Fish Oils

Scientific Name(s): DHA , EPA

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)

Clinical Overview

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Uses of Fish Oils

Clinical benefit is strongest for lowering the risk of coronary artery disease (CAD), decreasing serum triglycerides, and improving symptoms of rheumatoid arthritis. However, clinical data have produced conflicting results. Other areas of potential use include schizophrenia, respiratory diseases, reduction of menstrual pain, and promotion of postnatal growth and development, but these require further study.

Fish Oils Dosing

A variety of clinical studies have used DHA at dosages of 0.4 to 2 g/day, while the emulsion PLT 3514 has been used at daily doses of 10 to 15 g. Studies of omega-3 PUFAs have included dosages between 2 and 10 g/day.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Documented adverse effects. Potential for mercury ingestion. Avoid use.

Fish Oils Interactions

Fish oil ingestion may increase the anticoagulant effect of warfarin. Because warfarin has a narrow therapeutic index, patients taking warfarin should avoid concurrent use of fish oil.

Fish Oils Adverse Reactions

Fish oil, at dosages of 2 to 5.4 g/day of EPA and DHA, is well accepted and tolerated. Mild gastrointestinal discomfort was the most serious adverse reaction noted occasionally for any of the doses studied and was also reported in some control groups. An increase in low-density lipoprotein (LDL) cholesterol has been reported occasionally; however, evidence does not suggest the risk to be greater than health benefits related to increased fish oil consumption.

Toxicology

Research reveals little or no information.

Fish oils are predominantly comprised of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (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 (because of its common consumption), seal, and shellfish (eg, oysters) are additional sources. 1 , 2 , 3 , 4

EPA and DHA are present in human milk and 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; as well as vegetables. Additionally, DHA can be synthesized from EPA. 1 , 2 , 3

Dietary supplements containing varying concentrations of EPA and DHA are available commercially, usually as oil-filled capsules. However, daily allowance in otherwise healthy individuals is probably best achieved by consuming fish approximately 2 times per week. 2 , 3

Because marine fish stocks are limited, it has been proposed that the algal genes responsible for EPA and DHA production be cloned into plants. In addition, many fish stocks are currently contaminated by pollutants such as methylmercury and organochlorine pesticides. 5 , 6 Oils from the transgenic plants would be rich in EPA and DHA. Some success has been achieved; however, bottlenecks in the biosynthetic pathways in higher plants have not yet been surmounted. 7

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. 8 , 9 Historically, deficiencies were noted in infants fed nonfat or low-fat diets or in patients receiving long-term (eg, 2 to 3 weeks) parenteral nutritional formulations lacking PUFAs. 2 , 3

Chemistry

EPA and DHA are omega-3, long-chain (20 carbons or more) 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. 10 Homogenization of fish oils into milk has been explored. 11 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.

Fish Oils 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. 2

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). 2 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

Deficiency of omega-3 fatty acids has been associated with growth retardation, reproductive failure, skin lesions, renal and hepatic disorders, neurological disturbances (eg, behavioral, incoordination, learning disability, paresthesias, weakness), diarrhea, and visual problems. 2 , 3 , 12

Fish oil, as part of a cholesterol-rich diet of older rats, has been found to modulate cholesterol metabolism. 13 In apo E knockout mice, fatty acid profiles were altered, but atherogenesis was unchanged. 14 Calcification of vasculature, which is blocked by fish oil fatty acids, was shown to depend on the p38-mitogen-activated protein kinase and peroxisome-proliferator-activated receptor gamma pathways. 15 Another mechanistic study examining macrophage interactions with smooth muscle cells in mice found favorable effects on atherogenesis with a combination of fish oil and plant oils. 16

A potential role for fish oils in cardiovascular disease risk reduction first came from observations of Inuit populations in Greenland. 8 , 9 Despite ingesting up to 40% of calories as fat (mostly from marine sources), this group exhibited a lower incidence of CAD compared with individuals on a more conventional diet. 9

Conflicting evidence has been reported on the cardiovascular protective effects of foods rich in marine n-3 fatty acids. 17 , 18 , 19 , 20 Despite the well-documented activity on eicosanoid metabolism, inflammation, tissue factor, beta-oxidation, endothelial dysfunction, cytokine growth factors, and gene expression of adhesion molecules, evidence has been lacking on the effects on atherosclerotic-thrombotic events. 21 , 22 , 23 , 24 , 25 , 26 However, a growing body of evidence strongly suggests protective effects.

Important associations between fish intake and lower risk of CAD have been shown in a 30-year follow-up of the Western Electric study, an observational cohort of the Multiple Risk Factor Intervention Trial and the Honolulu Heart Program. 22 In 1989, the Diet and Reinfarction Trial found almost a 30% decrease over 2 years in overall mortality in men who ate fatty fish twice a week. These results have been reproduced in 2 large-scale observational studies (the Health Professionals Study and the US Physicians Health Study) and a multicenter, open-label, Italian trial that studied more than 11,000 patients for 3.5 years. 22 , 27 This latter study, the GISSI-Prevenzione trial, determined that long-term dietary supplementation with 1 g of n-3 PUFA (equivalent to approximately 100 g of fatty fish per day) significantly decreased the rate of death, nonfatal myocardial infarction, and stroke. 22

Documented inhibition of platelet function and effects on smooth muscle cells highlighted the potential role of n-3 fatty acids in prevention of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Results from clinical trials using various study designs, however, have been contradictory. 17 , 18 , 19 , 20 A well-designed, double-blind, randomized, placebo-controlled trial in 205 patients using higher doses of EPA and DHA (4.5 g/day) and implementing supplementation 3 weeks prior to PTCA reported a statistically significant reduction ( P ≤ 0.03) in restenosis frequency in the fish oil group (22% to 36%, depending on the definition of restenosis used) versus the olive oil control group (40% to 53%) at 6 months. 17 This reproduced the findings of an earlier study using the same dose. 20 However, 2 studies using dosages of 3 g/day found no reduction in the incidence of restenosis. 18 , 19

People with type 2 diabetes mellitus are at increased risk for cardiovascular disease. 9 Dietary fish oil supplementation has been shown to improve hypertriglyceridemia in nondiabetic individuals, but, in initial trials, also was associated with reduced glycemic control. 9 Recently, a systematic review of patients with type 2 diabetes mellitus revealed that 3 to 18 g/day of fish oil supplementation lowered triglycerides and had no statistically significant effect on glycemic control, total cholesterol, or high-density lipoprotein (HDL) cholesterol. However, it did raise LDL cholesterol by 0.21 mmol/L (especially in hypertriglyceridemic patients on doses greater than 2 g of EPA). 9

Hypertension is a major risk factor for cardiovascular disease. The relationship between hypertension and atherosclerotic disease is well established to be one of cause and effect. 28 A 1989 review concluded that some available evidence supported an influence of dietary marine oil on blood pressure but not of a substantial hypotensive nature. 28 Some studies in mild essential hypertensive patients have reported blood pressure reductions in fish oil groups, another trial in pharmacologically treated patients documented less of an increase in systolic blood pressure when antihypertensive medication was stopped, and 1 randomized controlled trial in late pregnancy failed to show any effect on blood pressure in 533 healthy women. 29 , 30 , 31 , 32 Evidence is inconclusive.

Recent reviews have examined the utility of fish oils for treating arrhythmias. 33 , 34 The mechanism of protection is not well understood, and some classes of patients may not receive benefit. In fact, some workers have found pro-arrhythmic properties with fish oil supplementation in humans, 35 as well as in guinea pigs. 36

Several reviews have summarized results of cardiovascular benefits of fish oils and related supplements. 37 , 38 , 39 , 40

Hypercholesterolemia and elevated LDL and total cholesterol, as well as reduced HDL cholesterol, are well-established risk factors for the development of CAD. 41 A decrease in serum cholesterol in hypercholesterolemic patients is associated with a reduction in incidence and mortality of CAD. 29

Research reveals no animal data regarding the use of fish oils for lipid-lowering effects.

Fish oil consumption consistently is reported to reduce triglycerides, but yields marginal, if any, effect on HDL or total cholesterol. 9 , 18 , 19 , 22 , 24 , 26 , 29 , 31 , 41 , 42 , 43 , 44 , 45 An increase in LDL cholesterol has been reported occasionally; however, evidence is not strong or consistent enough to suggest the risk to be greater than the health benefits related to increased fish oil consumption. 9 , 18 , 19 , 22 , 24 , 26 , 29 , 41 , 42 , 43 , 44

Research reveals no animal data regarding the use of fish oils for reduction of menstrual pain.

Levels of PUFAs have been correlated with menstrual pain; higher levels of omega-3 fatty acids are associated with milder menstrual symptoms. A recent systematic review of herbal and dietary therapy for primary and secondary dysmenorrhea found 1 small, placebo-controlled trial of 42 women who reported a significant improvement in use of additional medication ( P < 0.001) and in menstrual pain ( P = 0.004) in the fish oil group compared with placebo after 2 months of supplementation. However, poor reporting of the menstrual pain data prevents an adequate assessment of efficacy related to this particular outcome. Adverse reactions were higher in the fish oil group, but they were not serious (eg, nausea, acne exacerbation, difficulty swallowing the capsules). 46

EPA is a competitive substrate with arachidonic acid for the generation of less active eicosanoid metabolites (eg, leukotrienes) and acts to reduce inflammation. 8

Research reveals no animal data regarding the use of fish oils for rheumatoid arthritis.

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 such as rheumatoid arthritis, psoriasis, cystic fibrosis, and inflammatory bowel disease (IBD). 8 , 47 Epidemiological studies support this, but results are often confounded by the potential beneficial effects ascribed to corn and olive oils, commonly used as placebos. 8 , 48 , 49 , 50 , 51 Eskimos and Inuit populations with a diet high in LCPUFAs (especially EPA and DHA from seal and fish oils), have been found to have a low incidence of rheumatoid arthritis and psoriasis. 4 , 8

Evidence is accumulating to support clinical improvement in tender joints and morning stiffness, and reduced antirheumatic medication doses in rheumatoid arthritis patients receiving 3 to 6 g/day of n-3 fatty acids. 48 , 52 , 53 , 54 A minimum daily dose of 3 g of EPA and DHA appears to be necessary to reduce the release of leukotriene B ₄ from stimulated neutrophils and of interleukin-1 from monocytes. 48 It has been reported that dosages of more than 6 g/day do not appear to confer any additional benefit. 48

Malnutrition and malabsorption are often consequences of IBD, such as Crohn disease and ulcerative colitis. 43 These conditions can lead to nutritional deficiencies, which in turn can be associated with reduced immunological competence. 43

Research reveals no animal data regarding the use of fish oil in IBD.

Fish oil has been reported to improve host immune response in intensive care unit patients with trauma, sepsis, or cancer, but results in patients with IBD have been contradictory. 43 However, it has been shown that the fatty acid profile in IBD patients can be changed with oral supplements containing n-3 fatty acids. 43 , 50 These results indicate that oral immunomodulating formulations can be absorbed in these patients and, thus, may have a role to play in treatment. 43

Preliminary data support a modest clinical benefit in patients with IBD, but such benefit may be favored in patients with ulcerative colitis more than in those with Crohn disease. 46 , 55 , 56 In patients with active ulcerative colitis supplemented with 3 to 6 g of n-3 fatty acids per day for 4 months, 3 small studies noted a reduction in disease activity and in concomitant anti-inflammatory medication doses, with limited to no change in histology index or colonic mucosal leukotriene B ₄ levels. 46 , 55 , 56 One study also noted a weight gain of 1.74 kg. 56 Another small study reported no therapeutic effect of fish oils in ulcerative colitis despite changes exerted on cell membrane fatty acids. 50

Reviews of fish oil in ulcerative colitis 57 , 58 and Crohn disease 59 are available; however, evidence for efficacy of fish oil in these disorders is sparse. The 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. 60 A molecular effect on lipid-modified protein trafficking was postulated as a mechanism by one review, 61 while immunomodulatory effects on T-cell function and subsets were invoked by the same group. 62 Other molecular targets of n-3 PUFAs in cancer have been reviewed. 63

Research reveals no animal data regarding the use of fish oil in respiratory diseases.

To date, clinical benefit of fish oil in asthma is controversial. 8 , 64 n-3 fatty acids do not have an effect on eosinophils and mast cells, which may explain a relative lack of efficacy in this particular inflammatory condition. 8 The role of other constituents in fish oil is unknown. It remains to be determined whether the benefit noted by 1 small study implementing dietary manipulation of fish oils, as opposed to supplementation, in asthmatic children can be duplicated. 8 A recent systematic review provided little evidence to recommend dietary supplementation with fish oil to improve asthma control, but also revealed no evidence of untoward risk. 8

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 also has been suggested. 65

Research reveals no animal data regarding the use of fish oil in schizophrenia.

Several studies have shown that levels of certain essential fatty acids in patients with schizophrenia are often lower than required for normal neuronal membrane metabolism. A systematic review indicates that dietary influences can affect the occurrence and course of schizophrenia. Early results from a few trials suggest a positive effect of EPA on mental state outcomes. 66

One small study randomized previously unmedicated individuals experiencing a new schizophrenic episode to determine the effects of fish oil supplementation on the need for antipsychotic medication. After 12 weeks of supplementation, the need for antipsychotics was greater in the placebo (15/15) than the fish oil group (9/15). No pronounced adverse reactions were noted for fish oil. 66

Data are preliminary; results are encouraging but inconclusive. There appear to be few adverse reactions and possibly some benefit of fish oil supplementation in patients suffering from schizophrenia. There is no reason to encourage or discourage the use of essential fatty acids to supplement antipsychotic therapy. 66

Dietary fat is fundamental for the growth and development of infants. However, controversy exists over whether LCPUFAs such as DHA are essential nutrients for infants born preterm or at term. 67 , 68 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. 69 , 70 Its accretion occurs primarily during the last trimester of pregnancy and the infant's first year of life. 67 , 68

Fetuses and preterm infants do not appear to synthesize sufficient amounts of DHA from the ALA precursor, indicating that DHA may be conditionally essential in the perinatal period. 68 , 71 During pregnancy, DHA crosses the placenta and appears in breast milk postnatally. 67 , 68 The fatty acid composition of breast milk, however, is somewhat dependent on the maternal diet; much higher DHA levels have been found in the milk of women with high intakes of marine foods.

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

Several supplementation studies with fish oil rich in omega-3 LCPUFAs or DHA have shown dose-dependent effects on breast milk EPA and DHA levels. 70

While the evidence seems to indicate that the DHA and EPA composition of breast milk is affected by fish oil supplementation, evidence from 2 systematic reviews provide little support for benefit of supplementation to the infant. 67 , 68 , 69 , 70 , 71 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. 67 However, some evidence did show that omega-3 LCPUFA supplementation of formula increases the early rate of visual maturation in preterm infants. 68 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. 72

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 cyclo-oxygenase and other eicosanoid enzymes, formula-fed infants should be supplemented with both omega-3 as well as omega-6 LCPUFAs if their fatty acid status is to be comparable with that of the breast-fed infant. 69 , 70 , 73

Various outcomes in late pregnancy have been studied with an emphasis on prostaglandin metabolism and the potential effects of omega fatty acids on preventing pre-eclampsia (characterized in the third trimester by hypertension, edema, and proteinuria). 74 , 75 , 76 Additionally, results in 533 pregnant women investigating the effects of fish oil on pregnancy duration and birth weight appear to be positive. 77 Data and study designs are variable and inconclusive to date.

Evidence is inconclusive to support clinical benefit of n-3 fatty acid supplementation in patients with psoriasis or atopic dermatitis. 4 , 49 , 51 , 78 , 79 Of theoretical interest, a review assessing effectiveness of treatments for guttate psoriasis found 1 small trial of hospitalized patients that reported apparent benefit with an intravenous (IV) infusion of an n-3 fatty acid–rich lipid emulsion compared with a placebo emulsion with n-6 fatty acids. 80

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. 44 A meta-analysis of fish oil in kidney transplant patients found little utility. 81

A pilot trial of IV fish oil emulsion in cystic fibrosis found no benefits and some potential deleterious effects. 82

While there is evidence of an association of dementia with low levels of n-3 fatty acids in diet and plasma, it has not been shown that supplementation with fish oil can reverse or prevent dementia. 83

Dosage

A variety of clinical studies have used DHA at doses of 0.4 to 2 g/day, while the emulsion PLT 3514 has been used at daily dosages of 10 to 15 g. Studies of omega-3 polyunsaturated fatty acids have included dosages between 2 and 10 g/day. 84 , 85 , 86 , 87 , 88 , 89 , 90

Pregnancy/Lactation

Documented adverse effects have occurred regarding pregnancy and lactation. There is a potential risk of mercury ingestion. Avoid use. Effects of fish oil on lipids and blood pressure appear to be lost during pregnancy. 91

Interactions

The anticoagulant effect of warfarin may be increased by fish oil ingestion. An increase in the international normalized ratio (from 2.8 to 4.3) occurred in a woman 67 years of age stabilized on warfarin (1.5 mg/day) 1 month after she increased her fish oil dosage from 1 to 2 g/day. 92 It was necessary to reduce her weekly warfarin dosage. When the fish oil dosage was reduced to 1 g/day, it was necessary to change the warfarin dosage to the original regimen (1.5 mg/day). The mechanism for this interaction is unknown.

Adverse Reactions

Fish oil, at dosages of 2 to 5.4 g/day of EPA and DHA, is well accepted and tolerated. Mild GI discomfort was the most serious adverse reaction (noted occasionally) for any of the doses studied and also was reported in some control groups.

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. 9 , 18 , 19 , 22 , 24 , 26 , 29 , 43 , 44 , 45 , 46

Toxicology

Research reveals little or no information regarding toxicology with the use of this product.

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Rheumatoid Arthritis, Hypertriglyceridemia, Dietary Supplementation, Attention Deficit Hyperactivity Disorder

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