Prostate cancer and fish consumption
BOSTON, MASSACHUSETTS. Epidemiological studies investigating a possible association between fish consumption and prostate cancer have produced inconclusive results. Some have found that an increased intake of fish may help reduce the risk of prostate cancer, but other studies have found no such effect. There is, however, fairly conclusive evidence that, while an increased fish intake may not prevent the cancer, it does reduce its growth and aggressiveness.

Researchers at the Harvard Medical School now report the results of a large study aimed at determining the association between fish intake and prostate cancer incidence and mortality. The study involved over 22,000 male physicians (ages 40 to 84 years) who were enrolled in 1983 and, at that time, completed a detailed food frequency questionnaire. During an average 19 years of follow-up, 2161 (0.6%/year) of the men were diagnosed with prostate cancer (biopsy-confirmed) and 230 (1.1% of all participants or 0.06%/person-year) died from the disease. Fish intake was positively associated with the intake of tomato products and alcohol, the use of multivitamins and vitamin E supplements, and vigorous physical activity and was inversely related to the intake of whole milk and meats. Most cases (71.6%) were diagnosed when still localized.

The Harvard researchers found no statistically significant association between fish intake and the diagnosis of prostate cancer, and conclude that a high fish intake does not protect against the initial development of the cancer. However, there was a clear correlation between increased survival and fish intake, particularly from oily fish, with men eating fish 5 or more times weekly having half the risk of dying from prostate cancer when compared to men eating fish less than once a week.

The researchers suggest that a high fish intake may delay tumor progression. They also point to a recent study that found men who had undergone a radical prostatectomy for clinically localized cancer were less likely to experience biochemical recurrence if their non-cancerous prostate tissue had a higher level of long-chain n-3 fatty acids such as EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). They also point to laboratory data suggesting that EPA suppresses the proliferation of several prostate cancer cell lines. Their final conclusion was that fish intake is not associated with the risk of developing prostate cancer, but a high intake (especially oily fish) does reduce the mortality among men already diagnosed with the disease.
Chavarro, JE, et al. A 22-year prospective study of fish intake in relation to prostate cancer incidence and mortality. American Journal of Clinical Nutrition, Vol. 88, 2008, pp. 1297-303

Fish oils reduce risk of heart attack
BOSTON, MASSACHUSETTS. There is significant evidence that a moderate to high fish intake protects against fatal coronary heart disease or sudden cardiac death. There is also evidence that supplementation with fish oil (EPA + DHA) can reduce coronary death among patients who have survived a heart attack (myocardial infarction). Now researchers at the Harvard Medical School report that women with a high blood plasma level of EPA (eicosapentaenoic acid), DPA (docosapentaenoic acid) and DHA (docosahexaenoic acid) have a substantially reduced risk of suffering a non-fatal heart attack.

The study involved 32,826 nurses (average age of 60 years) who had blood samples drawn in 1989 or 1990. During a 6-year follow-up, 147 non-fatal heart attacks occurred in the group (0.07%/person year). The 147 heart attack (MI) patients were matched with 288 controls and the fatty acid content of their plasma and red blood cells (erythrocytes) measured. The researchers observed that the average plasma concentrations of EPA, DPA and DHA were significantly lower in MI patients than in controls. They conclude that the nurses in the highest quartile of EPA plasma level have a 77% lower risk of suffering a non-fatal MI (myocardial infarction) than do those in the lowest quartiles (after adjusting for confounding variables). Corresponding risk reductions for DPA and DHA were 60% and 54% (not statistically significant). The association between fatty acid levels in erythrocytes and MI risk was statistically non-significant. Similarly, there was no statistically significant correlation between high plasma levels of alpha-linolenic acid (ALA) and a lower risk of non-fatal MI.

The researchers also noted that high plasma concentrations of EPA and DPA and, to a lesser extent, DHA were associated with more favorable levels of triglycerides, HDL cholesterol, and several inflammatory markers. They conclude that higher plasma levels of EPA and DPA are associated with a lower risk of non-fatal MI among American women.
Sun, Q, et al. Blood concentrations of individual long-chain n-3 fatty acids and risk of nonfatal myocardial infarction. American Journal of Clinical Nutrition, Vol. 88, 2008, pp. 216-23

DHA may help protect against Alzheimer's disease
NEW ORLEANS, LOUISIANA. DHA (docosahexaenoic acid), a major component of fish oils, is an absolute requirement for the development of the human central nervous system and the continuous maintenance of brain cell function. DHA is an important part of the plasma membranes of nerve (neuronal) cells and is essential in the maintenance of their fluidity and integrity. It is also involved in the generation of certain metabolites (docosanoids) of which the most important is neuroprotection D1 or NPD1. Both DHA and NPD1 are involved in ensuring membrane stability and fluidity and inhibiting the activation of inflammatory signaling mediators such as cyclooxygenase-2 (COX-2). NPD1 is also beneficial in preventing excessive oxidative stress from degrading DHA. Furthermore, a recent clinical trial concluded that supplementation with DHA and lutein significantly improved cognitive abilities in elderly people.

Unfortunately, as DHA is a highly unsaturated fatty acid, it is subject to lipid peroxidation which, in turn, is associated with retinal and neurological dysfunction and visual and cognitive decline. The free radical initiated oxidation of DHA is also believed to be one of the first steps in the cascade of events (brain cell membrane instability and neural cell dysfunction) leading to Alzheimer's disease with the characteristic formation of amyloid plaques. On the other hand, the DHA metabolite, NPD1 has been found to be neuroprotective by inhibiting oxidative stress, cell death, and inflammation-triggered neuronal decline while promoting brain cell survival and maximizing cognitive function throughout the human lifespan.
Lukiw, WJ and Bazan, NG. Docosahexaenoic acid and the aging brain. Journal of Nutrition, Vol. 138, 2008, pp. 2510-14

Editor's comment: There is no question that DHA is crucial for the development and maintenance of the central nervous system and its neuronal cells. This article further suggests that an adequate DHA supply may also help prevent cognitive decline and progression of Alzheimer's disease. However, since DHA is easily oxidized its intake should always be accompanied by supplementation with vitamin E (gamma-tocopherol) and its regenerator, vitamin C.

Omega-3 fatty acids and child development
BOSTON, MASSACHUSETTS. Fetal life and early infancy are recognized as critical periods for brain development and growing evidence suggests that early nutrition plays a role in neurodevelopment. Furthermore, the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is an essential structural component of the brain. Humans must get DHA from food (or the health food store) and the primary dietary source is fish and other seafood. DHA is present in breast milk but only recently has it been added to infant formulas. This is a particularly important issue since a dislike of fish is not uncommon nor are fears of fish consumption due to the presence of mercury and other contaminants. Furthermore, the culture of mainstream medicine works against the physician suggesting supplementation, although folic acid supplementation is an exception due to its success in reducing a common birth defect. A recent study has addressed this issue by examining the association between maternal fish or DHA intake during pregnancy and the duration of infant breastfeeding with the attainment of so-called child development milestones.

Dr. Emily Oken and colleagues at the Harvard Medical School studied over 25,000 children of mothers participating in the Danish National Birth Cohort, a prospective population-based study that enrolled pregnant women between 1997 and 2002. Data was collected on maternal fish intake, the duration of breastfeeding and measures of child development milestones. The primary outcome was total development at 18 months ascertained by an interview. Mothers were questioned about whether the child could climb stairs, remove socks and shoes, drink from a cup, be occupied for 15 minutes with adult participation, fetch an object when requested, write or draw, orient a book correctly, use word-like sounds, and put two words together. Ages at which the child could first sit unsupported and could walk unassisted and the total number of words the child could correctly say was recorded. Data was also collected at 6 months with an appropriate set of questions. From this data scales were constructed and scores derived. Other data collected included birth weight and evidence of early or late delivery (gestational age), maternal smoking and alcohol use and other information which allowed correcting for confounding. It was found that higher maternal fish intake during pregnancy and the duration of breastfeeding were associated with higher child development scores at 18 months. For example, 5.7% of children with a mother in the lowest quintile of fish intake had the lowest total development score at 18 months whereas only 3.5% of children with their mother in the highest quintile of fish intake had the lowest total development score. Women in the lowest quintile consumed < 1 fish serving/week whereas in the highest quintile it was about 3.5 servings/week. Fish most frequently consumed were cod, plaice, salmon, herring and mackerel. Species with high mercury content are not commonly consumed in Denmark.

Longer duration of breastfeeding was associated with better development at 18 months. After adjusting for maternal fish intake, longer breast-feeding remained associated with a greater achievement of developmental milestones with a 28% increase when = 10 months was compared with = 1 month. This pattern of association with fish intake and duration of breastfeeding was a robust result which persisted after a number of different corrections for potential confounding.

The authors comment that in the U.S. and Europe, expert panels have advised that pregnant women consume a minimum of 200 mg/day of DHA. They point out that most women do not consume this much DHA from fish or other dietary sources, and thus supplements may offer a reasonable alternative. They cite studies which found improved development in children of women randomly assigned to take supplemental DHA although doses were much higher (1-2 g/day) than the experts recommended. The authors cite evidence that in the case of the long-chain polyunsaturated fatty acids, supplementation with a single acid may be less desirable than providing a more natural balance of these nutrients. Fish oil, for example contains both DHA and EPA.
Oken E, et al. Associations of maternal fish intake during pregnancy and breastfeeding duration with attainment of developmental milestones in early childhood: a study from the Danish National Birth Cohort. Am J Clin Nutr 2008 September;88(3):789-96

High fish oil intake equals less atherosclerosis
PITTSBURGH, PENNSYLVANIA. It is a well-established fact that Japanese men have far less coronary artery disease than do American men. A recent, large autopsy-based study concluded that raised lesions in the coronary arteries (a sign of atherosclerosis) were far more common among white men in the US (50% had such lesions) than among Japanese men (15% had such lesions) in the age group 30-34 years. An obvious conclusion would be that this is likely due to genetic differences, but is it? An extensive team of scientists from the US (Universities of Pittsburgh and Honolulu) and Japan (University of Medical Science) recently set out to answer this question.

Their study included 281 Japanese men (born and living in Japan), 306 white Americans (born and living in the US), and 281 Japanese-American men who were 3rd or 4th generation living in Hawaii. The average age of the participants was 45 years (range of 40 to 49 years). Somewhat surprisingly, Japanese men had less favorable or similar risk profiles in regard to hypertension, LDL cholesterol, triglycerides, diabetes and cigarette smoking when compared to white American men. Japanese men were, however, significantly less likely to be obese than American and Japanese-American men. All study participants had blood samples taken, had their intima-media thickness (IMT) of their carotid artery measured, and underwent electron beam computed tomography to measure their degree of coronary artery calcification (CAC).

Japanese men had substantially less CAC (9.3%) than did American (26.1%) and Japanese-American men (31.4%). They also showed substantially less plaque formation in the carotid artery (0%) than did American men (0.7%) and Japanese-American men (16.7%). These findings pretty well demolish the hypothesis that the lower level of atherosclerosis in Japanese men is a genetic trait. So what does account for the lower level of atherosclerosis?

After considering the results of the blood tests, the research team concluded that it is the high serum level of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), the main components of fish oils, that provides the protection against atherosclerosis. While there was no significant difference in total fatty acid content between the three groups, there was a very marked difference in the percentage of these fatty acids constituted by EPA + DHA. In Japanese men the EPA + DHA percentage was 8.4% versus 3.2% in American men and 4.2% in Japanese- American men. Furthermore, the researchers also noted a direct inverse relationship (in Japanese men only) between serum levels of EPA + DHA and extent of coronary and carotid artery calcification. They conclude that the habitual consumption of large amounts of fish protects against atherosclerosis and urge large-scale trials to ascertain whether a vastly increased intake of fish oil among American men would similarly protect them against atherosclerosis and coronary artery disease.
Seikikawa, A, et al. Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese-American, and white men. Journal of the American College of Cardiology, Vol. 52, No. 6, August 5, 2008, pp. 417-24

Lowering serum triglycerides with omega-3 fatty acids
UNIVERSITY PARK, PENNSYLVANIA. Since the 1970s, epidemiologic, clinical and experimental evidence have all indicated that omega-3 fatty acids provide protective benefits against coronary heart disease (CHD) and this may in part be due to their ability to significantly reduce triglyceride levels. For a number of years, a pharmaceutical grade preparation called Omacor, which contains the long-chain omega-3 fatty acids EPA and DHA, has been used in Europe both for intervention trials and as a prescription drug. Recently the FDA approved essentially the same product, which sells in the US under the different name of Lovaza, and is also called P-OM3. This prescription form of the pharmaceutical grade EPA + DHA sold in health food stores was featured in a recent review of the use of omega-3 fatty acids for the treatment of moderately elevated triglycerides (150-500 mg/dL). The pharmaceutical product is promoted on the basis of a high concentration of EPA + DHA per one gram capsule, guaranteed purity that is a priori assumed with prescription drugs and, while not emphasized, the fact that the patient is provided with a prescription which may be covered by insurance rather than being told to go to the local health food store and acquire the vastly less expensive pharmaceutical grade also available there. Patients feel good about getting a real prescription, doctors may feel good about writing it, and as long as someone else pays, everybody is happy. While there may well be differences in the standards of purity between the over-the-counter highly purified pharmaceutical grade EPA + DHA and Lovaza, the two products do not appear to have been compared directly in this context. But it is of interest to examine the claim that taking the prescription product considerably reduces the number of capsules required daily.

The prescription preparation involves what are called ethyl esters of the free fatty acids, whereas the over-the- counter product is generally the free acid. Thus when the grams of EPA and DHA are compared, one must correct for this which means reducing the EPA and DHA content of the prescription drug by about 10% in order to compare with the free acid. The recommended dose of Lovaza is 4 capsules which provides about 1.7 g of EPA and 1.32 g of DHA for a total of about 3 g. Natural Factors makes a pharmaceutical grade and 5 capsules will provide 3 g of EPA + DHA with slightly less EPA and slightly more DHA. Life Extension also sells a highly purified preparation with 5 capsules containing 3 g of EPA + DHA with almost the same ratio of EPA top DHA as the prescription drug. Thus the prescription drug does not drastically reduce the number of capsules required per day but rather simply reduces it from 5 to 4 and appears to be identical with regard to the active ingredient unless one is concerned that the acids are esterified.

The just-published review of randomized placebo controlled intervention trials for the lowering of triglycerides (TG) with omega-3 fatty acids allows a comparison of the prescription preparation and ordinary fish-oil preparations. The TG lowering is roughly dose dependent and ordinary fish oil products produced declines ranging from 39% for 4.5 g/d of EPA + DHA to around 26% for intakes of 2.2 to 2.5 g/day. Correcting the prescription intake to account for the fact that it is the ester, one gets an average TG lowering of 28% ± 5% for a dose equivalent to about 3 g/d of EPA + DHA free acid. This falls nicely on the dose response curve and agrees well with the lowering obtained from an equivalent amount of the non-prescription preparation.

The bottom line appears clear. If one can be confident of the claims of over-the-counter suppliers of EPA + DHA regarding purity, then there is no apparent significant difference between the health store product and the vastly more expensive prescription drug, even when the comparison involves TG lowering.
Skulas-Ray AC, et al. Omega-3 fatty acid concentrates in the treatment of moderate hypertriglyceridemia. Expert Opin Pharmacother 2008 May;9(7):1237-48
Brunton S and Collins N. Differentiating prescription omega-3-acid ethyl esters (P-OM3) from dietary-supplement omega-3 fatty acids. Curr Med Res Opin 2007 May;23(5):1139-45

Recommendations for fish oil intake
SIOUX FALLS, SOUTH DAKOTA. It is now well established that fish and fish oil are protective against coronary heart disease (CHD) and reduces the risk of dying from CHD by about 40%. The American Heart Association (AHA) recommends that patients with existing CHD consume 1000 mg/day of EPA (eicosapentaenoic acid) plus DHA (docosahexaenoic acid), the main components of fish oils. AHA also recommends that healthy adults consume at least two servings a week of fish (preferably oily). Considering that oily fish, such as sardines, mackerel, salmon and tuna contain anywhere between 800 and 1500 mg of EPA + DHA per 3-oz (85 grams) serving means that people eating two oily fish meals a week would obtain between 230 and 430 mg/day of EPA + DHA.

Researchers at the University of South Dakota believe it is time to issue an official recommendation for a minimum daily intake of EPA + DHA in the USA. They suggest that the minimum intake should be 400 – 500 mg/day of EPA + DHA. They point out that several other countries already have such recommendations with France specifying an intake of 500 mg/day of EPA + DHA (minimum 120 mg/day of DHA), the UK 450 mg/day, Australia and New Zealand 442 mg/day of EPA + DHA for men and 318 mg/day for women. Both the American and Canadian Dietetic Association recommend 500 mg/day with a minimum of 120 mg/day of DHA. The US FDA has set an upper limit of safe EPA + DHA intake at 3000 mg/day, so the 500 mg/day recommendation is well within generally accepted safe limits.

The researchers point out that some fish are very contaminated with methylmercury and should be consumed only rarely if at all. Among the worst offenders are tile fish, king mackerel, shark and swordfish, but the FDA also warns that albacore (white) tuna should be consumed no more than once a week by pregnant women. Finally, they suggest that if the recommended EPA + DHA intake cannot be achieved by fish consumption, then fish oil supplements may be used instead to achieve the recommended minimum target of 500 mg/day of EPA + DHA.
Harris, WS, et al. Intakes of long-chain omega-3 fatty acid associated with reduced risk for death from coronary heart disease in healthy adults. Current Atherosclerosis Report, Vol. 10, 2008, pp. 503-09