Abstract
Background: Fish oil (Ω-3 fatty acids) has been studied for more than 30 years. However, recent concerns of mercury and environmental toxins have clouded fish oil’s potential clinical benefits. This article aims to review practical, evidence-based applications of fish oil for the primary care physician.
Methods: PubMed search using key words ‘fish oil,’ ‘docosahexaenoic,’ and ‘eicosapentaenoic’ in title/abstract. Limited to human clinical trials. Articles were further scanned for relevant sources.
Results: For secondary prevention of cardiovascular disease, 1 g of fish oil has shown to reduce overall and cardiovascular mortality, myocardial infarction, and sudden cardiac death. Higher doses may be used for its potent triglyceride-lowering effects and for patients with rheumatoid arthritis to reduce nonsteroidal anti-inflammatory use. Ω-3 fatty acid supplementation of infant formula has shown benefit in infant neural growth and development. With the potential health benefits of fish, women of childbearing age should be encouraged to eat 1 to 2 low-mercury fish meals per week.
Conclusions: Fish oil has numerous practical applications for the primary care physician. Understanding the diverse clinical research of Ω-3 fatty acids and fish oil is important in determining its role in primary care practices.
More than 30 years ago, Danish researchers hypothesized that lower rates of heart disease of Greenland Eskimos were associated with higher consumption of whale, seal, and fish.1,2 Since then, from research unraveling the mechanism of Ω-3 fatty acids, to clinical trials in cardiovascular disease, treatments of hyperlipidemia, rheumatoid arthritis, and the prevention of preterm labor, there have been more than 7000 reports—including nearly 900 human clinical trials on the study of fish oil and Ω-3 fatty acids.3,4 However, recent concerns regarding mercury and other environmental toxins have clouded the waters of fish oil research and its potential health benefits. This article will discuss the evidence behind fish oil—emphasizing current, practical information for conditions family physicians can effectively impact today.
Methods
Medline and Cochrane database search using the key words “fish oil” or “docosahexaenoic” or “eicosapentaenoic.” These were combined with the keywords “cardiovascular disease,” “myocardial infarction,” “hypertriglyceridemia,” “pregnancy,” “rheumatoid arthritis,” or “infants.” Search was further limited to humans, clinical trials. References from key articles were also scanned for relevant sources.
Results and Discussion
Mechanism of Action
There are 2 classes of essential fatty acids, the Ω-6 and Ω-3 fatty acids (FA). Ω-3 FA, found primarily in fatty fish with high oil content, consists of both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Research has shown increasing evidence for anti-inflammatory, antithrombotic, antiarrhythmic and antiatherogenic effects of fish oil.5 Fish oil is the most significant source of dietary Ω-3 FA. The terms will be used interchangeably.
Arachidonic acid, an Ω-6 FA, is converted into inflammatory prostaglandins and leukotrienes via the enzymes cyclooxygenase and lipoxygenase, respectively (Figure 1). Increased intake of Ω-3 FA reduces incorporation of arachidonic acid into cell membranes, thereby promoting a net anti-inflammatory response. Indeed, fish oil has been shown to significantly decrease potent inflammatory markers, including leukotrienes, prostaglandins, interleukins, and tumor necrosis factor.6,7 The inhibition of arachidonic acid by Ω-3 FA also produces a potential antithrombotic effect by decreasing production of thromboxane A2. Membrane stabilization in cardiac tissue by Ω-3 FA confers potential antiarrhythmic effects,8 whereas triglyceride-lowering effects are caused by the reduction and secretion of very low density lipoprotein particles from the liver.5 With its unique and varied mechanism of actions, the potential uses of fish oil have been studied in various clinical situations.
Arachidonic acid is converted to leukotrienes by the enzyme lipoxygenase (LPO) and to thromboxane A2 and prostaglandins by the enzyme cyclooxygenase (COX). Ω-3 fatty acids, in essence, reduce the breakdown of arachidonic acids.
Clinical Uses
Cardiovascular Disease
The benefits of fish oil in cardiovascular disease provide the strongest and most compelling evidence favoring its use in practice. Numerous observational studies have shown that Ω-3 FA enriched diets are associated with reduction of cardiovascular mortality, myocardial infarction, and sudden death. Higher fish intake was associated with decreased incidence of coronary artery disease and cardiovascular mortality in several prospective cohort studies.9–11 Another large prospective cohort study reported a marked reduction in sudden cardiac death associated with dietary fish intake.12,13 Putting it in perspective, a minimum of one fish meal a week was associated with a 52% reduction in sudden cardiac death. Some observational trials do not show a beneficial relationship for fish intake. This may be related to differences in background cardiovascular risk, fish intake, or lifestyle behaviors of study populations and study definitions of sudden death and fish intake.14 Although the intake of fish oil in these studies was not sufficient to produce a marked anti-inflammatory or triglyceride-lowering effect, both antiarrhythmic properties and membrane stabilization of cardiac tissue by fish oils has been proposed as its mechanism of action.8
Randomized clinical trials add to the growing evidence—especially for secondary prevention of cardiovascular disease. A randomized placebo-controlled trial showed that supplementing patients with recent history of a myocardial infarction (MI) with 1.8 g of fish oil for 1 year decreased total cardiac events by 29% [number needed to treat (NNT) = 10 for 1 year; P < .05]. Both total cardiac deaths and nonfatal MI were also reduced by 48% (NNT = 8.1 for 1 year; P < .01 and NNT = 9.8 for 1 year; P < .01; respectively)15 [level of evidence-1 (LOE)]. The Diet and Reinfarction Trial (DART),16 randomized 2033 men with myocardial infarction into different dietary groups. Men randomized to fatty fish diet had a 29% reduction in the 2-year all-cause mortality compared with those who did not receive this advice (NNT = 28 for 2 years; P < .05). Most of the benefits resulted from the reduction of cardiovascular deaths (NNT = 27 for 2 years; P < .01) (LOE-1). The GISSI17 trial randomized 11,324 Italian men who had suffered a myocardial infarction within 3 months. Compared with the control group, patients supplemented with fish oil 850 mg showed a 15% reduction in the primary endpoints (death, nonfatal myocardial infarction and stroke) after 3.5 years (NNT = 48 for 3.5 years; P = .008) (LOE-1). It is striking that most of the benefit was derived from a 30% reduction in cardiac mortality and a 45% reduction in sudden death. Mortality reduction was significant in just 3 months of fish oil therapy—even in light of optimal pharmacologic therapy with antiplatelet agents, angiotensin inhibitors, and lipid lowering therapy.18
Finally, a meta-analysis19 and a recent systematic review20 launched by the Agency for Health Care Research and Quality (AHRQ), found favorable effects of fish oil on cardiovascular and overall mortality. With this mounting evidence, the American Heart Association,14 recommends 1 g of fish oils in all patients with documented coronary artery disease via diet or through supplementation after consultation with their physician [strength of recommendation (SOR)-A] (Table 1).
American Heart Association (AHA) Recommendations for Fish Oil*
Hypertriglyceridemia
High triglycerides have been recognized as an independent risk factor for coronary artery disease. The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III),21 recommends treating hypertriglyceridemia more aggressively. However, medications to treat hypertriglyceridemia (such as fibric acid derivatives and niacin) are limited and can have serious side effects. Even with medications, hypertriglyceridemia can be difficult to treat without using a combination of drugs.
A review of over 70 clinical trials22 and a recent systematic review by the AHRQ23 have demonstrated the consistent and potent triglyceride lowering effects of fish oil supplementation. In an early trial, mean triglycerides were reduced 79% (from 1432 to 282 mg/dL) using 20 g of fish oil. (P < .01).24 More recently, in patients with severe hypertriglyceridemia (mean = 919 mg/dL), 3.4 g of fish oil showed a triglyceride reduction 45% compared with controls (P < .0001).25
Although studies are limited, combination therapy with a statin seems to be safe and the results additive. Adding 3 g of fish oil to 40 mg of pravastatin reduced triglycerides an additional 33%.26 Another study, combining 3.4 g of fish oil daily in patients with persistent hypertriglyceridemia on 10 to 40 mg simvastatin, showed additional reduction in triglycerides by 20% to 30%, without serious adverse effects.27 Another trial, however, using 10 mg of atorvastatin and 1.7 g of fish oil, did not show significant difference from baseline. This trial may have been limited by their lower dosage of fish oil and the higher background fish consumption by the patients.28
Overall, there is a dose-dependent lowering of triglycerides with higher fish oil supplementation. Although on average, low density lipoprotein (LDL) cholesterol rose 10 mg/dL and high-density lipoprotein 3 mg/dL, these were nonsignificant.23 There were no significant changes in total cholesterol. Use of 2 to 4 g of fish oil, which lowers triglycerides by 20% to 50%, may be recommended for patients with mild or persistent hypertriglyceridemia to reach ATP III goals (SOR-A) (Table 1).14,21
Rheumatoid Arthritis
In patients with rheumatoid arthritis (RA), over 15 clinical trials and 2 meta-analyses favor the use of fish oil.29,30 Fish oil supplementation consistently shows modest clinical improvement and reduction of nonsteroidal anti-inflammatory drug (NSAID) use in randomized clinical trials. One trial compared approximately 2.8 g of fish oil versus placebo in 64 patients with stable RA. In 3 months, the fish oil group showed significant reduction of NSAID use compared with placebo. This effect peaked at 12 months and was not associated with any clinical deterioration (LOE-2).31 A double-blind placebo-controlled trial showed that fish oil supplementation of 130 mg/kg/day decreased the number of tender joints, duration of morning stiffness, pain, and global arthritis activity versus placebo (LOE-2).32
Reduction of tumor necrosis factor, interleukin levels, and other anti-inflammatory mediators has been hypothesized as the main effect of Ω-3 FA in RA. However, others recognize the importance and synergistic effects of a higher intake of Ω-3 FA in conjunction with lower dietary intake of Ω-6 FA. A double-blind placebo controlled trial using lower doses of fish oil (40 mg/kg; average, 2.3 g) in a background of low dietary Ω-6 showed clinical improvement compared with placebo over 15 weeks (P < .02) (LOE-2).33 Clinical improvements were similar to studies using higher doses. Another recent randomized controlled trial showed clinical benefits, reduction of NSAID, and corticosteroid use with low-dose fish oil supplementation (30 mg/kg; average, 2 g) in patients with diets low in Ω-6 FA.34 Effects were significant at 3 months and peaked at 6 to 8 months (LOE-1).
For the family physician, although fish oil supplementation may benefit clinical symptoms of RA, its potential to reduce or even eliminate NSAID use35 may be the most useful in clinical practice. NSAIDs, although highly effective for pain control, has serious side effects that often limits its use. Overall, doses of 2.6 to 6 g (or weight-based) of fish oil given for a minimum of 8 to 12 weeks is optimal (SOR-A) (Table 2).32,36
Clinical Uses and Recommendations
Mothers and Infants
Ω-3 FA use in pregnancy has shown promise in prolonging gestation and the prevention of preterm labor.37 A randomized double-blind controlled trial showed that supplementation with eggs enriched with 133 mg of DHA prolonged gestation by 6 days compared with women given regular eggs (P < .01).38 Looking at women at high risk for preterm delivery, a multicenter study supported the use of fish oil in prolonging gestation.39 Women supplemented with 2.7 g of fish oil showed significantly reduced preterm delivery rates, increased mean birth weight by 209 g, and increased duration of pregnancy by 8.5 days compared with the control group (LOE-1). Fish oil’s inhibition of arachidonic acid and its subsequent reduction of prostaglandins have been thought to be a potential mechanism of action.
In 2002, the Food and Drug Administration (FDA) approved supplementation of both Ω-3 and Ω-6 FA in infant formula. Both are potentially important in fetal and infant neural development, in that DHA and arachidonic acid have been shown to be incorporated into brain and retinal cell membranes—particularly during the third trimester and early infant life. In both preterm and term infants, evidence consistently shows benefit of visual improvement at 4 months compared with infants fed nonsupplemented formula.40,41 Systematic analysis and meta-analysis have shown that higher DHA content of formula is significantly related to improved visual acuity (LOE-1).42,43 However, benefit beyond 4 months is controversial. One recently completed trial showed visual improvement at 12 months in term infants given formula supplemented with Ω-3 FA compared with nonsupplemented formula.44 Another study showed sustained increase in intelligence at 4 years of age in children whose mothers were supplemented with fish oil from 18 weeks of pregnancy to 3 months postpartum (LOE-2).45
It is important to emphasize that breast-fed infants have outperformed infants fed Ω-3/Ω-6 FA enriched formula in visual acuity measures. Although increasing dietary intake of fatty fish during the antepartum or breast-feeding period is a potentially attractive alternative to fish oil supplementation, it is unclear how much dietary Ω-3 FA intake is essential to maintain the benefit of DHA in breast milk.46 Concerns of mercury content in fish also cloud its potential health benefits.47
With fish oils’ potential benefits in reduction of preterm labor, and improved neural and retinal growth for infants, it is prudent to recommend up to 2 low-mercury fish meals a week for women of childbearing age (SOR-C).48 For infants, whereas breast milk continues to be superior over any formula, Ω-3 FA enriched formula should be considered in mothers who are not breast-feeding or have contraindications to breast-feeding.49 It may be especially beneficial for preterm infants (SOR-B).
Other Conditions
With its potential anti-inflammatory actions and membrane stabilization properties, fish oil supplementation has been studied in a wide spectrum of conditions. Studies in inflammatory bowel disease,30,50–52 asthma,53,54 atopic dermatitis,55 psoriasis,56,57 renal disease,30,58,59 and psychiatric illnesses60,61 are either inconsistent or the studies are limited. Studies in neurologic disorders such as ischemic stroke62,63 and Alzheimer disease64 are beginning to be explored.
Safety Profile
Environmental Concerns
Concerns about mercury contamination and other environmental pollutants of fish have recently emerged.47,65 The FDA and the Environmental Protection Agency (EPA) jointly released an updated consumer advisory on fish intake in March 2004.47 Pregnant women (including women planning to conceive), nursing mothers, and children should avoid eating fish high in mercury—shark, king mackerel, swordfish, and tile fish. More significantly, this consumer advisory highlighted the importance of dietary fish. Women should eat 2 meals per week (up to 12 oz) of low-risk fish for its potential benefits in heart health and childhood growth and development. Fish should not be eliminated from the diet. Similar recommendations were recently issued from the United Kingdom’s Food Standards Agency.66
For men and those with known cardiovascular disease, physicians must be aware of the risks and benefits of Ω-3 FA to appropriately discuss any recommendations of fish intake or supplementation with their patients. Overall benefits of Ω-3 FA in secondary prevention of cardiovascular disease far outweigh any small potential risk for cancer and should not prevent the recommendation of fish oil supplementation for patients at-risk. EPA recommendations are based on the amount of fish intake necessary to raise risk of cancer by 1 case per 100,000.67 The reduction of all-cause mortality of fish oil (NNT = 28 to 48) in secondary prevention of cardiovascular disease is similar to the landmark 4S (NNT = 30 for 5.4 years),68 and CARE (NNT = 30 for 5 years)69 trials of statin drugs. Although concerns regarding mercury in fish attenuating its cardiovascular benefits are debatable,70,71 it would be reasonable for patients to avoid those fish high in mercury.
Side Effects
Beyond the common and benign “fishy taste,” increases in LDL levels, bleeding times, and a worsening glycemic profile in diabetics have all been raised as safety concerns of Ω-3 FA. Despite these concerns, Ω-3 FA is remarkably safe.72 LDL levels rose on average 10 mg/dL, but overall range was inconsistent and has no appreciable effects and may be caused by abnormally suppressed LDL levels.23–25 Although early studies raised concerns of a potential for clinical bleeding with high fish oil doses, use of 16 g of fish oil was clinically insignificant.73 Finally, systematic reviews noted no significant difference in fasting glucose levels or glycemic control in patients with diabetes who received fish-oil supplements.30,74 In patients taking doses higher than 3 g/day, clinicians may consider monitoring for clinical bleeding and both LDL and glycemic response.
Dosing, Diet and Formulation
A recent international working group convened by the National Institutes of Health recognized the dietary importance and potential essentiality of Ω-3 FA.49 Adequate intake of 650 mg/day of foods rich in Ω-3 FA was recommended. The American Heart Association (AHA) issued similar guidance, advocating 1 g of Ω-3 enriched foods daily. However, consistent supplementation may be difficult to maintain through dietary intake because of differences and awareness of Ω-3 FA content in different species of fish and food preparation techniques (Table 3).
Ω -3 Content in Fish (Cooked, Dry Heat)*
Fish oil supplements provide the most consistent way of supplying higher doses of Ω-3 FA. Supplementation can be considered as an alternative to dietary intake for persons who are averse to a fish-enriched diet and may also be lower in mercury content and other environmental pollutants.75 Most preparations provide approximately 300 mg of total Ω-3 FA, divided between EPA and DHA. Dose requirements greater than 3 g could potentially require more than 10 capsules per day. However, some highly concentrated versions provide up to 850 mg. Because the FDA does not regulate supplements, consumers are cautioned to buy from reputable and reliable brands. United States Pharmacopeia (USP) is an independent, nonprofit organization that verifies manufacturing, quality, and purity claims of supplements for supplement manufacturers who wish to participate. Those supplements branded as USP verified may improve its reliability and safety. Other companies guarantee purity content of their supplements (Table 4).
Components of Selected Fish Oil Products
Conclusion
Fish saves lives, and physicians must recognize this potential life-saving treatment choice in patients with cardiovascular disease. In addition, family physicians can safely offer patients an alternative therapeutic approach for difficult-to-treat conditions such as hypertriglyceridemia and rheumatoid arthritis. For those without cardiovascular disease, including young mothers and women, it is reasonable to recommend 650 to 1000 mg of low-risk fish oils per day through dietary approaches as suggested by the National Institutes of Health working group, AHA, and the FDA—easily achieved by 1 to 2 fatty fish meals per week.
Understanding the diverse clinical research behind Ω-3 FA can aid family physicians—adding yet another weapon in their therapeutic arsenal for many diverse clinical conditions. This fish story however, is far from complete. Areas of future research include primary prevention trials, optimal intake of the ratio of Ω-6, Ω-3, DHA, and EPA, and continued research for various clinical indications. The availability of safe and reliable fish and supplements are paramount in further exploring and unlocking the health benefits of fish.
Acknowledgments
I thank the faculty development fellowship at Madigan Army Medical Center for their thoughtful and critical review of the manuscript.
Notes
The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of Defense.
- Received for publication July 26, 2004.
- Revision received July 26, 2004.
