N-3 fatty acids can cause an increase of approximately 5% in LDL cholesterol in some people. As mentioned above, the elevation in LDL appears to be most pronounced in people with elevated TG because fish oil may enhance the conversion of VLDL to LDL;(6) the LDL consists of the less-pathogenic, larger, less-dense LDL particles. Also, the effect of n-3 fatty acids is more pronounced in carriers of the apoE4 polymorphism, which confers a tendency to have higher baseline serum cholesterol and higher risk of CHD.(9)

There are concerns about the contamination of fish with methylmercury, PCBs, and dioxins.(2) Because of the dangers of these contaminants, the FDA and the Environmental Protection Agency recommend that women who might become pregnant, who are pregnant, or who are breastfeeding, and young children should not eat more highly contaminated fish species such as shark, swordfish, king mackerel, or tilefish, and should eat only 12 oz/wk of less contaminated fish species (canned light tuna, salmon, Pollock, catfish).(2,20) Of note, albacore ("white") tuna is higher in mercury than canned light tuna, and only up to 6 oz should be consumed per week.

There are conflicting reports about whether n-3 fatty acids increase fasting glucose in people with diabetes. One randomized, double-blind trial investigated the use of 4 g/d of EPA, DHA, or olive oil placebo for six weeks in 59 people with Type 2 diabetes mellitus, and found a slight, but significant increase in fasting glucose of 1.40 and 0.98 mol/L in the EPA and DHA groups, respectively, when compared with placebo. There was no change in glycosylated hemoglobin, fasting insulin or C-peptide, insulin sensitivity or secretion, or blood pressure.(21) This result is in contrast to other studies that have not found blood glucose elevations.(14)

There are also dose-dependent adverse effects of n-3 supplementation such as a fishy aftertaste, gastrointestinal disturbances, and increased bleeding time, though no clinically significant abnormal bleeding events have been documented in the medical literature.(2)

Cohort studies and some, but not all, epidemiological studies demonstrate an increased risk of prostate cancer with dietary consumption of LNA, an interesting finding given that EPA and DHA appear to be protective of prostate cancer and that LNA may be protective against breast cancer.(22,23) Some experts state that there is less of a prostate cancer risk, and maybe even a benefit, with the use of ground or whole flaxseeds due to the lignan content; lignans act as phytoestrogens and antioxidants, showing anticancer effects in animal models.(24,25)

Conclusion

The use of n-3 fatty acids, either as LNA or as EPA + DHA, has been studied extensively in both animals and humans, and been subject to numerous reviews examining their clinical effects. LNA has negligible effects on serum lipids, except for a modest decrease in serum TG when high doses of flaxseed oil that are difficult to achieve are consumed daily. The bulk of the convincing clinical effects have been from the use of supplemental EPA and DHA, the n-3 fatty acids from marine sources. Most research shows that 3-4 g/d of EPA + DHA can lead to a 25-30% decrease in TG, an effect more pronounced for people with higher serum TG. There are also variable effects on other serum lipids, such as a small increase in LDL (again, mainly in people with elevated TG) and HDL, the specifics of which depend on many factors, including genetic differences in LDL metabolism. Some of these effects can be achieved with dietary modifications that include daily fish consumption; it remains to be definitively proven whether the sporadic ingestion of n-3 fatty acids leads to similar clinical effects. The generally recommended dose is approximately 3 g/d of EPA + DHA, about 10 capsules daily of most commonly sold preparations. Some of the adverse effects mentioned in the medical literature include elevated LDL cholesterol, increased fasting glucose in people with diabetes, exposure to environmental contamination of fish (not usually a problem with tested supplements), aberrations of bleeding time, and an increased risk of prostate cancer with LNA consumption.

Recommendation

The n-3 fatty acids, LNA, EPA, and DHA, have documented beneficial effects on plasma TG, especially in people with elevated plasma TG. It is possible to lower TG with a supplement, most effectively by consuming approximately 3 g/d of EPA + DHA due to the inefficient conversion of ingested LNA to EPA and DHA, although regular daily consumption of LNA and/or fish also conveys some benefits. There are official warnings about fish consumption due to environmental contaminants, but these dangers can be avoided by consuming tested fish oil capsules or focusing on LNA ingestion. N-3 fatty acids are generally well-tolerated with minimal side effects, though n-3 fatty acids may affect other lipid parameters, such as causing an increase in LDL; it would be a good idea to monitor patients' lipid levels regularly to detect any undesirable abnormalities. The consumption of LNA oils or supplements should be avoided in people with prostate cancer, though flax seeds may be safe in reasonable doses; more research is needed to clarify this point.

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