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Omega-3 Fatty Acids - July 1, 2004 - American Family
Physician
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COMPLEMENTARY AND
ALTERNATIVE MEDICINE
Omega-3 Fatty Acids
MAGGIE B. COVINGTON, M.D.,
University of Maryland School of Medicine,
Baltimore, Maryland
Omega-3 fatty acids have been shown to
significantly reduce the risk for sudden death caused by cardiac arrhythmias
and all-cause mortality in patients with known coronary heart disease. Fatty
fish, such as salmon and tuna, and fish oil are rich sources of the omega-3
fatty acids eicosapentaenoic acid and docosahexaenoic acid. Flaxseed, canola
oil, and walnuts also are good dietary sources of omega-3 fatty acids. In
addition to being antiarrhythmic, the omega-3 fatty acids are antithrombotic
and anti-inflammatory. In contrast, omega-6 fatty acids, which are present in
most seeds, vegetable oils, and meat, are prothrombotic and proinflammatory.
Omega-3 fatty acids also are used to treat hyperlipidemia, hypertension, and
rheumatoid arthritis. There are no significant drug interactions with omega-3
fatty acids. The American Heart Association recommends consumption of two
servings of fish per week for persons with no history of coronary heart disease
and at least one serving of fish daily for those with known coronary heart
disease. Approximately 1 g per day of eicosapentaenoic acid plus
docosahexaenoic acid is recommended for cardioprotection. Higher dosages of
omega-3 fatty acids are required to reduce elevated triglyceride levels (2 to 4
g per day) and to reduce morning stiffness and the number of tender joints in
patients with rheumatoid arthritis (at least 3 g per day). Modest decreases in
blood pressure occur with significantly higher dosages of omega-3 fatty acids.
(Am Fam Physician 2004;70:133-40. Copyright© 2004 American Academy of
Family Physicians.)
Editorial:
page 34.
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See page 13 for
definitions of strength-of-recommendation labels.
Over the
past 20 years, there has been a dramatic increase in the scientific scrutiny of
and public interest in omega-3 and omega-6 fatty acids and their impact on
personal health. Omega-3 fatty acids possess anti-inflammatory, antiarrhythmic,
and antithrombotic properties; omega-6 fatty acids are proinflammatory and
prothrombotic. Increased consumption of vegetable oils high in omega-6 fatty
acids (such as corn, safflower, sunflower, and cottonseed oils) and meats from
animals that were fed grains high in omega-6 fatty acids has drastically
shifted the dietary ratio of omega-6 to omega-3 fatty acids from an estimated
1:1 in the early human diet to approximately 10:1 in the typical modern
American diet.1
Fish and fish oil are rich sources of omega-3 fatty
acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),
which are present in fatty fish (Table
1)2,3 and
algae. Alpha-linolenic acid (ALA) is an omega-3 fatty acid present in seeds and
oils (Table 2), green leafy
vegetables, and nuts and beans (such as walnuts and soybeans).1 Linoleic acid, an
omega-6 fatty acid, is present in grains, meats, and the seeds of most plants.
While omega-3 fatty acids have been used for treatment of many conditions, this
article discusses only the most common and well-researched treatment uses.
TABLE 1
Approximate EPA Plus DHA Content in
Fish and Amount of Fish Required to Provide 1 g of EPA plus DHA
Type of fish
EPA plus DHA content, g per
3-oz serving of fish (edible portion)
Amount of fish (oz) required
to provide approximately 1 g of EPA plus DHA per day*
Catfish
Farmed
0.15
20.0
Wild
0.20
15.0
Crab, Alaskan King
0.35
8.5
Flounder/sole
0.42
7.0
Haddock
0.20
15.0
Halibut
0.40 to 1.00
3.0 to 7.5
Herring
Atlantic
1.71
2.0
Pacific
1.81
1.5
Mackerel
0.34 to 1.57
2.0 to 8.5
Salmon
Atlantic, farmed
1.09 to 1.83
1.5 to 2.5
Atlantic, wild
0.90 to 1.56
2.0 to 3.5
Chinook
1.48
2.0
Sockeye
0.68
4.5
Sardines
0.98 to 1.70
2.0 to 3.0
Shrimp, mixed species
0.27
11.0
Tuna
Fresh
0.24 to 1.28
2.5 to 12.0
White, canned in water, drained
0.73
4.0
EPA = eicosapentaenoic acid; DHA = docosahexaenoic
acid.
*-The intakes of fish given are very
rough estimates because oil content can vary markedly (more than 300 percent)
with species, season, diet, and packaging and cooking methods.
Adapted with
permission from Kris-Etherton PM, Harris WS, Appel LJ; American Heart
Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty
acids, and cardiovascular disease. Circulation 2002;106:2753, with information
from reference 3.
Pharmacology
TABLE 2
Predominant Essential Fatty Acids in
Common Oils
Omega-3 oils
Omega-6 oils
Canola oil
Borage oil
Fish oil
Corn oil
Flaxseed oil
Cottonseed oil
Soybean oil*
Grapeseed oil
Walnut oil
Peanut oil
Primrose oil
Safflower oil
Sesame oil
Soybean oil*
Sunflower oil
*-Soybean oil is
included in both categories because it is higher in omega-6 fatty acids than
most omega-3 oils.
Omega-3 and omega-6 fatty acids are
essential because they are not synthesized by the body and must be obtained
through diet or supplementation. Through an inefficient enzymatic process of
desaturation (the rate of conversion is less than 1 percent), ALA produces EPA
(20 carbons) and DHA (22 carbons), precursors to a group of eicosanoids
(prostaglandins, thromboxanes, and leukotrienes) that are anti-inflammatory,
antithrombotic, antiarrhythmic, and vasodilatory. The longer chain fatty acid
derivative of linoleic acid is arachidonic acid (20 carbons), which is a
precursor to a different group of eicosanoids that are proinflammatory and
prothrombic. ALA and linoleic acid use and compete for the same enzymes in the
production of their longer chain fatty acids, EPA, and arachidonic acid. The
ingestion of fish and fish oil provides EPA and DHA directly, therefore
avoiding the competition for enzymes to convert ALA to EPA.
Uses and Efficacy
cardiac mortality, sudden death, and all-cause
mortality
The Diet and Reinfarction Trial (DART)4 was one of the first
studies to investigate a relationship between dietary intake of omega-3 fatty
acids and secondary prevention of myocardial infarction. In this study, 1,015
men were advised to eat at least two servings of fatty fish per week, and 1,018
men were not so advised. At the two-year follow-up, the men who had been
advised to consume fish had a 29 percent reduction in all-cause mortality but
no reduction in the incidence of myocardial infarction.4
Sudden death caused by sustained ventricular
arrhythmias accounts for 50 to 60 percent of all deaths in persons with
coronary heart disease (CHD).5 To date, the largest, prospective, randomized controlled
trial on the effects of omega-3 fatty acids is the GISSI-Prevenzione
Trial.6 This study
included 11,324 patients with known CHD who were randomized to receive either
300 mg of vitamin E, 850 mg of omega-3 fatty acids, both, or neither. After
three and one-half years, the group given omega-3 fatty acids alone had a 45
percent reduction in sudden death and a 20 percent reduction in all-cause
mortality.6
A meta-analysis7 of 11 randomized
controlled trials conducted between 1966 and 1999 and including 7,951 patients
with heart disease found that dietary and nondietary fatty acids reduced
overall mortality, mortality caused by myocardial infarction, and sudden death.
The number needed to treat in patients at low risk to prevent one premature
death was 250 for one and one-half years, and 24 patients at high risk to
prevent one death.7
The U.S. Physicians' Health Study8 surveyed roughly 20,000
male physicians and found no apparent association between fish consumption or
supplementation with omega-3 fatty acids and risk for myocardial infarction,
nonsudden cardiac death, or total cardiovascular mortality. However, men who
consumed fish at least once per week had a 50 percent reduction in the risk for
sudden death and a significant reduction in all-cause mortality.8
A reanalysis9 of the U.S. Physicians' Health Study found a significant
inverse relationship between blood levels of omega-3 fatty acids and the risk
of sudden death in men with no history of CHD. In another study,10 consumption of 5.5 g of
omega-3 fatty acids per month (equivalent to one weekly serving of a fatty
fish) was associated with a 50 percent reduction in the risk of primary cardiac
arrest. However, these findings were not supported by the EURAMIC (EURopean
multicenter case-control study on Antioxidants, Myocardial Infarction and
breast Cancer) study,11 which concluded that
fish consumption offered no protection against the risk of a first myocardial
infarction.
One study12 showed increased regression and decreased progression of
coronary lesions in patients taking 1.5 g of fish oil per day for two years, as
assessed by angiography. Evidence for the protective effects of fish and ALA in
women comes from the U.S. Nurses' Health Study,13 which analyzed the
diets of 84,688 female nurses and found that higher consumption levels of fish
and ALA were associated with a decreased risk of CHD and CHD-related
deaths.
hyperlipidemia
Omega-3 fatty acids lower plasma
triglyceride levels, particularly in persons with hypertriglyceridemia,14 by inhibiting the
synthesis of very-low-density lipoprotein (VLDL) cholesterol and triglycerides
in the liver. A review15 of human studies concluded that approximately 4 g per day
of omega-3 fatty acids reduced serum triglyceride concentrations by 25 to 30
percent, increased serum low-density lipoprotein (LDL) cholesterol levels by 5
to 10 percent, and increased high-density lipoprotein (HDL) cholesterol levels
by 1 to 3 percent. Total cholesterol was not significantly affected.15
A randomized controlled trial16 compared two groups of
patients with persistent hypertriglyceridemia. One group received simvastatin
in a dosage of 10 to 40 mg per day plus 4 g per day of Omacor (which contains
90 percent omega-3 fatty acid; 840 mg EPA plus DHA per capsule), while those in
the second group received the same dosage of simvastatin and a placebo.
Patients who received simvastatin plus Omacor had 20 to 30 percent decreases in
serum triglyceride concentrations and 30 to 40 percent decreases in VLDL
cholesterol levels compared with those receiving simvastatin and placebo.16 No increases in LDL
cholesterol levels were observed. Overall, results have shown variable effects
of omega-3 fatty acids on total cholesterol, LDL, and HDL cholesterol
levels.14-17
hypertension
Omega-3 fatty acids appear to have a
dose-response hypotensive effect in patients with hypertension and have little
to no effect in normotensive patients.18 A meta-analysis19 of 31 trials and a
total of 1,356 patients found that 5.6 g per day of fish oil reduced blood
pressure by 3.4/2.0 mm Hg. Similarly, another study20 found modest blood
pressure reductions of 5.5/3.5 mm Hg in trials in which patients received at
least 3 g per day of fish oil. A meta-analysis21 of 36 trials found that
a median dosage of 3.7 g per day of fish oil reduced systolic blood pressure by
only 2.1/1.6 mm Hg.
rheumatoid arthritis
Several small studies21-24 have found that fish
oil at dosages of at least 3 g per day (one study22 used 18 g per day)
significantly reduced morning stiffness and the number of tender, swollen
joints in patients with rheumatoid arthritis. These beneficial effects were
more common in patients receiving higher dosages of fish oil and were not
apparent until fish oil had been consumed for at least 12 weeks.22,24
It has been reported that reducing dietary intake
of omega-6 fatty acids while increasing consumption of omega-3 fatty acids
reduces the inflammatory mediators of rheumatoid arthritis and, consequently,
allows some patients to reduce or discontinue use of nonsteroidal
anti-inflammatory drugs.24-26 One study27 showed no improvements in symptoms of rheumatoid arthritis
after three months of supplementation with ALA in the form of flaxseed oil.
Interactions and Adverse Effects
Omega-3 fatty acids exert a dose-related effect on
bleeding time; however, there are no documented cases of abnormal bleeding as a
result of fish oil supplementation, even at high dosages and in combination
with other anticoagulant medications.28 High dosages of fish oil may increase LDL cholesterol
levels, but the clinical relevance of this finding remains unclear.14,15 Other potential side
effects of omega-3 fatty acids include a fishy aftertaste and gastrointestinal
disturbances, all of which appear to be dose-dependent.2
Significant amounts of methylmercury,
polychlorinated biphenyls, dioxins, and other environmental contaminants may be
concentrated in certain species of fish, such as shark, swordfish, king
mackerel, and tilefish (also known as golden bass or golden snapper).29 In March 2004, the U.S.
Food and Drug Administration (FDA) and the Environmental Protection Agency
issued a new statement29 advising women who may become pregnant, women who are
pregnant, breastfeeding mothers, and young children to avoid eating some types
of fish and to eat fish and shellfish that are lower in mercury. These
recommendations29
are summarized in Table 3. According
to a recent survey,30 farmed salmon have
significantly higher levels of polychlorinated biphenyls and other
organochlorine contaminants than wild salmon. There is disagreement among
researchers, however, about the amount of farmed salmon that is safe to eat.
High-quality fish oil supplements usually do not contain these
contaminants.
TABLE
EPA and FDA Recommendations for Fish
and Shellfish Consumption by Women* and Young Children
Do not eat shark, swordfish, king mackerel, or
tilefish, because they contain high levels of mercury.
Eat up to 12 oz (two average meals) a week of a
variety of fish and shellfish that are lower in mercury.
Five of the most commonly eaten fish that are low
in mercury are shrimp, canned light tuna, salmon, pollock, and catfish.
Another commonly eaten fish, albacore ("white")
tuna has more mercury than canned light tuna. Albacore tuna should be limited
to no more than 6 oz (one average meal) per week.
Check local advisories about the safety of fish
caught by family and friends in your local lakes, rivers, and coastal areas. If
no advice is available, eat up to 6 oz (one average meal) per week of fish you
catch from local waters but don't consume any other fish during that week.
Follow these same recommendations when feeding
fish and shellfish to children, but serve smaller portions.
EPA = Environmental Protection Agency; FDA = U.S. Food
and Drug Administration.
*-Recommendations apply to women who
might become pregnant, women who are pregnant, and breastfeeding mothers.
Information from U.S. Food and Drug Administration. What
you need to know about mercury in fish and shellfish. FDA/CFSAN Consumer
Advisory. EPA-823-R-04-005. March 2004. Acccessed online April 20, 2004, at:
http://www.cfsan.fda.gov/~dms/admehg3.html.
Although there is conflicting evidence for the
effect of fish oil on glucose control,17,31 most evidence shows that fish oil does not
significantly elevate glucose or hemoglobin A1C levels.32,33
Dosage
The American Heart Association's recommendations for intake of
omega-3 fatty acids (Table 4)2 state that patients
without documented CHD should eat at least two servings of fatty fish per week
along with other foods rich in omega-3 fatty acids. Persons with CHD are
encouraged to eat at least one daily meal that includes a fatty fish or take a
daily fish oil supplement to achieve a recommended level of 0.9 g per day of
EPA.2
TABLE 4
Summary of AHA Recommendations for
Omega-3 Fatty Acid Intake
Patient population
Recommendation
No documented history of CHD
Eat a variety of fish (preferably oily) at least
twice per week. Include oils and foods rich in alpha-linolenic acid (flaxseed,
canola, and soybean oils; flaxseeds and walnuts).
Documented history of CHD
Consume approximately 1 g of EPA plus DHA daily,
preferably from oily fish. EPA plus DHA capsule supplements may be used in
consultation with a physician.
Needs to lower triglyceride level
Consume 2 to 4 g of EPA plus DHA daily in capsules
in consultation with a physician.
AHA = American Heart Association; CHD = coronary heart
disease; EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid.
Adapted with permission from Kris-Etherton PM, Harris
WS, Appel LJ; American Heart Association. Nutrition Committee. Fish
consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
Circulation 2002;106:2755.
Most commercial fish oil capsules (1 g) contain 180 mg of EPA and
120 mg of DHA. Therefore, three 1-g capsules per day in divided doses provides
the recommended dosage of 0.9 g of omega-3 fatty acids. Fish oil is also
available in a more highly concentrated liquid form that provides 1 to 3 g of
omega-3 fatty acids per teaspoon, depending on the product and manufacturer.
The effective dosage for treating hypertriglyceridemia is 2 to 4 g per
day,2 which is
significantly higher than the dosage recommended for cardiovascular protection.
The FDA has concluded that dietary dosages of up to 3 g per day of omega-3
fatty acids from marine sources are "Generally Recognized as Safe."34 For persons who are
vegetarians or nonfish eaters, a total daily intake of 1.5 to 3 g per day of
ALA seems to be beneficial.2
TABLE 5
Key Points About Fish Oil
Supplements
Efficacy
Reduces risk for sudden death
Reduces all-cause mortality
Lowers serum triglyceride levels*
Modest effect on lowering blood pressure in
patients with hypertension*
Reduces morning stiffness and number of tender,
swollen joints in patients with rheumatoid arthritis*
Adverse effects
Generally well tolerated. Side effects may include
fishy aftertaste, gastrointestinal disturbances (e.g., nausea, bloating,
belching), prolonged bleeding time, elevations in LDL-C, and exposure to
environmental contaminants with certain fish species.
Interactions
No significant drug interactions
Dosage
Capsules: 1 g generally contains 180 mg of
EPA and 120 mg of DHA.
Liquid concentrate: 1 tsp contains approximately 1
to 3 g of EPA plus DHA.
For cardiac health, approximately 1 g of EPA plus
DHA daily
For lowering triglycerides, 2 to 4 g of EPA plus
DHA daily
For rheumatoid arthritis,
>=3 g of EPA plus DHA
daily
Types of fish oil supplements
Cod liver oil†
Standard fish body oil (e.g., herring, salmon)
Omega-3 fatty acid concentrate
Cost
Capsules: $0.13 to $0.42 per capsule‡
Liquid: $0.95 to $9.77 per
oz‡
Bottom line
Safe complementary medication; reduces risk for
sudden death caused by cardiac arrhythmias and all-cause mortality in patients
with known coronary heart disease. Higher dosages may be effective in
hypertriglyceridemia, hypertension, and rheumatoid arthritis, but data are
limited.
LDL-C = low-density lipoprotein cholesterol; EPA =
eicosapentaenoic acid; DHA = docosahexaenoic acid.
*-Higher doses required.
†-Also provides vitamins A and
D.
‡-Prices vary according to
brand and manufacturer.
Final Comment
Therapy with low-dose omega-3 fatty acids
(approximately 1 g per day of EPA plus DHA) significantly reduces the incidence
of sudden death caused by cardiac arrhythmias and all-cause mortality in
patients with known CHD. More studies are needed to confirm the benefits of
omega-3 fatty acids in the primary and secondary prevention of CHD. Although
higher dosages of omega-3 fatty acids (2 to 4 g per day) are effective in
lowering triglyceride levels in patients with hypertriglyceridemia, the
clinical significance of elevations in LDL cholesterol resulting from high-dose
fish oil therapy remains unclear.
While consumption of omega-3 fatty acids may
benefit patients with rheumatoid arthritis and hypertension, the higher dosage
requirement of at least 3 g per day may limit its usefulness in the medical
management of these disorders. Table
5 outlines the efficacy, safety, tolerability, dosage, and cost of fish
oil supplements.
Strength of Recommendation (SOR)
Labels
Key clinical recommendations
SOR labels
References
Omega-3 fatty acids appear to have a
dose-response hypotensive effect in patients with hypertension and have little
to no effect in normotensive patients.
A
18
In March 2004, the U.S. Food and Drug
Administration and the Environmental Protection Agency issued a new statement
advising women who may become pregnant, women who are pregnant, breastfeeding
mothers, and young children to avoid eating some types of fish and to eat fish
and shellfish that are lower in mercury.
C
29
The American Heart Association
recommends that patients without documented congestive heart disease eat at
least two servings of fatty fish per week along with other foods rich in
omega-3 fatty acids.
C
2
The author thanks Edward E. Cornwell III, M.D.,
Janine Blackman, M.D., and Brian Berman, M.D., for editorial assistance, and
Kimberley Collins for assistance with the manuscript.
The author indicates that she does not have any
conflicts of interest. Sources of funding: Dr. Covington's work is supported in
part by the LAING Foundation and the NIH Center grant no. P50 AT00084.
The Author
MAGGIE B. COVINGTON, M.D., is clinical assistant
professor of family medicine with the Center for Integrative Medicine at the
University of Maryland School of Medicine, Baltimore. She also has a private
practice in integrative medicine in Bethesda, Md. Dr. Covington received her
medical degree from Howard University College of Medicine, Washington, D.C.,
and completed residency training at the University of Maryland School of
Medicine. She also completed postgraduate training in acupuncture through the
Helms Medical Institute and the University of California, Los Angeles, School
of Medicine.
Address
correspondence to Maggie B. Covington, M.D., University of Maryland School of
Medicine, Center for Integrative Medicine, 2200 Kernan Dr., Baltimore, MD 21207
(e-mail: mcovington@compmed.umm.edu)
Reprints are not available from the author.
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34. U.S. Food and Drug Administration Center for Food Safety and
Applied Nutrition. Agency Response Letter. GRAS notice no. GRN 000105. October
15, 2002. Accessed online March 29, 2004, at:
http://www.cfsan.fda.gov/~rdb/opa-g105.html.
Copyright © 2004 by the American
Academy of Family Physicians. This content is owned by the AAFP. A person
viewing it online may make one printout of the material and may use that
printout only for his or her personal, non-commercial reference. This material
may not otherwise be downloaded, copied, printed, stored, transmitted or
reproduced in any medium, whether now known or later invented, except as
authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions
and/or permission requests.
July 1, 2004
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