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Essential Fatty Acids


Summary

Introduction

Omega-6 and omega-3 fatty acids are polyunsaturated fatty acids (PUFA), meaning they contain more than one cis double bond (1). In all omega-6 fatty acids, the first double bond is located between the sixth and seventh carbon atom from the methyl end of the fatty acid (n-6). Similarly, in all omega-3 fatty acids, the first double bond is located between the third and fourth carbon atom counting from the methyl end of the fatty acid (n-3). Scientific abbreviations for fatty acids tell the reader something about their chemical structure. One 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 the first double bond is in the n-3 position, which defines it as an omega-3 fatty acid (Figures 1a & b). Double bonds introduce kinks in the hydrocarbon chain that influence the structure and physical properties of the fatty acid molecule (Figure 1c).

Although humans and other mammals can synthesize saturated fatty acids and some monounsaturated fatty acids from carbon groups in carbohydrates and proteins, they lack the enzymes necessary to insert a cis double bond at the n-6 or the n-3 position of a fatty acid (1). Consequently, omega-6 and omega-3 fatty acids are essential nutrients. The parent fatty acid of the omega-6 series is linoleic acid (LA; 18:2n-6), and the parent fatty acid of the omega-3 series is ALA (Figure 2 and Table). Humans can synthesize long-chain (20 carbons or more) omega-6 fatty acids, such as dihomo-gamma-linolenic acid (DGLA; 20:3n-6) and arachidonic acid (AA; 20:4n-6), from LA and long-chain omega-3 fatty acids, such as eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), from ALA (see Metabolism and Bioavailability below).

Metabolism and Bioavailability

Prior to absorption in the small intestine, fatty acids must be hydrolyzed from dietary fats (triglycerides and phospholipids) by pancreatic enzymes (2). Bile salts must also be present in the small intestine to allow for the incorporation of fatty acids and other fat digestion products into mixed micelles. Fat absorption from mixed micelles occurs throughout the small intestine and is 85-95% efficient under normal conditions.

Blood concentrations of fatty acids reflect both dietary intake and biological processes (3). Humans can synthesize longer omega-6 and omega-3 fatty acids from the essential fatty acids LA and ALA, respectively, through a series of desaturation (addition of a double bond) and elongation (addition of two carbon atoms) reactions (Figure 3) (4, 5). LA and ALA compete for the same elongase and desaturase enzymes in the synthesis of longer polyunsaturated fatty acids, such as AA and EPA.

The capacity to generate DHA from ALA is higher in women than men. Studies of ALA metabolism in healthy young men indicate that approximately 8% of dietary ALA is converted to EPA and 0-4% is converted to DHA (6). In healthy young women, approximately 21% of dietary ALA is converted to EPA and 9% is converted to DHA (7). The better conversion efficiency of young women compared to men appears to be related to the effects of estrogen (8, 9). Although ALA is considered the essential omega-3 fatty acid because it cannot be synthesized by humans, evidence that human conversion of EPA and, particularly, DHA is relatively inefficient suggests that EPA and DHA may be considered conditionally essential nutrients.

In addition to gender differences, genetic variability in enzymes involved in fatty acid metabolism influences one's ability to generate long-chain polyunsaturated fatty acids (LC-PUFA). Two key enzymes in fatty acid metabolism are delta 6 desaturase (FADS2) and delta 5 desaturase (FADS1) (Figure 3) (10). Two common haplotypes (a cluster of polymorphisms) in the FADS genes differ dramatically in their ability to generate LC-PUFA: haplotype D is associated with increased FADS activity (both FADS1 and FADS2) and is more efficient in converting fatty acid precursors (LA and ALA) to LC-PUFA (EPA, GLA, DHA, and AA) (11). These FADS polymorphisms are relatively common in the population and may explain up to 30% of the variability in blood levels of omega-3 and omega-6 fatty acids among individuals (3).

Finally, DHA is retroconverted to EPA at a low basal rate and following supplementation (Figure 3) (12). After supplementing omnivores (n=8) and vegetarians (n=12) for six weeks with an EPA-free preparation of DHA (1.62 g/day), both EPA and DHA levels increased in serum and platelet phospholipids (13). Based on the measured changes, the estimated percent retroconversion of DHA to EPA was 7.4-11.4% (based on serum phospholipid data) and 12.3-13.8% (based on the platelet phospholipid data), with no significant difference between omnivores and vegetarians. Due to this nontrivial retroconversion efficiency, DHA supplementation represents an alternative to fish oil to increase blood and tissue levels of EPA, DPA, and DHA (5) (see Supplements).

Biological Activities

Membrane structure and function

Omega-6 and omega-3 PUFA are important structural components of cell membranes. When incorporated into phospholipids, they affect cell membrane properties, such as fluidity, flexibility, permeability, and the activity of membrane-bound enzymes (14). In addition to endogenous metabolism, dietary consumption of fatty acids can modify the composition and molecular structure of cellular membranes. Thus, increasing omega-3 fatty acid intake increases the omega-3 content of red blood cells, immune cells (15), atherosclerotic plaques (16), cardiac tissue (17), and other cell types throughout the body.

DHA is selectively incorporated into retinal cell membranes and postsynaptic neuronal cell membranes, suggesting it plays important roles in vision and nervous system function.

Vision

DHA is found at very high concentrations in the cell membranes of the retina; the retina conserves and recycles DHA even when omega-3 fatty acid intake is low (18). Animal studies 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. 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 hitting the retina to visual images in the brain (19).

Nervous system

The phospholipids of the brainís gray matter contain high proportions of DHA and AA, suggesting they are important to central nervous system function (20). Brain DHA content may be particularly important, since animal studies have shown that depletion of DHA in the brain can result in learning deficits. It is not clear how DHA affects brain function, but changes in DHA content of neuronal cell membranes could alter the function of ion channels or membrane-associated receptors, as well as the availability of neurotransmitters (21).

Synthesis of lipid mediators

Eicosanoids

Eicosanoids are potent chemical messengers that play critical roles in immune and inflammatory responses. The term 'eicosanoid' encompasses numerous bioactive lipid mediators that are derived from 20-carbon LC-PUFA. Following stimulation by hormones, cytokines, and other stimuli, DGLA, AA, and EPA are released from cell membranes and become substrates for eicosanoid production (Figure 4). Eicosanoid synthesis relies primarily on three families of enzymes: cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome p450 mono-oxygenases (P450s) (22). From 20-carbon lipid precursors, COX enzymes produce prostaglandins, prostacyclins, and thromboxanes (collectively known as prostanoids); LOX produces leukotrienes and hydroxy fatty acids; and P450s produce hydroxyeicosatetraenoic acids ("HETEs") and epoxides (Figure 5).

Physiological responses to AA-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 coagulation than eicosanoids derived from AA (23). Nonetheless, it is an oversimplification to label all AA-derived eicosanoids as pro-inflammatory. AA-derived prostaglandins induce inflammation but also inhibit pro-inflammatory leukotrienes and cytokines and induce anti-inflammatory lipoxins, thereby modulating the intensity and duration of the inflammatory response via negative feedback (Figure 5) (16).

Pro-resolving mediators

A separate class of PUFA-derived bioactive lipids, specialized pro-resolving mediators (SPMs), has been recently identified (reviewed in 24). These molecules function as local mediators of the resolution phase of inflammation, actively turning off the inflammatory response. SPMs are derived from both omega-6 and omega-3 PUFA (Figure 5) (25). The S-series of SPMs results from the LOX-mediated oxygenation of EPA and DHA, giving rise to S-resolvins, S-protectins, and S-maresins. A second class of SPMs, the R-series, is generated from the aspirin-dependent acetylation of COX-2 and subsequent generation of aspirin-triggered SPMs from AA, EPA, and DHA. It appears that these mediators may explain many of the anti-inflammatory actions of omega-3 fatty acids that have been described (15, 26).

Isoprostanes

Isoprostanes are prostaglandin-like compounds that are formed by non-enzymatic, free radical-induced oxidation of any PUFA with three or more double bonds (Figure 5) (22). Because they are produced upon exposure to free radicals, isoprostanes are often used as markers for oxidative stress. In contrast to prostanoids, isoprostanes are synthesized from esterified PUFA precursors and remain bound to the membrane phospholipid until cleaved by PLA2 and released into circulation. In addition to being used as markers of oxidative stress, isoprostanes may also function as inflammatory mediators, exerting both pro- and anti-inflammatory effects (22).

Regulation of gene expression

The results of cell culture and animal studies indicate that omega-6 and omega-3 fatty acids can modulate the expression of a number of genes, including those involved with fatty acid metabolism and inflammation (27, 28). Omega-6 and omega-3 fatty acids regulate gene expression by interacting with specific transcription factors, such as peroxisome proliferator-activated receptors (PPARs) (29). In many cases, PUFA act like hydrophobic hormones (e.g., steroid hormones) to control gene expression and bind directly to receptors like PPARs. These ligand-activated receptors then bind to the promoters of genes and function to increase/decrease transcription.

In other cases, PUFA regulate the abundance of transcription factors inside the cell's nucleus (30). Two examples include NFκB and SREBP-1. NFκB is a transcription factor involved in regulating the expression of multiple genes involved in inflammation. Omega-3 PUFA suppress NFκB nuclear content, thus inhibiting the production of inflammatory eicosanoids and cytokines. SREBP-1 is a major transcription factor controlling fatty acid synthesis, both de novo lipogenesis and PUFA synthesis. Dietary PUFA can suppress SREBP-1, which decreases the expression of enzymes involved in fatty acid synthesis and PUFA synthesis. In this way, dietary PUFA function as feedback inhibitors of all fatty acid synthesis.

Deficiency

Essential fatty acid deficiency

Clinical signs of essential fatty acid deficiency include a dry scaly rash, decreased growth in infants and children, increased susceptibility to infection, and poor wound healing (31). Omega-3, omega-6, and omega-9 fatty acids compete for the same desaturase enzymes. The desaturase enzymes show preference for the different series of fatty acids in the following order: omega-3 > omega-6 > omega-9. Consequently, synthesis of the omega-9 fatty acid eicosatrienoic acid (20:3n-9, mead acid, or 5,8,11-eicosatrienoic acid) increases only when dietary intakes of omega-3 and omega-6 fatty acids are very low; therefore, mead acid is one marker of essential fatty acid deficiency (32). A plasma eicosatrienoic acid:arachidonic acid (triene:tetraene) ratio greater than 0.2 is generally considered indicative of essential fatty acid deficiency (31, 33). In patients who were given total parenteral nutrition containing fat-free, glucose-amino acid mixtures, biochemical signs of essential fatty acid deficiency developed in as little as 7 to 10 days (34). In these cases, the continuous glucose infusion resulted in high circulating insulin levels, which inhibited the release of essential fatty acids stored in adipose tissue. When glucose-free amino acid solutions were used, parenteral nutrition up to 14 days did not result in biochemical signs of essential fatty acid deficiency. Essential fatty acid deficiency has also been found to occur in patients with chronic fat malabsorption (35) and in patients with cystic fibrosis (36). Recently, it has been proposed that essential fatty acid deficiency may play a role in the pathology of protein-energy malnutrition (32).

Omega-3 fatty acid deficiency

At least one case of isolated omega-3 fatty acid deficiency has been reported. A young girl who received intravenous lipid emulsions with very little ALA developed visual problems and sensory neuropathy; these conditions were resolved when she was administered an emulsion containing more ALA (37). Isolated omega-3 fatty acid deficiency does not result in increased plasma triene:tetraene ratios, and skin atrophy and dermatitis are absent (1). Plasma DHA concentrations decrease when omega-3 fatty acid intake is insufficient, but no accepted plasma omega-3 fatty acid or eicosanoid concentrations indicative of impaired health status have been defined (1). Studies in rodents have revealed significant impairment of n-3 PUFA deficiency on learning and memory (38, 39) prompting research in humans to assess the impact of omega-3 PUFA on cognitive development and cognitive decline (see Visual and neurological development and Alzheimer's disease).

Omega-3 index

The omega-3 index is defined as the amount of EPA plus DHA in red blood cell (RBC) membranes expressed as the percent of total RBC membrane fatty acids (40). The EPA + DHA content of RBCs correlates with that of cardiac muscle cells (41, 42), and several observational studies indicate that a lower omega-3 index is associated with an increased risk of coronary heart disease (CHD) mortality (43). It is therefore proposed that the omega-3 index be used as a biomarker for cardiovascular disease risk, with proposed zones being high risk, <4%; intermediate risk, 4-8%; and low risk, >8% (44).

Supplementation with EPA + DHA from fish oil capsules for approximately five months dose-dependently increased the omega-3 index in 115 healthy, young adults (20-45 years of age), validating the use of the omega-3 index as a biomarker of EPA + DHA intake (45). Before the omega-3 index can be used in routine clinical evaluation, however, clinical reference values in the population must be established (46). Additionally, fatty acid metabolism may be altered in certain disease states, potentially making the omega-3 index less relevant for some cardiovascular conditions (5).

Disease Prevention

Visual and neurological development

The last trimester of pregnancy and first six months of postnatal life are critical periods for the accumulation of DHA in the brain and retina (47). Human milk contains a mixture of saturated fatty acids (~46%), monounsaturated fatty acids (~41%), omega-6 PUFA (~12%), and omega-3 PUFA (~1.3%) (48). Although human milk contains DHA in addition to ALA and EPA, ALA was the only omega-3 fatty acid present in conventional infant formulas until the year 2001.

Infant formulas

Although infants can synthesize DHA from ALA, they generally cannot synthesize enough to prevent declines in plasma and cellular DHA concentrations without additional dietary intake. Therefore, it was proposed that 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 (49). Although formulas enriched with DHA raise plasma and red blood cell DHA concentrations in preterm and term infants, the results of randomized controlled trials (RCTs) examining measures of visual acuity and neurological development in infants fed formulas with or without added DHA have been mixed (50, 51). A 2012 meta-analysis of RCTs (12 trials, 1,902 infants) testing LC-PUFA supplemented versus unsupplemented formula, started within one month of birth, found no effect of LC-PUFA supplementation on infant cognition assessed at approximately one year of age (52). A lack of effect was observed regardless of the dose of LC-PUFA or the prematurity status of the infant. With respect to visual acuity, a 2013 meta-analysis of RCTs (19 trials, 1,949 infants) found a beneficial effect of LC-PUFA-supplemented formula, started within one month of birth, on infant visual acuity up to 12 months of age (53). Notably, two different types of visual acuity assessment were evaluated in the meta-analysis. Visual acuity assessed by using the visually evoked potential (VEP) (10 trials, 852 infants) showed a significant positive effect of LC-PUFA supplemented formula at 2, 4, and 12 months of age. When assessed by the behavioral method (BM) (12 trials, 1,095 infants), a significant benefit of LC-PUFA-supplemented formula on visual acuity was found only at the age of two months. No moderating effects of dose or prematurity status were observed.

Maternal supplementation (placental transfer and breast milk)

The effect of maternal omega-3 LC-PUFA supplementation on early childhood cognitive and visual development was evaluated in a 2013 systematic review and meta-analysis (54). Included in this assessment were 11 RCTs (a total of 5,272 participants) that supplemented maternal diet with omega-3 LC-PUFA during pregnancy or during pregnancy and lactation. Visual outcomes (eight trials) could not be evaluated in the meta-analysis due to variability in assessments; overall, four of six trials had null findings and the remaining two trials had very high rates of attrition. Cognitive outcomes (nine trials) included the Developmental Standard Score (DSS; in infants, toddlers, and preschoolers) or Intelligence Quotient (IQ; in children) and other aspects of neurodevelopment, such as language, behavior, and motor function. No differences were found between DHA and control groups for cognition measured with standardized psychometric scales in infants (<12 months), toddlers (12-24 months), and school aged children (5-12 years); preschool children (2-5 years) in the DHA treatment group had a 3.92 point increase in DSS compared to controls. The authors note that many of the trials of LC-PUFA supplementation in pregnancy had methodological weaknesses (e.g., high rates of attrition, small sample sizes, high risk of bias, multiple comparisons) limiting the confidence and interpretation of the pooled results.

Although epidemiological investigations have demonstrated that higher intakes of omega-3 LC-PUFA from fish and seafood during pregnancy are associated with improved developmental outcomes in offspring (54), trial evidence does not conclusively support or refute this relationship. At present, the potential benefits associated with obtaining long-chain omega-3 fatty acids through moderate consumption of fish (e.g., 1-2 servings weekly) during pregnancy and lactation outweigh any risks of contaminant exposure, though fish with high levels of methylmercury should be avoided (55). For information about contaminants in fish and guidelines for fish consumption by women of childbearing age, see Contaminants in fish below.

Gestation and pregnancy

The results of randomized controlled trials (RCTs) during pregnancy suggest that omega-3 fatty acid supplementation does not decrease the incidence of gestational diabetes, pregnancy-induced hypertension, or preeclampsia (56-58) but may result in modest increases in length of gestation, especially in women with low omega-3 fatty acid consumption. A 2006 meta-analysis of six randomized controlled trials in women with low-risk pregnancies found that omega-3 PUFA supplementation during pregnancy resulted in an increased length of pregnancy by 1.6 days (59). A 2007 meta-analysis of randomized controlled trials in women with high-risk pregnancies found that supplementation with long-chain PUFA did not affect pregnancy duration or the incidence of premature births but decreased the incidence of early premature births (<34 weeks of gestation; 2 trials, N=291; Relative Risk [RR]: 0.39 (95% CI: 0.18-0.84) (60).

Because maternal dietary intake of LC-PUFA determines the DHA status of the newborn, several expert panels in the US recommend that pregnant and lactating women consume at least 200 mg DHA per day, close to the amount recommended for adults in general (250 mg/day) (47, 61). The European Food and Safety Authority (EFSA) recommends that pregnant and lactating women consume an additional 100-200 mg of preformed DHA on top of the 250 mg/day EPA plus DHA recommended for healthy adults (62).

Cardiovascular disease

Omega-6 fatty acids: linoleic acid

LA is the most abundant dietary PUFA and accounts for approximately 90% of dietary omega-6 PUFA intake (63). Taking into consideration the results from RCTs and observational cohort studies, a 2009 American Heart Association scientific advisory concluded that obtaining at least 5-10% of total caloric intake from omega-6 PUFA is associated with a reduced risk of coronary heart disease (CHD) relative to lower intakes (64, 65). A pooled analysis of 11 cohort studies, encompassing 344,696 individuals followed for 4 to 10 years, found that replacing 5% of energy from saturated fatty acids (SFAs) with PUFA was associated with a 13% lower risk of coronary events (95% CI: 0.77, 0.97) and a 26% lower risk of coronary deaths (95% CI: 0.61, 0.89) (66). A 2012 meta-analysis of seven RCTs corroborated this beneficial effect, with an estimated 10% reduction in CHD risk (RR: 0.90, 95% CI: 0.83-0.97) for each 5% energy increase in PUFA consumption (67).

In controlled feeding trials, replacing dietary SFA with PUFA consistently lowers serum total and LDL cholesterol concentrations (68, 69). In fact, LA has been shown to be the most potent fatty acid for lowering serum total and LDL cholesterol when substituted for dietary SFA (70). The mechanisms by which linoleic acid lowers blood cholesterol include (1) the upregulation of LDL receptor and redistribution of LDL-C from plasma to tissue, (2) increased bile acid production and cholesterol catabolism, and (3) decreased conversion of VLDL to LDL (71).

Although dietary LA lowers blood cholesterol levels, supplementation with concentrated sources of LA may have adverse cardiovascular effects in individuals with preexisting CHD (see Disease Treatment).

Omega-3 fatty acids: alpha-linolenic acid

Several prospective cohort studies have examined the relationship between dietary ALA intake and cardiovascular disease (CVD). A 2012 meta-analysis of observational studies evaluated the risk of incident CVD related to dietary consumption or biomarkers of ALA (72). The analysis included 27 studies, 251,049 individuals and 15,327 CVD events (fatal coronary heart disease [CHD], nonfatal CHD, total CHD, and stroke). Overall, the pooled analysis found a moderately lower risk of CVD with higher ALA exposure (Relative Risk [RR]: 0.86; 95% CI: 0.77, 0.97).

Unlike LA, the cardioprotective effects of higher ALA intakes do not appear to be related to changes in serum lipid profiles. A meta-analysis of 14 randomized controlled trials concluded that ALA supplementation had no effect on total cholesterol, LDL cholesterol, or triglyceride levels (73). However, several controlled clinical trials have found that increasing ALA intake decreased serum concentrations of C-reactive protein (CRP), a marker of inflammation that is strongly associated with the risk of cardiovascular events, such as MI and stroke (74-76).

Long-chain omega-3 fatty acids: eicosapentaenoic acid and docosahexaenoic acid

Evidence is accumulating that increasing intakes of long-chain omega-3 fatty acids (EPA and DHA) can decrease the risk of cardiovascular disease by (1) preventing arrhythmias that can lead to sudden cardiac death, (2) decreasing the risk of thrombosis (a clot) that can lead to myocardial infarction (MI) or stroke, (3) decreasing serum triglyceride levels, (4) slowing the growth of atherosclerotic plaque, (5) improving vascular endothelial function, (6) lowering blood pressure slightly, and (7) decreasing inflammation (77).

In spite of these possible biological effects, clinical trials have not shown a significant effect of long-chain omega-3 supplementation on major cardiovascular events. A 2006 systematic review and meta-analysis of randomized controlled trials and prospective cohort studies concluded that long-chain omega-3 fatty acids do not significantly reduce the risk of total mortality or cardiovascular events (78). Likewise, a 2012 meta-analysis of secondary prevention trials (20 RCTs, including 68,680 patients) found no significant effect of omega-3 supplements (~1.5 g/day of EPA + DHA for a median of 2 years) on all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke (79). The same lack of effect was observed in a 2012 systematic review and meta-analysis of RCTs investigating the impact of omega-3 supplementation on inflammatory biomarkers in both healthy and ill individuals (80).

Although supplementation trials have not demonstrated a clear clinical benefit of omega-3 supplements, a recent multicenter, prospective, observational cohort study found a strong relationship between plasma phospholipid omega-3 PUFA levels (a biomarker of omega-3 status) and cardiovascular mortality (81). The Cardiovascular Health Study (CHS) related circulating levels of total and individual LC-PUFA (EPA, DPA, and DHA) to risk of total and CVD-specific mortality in 2,692 older (≥65 years) US adults. Higher levels of individual and combined total omega-3 PUFA in plasma phospholipids were associated with lower total mortality (HR for total omega-3: 0.73, 95% CI: 0.61-0.86). Looking more closely at cause-specific mortality, the observed reduction in risk was attributed mainly to fewer arrhythmic cardiac deaths (HR: 0.52, 95% CI: 0.31-0.86) and specifically with higher circulating DHA content (45% lower risk). Only EPA was associated with nonfatal MI (28% lower risk), while DPA was most strongly associated with stroke death (47% lower risk).

Coronary heart disease: A 2012 meta-analysis of 17 cohort studies with 315,812 participants and an average follow-up of 15.9 years calculated the pooled effect of fish consumption on coronary heart disease (CHD) mortality (82). Low (1 serving/week) or moderate fish consumption (2-4 servings/week) had a significant beneficial effect on the prevention of CHD mortality. Specifically, compared with the lowest fish consumption (<1 serving/month or 1-3 servings/month), consumption of 1 serving of fish per week and 2-4 servings/week was associated with a 16% (RR: 0.84, 95% CI: 0.75, 0.95) and 21% (RR: 0.79, 95% CI: 0.67,0.92) lower risk of fatal CHD, respectively.

Overall, among the various CVD outcomes (Figure 6), findings from prospective cohort studies and RCTs consistently indicate that consumption of fish or fish oil significantly reduces CHD mortality, including fatal myocardial infarction and sudden cardiac death (77, 83, 84). There is little evidence that these effects differ by sex, age, or race/ethnicity (77).

Sudden cardiac death: Sudden cardiac death (SCD) is the result of a fatal ventricular arrhythmia, which usually occurs in people with CHD. Studies in cell culture indicate that long-chain omega-3 fatty acids decrease the excitability of cardiac muscle cells (myocytes) by modulating ion channel conductance (85). The results of epidemiological studies suggest that regular fish consumption is inversely associated with the risk of SCD. A 2011 systematic review and meta-analysis of eight prospective cohort studies evaluated the impact of consuming <250 mg versus ≥250 mg omega-3 PUFA per day on various CHD outcomes (86). Consumption of ≥250 mg omega-3 PUFA per day was associated with a significant, 35% reduction in the risk of SCD (RR: 0.65; 95% CI: 0.54, 0.79).

A meta-analysis of nine randomized controlled trials found no significant effect of omega-3 supplements on SCD or ventricular arrhythmias in patients with previous MI compared to those taking placebo (87). Notably, although the pooled analysis reported no significant effect, the included trials reported either a protective effect (six trials) or null effect (three trials), with no harmful outcomes reported.

Stroke: Ischemic strokes are the result of insufficient blood flow to an area of the brain, which may occur when an artery supplying the brain becomes occluded by a clot. Hemorrhagic strokes occur when a blood vessel ruptures and bleeds into the brain. In the United States, 87% of strokes are ischemic strokes (88). A 2012 meta-analysis of 16 prospective studies, encompassing 402,127 individuals for a mean of 12.8 years, found that increased fish intake was associated with a decreased risk of ischemic stroke, but not hemorrhagic stroke (89). According to this analysis, consuming fish even once per week may significantly reduce the risk of ischemic stroke. In a separate dose-response meta-analysis of these prospective studies, a 3-servings/week increase in fish consumption was associated with a 6% decreased risk of total stroke (95% CI: 0.89-0.99) (90). Again, the association remained significant only for ischemic stroke (RR: 0.90, 95% CI: 0.84-0.97).

Although the protective effect of fish intake could be attributed to many things (e.g., the displacement of red meat, a marker of an overall healthier lifestyle and dietary pattern, nutrient interactions (91, 92)), its high content of omega-3 PUFA may be a major contributing factor. A meta-analysis of eight prospective studies that assessed the association between omega-3 PUFA intake on stroke risk found evidence of a nonlinear relationship between LC-PUFA intake and stroke risk, with only moderate intakes of 200-400 mg/day omega-3 PUFA associated with significantly reduced risk of total stroke (93). Additionally, when analyzed by stroke type, the risk for ischemic stoke was lower in the highest versus lowest category of long-chain omega-3 PUFA intake (RR: 0.82, 95% CI: 0.71-0.94).

Another 2012 systematic review and meta-analysis assessed both prospective cohort studies and RCTs that investigated fish consumption or omega-3 supplementation on cerebrovascular disease (any fatal or non-fatal ischemic stroke, hemorrhagic stroke, cerebrovascular accident, or transient ischemic attack) (91). From 26 prospective cohort studies, the pooled relative risk (RR) for cerebrovascular disease for 2-4 versus ≤1 serving of fish per week was 0.94 (95% CI: 0.90-0.98); for >5 servings versus ≤1 serving per week, the RR was 0.88 (95% CI: 0.81-0.96). No significant association was found between long-chain omega-3 biomarkers and risk of cerebrovascular disease. From the 12 RCTs analyzed, 10 of which recruited subjects with preexisting cardiovascular disease at baseline, no significant effect of omega-3 supplementation (mean dose of 1.8 g/day for a mean duration of 3 years) on cerebrovascular disease outcomes was observed. The same lack of effect of omega-3 supplementation on total stroke risk was observed in a second meta-analysis of RCTs (nine trials) (79).

Serum triglycerides: A meta-analysis of 17 prospective studies found hypertriglyceridemia (serum triglycerides >200 mg/dL) to be an independent risk factor for cardiovascular disease (94). Numerous controlled clinical trials have demonstrated that increasing intakes of EPA and DHA significantly lower serum triglyceride concentrations (95). The triglyceride-lowering effects of EPA and DHA increase with dose (96), but clinically meaningful reductions in serum triglyceride concentrations have been demonstrated at doses of 2 g/day of EPA + DHA (97). In its recommendations regarding omega-3 fatty acids and cardiovascular disease (see Intake Recommendations below), the American Heart Association indicates that an EPA + DHA supplement may be useful in patients with hypertriglyceridemia (23).

A 2011 meta-analysis of RCTs compared the effect of EPA alone (10 trials), DHA alone (17 trials), or EPA versus DHA (6 trials) on serum lipids (98). Although both EPA and DHA reduce triglyceride levels, they have different effects on LDL and HDL levels. DHA raises LDL and HDL, whereas EPA has no significant effect. Importantly, DHA may increase LDL via increased conversion of VLDL to LDL and by producing larger, more buoyant LDL particles (3).

Summary: omega-3 and omega-6 PUFA and cardiovascular disease prevention

The results of observational studies and randomized controlled trials suggest that replacing dietary SFA with omega-6 and omega-3 PUFA (from both plant and marine sources) lowers LDL cholesterol and decreases cardiovascular disease risk. Additionally, the results of epidemiological studies provide consistent evidence that increasing dietary omega-3 fatty intake is associated with significant reductions in cardiovascular disease risk through mechanisms other than lowering LDL cholesterol. In particular, increasing fish consumption to at least two servings of oily fish per week has been associated with significant reductions in fatal myocardial infarction and sudden cardiac death (77). This amount would provide about 400-500 mg/day of EPA + DHA (23).

Alzheimer's disease

Alzheimer's disease is the most common cause of dementia in older adults. Alzheimer's disease is characterized by the formation of amyloid plaque in the brain and nerve cell degeneration. Disease symptoms, including memory loss and confusion, worsen over time (99). Some epidemiological studies have associated high intake of fish with lower risks of impaired cognitive function (100), dementia (101), and Alzheimer's disease (101, 102). Proposed mechanisms for a protective effect of long-chain omega-3 fatty acids in the brain and vascular system include (1) the mitigation of inflammation, (2) improved cerebral blood flow, and (3) reduced amyloid aggregation (103).

A 2009 systematic review reported on the association between eating fish (as a source of long-chain omega-3 fatty acids) or taking an omega-3 supplement and the risk of cognitive decline or Alzheimer's disease (103). Out of 11 observational studies, three reported a significant benefit of omega-3 fatty acids on cognitive decline; four of eight observational studies reported positive findings on incident Alzheimer's disease or dementia. The four small clinical trials reviewed showed no evidence for prevention or treatment of any form of dementia (103).

DHA, the major omega-3 fatty acid in the brain, appears to be protective against Alzheimer's disease (104). Observational studies have found that lower DHA status is associated with increased risk of Alzheimer's disease (105-107), as well as other types of dementia (106). The relationship between DHA status and cognitive decline may be dependent on apolipoprotein E (APOE) genotype. Of three common APOE alleles (epsilon 2 [ε2], ε3, and ε4), the presence of the APOE ε4 (E4) allele is associated with increased risk and earlier onset of Alzheimer's disease (108). A protective effect of consumption of fatty fish on the risk for dementia and AD may not apply to carriers of the E4 allele (109, 110). EPA + DHA supplementation did not increase plasma levels of these n-3 PUFA to the same extent in E4 carriers compared to non-carriers (111), and [13C]DHA tracer studies indicate that DHA metabolism differs in E4 carriers, with greater oxidation and lower plasma levels in E4 positive versus negative individuals (112).

Overall, the data favor a role for diets rich in long-chain omega-3 fatty acids in slowing cognitive decline but not for supplementation in the prevention or treatment of any type of dementia. The efficacy of omega-3 supplementation may depend on the underlying pathology of AD (i.e., the involvement of a vascular issue) (103) or the presence of the APOE4 allele (110, 111). Additionally, consistency in outcome measures and diagnostic criteria, and longer duration trials may be necessary to see a consistent effect.

Disease Treatment

Coronary heart disease

Dietary intervention trials

Omega-6 fatty acids (linoleic acid): In a reanalysis of the Sydney Heart Health Study (SHHS), a single-blind, RCT in 458 men (ages 30-59 years) with a recent coronary event, the replacement of dietary saturated fat with omega-6 linoleic acid led to higher rates of death from all-causes, cardiovascular disease, and coronary heart disease (CHD) compared to controls (113). Furthermore, a meta-analysis that included the SHHS and two other secondary prevention trials revealed an increased risk of mortality when saturated fat is replaced with concentrated sources of linoleic acid. There are some important limitations and considerations with the SHHS to keep in mind: (1) LA intake went from 6% to 15% of total energy for the study participants; in US adults, the average intake of LA is approximately 7% of total energy (114); (2) there may have been displacement of monounsaturated fatty acids and other PUFA in addition to saturated fats in the experimental intervention; and (3) the experimental formulation of safflower oil margarine may have provided trans fat. Regardless of these issues, substituting dietary saturated fat with mixed PUFA (both omega-6 and omega-3) rather than linoleic acid alone reduces CVD risk (113) and is recommended for both the primary and secondary prevention of CVD (65, 67).

Omega-3 fatty acids: In the Diet and Reinfarction Trial (DART), total mortality and fatal MI decreased by 29% in male MI survivors advised to increase their weekly intake of oily fish to 200-400 g (7-14 oz)—an amount estimated to provide an additional 500-800 mg/day of long-chain omega-3 fatty acids (EPA + DHA) (115). The Diet and Reinfarction Trial 2 (DART-2) administered similar dietary advice but to a different cohort of high-risk individuals: those with stable angina (116). In this case, advice to eat oily fish or fish oil did not affect all-cause mortality but was associated with an increased risk of sudden cardiac death. This increased risk was confined to the use of fish oil capsules rather than dietary fish intake. Though the results of the DART trials seem to contradict each other, there are important differences that offer explanations, namely the timing of the intervention (shortly after first MI in the first trial) and the stage of CHD (early versus stable) in the study population. These trials suggest that fish oil may reduce mortality during recovery from MI but perhaps not during later stages of the disease.

The Alpha Omega Trial tested if low doses of EPA + DHA (400 mg per day), ALA (2 g per day), or both in margarines reduced the risk of cardiovascular (CV) events among 4,837 patients (78% male; mean age, 69 years) who had a MI in the previous 10 years (117). After 40 months, none of the n-3 PUFA treatments significantly affected the rate of major CV events compared to placebo. Notably, medication use in the study population was high: antithrombotic agents (97.5%), antihypertensive drugs (89.7%), and statins (85%).

Supplementation trials

In the largest randomized controlled trial of supplemental omega-3 fatty acids to date, the GISSI-Prevenzione Trial, 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; supplement users also experienced a 20% lower risk of death from all causes compared to non-supplement users (118). 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 (119).

The results of a meta-analysis that pooled the findings of 29 randomized controlled trials of dietary or supplementary omega-3 fatty acids indicated that omega-3 fatty acids were not associated with a statistically significant reduction in all-cause mortality or risk of restenosis in high-risk cardiovascular patients (120). Heterogeneity in trial size and follow-up time limited the analysis, and the authors note that the probability of benefit from omega-3 fatty acids still remains high for both endpoints.

Summary

The results of randomized controlled trials in individuals with documented CHD suggest a beneficial effect of dietary and supplemental omega-3 fatty acids. Based on the results of these trials, the American Heart Association recommends that individuals with documented CHD consume approximately 1 g/day of EPA + DHA, preferably by consumption of oily fish (see Intake Recommendations below) (121).

Diabetes mellitus

Cardiovascular diseases are the leading causes of death in individuals with diabetes mellitus (DM). The dyslipidemia typically associated with diabetes is characterized by a combination of hypertriglyceridemia (serum triglycerides >200 mg/dL), low HDL-C, and abnormal LDL composition (122).

A 2009 meta-analysis of 23 randomized controlled trials (RCTs), including 1,075 individuals with type 2 diabetes, found that omega-3 fatty acid supplementation (mean dose, 3.5 g/day) lowered serum triglyceride levels by 0.45 mmol/L, lowered VLDL-C by 0.07 mmol/L, but raised LDL-C by 0.11 mmol/L (123). No significant changes in total cholesterol, HDL-C, HbA1c, fasting glucose, fasting insulin, or body weight were observed.

Since 2009, the results of two additional trials of omega-3 supplementation in diabetic patients have been published. The Alpha Omega Trial evaluated the effect of low-dose supplementation with omega-3 fatty acids on ventricular arrhythmias and fatal CHD in stable, post-MI patients (117). While the main analysis found no effect of supplementation, a secondary analysis of 1,014 diabetic participants found that low-dose supplementation of combined omega-3 fatty acids (~400 mg EPA + DHA and 2 g ALA per day in an experimental margarine spread for 40 months) resulted in fewer ventricular arrhythmia-related events (HR 0.16, 95% CI 0.04-0.69) compared to placebo margarine (124). In the ORIGIN trial, 1 g/day of n-3 fatty acids (465 mg EPA + 375 mg DHA per day for 6 years) had no effect on rates of major vascular events, all-cause mortality, cardiovascular mortality, or death from arrhythmia in 12,536 dysglycemic patients at high risk for cardiovascular events compared to placebo (125). Triglyceride levels were reduced by 14.5 mg/dL (0.16 mmol/L), but no other blood lipids were affected by supplementation. In both of these trials, a high proportion of study participants used cardiovascular medications.

Summary

Increasing EPA and DHA intakes may be beneficial to diabetic individuals, especially those with elevated serum triglycerides or with a history of MI (126). There is no compelling evidence that daily EPA + DHA intakes of less than 3 g/day adversely affect long-term glycemic control in diabetics (127-129). The American Diabetes Association recommends that diabetic individuals increase omega-3 fatty acid consumption by consuming two to three 3-oz servings of fish weekly (121).

Inflammatory diseases

Rheumatoid arthritis

A 2012 meta-analysis of 10 randomized controlled trials, involving 270 rheumatoid arthritis (RA) patients, assessed the efficacy of high-dose omega-3 PUFA supplementation on clinical outcomes of RA (130). Omega-3 consumption of ≥2.7 g/day for a minimum of three months reduced nonsteroidal anti-inflammatory drug (NSAID) use but had no significant effect on tender joint count, swollen joint count, morning stiffness, or physical function compared to placebo. On the other hand, a 2012 systematic review, which included 23 trials investigating omega-3 supplementation (mainly as fish oil) in RA patients, concluded that there appears to be a consistent, though modest, benefit of marine-derived n-3 PUFA (average intake ~3g/day) on some clinical symptoms of RA (131). Thus, high-dose supplementation of long-chain omega-3 PUFA spares the need for anti-inflammatory medications and may reduce joint pain and swelling in some RA patients.

Inflammatory bowel disease

Crohnís disease: A 2013 systematic review evaluated the efficacy of omega-3 supplementation in Crohnís disease (CD) patients, considering the evidence base from both short-term (9 to 24 weeks) and long-term (1 year) trials (132). Among five trials that evaluated the efficacy of omega-3 supplementation on CD relapse rates, conflicting outcomes were reported. Most trials were limited by small sample sizes and short duration; up to three years may be necessary to see an effect on CD relapse rates given the natural relapsing-remitting course of the disease. The two largest and most recent trials (EPIC-1 and EPIC-2) showed no significant effect of omega-3 supplementation on symptoms of CD remission compared to placebo (133). Two additional systematic reviews and a meta-analysis reached similar conclusions (134, 135). Three short-term trials showed positive effects of omega-3 supplementation on plasma biochemical parameters (e.g., reduced inflammatory cytokine expression, increased plasma EPA and DHA levels) compared to controls (132). In spite of its impact on biochemical changes in the short-term, however, the ability of omega-3 supplementation to maintain remission or effect clinically meaningful changes in CD is not supported by the current evidence.

Ulcerative colitis: Seven randomized controlled trials of fish oil supplementation in active ulcerative colitis (UC) patients reported significant improvement in at least one outcome measure, such as decreased corticosteroid use, improved disease activity scores, or improved histology scores (135). In inactive UC patients, omega-3 supplementation had no effect on relapse rates compared to placebo in four separate trials (134, 135).

While no serious side effects were reported in any trials of fish oil supplementation for the maintenance or remission of inflammatory bowel disease, diarrhea and upper gastrointestinal symptoms occurred more frequently with omega-3 treatment (134, 135).

Asthma

Inflammatory eicosanoids (leukotrienes) derived from arachidonic acid (AA; 20:4n-6) are thought to play an important role in the pathology of asthma (28). Since increasing omega-3 fatty acid intake has been found to decrease the formation of AA-derived leukotrienes, a number of clinical trials have examined the effects of long-chain omega-3 fatty acid supplementation on asthma. Although there is some evidence that omega-3 fatty acid supplementation can decrease the production of inflammatory mediators in asthmatic patients (136, 137), evidence that omega-3 fatty acid supplementation decreases the clinical severity of asthma in controlled trials has been inconsistent (138). Three systematic reviews of randomized controlled trials of long-chain omega-3 fatty acid supplementation in asthmatic adults and children found no consistent effects on clinical outcome measures, including pulmonary function tests, asthmatic symptoms, medication use, or bronchial hyperreactivity (139-141).

Immunoglobulin A nephropathy

Immunoglobulin A (IgA) nephropathy is a kidney disorder that results from the deposition of IgA in the glomeruli of the kidney. The cause of IgA nephropathy is not clear, but progressive renal failure may eventually develop in 15-40% of patients (142). 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.

A 2012 meta-analysis assessed the efficacy of omega-3 fatty acid treatment on adult IgA nephropathy (143). Five randomized controlled trials were included in an analysis involving 239 patients (mean age range, 37 to 41 years) who received placebo or supplemental EPA + DHA at doses of 1.4 to 5.1 g/day for 6 to 24 months. Compared with control groups, omega-3 treatment had no significant effect on urine protein excretion or glomerular filtration rate. Only two trials measured changes in serum creatinine, a marker of renal function, and end-stage renal disease; in both trials, omega-3 treatment had a beneficial effect on these two parameters. No adverse events associated with omega-3 treatment were reported in any of the trials.

Neuropsychiatric disorders

Major depression and bipolar disorder

Data from ecological studies across different countries suggest an inverse association between seafood consumption and national rates of major depression (144) and bipolar disorder (145). Several small studies have found omega-3 fatty acid concentrations to be lower in the plasma (146-148) and adipose tissue (fat) (149) of individuals suffering from depression compared to controls. Although it is not known how omega-3 fatty acid intake affects the incidence of depression, modulation of neuronal signaling pathways and eicosanoid production have been proposed as possible mechanisms (150).

There may be some benefit of omega-3 PUFA supplementation on depressive disorders, but it is difficult to compare studies and draw conclusions due to great heterogeneity among the trials (151, 152). Small sample sizes, lack of standardization of therapeutic doses, type of n-3 PUFA administered, co-treatment with pharmacological agents, and diagnostic criteria vary among the trials.

A 2012 systematic review of all published RCTs investigated the effect of omega-3 PUFA supplementation on the prevention and treatment of several types of depression and other neuropsychiatric disorders (151). With respect to major depression, a majority of studies reported a positive effect for omega-3 supplements on depressive symptoms, though efficacy is still considered inconclusive given the great variability among trials. A few themes emerged from this review: more trials reported positive effect for omega-3 PUFA supplements as an adjunct to pharmacological treatment; in monotherapy trials, EPA alone was more effective than DHA alone; and in combination trials, positive effects were more likely if an EPA:DHA ratio of >1.5Ė2.0 was administered.

Unipolar depression and bipolar disorder are considered distinct psychiatric conditions, although major depression occurs in both. As with major depression, the 2012 review of RCTs indicated that omega-3 supplementation may have a positive effect as an adjunct to therapy in patients with bipolar disorder (151).

While there is some promising evidence for the use of omega-3 fatty acids for major depression and bipolar disorder, additional trials that account for dietary omega-3 intake, changes in red blood cell PUFA levels, the ratio of EPA:DHA provided, co-treatment with medications, and of sufficient duration are necessary.

Schizophrenia

A 2013 meta-analysis of 18 studies compared the PUFA composition of red blood cell (RBC) membranes in schizophrenic patients to those of normal controls (153). The majority of studies investigated medicated patients, though the authors separated the analysis into three groups of patients at time of measurement in order to account for possible confounding from pharmacologic agents: antipsychotic-medicated, antipsychotic-naïve, and antipsychotic-free. Overall, decreased levels of DPA, DHA, and AA in RBC membranes were associated with the schizophrenic state. Several mechanisms may account for the altered PUFA levels in schizophrenia, such as altered lipid metabolism, increased oxidative stress, or changes in diet consequent to disease-related behavior.

The use of long-chain omega-3 fatty acid supplements to alleviate symptoms of schizophrenia or to mitigate adverse effects of antipsychotic medications has been investigated in a number of clinical trials (154). Overall, there was no effect of fish oil or LC-PUFA supplements on symptoms of schizophrenia. However, given the high safety profile of fish oil supplements and some evidence of a positive effect of EPA supplementation in a subset of trials, some clinicians may consider EPA a useful adjunct to antipsychotic therapy in schizophrenic patients.

Alzheimer's disease and dementia

Some epidemiological studies have associated decreased DHA status with Alzheimerís disease and other types of dementia (see above). Although results of studies in animal models have been promising (reviewed in 155), the existing clinical trial data do not support a recommendation for DHA supplementation in the treatment of Alzheimer's disease in humans. A randomized controlled trial (RCT) was conducted to determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease (156). Two hundred ninety-five individuals with mild to moderate Alzheimer's disease (Mini-Mental State Examination [MMSE] scores, 14-26) received algal DHA supplement (1g twice daily) or placebo (corn or soy oil) for 18 months. Although DHA supplementation significantly increased levels of DHA in plasma phospholipids and cerebrospinal fluid, it had no effect on the rate of change on the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog), the Clinical Dementia Rating (CDR) sum of boxes, or brain atrophy compared to placebo. No adverse effects were associated with DHA treatment in this trial.

Sources

Food sources

Omega-6 fatty acids

Linoleic acid: Food sources of LA include vegetable oils, such as soybean, safflower, and corn oil; nuts; seeds; and some vegetables. Dietary surveys in the US indicate that the average adult intake of LA ranges from 17-20 g/day for men and 12-13 g/day for women (63). Some foods that are rich in LA are listed in the table below.

Food Sources of Linoleic Acid (18:2n-6) (157)
Food Serving
Linoleic Acid (g)
Safflower oil
1 tablespoon
10.1
Sunflower seeds, oil roasted 1 oz
9.7
Pine nuts 1 oz
9.4
Sunflower oil 1 tablespoon
8.9
Corn oil 1 tablespoon
7.3
Soybean oil 1 tablespoon
6.9
Pecans, oil roasted 1 oz
6.4
Brazil nuts 1 oz
5.8
Sesame oil 1 tablespoon
5.6

 

Arachidonic acid: Animals, but not plants, can convert LA to AA. Therefore, AA is present in small amounts in meat, poultry, and eggs.

Omega-3 fatty acids

Alpha-linolenic acid (ALA): Flaxseeds, walnuts, and their oils are among the richest dietary sources of ALA. Canola oil is also an excellent source of ALA. Dietary surveys in the US indicate that average adult intakes for ALA range from 1.8-2.0 g/day for men and from 1.4-1.5 g/day for women (63). Some foods that are rich in ALA are listed in the table below.

Food Sources of Alpha-linolenic Acid (18:3n-3) (157)
Food Serving
Alpha-linolenic acid (g)
Flaxseed oil 1 tablespoon
7.3
Chia seeds, dried 1 oz
5.1
Walnuts, English 1 oz
2.6
Flaxseeds, ground 1 tablespoon
1.6
Walnut oil 1 tablespoon
1.4
Canola oil 1 tablespoon
1.3
Soybean oil 1 tablespoon
0.9
Mustard oil 1 tablespoon
0.8
Walnuts, black 1 oz
0.6
Tofu, firm ½ cup
0.2

 

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA): Oily fish are the major dietary source of EPA and DHA. Dietary surveys in the US indicate that average adult intakes of EPA range from 0.03-0.06 g/day, and average adult intakes of DHA range from 0.05-0.10 g/day (63). Omega-3 fatty acid-enriched eggs are also available in the US. Some foods that are rich in EPA and DHA are listed in the table below.

Food Sources of EPA (20:5n-3) and DHA (22:6n-3) (97)
Food Serving
EPA (g)
DHA (g)

Amount providing
1 g of EPA + DHA

Herring, Pacific 3 oz*
1.06
0.75
1.5 oz
Salmon, chinook 3 oz
0.86
0.62
2 oz
Sardines, Pacific 3 oz
0.45
0.74
2.5 oz
Salmon, Atlantic 3 oz
0.28
0.95
2.5 oz
Oysters, Pacific 3 oz
0.75
0.43
2.5 oz
Salmon, sockeye 3 oz
0.45
0.60
3 oz
Trout, rainbow 3 oz
0.40
0.44
3.5 oz
Tuna, canned, white 3 oz
0.20
0.54
4 oz
Crab, Dungeness 3 oz
0.24
0.10
9 oz
Tuna, canned, light 3 oz
0.04
0.19
12 oz

*A 3-oz serving of fish is about the size of a deck of cards.

Biosynthesis of EPA and DHA

Humans can synthesize AA from LA and EPA and DHA from ALA through a series of desaturation and elongation reactions. EPA and DPA are also obtained from the retroconversion of DHA (see Metabolism and Bioavailability above). Due to low conversion efficiency, it is advised to obtain EPA and DHA from additional sources.

Supplements

Omega-6 fatty acids

Borage seed oil, evening primrose oil, and black currant seed oil are rich in gamma-linolenic acid (GLA) and are often marketed as GLA or essential fatty acid (EFA) supplements (158).

Omega-3 fatty acids

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. The omega-3 fatty acids from natural fish oil are in the triglyceride form, often with only one of three attached fatty acids an omega-3; thus, up to 70% of fatty acids provided may be other types (3). Ethyl esters of EPA and DHA (ethyl-EPA and ethyl-DHA) are concentrated sources of long-chain omega-3 fatty acids that provide more EPA and DHA per gram of oil. Krill oil contains both EPA and DHA and is considered comparable to fish oil as a source of these long-chain PUFA (159). Cod liver oil is also a rich source of EPA and DHA, but some cod liver oil preparations may contain excessive amounts of preformed vitamin A (retinol) (158). DHA supplements derived from algal and fungal sources are also available. Because dietary DHA is retroconverted to EPA and DPA in humans, DHA supplementation represents yet another alternative to fish oil supplements (see Metabolism and Bioavailability).

EPA and DHA content varies in each of these preparations, making it necessary to read product labels in order to determine the EPA and DHA levels provided by a particular supplement. All omega-3 fatty acid supplements are absorbed more efficiently with meals. Dividing oneís daily dose into two or three smaller doses throughout the day will decrease the risk of gastrointestinal side effects (see Safety below).

Infant formula

In 2001, the FDA began permitting the addition of DHA and AA to infant formula in the United States (160). Presently, manufacturers are not required to list the amounts of DHA and AA added to infant formula on the label. However, most infant formula manufacturers provide this information. The amounts added to formulas in the US range from 8-17 mg DHA/100 calories (5 fl oz) and from 16-34 mg AA/100 calories. For example, an infant drinking 20 fl oz of DHA-enriched formula daily would receive 32-68 mg/day of DHA and 64-136 mg/day of AA.

Safety

Adverse effects

Gamma-linolenic acid (18:3n-6)

Supplemental gamma-linolenic acid is generally well tolerated, and serious adverse side effects have not been observed at doses up to 2.8 g/day for 12 months (161). High doses of borage seed oil, evening primrose oil, or black currant seed oil may cause gastrointestinal upset, loose stools, or diarrhea (158). Because of case reports that supplementation with evening primrose oil induced seizure activity in people with undiagnosed temporal lobe epilepsy (162), people with a history of seizures or seizure disorder are generally advised to avoid evening primrose oil and other gamma-linolenic acid-rich oils (158).

Alpha-linolenic acid (18:3n-3)

Although flaxseed oil is generally well tolerated, high doses may cause loose stools or diarrhea (163). Allergic and anaphylactic reactions have been reported with flaxseed and flaxseed oil ingestion (164).

Eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)

Serious adverse reactions have not been reported in those using fish oil or other EPA and DHA supplements. The most common adverse effect of fish oil or EPA and DHA supplements is a fishy aftertaste. Belching and heartburn have also been reported. Additionally, high doses may cause nausea and loose stools.

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 US FDA has ruled that intakes up to 3 g/day of long-chain omega-3 fatty acids (EPA and DHA) 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 (97). Although the Institute of Medicine did not establish a tolerable upper intake level (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 Drug interactions and Nutrient interactions below) (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 (165). Studies comparing measures of immune cell function outside the body (ex vivo) 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 in vivo, caution should be observed when considering omega-3 fatty acid supplementation in individuals with compromised immune systems.

Infant formula

In early studies of DHA-enriched infant formula, EPA- and DHA-rich fish oil was used as a source of DHA. However, some preterm infants receiving fish oil-enriched formula had decreased plasma AA concentrations, which were associated with decreased weight (but not length and head circumference) (166, 167). This effect was attributed to the potential for high concentrations of EPA to interfere with the synthesis of AA, which is essential for normal growth. Consequently, EPA was removed and AA was added to DHA-enriched formula. Currently available infant formulas in the US contain only AA and DHA derived from algal or fungal sources, rather than fish oil. Randomized controlled trials have not found any adverse effects on growth in infants fed formulas enriched with AA and DHA for up to one year (168).

Pregnancy and lactation

The safety of supplemental omega-3 and omega-6 fatty acids, including borage seed oil, evening primrose oil, black currant seed oil, and flaxseed oil, has not been established in pregnant or lactating (breast-feeding) women (158). Studies of fish oil supplementation during pregnancy and lactation have not reported any serious adverse effects (see Contaminants in fish and Contaminants in supplements below).

Contaminants in fish

Some species of fish may contain significant levels of methylmercury, polychlorinated biphenyls (PCBs), or other environmental contaminants (55). In general, 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 (169). However, methylmercury is found throughout the muscle of fish, so these cooking precautions will not reduce exposure to methylmercury. Organic mercury compounds are toxic and excessive exposure can cause brain and kidney damage. The developing fetus, 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 US Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) have made the following joint recommendations for women who may become pregnant, pregnant women, breast-feeding women, and parents:

1) Eat 8-12 ounces of a variety of fish a week.

  • Thatís 2 or 3 servings of fish a week.
  • For young children, give them 2 or 3 servings of fish a week with the portion right for the child's age and calorie needs.

2) Choose fish lower in mercury.

  • Many of the most commonly eaten fish are lower in mercury.
  • These include salmon, shrimp, pollock, tuna (light canned), tilapia, catfish, and cod.

3) Avoid 4 types of fish: tilefish from the Gulf of Mexico, shark, swordfish, and king mackerel.

  • These 4 types of fish are highest in mercury.
  • Limit white (albacore) tuna to 6 ounces a week.

4) When eating fish you or others have caught from streams, rivers, and lakes, pay attention to fish advisories on those waterbodies.

For more information about the FDA/EPA consumer advisory on methylmercury in fish, see their online brochure. More information about mercury levels in commercial fish and shellfish is available from the FDA.

Contaminants in supplements

Although concerns have been raised regarding the potential for omega-3 fatty acid supplements derived from fish oil to contain methylmercury, PCBs, and dioxins, several independent laboratory analyses in the US have found commercially available omega-3 fatty acid supplements to be free of methylmercury, PCBs, and dioxins (170). The absence of methylmercury in omega-3 fatty acid supplements can be explained by the fact that mercury accumulates in the muscle, rather than the fat of fish (97). 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 (171). Pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds, are found in various parts of the borage plant. People who take borage oil supplements should use products that are certified free of pyrrolizidine alkaloids (158).

Drug interactions

Gamma-linolenic acid supplements, such as evening primrose oil or borage seed oil, may increase the risk of seizures in people on phenothiazines, such as chlorpromazine (162). High doses of black currant seed oil, borage seed oil, evening primrose oil, flaxseed oil, and fish oil may inhibit platelet aggregation; therefore, these supplements should be used with caution in people on anticoagulant medications. In particular, people taking fish oil or long-chain omega-3 fatty acid (EPA and DHA) supplements in combination with anticoagulant drugs, including aspirin, clopidogrel (Plavix), dalteparin (Fragmin), dipyridamole (Persantine), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid), and warfarin (Coumadin), should have their coagulation status monitored using a standardized prothrombin time assay (INR). One small study found that 3 g/day or 6 g/day of fish oil did not affect INR values in 10 patients on warfarin over a 4-week period (172). However, a case report described an individual who required a reduction of her warfarin dose when she doubled her fish oil dose from 1 g/day to 2 g/day (173).

Nutrient interactions

Vitamin E

Outside the body, PUFA become rancid (oxidized) more easily than SFA. Fat-soluble antioxidants, such as vitamin E, play an important role in preventing the oxidation of PUFA. Inside the body, results of animal studies and limited data in humans suggest that the amount of vitamin E required to prevent lipid peroxidation increases with the amount of PUFA consumed (174). One widely used recommendation for vitamin E intake is 0.6 mg of alpha-tocopherol per gram of dietary PUFA. This recommendation was based on a small study in men and the ratio of alpha-tocopherol to LA in the US diet and has not been verified in more comprehensive studies. Although EPA and DHA are easily oxidized outside the body, it is presently unclear whether EPA and DHA are more susceptible to oxidative damage within the body (175). High vitamin E intakes have not been found to decrease biomarkers of oxidative damage when EPA and DHA intakes are increased (176, 177), but some experts believe that an increase in PUFA intake, particularly omega-3 PUFA intake, should be accompanied by an increase in vitamin E intake (1).

Intake Recommendations

US Institute of Medicine

The Food and Nutrition Board of the US Institute of Medicine has established adequate intake (AI) levels for omega-6 and omega-3 fatty acids (see the tables below) (1).

Adequate Intake (AI) for Omega-6 Fatty Acids (1)
Life Stage Age Source
Males (g/day)
Females (g/day)
Infants 0-6 months Omega-6 PUFA* 4.4 4.4
Infants 7-12 months Omega-6 PUFA*
4.6 4.6
Children 1-3 years LA# 7 7
Children 4-8 years LA 10 10
Children 9-13 years LA 12 10
Adolescents 14-18 years LA 16 11
Adults 19-50 years LA 17 12
Adults 51 years and older LA 14 11
Pregnancy All ages LA - 13
Lactation All ages LA - 13

*The various omega-6 polyunsaturated fatty acids (PUFA) present in human milk can contribute to the AI for infants. # LA, linoleic acid

Adequate Intake (AI) for Omega-3 Fatty Acids (1)
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
Lactation All ages ALA
-
1.3

*All omega-3 polyunsaturated fatty acids present in human milk can contribute to the AI for infants. ALA, alpha-linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid.

Given the established health benefits of consuming at least two servings of oily fish per week, providing approximately 400-500 mg EPA + DHA, some researchers have proposed that the US Institute of Medicine establish a dietary reference intake (DRI) for EPA + DHA (23). For now, there is no DRI for EPA and DHA specifically.

International recommendations

Upon request of the European Commission, the European Food Safety Authority (EFSA) proposed adequate intakes (AI) for the essential fatty acids LA and ALA, as well as the long-chain omega-3 fatty acids EPA and DHA (62). EFSA recommends an LA intake of 4% of total energy and an ALA intake of 0.5% of total energy; an AI of 250 mg/day is recommended for EPA plus DHA.

The World Health Organization recommends an acceptable macronutrient distribution range (AMDR) for omega-6 fatty acid intake of 6-11% of energy and for omega-3 fatty acid intake of 0.5-2% of energy (178). Their AMDR for EPA plus DHA is 0.250-2 g/day (the upper limit applying to the secondary prevention of CHD).

The International Society for the Study of Fatty Acids and Lipids (ISSFAL) recommends for healthy adults an LA intake of 2% energy, ALA intake of 0.7% energy, and a minimum of 500 mg/day of EPA plus DHA for cardiovascular health (179).

American Heart Association recommendation

The American Heart Association recommends that people without documented CHD eat a variety of fish (preferably oily) at least twice weekly (121). Two servings of oily fish provide approximately 500 mg of EPA plus DHA. Pregnant women and children should avoid fish that typically have higher levels of methylmercury (see Contaminants in fish). People with documented CHD are advised to consume approximately 1 g/day of EPA + DHA preferably from oily fish, or to consider EPA + DHA supplements in consultation with a physician. Patients who need to lower serum triglycerides may take 2-4 g/day of EPA + DHA supplements under a physician's care.

Linus Pauling Institute recommendation

The Linus Pauling Institute recommends that generally healthy adults increase their intake of omega-3 fats by eating fish twice weekly and consuming foods rich in alpha-linolenic acid, such as walnuts, flaxseeds, and flaxseed or canola oil. If you don't regularly consume fish, consider taking a two-gram fish oil supplement several times a week. If you are prone to bleeding or take anticoagulant drugs, consult your physician.

References


Written in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2014 by:
Giana Angelo, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in May 2014 by:
Donald B. Jump, Ph.D.
Professor, School of Biological and Population Health Sciences
Principal Investigator, Linus Pauling Institute
Oregon State University

The 2014 update of this article was underwritten, in part,
by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Copyright 2003-2014  Linus Pauling Institute


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The Linus Pauling Institute Micronutrient Information Center provides scientific information on the health aspects of dietary factors and supplements, foods, and beverages 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.

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