OMEGA 3 FATTY ACIDS

The American Food and Drug Administration (FDA) recommendations regarding n-3 fatty acids, argued that n-3 fatty acids are "important from womb to tomb."

Where do we get fatty acids?

Omega-3 fatty acids and their counterparts, n-6 fatty acids, are essential polyunsaturated fatty acids (PUFA) because they cannot be synthesized de novo in the body. The major sources of 18-carbon n-3 essential fatty acids (linolenic acid [LNA]), are flax seed, soybean, canola, wheat germ, and walnuts oils.

Linoleic acid (LA), the 18 carbon n-6 essential fatty acid, is found in safflower, corn, soybean, and cottonseed oils; meat products are a source of the LC n-6 fatty acid, arachidonic acid (AA) (C20:4n-6).

The 20-and 22-carbon PUFA sources are fish and fish oils.

How are fatty acids structured?

Table 1: Desaturation and elongation

Omega-3 Fatty Acids and Pregnancy

Craig L. Jensen, MD

There has been a wide range of studies related to n-3 fatty acids and pregnancy. Outcome measures include gestational length and birth weight, preeclampsia, recurrent miscarriages, and maternal depression. Observational studies have found positive associations between fish intake and gestational length and birth weight. In a randomized multicenter trial, supplementation of 2.7g EPA and DHA from 20 weeks gestation or 6.1 g EPA and DHA from 33 weeks gestation reduced risk of preterm delivery, while others found no effect on gestational length. A study by Smuts and colleagues found that 1 DHA egg supplementation (~133 g DHA per egg) during the last trimester increased duration of gestation by 6 days in a predominately African American sample compared to that in controls.

Although the literature is limited in the area of n-3 fatty acids and pregnancy-related outcomes, expert panels recommend 300 mg/day of DHA for pregnant or lactating females.

Omega-3 Fatty Acids and Cognitive and Visual Development in Infancy

Susan E. Carlson, MD

There is definitive evidence that DHA is essential in cognitive and visual development because DHA is concentrated in the brain and retina.

Supplementation of approximately 0.3% DHA and approximately 0.43% to 0.72% AA of total lipids in formulas may lead to improved visual acuity compared to formulas supplemented with LA and LNA.

Carlson discussed the positive long-term effects of early DHA supplementation related to higher Bayley Psychomotor Developmental Index (PDI) (gold standard for neurological development, measures body control, coordination and fine motor skills) in scores at 30 months, higher IQ at 4 years, higher MFFT (Matching Familiar Figures Test) score and speed at 6 years, and lower diastolic and mean blood pressure at 6 years of age.

Omega-3 Fatty Acids and Cardiovascular Disease

Jan Breslow, MD

There are a number of studies to support fish intake as a preventive measure in cardiovascular disease (CVD). In a prospective study of healthy males, low baseline total n-3 fatty acid, EPA, and DHA blood levels are associated with a greater risk of sudden death. The DART (Diet and Reinfarction Trial) study encouraged male myocardial infarction survivors to consume more oily fish (approximately 500 to 800 mg/day of n-3 fatty acids) and found a 29% reduction in total mortality. A subgroup from this study chose to take fish oil capsules providing 450 mg EPA and DHA per day; this group had a 62% reduction in CVD-related death and a 56% reduction in all-cause mortality. The GISSI prevention trial, an Italian study of post-myocardial infarction patients, showed that after 3.5 years, those receiving n-3 fatty acids (850 mg/day) had a 20% reduction in overall mortality, 30% reduction in coronary mortality, and 45% reduction in sudden death.

Omega-3 Fatty Acids and Mental Health

Joseph Hibbeln, MD

LC n-3 fatty acids have been shown to reduce risk and/or treat psychiatric disorders including depression, schizophrenia, and aggression/hostility; however, there are no data to support a clear dose response to n-3 fatty acids, but EPA and DHA appear to work better together than alone. Dietary supplementation of 1 g/day of EPA appears to be effective in reducing psychotic, depressive and aggressive symptoms.

Hibbeln also discussed the importance of balancing the n-6/n-3 ratio because both fatty acid groups compete for elongation and desaturation. Dietary intake of LA and LNA interact to determine pools of n-3 eicosanoid precursors in the tissue. Keeping dietary n-3 fatty acid intake constant, LC n-3 fatty acids in tissues can be increased by lowering the intake of LA.

Omega-3 Fatty Acids and Dementia

Ernst Schaefer, MD

Epidemiologic data indicate that in addition to age, there are at least 3 significant risk factors for dementia and Alzheimer's disease: apoE4 genotype, elevated plasma homocystine levels, and decreased plasma DHA. ApoE4 interacts with brain proteins to predispose people to dementia. Data from the Longitudinal Framingham Study suggest that ApoE4 carriers had approximately a 2.5-fold increased risk of dementia. Homocystine appears to be a direct vascular toxin. Those with increased homocystine levels in plasma were found to have a 1.9-fold increase in dementia. Approximately 40% of fatty acid phospholipids in the brain are DHA. Individuals with dementia have lower plasma phospholipid DHA levels in the brain compared to control. Prospective studies have reported consumption of at least 1 fish serving per week decreases risk of Alzheimer's disease by 60%. Preliminary data suggest that after adjustment for age, gender, apoE genotype, and homocystine levels, the top quartile of plasma DHA of approximately 2.7 or more servings of fish/week or 180 mg or more DHA/day is associated with 50% decreased risk of dementia.

Schaefer concluded that 3 or more fish servings per week or at least 1 fish oil capsule per day (greater than 180 mg DHA/day) to raise DHA levels and supplementing or consuming adequate amounts of vitamins B6, B12, and folate (to decrease homocystine levels) could decrease the incidence of dementia.

Omega-3 Fatty Acids and the Metabolic Syndrome

Yvon Carpentier, MD

"The Metabolic Syndrome" is a diagnosis given to individuals who have 3 or more of the following risk factors: abdominal obesity (waist circumference > 102 cm for males, > 88 cm for females), serum triglycerides (TG) > 150 mg/dL, high density lipoprotein (HDL) cholesterol < 40 mg/dL, blood pressure > 130/85 mm Hg, and fasting plasma glucose > 110 mg/dL. The prevalence of metabolic syndrome is approximately 44% of the US population 50 years of age or older.

The metabolic syndrome is associated with gene variations, insulin resistance, and dyslipidemia. In human studies, 3 weeks of fish oil supplementation (1.1 g EPA and .7 g DHA/day) in healthy volunteers decreased insulin response to oral glucose load by approximately 40% with lower glucose oxidation and higher fat oxidation. Glycogen storage was increased and an unchanged glycemic response suggested improved insulin sensitivity. Omega-3 fatty acids are considered a valuable nutritional tool to prevent insulin resistance associated with obesity; however, they do not appear to be efficient in reversing established type 2 diabetes.

The associations between fish oil and metabolic syndrome also apply to reduced risk of cardiovascular disease. The mechanisms for n-3 fatty acid's protective benefits are not fully understood. In summary, Carpentier suggested that the benefits of n-3 fatty acid supplementation (in those with the metabolic syndrome) might be caused by a reduction of inflammatory conditions, increased cellular antioxidant status, and improved endothelial function.

How Much Omega-3 Fatty Acid is Enough and From Whence Should It Come?

Penny Kris-Etherton, PhD, RD

The adequate intake (AI) for LNA was set as a median intake (without deficiency) to be 1.6 g for males and 1.1 g for females. AIs represent the least amount needed to deter deficiency, but does not take into account disease prevention. Several organizations and expert panels such as the American Heart Association (AHA), Acceptable Macronutrient Distribution Range (AMDR), 2005 dietary guidelines, the National Cholesterol Education Program (NCEP), World Health Organization (WHO), and the International Society for the Study of Fatty Acids and Lipids (ISSFAL) sub-committee have published recommendations for fish and fish oil intake (Table 2, below).

Some recommendations are to increase fish intake, while others recommend specific amounts of EPA and DHA either as supplemental or marine sources. Fish with high n-3 fatty acid contents are anchovies, mackerel, salmon, sardines, sea bass, swordfish, and trout. Some of these fish also need to be consumed in limited amounts because of mercury and other toxins. Swordfish, king mackerel, shark, and tilefish should be limited to 7 oz/week; tuna and red snapper should be limited to 14 oz/week; while salmon, catfish, mahi mahi and canned tuna have no restrictions. Water sources have differing toxic levels of mercury, PCBs, digoxins, and others that may alter these general suggestions.

Contrary to other lecturers, Kris-Etherton stated that walnut, flaxseed, soybean, and canola oil can contribute to meeting LNA recommendations. Support for this statement is from the landmark Lyon Diet Heart Study. A Mediterranean style diet would provide approximately 0.6% to 1% energy or 2 g LNA, no more than 7 g per day LA, be rich in oleic acid, poor in saturated fat, and low in n-6 fatty acid sources. The American diet, however, does not mimic these fatty acid intakes and is very high in n-6 fatty acid intake, which hinders the ability for LNA to be converted to EPA and DHA.

Epidemiologic studies in the United States report 500 mg/day of n-3 fatty acids can decrease CHD risk. The average American diet only provides 100 mg EPA and DHA per day. This is 5 times less than the amount observed for cardiovascular benefit and also 5 times less than the WHO's current dietary recommendation for EPA and DHA. Not only are consistent recommendations needed, strategies to increase intakes are also necessary.

Conclusions

Omega-3 fatty acid supplementation during pregnancy causes a probable increase in duration of gestation and birth weight, a possible benefit for those with a history of miscarriages, and a decrease in preterm delivery. However, no reduction in the risk of preeclampsia has been shown.

There is clear evidence that n-3 fatty acids promote improved visual acuity in infants and children when the mother or infant is supplemented with DHA. DHA may be an important nutrient for optimal development throughout gestation and until 2 years of age.

Studies support low DHA as a risk factor for dementia. Low total n-3 fatty acids levels, EPA and DHA associate with greater risk of CVD, dietary intake and/or supplementation is supported as a secondary or tertiary prevention measure. Omega-3 fatty acids also help to prevent type 2 diabetes and the metabolic syndrome, two common precursors to CVD. There is some support for schizophrenia, depressive or aggressive disorders; however, large multi-center clinical trials have yet to be conducted. The anti-inflammatory properties of n-3 fatty acids are helpful in decreasing symptoms of rheumatoid arthritis and may possibly increase remission length in Crohn's patients; however, studies involving asthma and irritable bowel disease have inconsistent results.

Dietary recommendations for n-3 fatty acid supplementation are still a matter of debate. Recommendations may vary depending on desired disease prevention: daily ranges for EPA and DHA begin at 180 mg (for dementia prevention) to 500 mg (decrease in heart disease) to 1000 mg (decrease in mental illness). Marine sources contain EPA and DHA and do not require elongation and desaturation to be effective LC n-3 fatty acids. More research is needed to tease out the conditions in which n-3 fatty acids are beneficial and then to determine the amount and source of n-3 fatty acids needed. Studies are also needed to test the efficacy of increased LNA in diets where there is a coincident reduction in the n6/n3 ratio. At this time, some studies suggest, that LNA sources are not likely to provide clinical benefit.

It is clear that n-3 fatty acids have preventative and therapeutic benefits; it appears prudent to ensure intake of the AI for LNA and include marine sources of n-3 fatty acids, via supplementation or fish consumption, throughout the lifespan.

Table 2. Recommendations From Various Organizations and Expert Panels

Organization, year	Recommendation
AHA, 2002	No CVD: should eat oily fish twice/week and foods rich in LNA (walnuts, canola, soy, and flaxseed)
	Documented CVD: should eat ~1 g EPA and DHA/day preferably from oily fish, but also in supplement form
	For triglyceride lowering effects:- 2-4 g of n-3 fatty acids per day as a supplement under a physician's care
AMDR, 2002	Recommends AI for n-3 fatty acids as 0.6%-1.2% energy, 133-267 mg/day for CVD prevention
ISSFAL, 2004	Recommends adequate LA intake of 2% energy, healthy LNA as 0.7 % energy, and for cardiovascular health a minimum of 500 mg EPA and DHA per day
NCEP, 2002	Recommends eating fish more often
NIH supported expert panel, 1999	300 mg DHA per day for pregnant or lactating females
WHO, 2003	Recommends 1-2 servings of fish per week each containing 200-500 mg EPA and DHA
USDA Dietary Guidelines, 2005	Recommends 8 oz. per week (2 servings) of fish high in EPA and DHA content to decrease risk of CVD

SOURCE: Medscape: MedStudents: MedPlus (2005) Medical Student Newsletter, (online) http://www.medscape.com/home Accessed: 14-10-2005