expert opinion

Controversies in omega-3 fatty acid research

December 1, 2014

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Philip Calder, PhD, Professor of Nutritional Immunology, University of Southampton, UK

“Omega-3 fatty acids are a family of polyunsaturated fatty acids that contribute to human health and well-being. Functionally the most important omega-3 fatty acids appear to be eicosapentaenoic acid (EPA) and docosahexaenoioc acid (DHA), but roles for docosapentaenoic acid (DPA) are now emerging. The effects of omega-3 fatty acids are evident right through the life course, meaning that there is a need for all sectors of the population to have a sufficient intake of these important nutrients. However, intakes of EPA and DHA are usually low, typically below the recommended intakes. EPA and DHA have a wide range of physiological roles which are linked to certain health or clinical benefits. Increased intakes are reflected in greater incorporation into blood lipid, cell and tissue pools. Increased content of EPA and DHA modifies the structure of cell membranes and the function of membrane proteins involved as receptors, signaling proteins, transporters, and enzymes. EPA and DHA modify the production of lipid mediators and through effects on cell signaling can alter patterns of gene expression. Through these actions, EPA and DHA alter cell and tissue responsiveness in a manner that seems to result in more optimal conditions for growth, development, and maintenance of health.

Almost half a century ago, it was recognized that populations who ate large quantities of marine lipids, e.g., the Inuit populations of Greenland and Northern Canada – and the Japanese, had a much lower incidence of cardiovascular disease than would have been predicted. It was found that in these populations, their blood was particularly rich in the omega-3 fatty acids EPA and DHA. In fact, EPA and DHA beneficially modify a broad range of risk factors, including blood triglycerides, blood pressure, and inflammatory markers. The practical results of this include improved blood flow and reduced buildup of atherosclerotic plaques. Such benefits were confirmed in a very large meta-analysis, where the data from 16 studies and 422,000 participants was analyzed (1). Marine omega-3 fatty acids have also been used as a treatment in patients with existing cardiovascular disease (CVD). The underlying mechanisms involved here are thought to be different from those already mentioned in primary prevention. These mechanisms can be summarized as a reduction in the rate and variation of the heart beat, reduced platelet aggregation (and thus improved blood flow), and finally resolved inflammation, including stabilization of existing atherosclerotic plaques. A typical positive large study was the GISSI-Prevenzione trial in Italy, where an intake of 885 mg EPA and DHA each day for 1 year resulted in a significant reduction in mortality in patients with existing cardiovascular disease (2).

Despite the many promising trials using EPA/DHA supplements, some of the most recent studies have been unable to replicate earlier positive results. As a result, meta-analyses based largely on these most recent publications and excluding earlier positive trials (e.g. GISSI) have resulted in headlines that fish oils do not have a protective effect against CVD (3). In many of these recent trials, the patients already had relatively high levels of EPA and DHA in their blood and were also being treated with a pharmaceutical cocktail for their condition. In such circumstances, it is hardly surprising that fish oil supplementation showed a negligible effect. This effect was exasperated by the fact that many of the studies had a small number of participants and relatively low doses of EPA and DHA were administered. Reassuringly, carrying out a meta-analysis using data gathered over past decades, as well as including the recent “null” studies, still clearly reveals impressive reductions in heart attacks and sudden death with increased EPA and DHA intake (4).

In 2013, a study caught global attention by suggesting a link between marine omega-3 intake and incidence of prostate cancer (5). This case–cohort study examined associations between plasma phospholipid fatty acids and prostate cancer risk among participants in the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The incidence of prostate cancers in relation to individual blood serum fatty acids was assessed by estimating hazard ratios using a Cox proportional hazard (CPH) statistical model. The model was then used to produce data that appeared to show dramatic increases in risk. However, it is questionable whether such a model was appropriate for use in these circumstances. The SELECT study itself was not specifically designed to look at the exact relationship between omega-3 fatty acid intake and prostate cancer. Careful examination of the data reveals the difference in mean blood/plasma phospholipid fatty acids: Blood levels of omega-3 fatty acids were 4.66% in the cancer group versus 4.48% in the control group – just a 0.18% difference. So it seems likely the dramatic headlines drawn from this study were due to the overextension of a dubious statistical model. Finally, if the findings were true, then prostate cancer would be rampant in any country with high seafood consumption (Scandinavia, Japan, etc.) and conversely, low in landlocked countries. Needless to say, such population-based evidence does not exist.

A more recent analysis examined data from seven prospective studies to look for an association between fatty acids in the blood and incidence of prostate cancer (6). While these results showed a slightly elevated prostate cancer risk associated with high EPA consumption, the authors said that a cause-and-effect relationship could not be established, and indeed in their conclusion stated “there is no strong evidence that fatty acids in blood are important predictors of prostate cancer risk.” As part of a public consultation exercise on the extension of use of DHA and EPA-rich algal oil in 2014, the NDA (Dietetic Products, Nutrition and Allergies) panel of the European Food Safety Authority (EFSA) was asked to look at the possible association of EPA and DHA with incidence of prostate cancer. The panel judged that on the grounds of available scientific evidence, there was no basis for any association (7).

Recent scientific reviews have analyzed how marine omega-3 fatty acids can play a role in reducing and slowing the proliferation of cancer tumor cells (8, 9). There are studies that appear to show benefits of marine omega-3 fatty acid supplementation in colorectal, breast, and even prostate cancer. In most of these studies, supplementation appears to improve the efficacy of existing radio or chemotherapy. However, the findings are not consistent and further work is required (10). It also appears that patients in the advanced stages of the disease can improve their quality of life through marine omega-3 oil supplementation because of reduced muscle loss (cachexia) and improved appetite. A recent literature review concludes that treatment of cancer patients with a daily dose of at least 1 g EPA and 0.8 g DHA can improve the efficacy of chemotherapy and reduce the extant of the some of the secondary complications (11).”

Based on: Calder P.C. Very long chain omega-3 (n-3) fatty acids and human health. European Journal of Lipids Science and Technology. 2014; 116:1280–1300.

 

References

  1.  Chowdhury R. et al., Association of dietary, circulating, and supplement fatty acids with coronary risk: A systematic review and meta-analysis. Ann. Intern. Med. 2014; 160:398–406.
  2.  Marchioli R. et al., Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: Time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002; 105:1897–1903.
  3.  Rizos E. C. et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: A systematic review and meta-analysis. J. Am. Med. Assoc. 2012; 308:1024–1033.
  4.  Wen Y. T. et al. Effects of omega-3 fatty acid on major cardiovascular events and mortality in patients with coronary heart disease: A meta-analysis of randomized controlled trials. Nutr. Metab. Cardiovasc. Dis. 2014; 24:470–475.
  5.  Brasky T. M. et al. Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial, JNCI J Natl Cancer Inst. 2013; 105(15):1132–1141.
  6.  Crowe F. L. et al. Circulating Fatty Acids and Prostate Cancer Risk: Individual Participant Meta-Analysis of Prospective Studies. J Natl Cancer Inst. 2014; 106(9).
  7.  EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Scientific Opinion on the extension of use for DHA and EPA-rich algal oil from Schizochytrium as a Novel Food Ingredient. EFSA Journal. 2014; 12(10):3843.
  8.  Gleissman H. et al. Omega-3 fatty acids in cancer, the protectors of good and the killers of evil? Exp. Cell Res. 2010; 316:1365–1373.
  9.  Merendino N. et al. Dietary omega-3 polyunsaturated fatty acids DHA: A potential adjuvant in the treatment of cancer. BioMed. Res. Int. 2013; 310186.
  10.  Gerber M. Omega-3 fatty acids and cancers: A systematic update review of epidemiological studies. Brit. J. Nutr. 2012; 107(Suppl 2):2228–2239.
  11.  Vaughan V. C. et al. Marine polyunsaturated fatty acids and cancer therapy. Brit. J. Cancer. 2013; 108:486–492.