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Fish Oils

Scientific Name(s):Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)

Common Name(s): Marine oils , marine oil fatty acids , n-3 fatty acids , omega-3 fatty acids , omega-3 polyunsaturated fatty acids ( PUFAs ), long-chain PUFAs ( LCPUFAs ), Lovaza

Uses

Clinical benefit is strongest for lowering the risk of coronary artery disease and decreasing serum triglycerides. Reductions in the risk for all-cause mortality, cardiac death, and sudden death have been established for omega-3 fatty acid supplementation for at least 1 year's duration. The United States Food and Drug Administration (FDA) has approved the use of fish oil for reducing very high triglyceridemia (at least 5.65 mmol/L) in adults as an adjunct to diet. Evidence for use of parenteral fish oil lipid emulsion is mounting in severely ill and surgical patients. Evidence for a role in rheumatoid arthritis remains equivocal but promising. No consistent relationship between fish oil consumption and reduction in the risk of stroke or maintenance in inflammatory bowel disease has been established. Other areas of interest in the therapeutic use of fish oils requiring further study include asthma and allergy, dysmenorrhea, mental health, and the promotion of postnatal growth and development.

Dosing

The American Heart Association (AHA) recommends a minimum of 2 fatty fish meals per week. Clinical trials suggest fish oil supplementation of omega-3 fatty acids 1 g/day in coronary heart disease, and where triglycerides are elevated, a minimum of omega-3 fatty acids 2 g/day up to a maximum of 4 g/day. Fish oil 1,000 mg approximates to omega-3 fatty acids (eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA]) 300 to 400 mg.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Potential for mercury ingestion. Avoid use.

Interactions

None well documented.

Adverse Reactions

Fish oil at dosages of EPA/DHA 2 to 5.4 g/day is well accepted and tolerated. Mild GI discomfort was reported in clinical trials.

Toxicology

Research reveals little or no information.

Fish oils are predominantly comprised of the omega-3 fatty acids EPA and DHA; “fish oil” is a term frequently used interchangeably with, and in reference to, EPA and DHA. Marine sources containing the highest content of omega-3 fatty acids are fatty fish (eg, mackerel, halibut, salmon, bluefish, mullet, sablefish, menhaden, anchovy, herring, lake trout, coho, sardines), which provide 1 g or more of omega fatty acids per 100 g (3.5 oz) of fish. Tuna, seal, and shellfish (eg, oysters) are additional sources. 1 , 2 , 3 , 4 , 5

Because marine fish stocks are limited and because many fish stocks are currently contaminated by pollutants (eg, methylmercury, organochlorine pesticides), it has been proposed that the algal genes responsible for EPA and DHA production be cloned into plants. 6 , 7 Oils from transgenic plants would be rich in EPA and DHA, and although some success has been achieved, challenges in the biosynthetic pathways in higher plants have not yet been surmounted. 8 , 9 EPA and DHA can be synthesized, albeit inefficiently, from the essential omega-3 fatty acid alpha-linolenic acid (ALA). ALA cannot be synthesized by humans and must be obtained from the diet. ALA is found in flaxseed, canola, soybean, walnut, and wheat germ oils, nuts and seeds, and vegetables. Additionally, DHA can be synthesized from EPA. 1 , 2 , 3

History

Most uses of fish oils have been based on the beneficial effects of EPA and DHA, specifically those related to cardiovascular, inflammatory, neural, and hormonal support. Interest in possible health benefits followed observations that populations with a high dietary intake of fish, such as Eskimo and Inuit populations, had low incidences of atherosclerotic and thrombotic disorders and inflammatory conditions. 10 , 11 In 1789, a publication described the beneficial effects of cod liver oil in rheumatism, and in 1824 the same oil was reported effective in the prevention of rickets. 12 Historically, deficiencies were noted in infants fed non- or low-fat diets or in patients receiving long-term (eg, 2 to 3 weeks) parenteral nutritional formulations lacking polyunsaturated fatty acids. 2 , 3

Chemistry

EPA and DHA are omega-3, long-chain (20 carbons or more) polyunsaturated fatty acids (PUFAs). EPA consists of a 20-carbon chain with 5 double bonds (20:5), while DHA is a 22-carbon chain with 6 double bonds (20:6). As represented by the omega-3 nomenclature, the first double bond is located at the third carbon from the methyl group (omega) end of the chain. 2 , 3 C-13 nuclear magnetic resonance pattern recognition has been used to analyze the species of fish from which commercial fish oil products are derived. 13 Homogenization of fish oils into milk has been explored. 14 Challenges for the incorporation of fish oils into other foodstuffs include the propensity of EPA and DHA to oxidize, as well as their off-tastes and smells. Thus, oil-filled capsules are the current preferred supplement product.

Uses and Pharmacology

Omega-3 fatty acids are metabolized into eicosanoids, which have important physiologic properties and include prostaglandins, prostacyclins, thromboxanes, and leukotrienes. Eicosanoids are potent regulators of blood pressure, blood clotting, childbirth, and gastric secretions, as well as immune and inflammatory responses. The actual location of the double bond in the fatty acid chain affects its metabolism such that the structure and function of omega-3–derived eicosanoids differ from those derived from omega-6 fatty acids (eg, arachidonic acid). For example, omega-3–derived eicosanoids tend to decrease blood clotting and inflammatory responses. This contrasts with the arachidonic acid (omega-6)–derived eicosanoids, which increase clotting and inflammatory responses. 2 , 3 , 15

Asthma/Allergy
Animal data

The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet make data from animal studies largely irrelevant.

Clinical data

To date, clinical benefit of fish oil in asthma is controversial. 10 , 16 Omega-3 fatty acids do not have an effect on eosinophils and mast cells, which may explain a relative lack of efficacy in this inflammatory condition. 10 The role of other constituents in fish oil is unknown. Limited evidence exists of an effect of fish oils on exercise-induced asthma. 17 A potential for an enteral nutritional formula containing EPA plus gamma-linolenic acid as adjuvant therapy in the clinical management of acute respiratory distress syndrome has been suggested. 18 Use of fish oil supplementation during pregnancy and breast-feeding to reduce the incidence of food allergy in infants has also been evaluated. 19

Older trials are inconclusive regarding clinical benefit of n-3 fatty acid supplementation in patients with psoriasis or atopic dermatitis. 4 , 20 , 21 , 22 , 23

Arrhythmias
Animal data

Studies in animals have demonstrated pro- and anti-arrhythmic properties of fish oil. 24 , 25 In experimental arrhythmias, fish oil prevented arrhythmias related to ischemia, but not to reperfusion injury. 24

Clinical data

Reviews have examined the utility of fish oils in treating arrhythmias. The mechanism of protection is not well understood, and some classes of patients may not benefit. 26 , 27 , 28 A meta-analysis of all studies up to the year 2008 for ventricular arrhythmias found only a trend of a protective effect of fish oil on time to first ventricular fibrillation. Dosages used in the included trials ranged from fish oil 900 to 2,600 mg. 29 , 30 A further meta-analysis found a nonsignificant reduction in the primary outcome of arrhythmias or death from all causes. For the secondary outcome of death from cardiac causes, a reduction was found. 31 Results from the 2003 Diet and Angina Randomized Trial (DART-2) found an increase in death in patients with angina pectoris, and in patients with implanted cardioverter defibrillators, no overall effect on the risk of discharge has been found, possibly because of the potential for fish oil to exhibit pro-arrhythmic properties. 25 , 32

Coronary heart disease
Animal data

The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies in cardiovascular conditions largely irrelevant.

Clinical data

A potential role for fish oils in cardiovascular disease risk reduction first came from observations of Inuit populations in Greenland. Despite ingesting up to 40% of calories as fat (mostly from marine sources), this group exhibited a lower incidence of coronary artery disease compared with individuals on a more conventional diet. 33

Systematic reviews and meta-analyses have been published on trials evaluating the effect of fish oil supplementation on coronary heart disease. Reductions in the risk for all-cause mortality, cardiac death, and sudden death have been established for omega-3 fatty acid supplementation for at least 1 year's duration. Evidence for secondary prevention of coronary heart disease (CHD) is greater than that for primary prevention and is informed mainly by 3 large trials; the GISSI trials (Italy) and the JELIS (Japan) trial. Evidence from these meta-analyses is inconclusive for prevention of stroke and nonfatal myocardial infarction (MI). 28 , 30 , 34 , 35 , 36

The GISSI-Prevenzione trial enrolled 11,324 patients with CHD (post-MI) and evaluated omega-3 fatty acid supplementation compared with vitamin E. A reduction was found for the primary end point of a combined outcome of death, nonfatal MI, and stroke for omega-3 fatty acids. 34 , 37 Data from the GISSI heart failure trial (N = 7,046) allows for a calculation of 56 patients with preexisting heart to be treated with omega-3 fatty acid supplementation for 3.9 years to avoid 1 death, or 44 patients to be treated for the same length of time to avoid 1 death or hospital admission for cardiac causes. No benefit for the prevention of stroke was found. For the primary prevention of CHD, the GISSI heart failure trial found a nonsignificant effect for omega-3 fatty acids. The JELIS trial enrolled 18,645 persons with hypercholesterolemia and found a reduction in the risk from a major coronary event, including sudden death and MI, and found evidence of secondary protection against the risk of stroke. 30 , 34

A large (N = 13,578), older study found no effect of ALA supplementation on cardiovascular outcomes. 30 Evidence is inconclusive for the effect of fish oils on hypertension and is based on older studies. 38 , 39 , 40 , 41 , 42 Reductions in heart rate, especially where the resting rate is higher than 69 bpm, have been demonstrated in some, but not all, studies of 12 weeks of fish oil supplementation. 43 , 44 , 45 Effects of fish oil supplementation on C-reactive protein (a marker for coronary heart disease) are equivocal. 46 , 47

CNS effects
Animal data

The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet makes data from animal studies largely irrelevant.

Clinical data

Polyunsaturated fatty acids, including DHA, are essential for normal brain development and any deviation from normal levels is associated with cognitive impairment. 12 Data from adequately controlled clinical trials are insufficient to make definitive statements about omega-3 fatty acid supplemental in specific mental health disease. Limited trials have evaluated fish oil supplementation in schizophrenia and in attention deficit hyperactivity disorder with equivocal results. 12 , 48 Clinical trials are more supportive of a place in therapy of depression for fish oils, although specific sub-populations are considered more likely to benefit, including perinatal depression, childhood/adolescent depression, and depression associated with bipolar disorder. 49 , 50 , 51 While there is evidence of an association of dementia with low levels of n-3 fatty acids in diet and plasma, supplementation with fish oil has not been shown to reverse or prevent dementia, 52 or to improve quality of life indices in elderly patients. 53

Critical illness and surgical patients
Animal data

The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies largely irrelevant.

Clinical data

Randomized, controlled trials have been conducted in severely ill patients in intensive care units (ICUs) and among elective surgical patients units comparing fish oil–enriched lipid emulsions with standard enteral formulations. Meta-analyses have been conducted that recognize the heterogenous nature of the study populations (including medical, surgical, and trauma related) and formulations used (ranging from EPA/DHA 1 to 6.6 g/L) 54 and the difficulty in recruiting patients into trials. 54 , 55 , 56 , 57

Findings from these meta-analyses are in favor of supplemental fish oil in terms of reduced length of stay in hospital and in ICU, decreased ventilator time, decreased new organ failure, and decreased postoperative infections. 54 , 55 , 56 , 57 , 58 Twenty-eight–day mortality was decreased in 1 meta-analysis of ICU patients, 54 but not in an analysis of major abdominal surgery. No serious adverse events were recorded in the included trials. 56 Further clinical trials in patients with GI surgery, not included in the meta-analyses, have been conducted with similar positive results. 59 , 60 , 61 , 62

Diabetes
Animal data

The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies in diabetes largely irrelevant.

Clinical data

A Cochrane systematic review of patients with type 2 diabetes mellitus revealed that fish oil 3 to 18 g/day supplementation lowered triglycerides and had no statistically significant effect on glycemic control, total cholesterol, or high-density lipoprotein (HDL) cholesterol. However, it did raise low-density lipoprotein (LDL) cholesterol by 0.21 mmol/L (especially in patients with hypertriglyceridemia on doses higher than EPA 2 g). 9 Further randomized controlled trials in overweight patients and in patients with type 2 diabetes do not demonstrate an effect of fish oils on insulin sensitivity or fasting blood glucose. 63 , 64 These findings are consistent with an Agency for Healthcare Research and Quality evidence report. 65

Infant development

Dietary fat is fundamental for the growth and development of infants. DHA is an important component of structural lipids of cell membranes, and its perinatal availability has been related to visual acuity development, neurological development, behavior, and brain growth. 66 , 67 Accretion occurs primarily during the last trimester of pregnancy via the placenta and the infant's first year of life from breast milk and dietary sources. 68 , 69

Animal data

Research reveals no animal data regarding the use of fish oil in postnatal growth and development.

Clinical data

Evidence from systematic reviews provides little support for benefit of supplementation with long-chain PUFAs (LCPUFAs), such as DHA, to either term or preterm infants. 68 , 69 Formula-fed infants have been shown to have less DHA than infants fed breast milk. Reduced neural function and visual acuity have been documented in preterm infants fed formula relative to those who were breast-fed. A review of LCPUFA supplementation studies demonstrated no benefit to visual or cognitive development in infants born at term receiving LCPUFA-supplemented formula. 68 However, some evidence did show that omega-3 fatty acid supplementation of formula increases the early rate of visual maturation in preterm infants. 69

Malnourished infants, who may have poor fat absorption, appear to also absorb fish oil supplements well and use this source of fatty acid for more than an energy source. 70

Although formula supplemented with omega-3 fatty acids increases DHA and EPA levels in healthy and malnourished infants, this may be at the expense of omega-6–derived fatty acids (eg, arachidonic acid). Because high levels of DHA and EPA appear to successfully compete for cyclooxygenase and other eicosanoid enzymes, formula-fed infants should be supplemented with omega-3 as well as omega-6 LCPUFAs if their fatty acid status is to be comparable with that of the breast-fed infant. 66 , 67 , 71

Inflammatory bowel disease
Animal data

In animal models of inflammatory bowel disease, fish oil has been shown to exert a protective effect, which is considered to be via anti-inflammatory mechanisms. 72

Clinical data

Cochrane meta-analyses and systematic reviews of randomized controlled trials have been undertaken for the effect of omega-3 fatty acids in induction of remission in ulcerative colitis and for maintenance of remission of ulcerative colitis and Crohn disease. 73 , 74 , 75 For induction of remission in ulcerative colitis, trials were of crossover and parallel design, and because of heterogeneity of outcomes and methodology, the data were not pooled. Of the 6 included studies, 1 small study showed benefit for induction within 3 months. The other trials showed benefit only for secondary outcome measures, and no recommendation can be made regarding the effect of fish oil supplementation. 73 For maintenance of remission in ulcerative colitis 74 and Crohn disease, 75 relapse rates were similar for omega-3 fatty acids and the control intervention. For Crohn disease, the meta-analysis included data from both of the large EPIC trials. The conclusion that omega-3 fatty acids have no effect on maintenance of remission is an update on previous meta-analyses. 75

Lipid-lowering effects
Animal data

The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies in hyperlipidemia redundant.

Clinical data

Several meta-analyses and systematic reviews of clinical trials in hyperlipidemia have been conducted. 76 , 77 , 78 , 79 Clinical reductions in triglycerides (−0.34 mmol/L [95% CI, −0.41 to −0.27]) were found in a meta-analysis of 47 randomized, controlled trials (N = 16,511). 76 In 2004, the FDA approved the use of a fish oil for reducing very high triglyceridemia (at least 5.65 mmol/L) in adults as an adjunct to diet. 78 The investigators of the effect of fish oil in maintenance of remission in Crohn disease (the EPIC trials) reported decreases in serum triglycerides in the study populations. 75 A place in therapy is also suggested for fish oil in hypertriglyceridemia consequent to type 2 diabetes and chronic kidney disease and as add-on therapy with statins in cardiovascular disease. 11 , 76 , 78 , 79 Increases in LDL cholesterol as well as HDL have been observed, and may be clinically important. 76 , 78 , 80 Other studies have noted changes in concentration and particle size of very low-density lipoproteins. 79 , 81

Rheumatoid arthritis

EPA is a competitive substrate with arachidonic acid for the generation of less active eicosanoid metabolites (eg, leukotrienes) and acts to reduce inflammation. 10 The most profound anti-inflammatory effects of n-3 fatty acids are on neutrophil function and mediator generation, providing a more likely benefit in neutrophilic inflammatory diseases, including arthritis. 82

Animal data

The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies largely irrelevant.

Clinical data

Inuit populations with a diet high in LCPUFAs (especially EPA and DHA from seal and fish oils), report a low incidence of rheumatoid arthritis. 83 Meta-analyses of controlled trials have been conducted with equivocal findings. 65 , 83 , 84 Issues raised by the analyses include confounding of results with the use of potentially active placebo oils (eg, corn and olive oil) and management of dropouts in the individual trials. 83 , 85 Reductions in patient-reported joint pain and morning stiffness and a reduced need for nonsteroidal anti-inflammatory drugs are potential benefits of fish oil therapy, while reduction in cardiovascular risk may also be a valuable attribute. 83

A minimum daily dose of EPA/DHA 3 g appears to be necessary to reduce the release of leukotriene B4 from stimulated neutrophils and of interleukin-1 from monocytes, while dosages of more than 6 g/day do not appear to confer any additional benefit. 48

Stroke
Animal data

The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies in stroke largely irrelevant.

Clinical data

Despite data from large trials being available (including the GISSI, JELIS, and EPIC-Norfolk trials), no consistent relationship between fish oil consumption and reduction in the risk of stroke has been established. 34 , 78 , 86 , 87 The etiology of the stroke may be of relevance, with omega-3 fatty acids considered to be more likely to demonstrate positive effects on stroke related to ischemic causes than hemorrhagic stroke because of platelet anti-aggregating properties. 78 , 86 A 2004 meta-analysis of prospective cohort studies found a higher incidence of stroke in people who never consumed fish or only consumed fish less than once per month versus a higher fish intake. A reduced risk for total stroke was found for intakes of fish at least once per week. Whole fish also contain the proteins taurine, arginine, and glutamine, which may be involved in cardiovascular function. 78

A randomized, controlled trial evaluated the effect of daily fish oil supplementation 3 g for 12 weeks on quality of life outcomes in CT-confirmed ischemic stroke. No effect was found for all outcome measures, including serum triglycerides, total cholesterol, blood pressure, mood, and quality of life indicators. 88

Other uses
Cancer

An apparent link between inflammation and colon cancer has prompted studies of EPA and DHA in cancer prevention. EPA reduced crypt cell proliferation and increased apoptosis in subjects with a history of colorectal adenomas. 89 A molecular effect on lipid-modified protein trafficking was postulated as a mechanism by 1 review, 90 while immunomodulatory effects on T-cell function and subsets were invoked by the same group. 91 Other molecular targets of n-3 PUFAs in cancer have been reviewed. 92

Cystic fibrosis

A pilot trial of intravenous fish oil emulsion in cystic fibrosis found no benefits and some potential deleterious effects. 92

Dysmenorrhea

Trials are limited, but suggest a role for fish oil in the management of dysmenorrhea. Reduced requirement for analgesia and reported reduction in pain have been found after 2 to 3 months supplementation. 93 , 94 , 95

Hepatic effects

A fish oil-based lipid emulsion is gaining popularity over conventional soybean oil-based parenteral nutrition because of its apparent ability to reduce the incidence of parenteral nutrition-associated liver disease or hepatobiliary dysfunction. 96 , 97 , 98 , 99

Renal effects

The ability of n-3 fatty acids to reduce eicosanoid production or action has led to the testing of dietary fish oil in patients with immunoglobulin A (IgA) nephropathy. In these patients, the initial immunological renal injury evokes cytokine and eicosanoid activity. Dietary fish oil has been tested in patients with several types of renal disease with varying results. Results in patients with IgA nephropathy are conflicting. 100 The use of fish oil on lipoprotein-a in end-stage renal disease and among kidney transplant recipients has also been evaluated. 101 , 102

Dosage

The AHA recommends a minimum of 2 fatty fish meals per week. 1 , 34 Clinical trials suggest fish oil supplementation of omega-3 fatty acid 1 g/day in coronary heart disease, and where triglycerides are elevated, a minimum of omega-3 fatty acid 2 g/day up to a maximum of 4 g/day. Fish oil 1,000 mg approximates to omega-3 fatty acid 300 to 400 mg (EPA/DHA). 34

Emulsified oral preparations have been developed to improve the taste over encapsulated fish oils and may increase digestion and absorption of the fatty acids via modifications in solubility. 103 Encapsulated oils have been found to oxidize and become rancid over time and with processing method, which may have an effect on total EPA/DHA delivered. 88 , 104

Pregnancy/Lactation

Documented adverse effects have occurred regarding pregnancy and lactation. Avoid use. The FDA recommends pregnant women avoid certain fish due to the potential for contamination with mercury. Farmed salmon may have greater contamination than wild sources. 78 , 86 , 104

Omega-3 fatty acids are postulated to be able to prevent preterm birth via delaying induction of labor and cervical ripening through inhibiting the production of prostaglandin F2-alpha and E2, and by relaxing the myometrium. A Cochrane meta-analysis found the mean gestation age was 2.6 days longer (95% confidence interval [CI], 1.03 to 4.07) in women who took fish oil supplementation. No significant difference was found for the relative risk (RR) of birth before 37 weeks, while a significant decrease in the risk of birth before 34 weeks gestation was found (RR 0.69; 95% CI, 0.5 to 0.99). 105

A study in which fish oil supplementation was taken after 22 weeks suggested an increase in oxidative stress in the plasma at week 30. 106 Effects of fish oil on lipids and blood pressure do not appear to be sustained during pregnancy. 107

While the evidence indicates that the DHA and EPA composition of breast milk is affected by fish oil supplementation, there is little evidence in support of benefit of supplementation to the infant. 66 , 67 , 68 , 69 Use of fish oil supplementation during pregnancy and breast-feeding to reduce the incidence of food allergy in infants has also been evaluated. 19

Interactions

The anticoagulant effect of warfarin may be increased by fish oil ingestion, although case reports are limited. 108 , 109

Adverse Reactions

Fish oil at dosages of EPA/DHA 2 to 5.4 g/day is well accepted and tolerated. In clinical trials, only mild GI-related adverse effects were reported, including dyspepsia, diarrhea, and nausea. 30 , 31 , 56 , 75 An increased risk of diarrhea was noted in a meta-analysis of trials conducted among patients with inflammatory bowel disease who were given enteric-coated, time-released capsules. 72

A safety study found adverse events similar for intervention (EPA 2 g/day for 12 weeks) and placebo groups. An increased body mass index and increased (but modest) bleeding time were reported. 110

An increase in LDL cholesterol has been reported occasionally; however, evidence does not suggest that the risk is greater than the health benefits related to increased fish oil consumption. 76 , 78

Toxicology

Research reveals little or no information regarding toxicology with the use of this product. Omega-3 acid ethyl esters have been shown to have an embryocidal effect in pregnant rats when given in doses resulting in exposures 7 times the recommended human dose of 4 g/day based on a body surface area comparison. 110

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