who consumed less than 50 grams (2 ounces) weekly (37). However, not all prospective studies have observed significant associations between fish or omega-3 fatty acid intake and cardiovascular disease mortality in men, including the Health Professionals Follow-up Study in the U.S. (38) and the Seven Countries Study (39). Less information is available regarding the effects of higher omega-3 fatty acid and fish intakes in women. In the Nurses’ Health Study, a large prospective study that followed 84,668 women for 16 years, CHD mortality was 29-34% lower in women who ate fish at least once a week compared to women who ate fish less than once a month (40).
Alpha-linolenic acid (ALA) consumption and coronary heart disease
There is some epidemiological evidence indicating that increased ALA intake is associated with decreased risk of MI and fatal CHD. In a prospective study of 43,757 male health professionals followed for six years, a relatively small increase in ALA intake (1% of total energy) was associated with a 59% decrease in the risk of acute MI (41). Similarly, among 76,283 female nurses followed for 10 years, women with the highest ALA intakes had a risk of fatal CHD that was 45% lower than women with the lowest intakes (42). Interestingly, oil and vinegar salad dressing was an important source of dietary ALA in this population. Women who consumed oil and vinegar salad dressing 5-6 times weekly had a risk of fatal CHD that was 54% lower than those who rarely consumed it even after adjusting the analysis for vegetable intake. In contrast, a study of 667 elderly Dutch men followed for 10 years found no beneficial effect of higher ALA intakes on the incidence of coronary artery disease (43). Although limited, evidence from large prospective studies suggests that increased ALA intakes may decrease the risk of CHD, especially in populations with relatively low levels of fish consumption.
Fish consumption and sudden cardiac death
Several studies have found inverse relationships between fish consumption and sudden cardiac death. In a prospective study, omega-3 fatty acid intakes equivalent to two fatty fish meals per week were associated with a 50% decrease in the risk of primary cardiac arrest (44). In a large prospective study of more than 20,000 male physicians, men who ate fish at least once a week had a risk of sudden death that was 52% lower than men who ate fish less than once a month (45). Plasma levels of EPA and DHA were also inversely related to the risk of sudden death, supporting the idea that omega-3 fatty acids are at least partially responsible for the beneficial effect of fish consumption on sudden cardiac death (46).
A stroke is a result of impaired blood flow to a region of the brain, which may be due to obstruction of a blood vessel by a blood clot (thrombotic or ischemic stroke) or the rupture of a blood vessel (hemorrhagic stroke). Some prospective studies that have examined the relationship between fish or omega-3 fatty acid intake and total stroke incidence have found increased fish intake to be beneficial (47, 48), while others found no beneficial effect (49, 50). More recently two large prospective studies found that increased fish and omega-3 fatty acid intakes were associated with significantly lower risks of thrombotic or ischemic stroke, but were not significantly associated with the risk of hemorrhagic stroke. In a study that followed 79,839 nurses for 14 years, women who ate fish at least twice weekly had a risk of thrombotic stroke that was 52% lower than women who ate fish less than once monthly (51). Similarly, in a study that followed 43,671 male health professionals for 12 years, men who ate fish at least once monthly had a risk of ischemic stroke that was 43% lower than men who ate fish less than once monthly (52). Although the effects of increased omega-3 fatty acid intake on the incidence of stroke has not been studied as thoroughly as that of CHD, available evidence suggests that increased fish intake may decrease the risk of thrombotic or ischemic stroke but not hemorrhagic stroke.
For additional information on omega-3 fatty acids and cardiovascular diseases, see the section on Disease treatment.
Unlike normal cells, cancer cells proliferate rapidly and are resistant to apoptosis. Marine-derived fatty acids have been found to inhibit proliferation and promote apoptosis in breast, prostate, and colon cancer cell lines cultured outside the body, and to inhibit proliferation in human colorectal mucosa (53). Studies in animal models of cancer also indicate that increased intake of EPA and DHA decreases the occurrence and progression of mammary, prostate, and intestinal tumors (54). Although numerous epidemiological studies have examined the relationships between dietary fish intake and cancer incidence in humans, few have demonstrated significant inverse relationships between fish or omega-3 fatty acid intake and the risk of breast, prostate, or colorectal cancer (54, 55). Findings of significant inverse relationships in a few studies conducted in areas where fish consumption is relatively high are encouraging (55). Future epidemiological studies that specifically assess EPA and DHA intake and tissue concentrations as well as dietary omega-6 to omega-3 fatty acid ratios may provide more information regarding omega-3 fatty acid intake and human cancer risk.
The results of randomized controlled trials in individuals with documented coronary heart disease (CHD) suggest a beneficial effect of dietary and supplemental omega-3 fatty acids. Based on the results of these studies, the American Heart Association has recommended that individuals with documented CHD consume approximately 1 g/day of EPA and DHA combined (EPA + DHA) (3).
Dietary intervention trials: CHD
Total mortality and fatal myocardial infarction (MI) decreased by 29% in male MI survivors advised to increase their weekly intake of oily fish to 200-400 g (7-14 ounces), which was estimated to provide an additional 500-800 mg/day of marine-derived omega-3 fatty acids (56). In another dietary intervention trial, patients who survived a first MI were randomly assigned to usual care or advised to adopt a Mediterranean diet that was higher in omega-3 fatty acids (especially ALA) and lower in omega-6 fatty acids than the standard western-style diet. After almost four years, those on the Mediterranean diet had a risk of cardiac death and nonfatal MI that was 38% lower than the group that was assigned to usual care (57). Although higher plasma ALA levels were associated with better outcomes, the benefit of the Mediterranean diet cannot be attributed entirely to increased ALA intakes since intakes of monounsaturated fatty acids and fruits and vegetables also increased.
Supplementation trials: CHD
In the largest randomized controlled trial of supplemental omega-3 fatty acids to date, CHD patients who received supplements providing 850 mg/day of EPA + DHA for 3.5 years had a risk of sudden death that was 45% lower than those who did not take supplements and a risk of death from all causes that was 20% lower (58). Interestingly, it took only three months of supplementation to demonstrate a significant decrease in total mortality and four months to demonstrate a significant decrease in sudden death (59). (For a more detailed discussion of this study see the article, Fish oil, Vitamin E, Genes, Diet, and CHAOS, in the Linus Pauling Institute Newsletter.) In another supplementation trial, patients admitted to the hospital with an acute MI were randomized to receive capsules containing fish oil (1.8 g/day of EPA + DHA), mustard oil (2.9 g/d of ALA) or a placebo (60). After one year, total cardiac events, including nonfatal MIs were significantly lower in the groups that received fish oil or mustard oil compared to the groups that received a placebo. In contrast, acute MI patients did not realize any additional benefit from supplementation with 3.5 g/d of EPA + DHA compared to corn oil in a region of Norway where fish intakes are relatively high (61). The results of a meta-analysis that pooled the findings of 11 randomized controlled trials of dietary or supplementary omega-3 fatty acids indicated that increased omega-3 fatty acid intakes significantly decreased overall mortality, mortality due to MI, and sudden death in patients with CHD (62).
Supplementation trials: coronary atherosclerosis
Two randomized controlled trials have examined the effect of fish oil supplementation on the progression of coronary artery atherosclerosis measured by coronary angiography. Although a study of 59 patients with coronary artery disease found no benefit after two years of supplementation with fish oil providing 6 g/day of EPA +DHA compared to olive oil (63), a larger trial of 223 patients found that supplementation with 3.3 g/day of EPA + DHA for three months and 1.65 g/day for an additional 21 months resulted in a modest decrease in the progression of coronary atherosclerosis compared to a placebo (64). A number of clinical trials have examined the effect of omega-3 fatty acids on restenosis after coronary angioplasty with conflicting results (65). However, a carefully conducted double blind, placebo-controlled trial found that supplementation with 5.3 g/day of EPA + DHA at least two weeks prior to coronary angioplasty and continued for six months after angioplasty did not reduce the incidence of restenosis (66). These findings are in agreement with another large multicenter trial that compared supplementation with 8 g/day of EPA + DHA with an equal amount of corn oil and demonstrated no significant difference in the rate of restenosis after coronary angioplasty (67).
Supplementation trials: serum triglycerides
When the results of 17 prospective studies of cardiovascular disease risk were analyzed together in a meta-analysis, the presence of elevated circulating triglycerides was found to be an independent risk factor of CHD (68). Numerous studies in humans have demonstrated that increasing intakes of marine-derived omega-3 fatty acids significantly lowers circulating triglyceride levels (69). The triglyceride-lowering effects of marine-derived omega-3 fatty acids increase with dose, but clinically meaningful reductions in serum or plasma triglycerides have been demonstrated at doses of 2 g/day of EPA + DHA (3). In its most recent recommendations regarding omega-3 fatty acids and cardiovascular disease, the American Heart Association indicates that an EPA + DHA supplement may be useful in patients with hypertriglyceridemia (fasting serum triglycerides of 200 mg/dl or higher). While 2-4 g/day of EPA + DHA can lower serum triglyceride levels 20-40%, the American Heart Association cautions that individuals taking more than 3 g/day should do so only under medical supervision, since doses higher than 3 g/day may increase the risk of uncontrolled bleeding (see the section on Safety) (32).
Cardiovascular diseases are the leading causes of death in individuals with diabetes. Hypertriglyceridemia (fasting serum triglycerides of 200 mg/dl or higher) is a common lipid abnormality in individuals with type 2 diabetes, and a number of randomized controlled trials have found that fish oil supplementation significantly lowers serum triglyceride levels in diabetic individuals (70). Although early uncontrolled studies raised concerns that fish oil supplementation adversely affected blood glucose (glycemic) control (71, 72), randomized controlled trials have not generally found fish oil supplementation to have adverse effects on long-term glycemic control. A systematic review that pooled the results of 18 randomized controlled trials including more than 800 diabetic subjects found that fish oil supplementation significantly lowered serum triglycerides, especially in those with hypertriglyceridemia (70). Although a significant increase in LDL cholesterol was observed in those studies using the highest doses of fish oil in hypertriglyceridemic patients, no statistically significant increases in fasting glucose or hemoglobin A1c (a measure of long term glycemic control) levels were observed. These findings are similar to an earlier meta-analysis that found that fish oil supplementation (3 g/day of EPA + DHA) significantly lowered serum triglycerides in diabetic individuals by almost 30% without significantly changing hemoglobin A1c levels (73). Although few controlled trials have examined the effect of fish oil supplementation on cardiovascular disease outcomes in diabetics, a prospective study that followed 5103 women diagnosed with type 2 diabetes but free of cardiovascular disease or cancer at the start of the study found that higher fish intakes were associated with significantly decreased risks of CHD over a 16-year follow up period (74). Thus, increasing EPA and DHA intakes may be beneficial to diabetic individuals especially those with elevated serum triglycerides. Moreover, there is little evidence that daily EPA + DHA intakes of less than 3 g/day adversely affect long-term glycemic control in diabetics.
Rheumatoid arthritis is the most common systemic inflammatory rheumatic (joint) disease. A meta-analysis of 10 randomized controlled trials including 395 rheumatoid arthritis patients confirmed consistent findings that supplementation with fish oil for at least 12 weeks decreased the number of tender joints on physical examination and reduced morning stiffness in individuals with rheumatoid arthritis (75). In most studies, marine-derived omega-3 fatty acid supplements were taken in addition to conventional medical therapy. In general, clinical benefits were observed at a minimum dose of 3 g/day of EPA + DHA, and were not apparent until at least 12 weeks of supplementation (76). Although a few investigators have reported that patients taking omega-3 fatty acid supplements were able to lower their doses of nonsteroidal anti-inflammatory drugs (NSAIDS) (77, 78), this finding has not been as consistent (76).
Inflammatory bowel disease (Ulcerative colitis and Crohn’s disease)
Clinical trials of omega-3 fatty acid supplementation have demonstrated beneficial effects less consistently in patients with inflammatory bowel disease than in patients with rheumatoid arthritis. Although two randomized controlled trials of fish oil supplementation in Crohn’s disease patients reported no benefit (79, 80), a significantly higher proportion of Crohn’s disease patients supplemented with 2.7 g/day of EPA + DHA remained in remission over a one-year period than those given a placebo (81). Three randomized controlled trials of EPA + DHA supplementation (4.2-5.4 g/day for 3-12 months) in ulcerative colitis patients reported significant improvement in at least one outcome measure, including decreased corticosteroid use, decreased production of inflammatory mediators, and improvements in disease activity scores, histology scores, and weight gain (82-84). In contrast, supplementation of ulcerative colitis patients in remission with 5.1 g/day of EPA + DHA did not significantly alter the incidence of relapse over a 2-year period (85).
Inflammatory eicosanoids derived from arachidonic acid are thought to play an important role in the pathology of asthma (4). Since increased omega-3 fatty acid intakes are known to decrease the amount of arachidonic acid available for the formation of these inflammatory mediators, a number of clinical trials have examined the effects of omega-3 fatty acid supplementation in asthmatic individuals. Although there is some evidence that omega-3 fatty acid supplementation can decrease the production of inflammatory mediators in asthmatic patients (86, 87), evidence that omega-3 fatty acid supplementation decreases the clinical severity of asthma in controlled trials has been inconsistent. A recent systematic review of nine randomized controlled trials of marine-derived omega-3 fatty acid supplementation in asthmatic patients found no consistent effects on clinical outcome measures, including pulmonary function tests, asthmatic symptoms, medication use, and bronchial hyperreactivity (88).
Immunoglobulin (Ig) A nephropathy is a kidney disorder that results from the deposition of the immune system protein IgA in the glomeruli (filtering organs) of the kidney. The cause of IgA nephropathy is not clear, but progressive renal failure may eventually develop in 15-40% of patients (89). Since glomerular IgA deposition results in increased production of inflammatory mediators, omega-3 fatty acid supplementation could potentially modulate the inflammatory response and preserve renal function. However, 6-months of fish oil treatment (3 g/day of EPA + DHA) did not decrease the urinary excretion of inflammatory mediators in IgA nephropathy patients (90). In a randomized placebo-controlled trial, supplementation of IgA nephropathy patients with fish oil (~ 3 g/day of EPA + DHA) for two years significantly slowed declines in renal function (91). Over the two-year treatment period 33% of the placebo group experienced a 50% increase in serum creatinine (evidence of declining renal function) compared to only 6% in the fish oil supplemented group. In contrast, three smaller studies failed to find a significant benefit of fish oil supplementation in IgA nephropathy patients (92-94). When the results of five controlled studies were examined together in a meta-analysis, the overall effect was not statistically significant (95). However, the probability of a minor beneficial effect was high enough (75%) to provide support for a large placebo-controlled trial of at least two years duration. A two-year supplementation trial comparing fish oil, to alternate day prednisone treatment and a placebo in children and young adults with IgA nephropathy is currently in progress (96). At present, it is not clear whether fish oil supplementation will prevent the progression of IgA nephropathy in children or adults.
Major depression and bipolar disorder
Data from ecologic studies across different countries suggest an inverse association between national seafood consumption and national rates of major depression (97) and postpartum depression (98). Several small studies have found omega-3 fatty acid levels to be lower in the plasma (99, 100) and fat (101) of individuals suffering from depression compared to controls. Although it is not known how increased omega-3 fatty acid intake can affect the incidence of depression, modulation of neuronal signaling pathways and eicosanoid production have been proposed as possible mechanisms (102). At present, there are no data from controlled trials on the efficacy of omega-3 fatty acid supplementation in patients with depression. A preliminary placebo-controlled trial that assessed the effects of very high doses of EPA (6.2 g/day) and DHA (3.4 g/day) in 30 patients with bipolar disorder (formerly known as manic-depressive disorder) found that those supplemented with EPA + DHA had a significantly longer period of remission than those on an olive oil placebo over a 4-month period (103). Patients who took the EPA + DHA supplements also experienced less depression than those who took the placebo. Although major depression occurs in both, bipolar disorder and depression are considered distinct psychiatric conditions. More recently, a pilot study in 30 women diagnosed with borderline personality disorder found that the 20 women randomized to treatment with 1 g/day of ethyl-EPA for eight weeks experienced less severe depressive symptoms than the 10 women randomized to treatment with a placebo (104). Although the results of these very limited pilot studies are somewhat optimistic, larger and long-term randomized controlled trials are required to determine the efficacy of marine-derived omega-3 fatty acid supplementation on major depression.
Schizophrenia is a chronic disabling brain disorder that affects approximately 1% of the population. Findings of decreased omega-3 fatty acid levels in the red blood cells (105) and brains (106) of a limited number of schizophrenic patients and the results of uncontrolled supplementation studies (107) have created interest in the use of omega-3 fatty acid supplementation as an adjunct to conventional antipsychotic therapy regimens for schizophrenia. A pilot study in 45 schizophrenic patients found that the addition of 2 g/day of EPA to standard antipsychotic therapy was superior to the addition of a 2 g/day of DHA or a placebo in decreasing residual symptoms (108). When EPA supplementation was used as the sole treatment for schizophrenic patients experiencing a relapse, 8 out of 14 patients supplemented with 2 g/day of EPA required antipsychotic medication by the end of the 12-week study period compared to 12 out of 12 of those on the placebo (108). Results of randomized controlled trials using ethyl-EPA as an adjunct to standard antipsychotic therapy in schizophrenic patients have been somewhat contradictory. In one trial, the addition of 3 g/day of ethyl-EPA to standard antipsychotic treatment for 12 weeks improved symptom scores and decreased dyskinesia scores (109), while in a larger trial, supplementation with the same dose of ethyl-EPA was not different than placebo in improving symptoms, mood, or cognition (110). In a placebo-controlled trial comparing the addition of 1, 2, or 4 g/day of ethyl EPA to different medication regimens, ethyl-EPA supplementation improved symptoms of schizophrenic patients on the antipsychotic medication clozapine, but not other medications (111). Although limited evidence suggests that EPA supplementation may be a useful adjunct to antipsychotic therapy in schizophrenic patients, larger long-term studies addressing clinically relevant outcomes are needed (112). For more information on schizophrenia visit the National Institute of Mental Health Web site.
Alpha-linolenic acid (ALA)
Flaxseeds, walnuts, and their oils are among the richest sources of ALA. Canola oil is also an excellent source of ALA. Dietary surveys in the U.S. indicate that average adult intakes for ALA range from 1.2-1.6 g/day for men and from 0.9-1.1 g/day for women (1). Some foods that are rich in ALA are listed in the table below. For more information on the nutrient content of foods you eat frequently, search the USDA food composition database, where the ALA content is listed under “Lipids” as 18:3.
| Food | Serving |
Alpha-Linolenic acid (g)
|
| Flaxseed oil | 1 tablespoon |
8.5
|
| Walnuts, English | 1 ounce |
2.6
|
| Flaxseeds | 1 tablespoon |
2.2
|
| Walnut oil | 1 tablespoon |
1.4
|
| Canola oil | 1 tablespoon |
1.2
|
| Mustard oil | 1 tablespoon |
0.8
|
| Soybean oil | 1 tablespoon |
0.9
|
| Walnuts, Black | 1 ounce |
0.6
|
| Olive oil | 1 tablespoon |
0.1
|
| Broccoli, raw | 1 cup, chopped |
0.1
|
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
Fish oils and fatty fish are major dietary sources of EPA and DHA. Dietary surveys in the U.S. indicate that average adult intakes of EPA range from 0.04-0.07 g/day and average adult intakes of DHA range from 0.05-0.09 g/day (1). Omega-3 fatty acid-enriched eggs are now available in the U.S. One such egg produced by adding flaxseed to hens’ feed is reported to contain 0.25 g of EPA and 0.15 g of DHA (113). Some foods that are rich in EPA and DHA are listed in the table below. For more information on the nutrient content of foods you eat frequently, search the USDA food composition database, where EPA and DHA are listed under “Lipids” as 20:5n-3 and 22:6n-3, respectively.
| Food | Serving |
EPA
(g)
|
DHA
(g)
|
Amount
providing |
| Herring, Pacific, cooked | 3 ounces* |
1.06
|
0.75
|
1.5 ounces
|
| Salmon, chinook, cooked | 3 ounces |
0.86
|
0.62
|
2 ounces
|
| Salmon, Atlantic, cooked | 3 ounces |
0.28
|
0.95
|
2.5 ounces
|
| Oysters, Pacific, cooked | 3 ounces |
0.75
|
0.43
|
2.5 ounces
|
| Salmon, sockeye, cooked | 3 ounces |
0.45
|
0.60
|
3 ounces
|
| Trout, rainbow, cooked | 3 ounces |
0.40
|
0.44
|
3.5 ounces
|
| Tuna, white, packed in water | 3 ounces |
0.20
|
0.54
|
4 ounces
|
| Crab, Dungeness, cooked | 3 ounces |
0.24
|
0.10
|
9 ounces
|
| Shrimp, cooked | 3 ounces |
0.15
|
0.12
|
11 ounces
|
| Cod, Pacific, cooked | 3 ounces |
0.09
|
0.15
|
12.5 ounces
|
| Fish oil, menhaden | 1 gram |
0.13
|
0.09
|
5
grams
|
| Fish oil, salmon | 1 gram |
0.13
|
0.18
|
3
grams
|
*A 3-ounce serving of fish is about the size of a deck of cards.
Biosynthesis of EPA and DHA
Humans can synthesize EPA and DHA from ALA through a series of desaturation (addition of a double bond) and elongation (addition of two carbon atoms) reactions (diagram). Recent studies of ALA metabolism indicate that approximately 8% of dietary ALA is converted to EPA and 0-4% is converted to DHA in healthy young men (114). In healthy young women, approximately 21% of dietary ALA is converted to EPA and 9% is converted to DHA (115). Variations in dietary omega-6 and long-chain omega-3 fatty acid levels may also affect the efficiency of ALA conversion to EPA and DHA (116).
Flaxseed oil (also known as flax oil or linseed oil) is available as an ALA supplement. A number of fish oils are marketed as omega-3 fatty acid supplements. Ethyl esters of EPA and DHA (ethyl-EPA and ethyl-DHA) are concentrated sources of marine-derived omega-3 fatty acids. Since EPA and DHA content will vary in fish oil and ethyl ester preparations, it is necessary to read the label to determine the EPA and DHA content of a particular supplement. DHA supplements derived from algae are also available. All omega-3 fatty acid supplements are absorbed more efficiently with meals. Dividing one’s daily dose into two or three smaller doses throughout the day will decrease the risk of gastrointestinal side effects (see the section on Safety). Although cod liver oil is a rich source of EPA and DHA, it should be avoided as an omega-3 fatty acid supplement since it also contains high levels of vitamin A and vitamin D (117).
In 2001, the U.S. Food and Drug Administration began permitting the addition of DHA and arachidonic acid to infant formula (see the section on Disease Prevention). Consequently, several infant formula manufacturers in the U.S. are marketing infant formula with DHA and arachidonic acid added. Presently, manufacturers are not required to list the amounts of DHA and arachidonic acid added to infant formula on the label. However, most infant formula manufacturers will provide this information when contacted by telephone or email. The amounts added to formulas in the U.S. range from 8-17 mg DHA/100 calories (5 fluid ounces) and from 16-34 mg arachidonic acid/100 calories. For example, an infant drinking 20 fluid ounces of formula daily would receive 32-68 mg/day of DHA and 64-136 mg/day of arachidonic acid.
Flaxseed oil (ALA)
Although flaxseed oil is generally well tolerated, high doses of flaxseed oil (30 g/day) may cause loose stools or diarrhea. Allergic and anaphylactic reactions have been reported with flaxseed and flaxseed oil ingestion (118).
Marine-derived omega-3 fatty acids (EPA and DHA)
Serious adverse reactions have not been reported in those using fish oil or marine-derived omega-3 fatty acid supplements. The most common adverse effect of fish oil or marine-derived omega-3 fatty acid supplements is a fishy aftertaste. Belching and heartburn have also been reported. High doses may cause nausea and loose stools (118).
Potential for excessive bleeding: The potential for high omega-3 fatty acid intakes, especially EPA and DHA, to prolong bleeding times has been well studied, and may play a role in the cardioprotective effects of omega-3 fatty acids. Although excessively long bleeding times and increased incidence of hemorrhagic stroke have been observed in Greenland Eskimos with very high intakes of EPA + DHA (6.5 g/day), it is not known whether high intakes of EPA and DHA are the only factor responsible for these observations (1). The U.S. Food and Drug Administration (FDA) has ruled that intakes up to 3 g/day of marine-derived omega-3 fatty acids are Generally Recognized As Safe (GRAS) for inclusion in the diet, and available evidence suggests that intakes less than 3 g/day are unlikely to result in clinically significant bleeding (3). Although the Institute of Medicine did not establish a tolerable upper level of intake (UL) for omega-3 fatty acids, caution was advised with the use of supplemental EPA and DHA, especially in those who are at increased risk of excessive bleeding (see the section on Drug interactions) (1).
Potential for immune system suppression: Although the suppression of inflammatory responses resulting from increased omega-3 fatty acid intakes may benefit individuals with inflammatory or autoimmune diseases, anti-inflammatory doses of omega-3 fatty acids could decrease the potential of the immune system to destroy pathogens. Studies comparing measures of immune function outside the body at baseline and after supplementing people with omega-3 fatty acids, mainly EPA and DHA, have demonstrated immunosuppressive effects at doses as low as 0.9 g/day for EPA and 0.6 g/day for DHA (1). Although it is not clear if these findings translate to impaired immune responses inside the body, caution should be observed when considering omega-3 fatty acid supplementation in individuals with compromised immune systems (118).
Pregnancy, lactation, and young children: Safety of supplemental omega-3 fatty acids (flaxseed oil and fish oil supplements) has not been demonstrated in pregnant or breastfeeding women. It is not recommended that fish oil or flaxseed oil supplements be given to infants or young children unless recommended and monitored by a qualified health care provider (117).
Flazseed oil (ALA)
High doses of flaxseed oil may decrease platelet aggregation (clotting) and should be used with caution in those on anticoagulant medications (118).
Marine-derived omega-3 fatty acids (EPA and DHA)
Anticoagulant medications: Patients taking fish oil or marine-derived omega-3 fatty acid supplements in combination with anticoagulant drugs, including aspirin, copidogrel (Plavix), dalteparin (Fragmin), dipyridamole (Persantine), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid), and warfarin (Coumadin) should have their coagulation status monitored using an assay of prothrombin time (PT) that has been standardized using the International Normalized Ratio (INR) (118). One small study found that 3 g/day or 6 g/day of fish oil did not affect PT/INR values in 10 patients on warfarin over a 4-week period (119).
Antihypertensive agents: Because fish oil or marine-derived fatty acid supplements may decrease blood pressure slightly, their use in combination with antihypertensive agents could result in additive effects and increased risk of hypotensive episodes (transient low blood pressure)(118).
Antidiabetes medications: Recent systematic reviews and meta-analyses found no adverse effects of fish oil supplementation on long-term blood glucose control in individuals with diabetes as measured by hemoglobin A1c (70, 73) (see the section on Disease Treatment)
Some species of fish may contain significant levels of methylmercury, polychlorinated biphenyls (PCBs), or other environmental contaminants. In general, older, larger, predatory fish, such as swordfish, tend to contain the highest levels of these contaminants. Removing the skin, fat, and internal organs of the fish prior to cooking, and allowing the fat to drain from the fish while it cooks will decrease exposure to a number of fat-soluble pollutants, such as PCBs (120). However, methylmercury is found throughout the muscle of fish, so these cooking precautions will not reduce exposure to methylmercury.
Methylmercury
Organic mercury compounds are toxic and excessive exposure can cause brain and kidney damage. Unborn children, infants, and young children are especially vulnerable to the toxic effects of mercury on the brain. In order to limit their exposure to methylmercury, the U.S. Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) made the following recommendations for women who may become pregnant, pregnant and breastfeeding women and young children (121):
For more information about the FDA/EPA consumer advisory on methylmercury in fish, see their online brochure "What You Need to Know About Mercury in Shellfish and Seafood."
Fish with the highest mercury levels and some fish with relatively low levels of mercury are listed along with their average mercury content in parts per million (ppm) in the tables below (122). More information about the methylmercury content of other kinds of fish and shellfish, is available on the FDA Web page titled, "Mercury Levels in Commercial Fish and Shellfish."
|
Fish With
the Highest Levels of Mercury
|
||
| Fish |
Average
Methylmercury (ppm)
|
Range
(ppm)
|
| King Mackerel |
0.73
|
0.23-1.67
|
| Shark |
0.99
|
ND*-4.54
|
| Swordfish |
0.97
|
0.10-3.22
|
| Tilefish |
1.45
|
0.65-3.73
|
*ND, not detected
|
Some Fish and Shellfish with Lower Levels of Mercury |
||
| Fish |
Average Methylmercury
(ppm)
|
Range
(ppm)
|
| Catfish |
0.05
|
ND-0.31
|
| Crab |
0.06
|
ND-0.61
|
| Pollock |
0.06
|
ND-0.78
|
| Salmon (Canned) | ND | ND |
| Salmon (Fresh or Frozen) |
0.01
|
ND-0.19
|
| Shrimp |
ND
|
ND-0.05
|
| Tuna (Canned, Light) |
0.12
|
0.08-0.85
|
*ND, not detected
Contaminants in supplements
Methylmercury
An independent laboratory analysis of 20 different omega-3 fatty acid supplements available in the U.S. did not detect methylmercury in any of them, indicating that methylmercury concentrations were less than 1.5 parts per billion (ppb) (123). Although there are several possible explanations for the absence of methylmercury in omega-3 fatty acid supplements, the most likely is that methylmercury accumulates in the muscle rather than the fat of fish (3).
Polychlorinated biphenyls (PCBs)
It is unclear whether fish oil supplements represent a significant source of exposure to PCBs. Appreciable amounts of PCBs have been found in some fish oil supplements, especially those derived from cod liver oil (124). In general, fish body oils contain lower levels of PCBs and other fat-soluble contaminants than fish liver oils. Additionally, fish oils that have been more highly refined and deodorized also contain lower levels of PCBs (125). Recently, independent testing of 16 top-selling fish oil supplements in the U.S. revealed no evidence of PCBs or dioxin (126).
Written by:
Jane
Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed
by:
Rosemary C. Wander, Ph.D.
Associate Provost for Research
Professor,
Department of Nutrition
University of North Carolina at Greensboro
Last updated 08/16/2004 Copyright 2003-2004 Linus Pauling Institute
Disclaimer
The Linus Pauling Institute Micronutrient Information Center provides scientific information on health aspects of micronutrients and phytochemicals for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional.
The information on micronutrients and phytochemicals contained on this Web site does not cover all possible uses, actions, precautions, side effects, and interactions. It is not intended as medical advice for individual problems. Liability for individual actions or omissions based upon the contents of this site is expressly disclaimed.