Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids

Abstract

There is considerable interest in the impact of (n-3) long-chain PUFA in mitigating the morbidity and mortality caused by chronic diseases. In 2002, the Institute of Medicine concluded that insufficient data were available to define Dietary Reference Intakes (DRI) for eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), noting only that EPA and DHA could contribute up to 10% toward meeting the Adequate Intake for alpha-linolenic acid. Since then, substantial new evidence has emerged supporting the need to reassess this recommendation. Therefore, the Technical Committee on Dietary Lipids of the International Life Sciences Institute North America sponsored a workshop on 4-5 June 2008 to consider whether the body of evidence specific to the major chronic diseases in the United States--coronary heart disease (CHD), cancer, and cognitive decline--had evolved sufficiently to justify reconsideration of DRI for EPA+DHA. The workshop participants arrived at these conclusions: 1) consistent evidence from multiple research paradigms demonstrates a clear, inverse relation between EPA+DHA intake and risk of fatal (and possibly nonfatal) CHD, providing evidence that supports a nutritionally achievable DRI for EPA+DHA between 250 and 500 mg/d; 2) because of the demonstrated low conversion from dietary ALA, protective tissue levels of EPA+DHA can be achieved only through direct consumption of these fatty acids; 3) evidence of beneficial effects of EPA+DHA on cognitive decline are emerging but are not yet sufficient to support an intake level different from that needed to achieve CHD risk reduction; 4) EPA+DHA do not appear to reduce risk for cancer; and 5) there is no evidence that intakes of EPA+DHA in these recommended ranges are harmful.

FIGURE 1

Development of coronary heart disease and potential sites of action of (n-3) fatty acids. At typical dietary doses (up to 1 g/d), the likely major site of action is the final pathway of ischemia-related cardiac arrhythmia (dotted circle), reducing the risk of cardiac death from fatal heart attack or sudden death. More modest effects on other pathways, such as atherosclerosis and plaque stability, may also reduce the risk of nonfatal myocardial infarctions (heart attacks) and acute coronary syndrome to a smaller extent.

FIGURE 2

Meta-analysis of estimated dietary EPA+DHA consumption from seafood and risk of cardiac death in generally healthy populations of individuals without known heart disease. The pooled analysis includes 4473 cardiac deaths in 326,572 generally healthy individuals in 16 prospective cohort studies (–18) from multiple countries in Europe, the United States, China, and Japan, using methods described by Mozaffarian and Rimm (28).

FIGURE 3

Relation between the omega-3 index and risk for primary cardiac arrest (right) and the estimated omega-3 index and SCD (left). The former were derived from a population-based case-control study (21), and the latter from a case-control study nested in the prospective Physicians' Health Study (P-trend = 0.001) (19). [The omega-3 index was estimated from the whole-blood (n-3) LCPUFA content using equations described by Harris and von Schacky; *P < 0.05 vs. quartile 1.] Reproduced with permission from William S. Harris (162).

FIGURE 4

Hierarchy of quality and strength of evidence of different study designs for evaluating causation of chronic disease. Studies of physiological endpoints may not fully account for all effects of an intervention, and thus, evidence is strongest when derived from well-conducted studies of disease endpoints. Well-controlled prospective observational studies and well-performed randomized clinical trials have different, and highly complementary, strengths and limitations. The major strength of randomized trials is to minimize residual confounding; limitations include potential lower generalizability to external populations, the inability to evaluate the effects of many risk factors of interest (e.g., smoking, biomarker levels) due to ethical or practical limitations, inadequacy of duration and/or dose tested, challenges in testing multiple doses, noncompliance, unblinding, differential loss to follow-up, and treatment crossover. The major limitation of prospective observational studies is potential residual confounding, whereas major strengths generally include the converse of each of the major limitations of randomized trials. Thus, evidence is most robust when studies of both designs provide concordant results, as is the case for EPA+DHA consumption and (especially fatal) CHD.