Fish Oil, Vitamin E, Genes, Diet, and CHAOS!

Maret G. Traber, Ph.D.
Associate Professor of Nutrition and Food Management
LPI Principal Investigator
Rosemary Wander, Ph.D.
Associate Professor of Nutrition and Food Management
LPI/OSU Faculty Affiliate Investigator

Summary: Investigators conducted a large study in Italy in which heart disease patients were given supplements of fish oil, vitamin E, both, or neither for three and a half years. According to the investigators, the group that got fish oil had fewer deaths due to heart disease, but vitamin E had no effect. However, Drs. Traber and Wander point out that the conclusion that vitamin E had no benefit is at odds with the statistical analysis presented in the paper and also with other published studies. Fish oil helps protect against heart disease, but the influence of vitamin E in the body is not yet certain.

The more we know, the less we know, or so it seems. The latest clinical study assessing the effect of vitamin E supplementation on heart disease, the "GISSI-Prevenzione study", reported that fish oil, but not vitamin E, is beneficial. Numerous studies have suggested that an increased fish oil intake is associated with decreased mortality from heart disease. This protective effect is thought to be derived primarily from the n-3 fatty acids (also called omega-3 fatty acids) found in fatty fish. These are long-chain polyunsaturated fatty acids (PUFA), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, these fatty acids may readily turn rancid, or oxidize, in the body as they do in food, resulting in substances that are associated with atherosclerosis and, thus, may increase the risk of heart disease.

Although we're not sure about the tendency of EPA and DHA to oxidize in the body, it is generally thought that vitamin E should be consumed together with PUFA to prevent their rancidity. When the primary dietary PUFA is linoleic acid, a ratio of 0.4 mg of alpha-tocopherol (vitamin E) to 1.0 gram of PUFA is considered appropriate. When EPA and DHA are eaten, the vitamin E intake should be even higher.

The GISSI-Prevenzione study was carried out by a group of over 50 Italian scientists who investigated the interaction between vitamin E and n-3 fatty acids on morbidity and mortality in patients who already had suffered one heart attack. Over 11,000 patients from various locations in Italy were randomly divided into four groups. For three and a half years, the groups were given either 1 gram of n-3 fatty acids daily, 300 mg of vitamin E daily, both of these, or neither supplement. They also received up-to-date pharmacological interventions. The investigators hypothesized that vitamin E and EPA/DHA, when consumed together, would decrease mortality from heat disease, non-fatal heart attacks, and non-fatal strokes.

These disease endpoints were significantly lower in the group receiving the fish oil supplement, but, according to one type of statistical analysis, not in the group that got only the vitamin E supplement. The combination of vitamin E and fish oil lowered the risk of disease about the same as fish oil alone. The researchers also examined several aspects of death due to events related to heart disease. The incidence of these events decreased in the patients receiving vitamin E or fish oil, but the decrease was larger in those receiving only the fish oil. Again, the combination of vitamin E and fish oil did not produce the greatest decrease.

These data do not support the argument that preventing the oxidation of EPA and DHA in the body by an increased intake of vitamin E will decrease the risk of heart disease. Of course, the supplementation period of the Italian study may have been too short or the amount of vitamin E may have been too little. There are other problems with the study that we will discuss later.

The results of this study are in accord with other human studies that have addressed the interaction of vitamin E and fish oil supplements in the oxidation of lipids (fat) in the human body. When specific and sensitive methods are used, one finds that the consumption of fish oil does not lead to an increase in lipid oxidation. In one study, one of us (Rosemary Wander) gave postmenopausal women daily supplements of fish oil (providing about 3.4 grams of EPA and DHA), supplements of safflower oil (providing 10.5 grams of linoleic acid), or supplements of sunflower oil (providing 12.3 grams of oleic acid) for five weeks. Lipid oxidation products in the blood were measured by two very specific assays. Supplementation with safflower oil resulted in the most lipid oxidation; fish oil resulted in the lowest. In addition to lipids, proteins may also be damaged by oxidation. In another study in the Wander lab, we gave 48 postmenopausal women 2.5 grams of EPA and 1.8 grams of DHA daily for 5 weeks and measured the amount of protein damage in blood. We found no damaging effect of the n-3 fatty acids on proteins.

Few studies have been conducted in humans to measure the impact of different doses of vitamin E on lipid oxidation when EPA and DHA are included in the diet. Dr. J. Allard and colleagues at the University of Toronto gave 80 men supplements of fish oil (providing 6.3 grams of n-3 fatty acids) or olive oil (providing 6.1 grams of oleic acid). Each oil was given with or without 900 IU of dl-alpha-tocopheryl acetate (a form of vitamin E). Consumption of the n-3 fatty acid supplement resulted in higher levels of lipid oxidation, which were not decreased by the vitamin E supplement.

In one of our studies mentioned above, we gave 48 postmenopausal women 4.3 grams of EPA and DHA, and three doses of natural vitamin E (RRR-alpha- tocopheryl acetate)—100, 200, or 400 mg/day—for five weeks. Again, vitamin E did not lower the levels of lipid oxidation products when measured in the urine by general methods, although the lipids isolated from blood were protected from oxidation by vitamin E.

Problems with the study

The human supplementation study carried out in Italy was not as simple as the newspaper stories might lead us to believe. First, the study was not "blinded", so the subjects knew whether they were given vitamin E, fish oil, both, or neither. The study was not placebo-controlled—the group that did not get a fish oil or vitamin E supplement did not get a dummy pill. Second, we don't know the precise composition of the supplements. The investigators reported that 300 mg of synthetic vitamin E were given to the vitamin E groups—equal to about 150 mg of natural vitamin E—and that the fish oil supplements contained 850-882 mg of fish oil (EPA/DHA in a ratio of 1:2). However, fish oil pills usually have added antioxidants, and the antioxidant content of the fish oil is not mentioned. Lastly, the subject population is from Italy, where the Mediterranean diet—a diet characterized by higher amounts of grains, olive oil, and red wine than in the usual Western diet—provides protection from heart disease. This population also consumes more dietary vitamin E than most Americans.

The results of this Italian heart disease study are in contrast to the English heart disease study, called CHAOS (Cambridge Heart Antioxidant Study), carried out by Dr. Nigel Stephens and colleagues and reported in the journal Lancet in 1996. The CHAOS study found that in 2002 heart attack victims, daily doses of 400-800 IU of vitamin E decreased the risk of a second non-fatal heart attack by 75%. A follow-up study showed that of the 59 subjects who died in the CHAOS study, only 6 were taking vitamin E. Indeed, the CHAOS study was stopped prematurely because vitamin E was so effective that it was considered unethical to continue to give the placebo group a dummy pill without vitamin E. Yet, in the Italian study, 300 IU of vitamin E had no effect on heart disease risk. What's the difference? It's been known for several years that there are huge differences in heart disease rates and diet between European countries. Also, low vitamin E levels in the blood, fairly common in England, have been associated with a greater risk of heart disease. Therefore, increasing these levels to normal by supplementation with vitamin E might be expected to result in a reduced risk of heart disease in English patients.

Dr. Morris Brown of the University of Cambridge has suggested that the clue to understanding the Italian study may be genetics. The subjects in England in the CHAOS study may have a genetic defect that impairs the function of nitric oxide, a critical molecule in maintaining healthy blood vessels. If so, then vitamin E may be protecting their nitric oxide, allowing the blood vessels to function normally. Recent studies suggest that vitamin E prevents abnormal clot formation and protects blood vessel walls.

Finally, and perhaps most confusingly, one type of statistical analysis reported in the Italian study showed that vitamin E supplementation actually reduced deaths due to heart disease by 20 to 25%, although the article's abstract claimed that "vitamin E had no benefit". Rather than discounting the possible benefit provided by vitamin E, this study suggests that vitamin E supplements may only offer slight benefit to those already at low risk for heart disease because of genetic factors. While we await the results of ongoing research to help understand these issues, it seems prudent to eat a diet like the Mediterranean diet, rich in monounsaturated fatty acids like olive oil but not too high in total fat (less than 30% of calories), and lots of fruits and vegetables, nuts, grains, and fish.

Please see the Linus Pauling Institute's Micronutrient Information Center for more information on vitamin E and omega-3 fatty acids.

Last updated November, 1999

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