Fish Oil - Thorne Research

Page 576 Alternative Medicine Review ? Volume 5, Number 6 ? 2000, Copyright©2000 Thorne Research, Inc.
Introduction
Many well-recognized problems are associated with excessive intake of dietary fat, including obesity, insulin resistance, coronary heart disease, and some forms of cancer. While intakes of saturated, trans, and arachidonic fatty acids have been linked to the development of chronic disease, research shows omega-3 (n-3) fatty acids, specifically fish oils, are essential in the prevention and treatment of disease.
Biochemistry
Fish oils are comprised of the essential fatty acids eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3). Both EPA and DHA fall into an even larger category of polyunsaturated fatty acids (PUFAs). Compared to saturated fats, PUFAs are more readily used for energy when initially ingested. Increasing the degree of unsaturation at a given carbon chain length increases the relative mobility of stored fat, making PUFAs more bioavailable.[1] EPA and DHA come from the PUFA, alpha-linolenic acid (ALA) and are classified as omega-3 fatty acids. The nomenclature of an omega-3 fatty acid indicates that the first carbon-carbon double bond occurs at the third carbon atom from the methyl end of the molecule.[2] Through a series of enzymatic reactions, the 18:3 PUFA is converted first to EPA and then finally to DHA. Both EPA and DHA are deemed conditionally essential as the body can synthesize them from ALA. However, while consumption of ALA can lead to significant increases in tissue EPA, it does not do so for DHA.[3] There are several circumstances where the requirements for DHA greatly exceed the rate of synthesis, making supplementation necessary.
Mechanism of Action
EPA and DHA compete with arachidonic acid (AA) for the enzyme cyclo-oxygenase. EPA is converted by platelet cyclo-oxygenase to thromboxane A3 (TXA3), which is only a very weak vasoconstrictor, unlike thromboxane A2 (TXA2), which is formed by the action of cyclo-oxygenase on AA and is a strong vasoconstrictor. However, prostacyclin I3 (PGI3), formed from EPA in the endothelium, is as potent a vasodilator and inhibitor of platelet aggregation as is protacyclin I2 (PGI2) formed from AA. The net effect, therefore, of an increased dietary EPA:AA ratio is relative vasodilation and platelet aggregation inhibition.2 EPA yields the 5-series of leukotrienes, which are only weakly chemotactic. A relative reduction in chemotaxis might be expected to be antiatherogenic. Fish oil decreases both very low density lipoproteins (VLDLs) and triglycerides due to inhibition of hepatic triglyceride synthesis. Because VLDL is a precursor to LDL, a reduction in LDL cholesterol is seen in some patients with hypertriglyceridemia; however, fish oil does not appear to lower plasma cholesterol in subjects with hypercholesterolemia.[4,5]
Clinical Indications

Arrhythmias
A series of animal studies by McLennan et al found that diets supplemented with tuna oil (n-3 PUFA) significantly reduced the incidence and severity of arrhythmias, preventing ventricular fibrillation during both coronary artery occlusion and reperfusion. These studies also found that severity of arrhythmias was significantly worsened by a diet supplemented with saturated fat.[6-8]

Coronary Heart Disease
The beneficial effects of fish oil on coronary heart disease (CHD) have been researched for more than two decades, particularly since the landmark study of Greenland Eskimos showed lower mortality rates from cardiovascular disease.[9] Fish oil has important metabolic effects, such as inhibiting platelet aggregation and lowering serum triglyceride levels, which could play a role in the prevention of CHD. A prospective study of European men found an inverse association between fatty fish consumption (but not lean or total fish consumption) and 20-year CHD mortality.[10] Fish oil has successfully been proven to reduce serum triglyceride levels in humans,[11] although the majority of studies have been conducted on men. More recently, a study has been conducted on the effects of n-3 fatty acid supplementation, specifically fish oil, on postmenopausal women either receiving or not receiving hormone replacement therapy (HRT). The fish oil supplement significantly reduced serum triglyceride concentrations by an average of 26 percent in both HRT-status groups, without affecting other lipid variables. The effect was estimated to decrease CHD risk by 27 percent in postmenopausal women.[12] A study by Thomas et al suggested fitness status, in addition to fish oil supplementation, may be an important factor in determining postprandial triglyceride levels. Sixty minutes of exercise, in addition to fish oil supplementation, decreased plasma triglyceride levels by 33 percent. It has been suggested that fish oil may inhibit lipoprotein lipase activity via its effect on insulin release.[13]

Cancer
Epidemiological, experimental, and mechanistic data implicate n-6 PUFAs as stimulators and long chain n-3 PUFAs (specifically fish oil) as inhibitors of development and progression of a range of human cancers.[14,15] Studies have found the antitumor effect of EPA is mainly related to its suppression of cell proliferation. On the other hand, the effect of DHA appears to be related to its ability to induce apoptosis.[16,17] The dietary n-3/n-6 fatty acid ratio, rather than the quantity administered, appears to be the principle factor in the antitumor effect of n-3 PUFAs. An effective ratio appears to be in the range of 1.8-1.9. EPA and DHA supplementation [16], in the form of fish oil, have also been found to suppress both breast and colon cancer tumor growth and metastasis.[18,19]

Cognitive Function
AA and DHA accrue rapidly in the prenatal human brain during the third trimester and the early postnatal period when the rate of brain growth is maximal and most vulnerable to nutritional deficiencies. Postnatal deficiencies of DHA have specifically been found to relate negatively to visual acuity, neurodevelopment, and behavior. In general, breast milk contains sufficient amounts of long chain PUFAs, including DHA, to meet these needs, assuming the maternal diet is adequate. A study examining breast milk and DHA content in Pakistani mothers versus Dutch mothers found significantly lower amounts of DHA which were directly correlated to the decreased amount of fish eaten in North Pakistan. [20] There is also controversy at present over whether or not the infant formulas that contain only linoleic acid and alpha-linolenic acid are sufficient for brain development.[21]

Depression
In several observational studies, low concentrations of n-3 PUFAs were predictive of impulsive behaviors and greater severity of depression.[22,23] Dopaminergic and serotonergic functions in the frontal cortex seem to be affected by the fatty acid composition of the diet. An n-3 deficiency may be related to catecholaminergic disturbances in depression.[24] Recently it was demonstrated that EPA, DHA, and total n-3 fatty acid levels are significantly lower in red blood cell membranes of depressed subjects compared to the control group.[25]

Diabetes
Rats fed diets high in fish oil and with a low n-6/n-3 PUFA ratio maintained normal insulin action. Diets high in saturated and mono-unsaturated fats led to profound insulin resistance in numerous tissues, as did diets high in omega-6 PUFAs.1 Similar studies by Storlien et al found providing 5-10 percent of dietary energy from fish oil accelerated glucose uptake and maintenance of normal glucose metabolism, even at high levels of fat intake.[26] More importantly, the ability of fish oil to enhance the rate of glycogen storage allows skeletal muscle to increase its uptake of glucose, even under conditions where fatty acid oxidation is accelerated.[27] Fish oil enhances insulin secretion by incorporation of n-3 fatty acids into the plasma membrane to compete with AA production. This reduces the concentration of AA in the plasma membrane, decreasing the production of PGE2, which, in turn suppresses the production of cAMP, a well-known enhancer of glucose-induced insulin secretion. Consequently, fish oil enhances insulin secretion from beta cells, regulating blood sugar.[28] The effect of fish oil on blood lipids should be evaluated in diabetics. A randomized trial conducted on 41 type 1 diabetics found 15 g fish oil per day resulted in statistically significant elevations in LDL cholesterol. [29] It should be pointed out, however, that this study used a very high daily dose of fish oil – 15 g daily versus an average therapeutic dose of 5 g daily.

Rheumatoid Arthritis
Clinical and biochemical studies have shown that fish oil, and to a lesser extent fish, can be used as a source of n-3 fatty acids in the treatment of rheumatoid arthritis. Studies found EPA and DHA reduced eicosanoid and proinflammatory cytokines. The synthesis of interleukin 1b decreased by 20 percent after a diet high in omega-3 fatty acids was consumed for two weeks and was decreased further at the end of four weeks. The synthesis of tumor necrosis factor-alpha decreased 40 percent after two weeks on the diet; at four weeks there was no significant change.[3]

Other Therapeutic Considerations

Studies also show fish oil to be effective in the treatment of acute respiratory distress syndrome, psoriasis, multiple sclerosis, and dysmenorrhea.[30-33]

Dosage
Clinical trials show dosages of 4g/day to be effective.13 Other literature suggests dosage ranges from 1-10g/day. The maximum tolerated dose was found to be 0.3g/kg per day of fish oil capsules. This means a 70-kg patient can tolerate up to 21 one-gram capsules/day.[34]

Safety
Fish oil supplementation is generally safe and well tolerated. Few side effects have been reported. Studies to determine the maximum tolerated dose and dose-limiting toxicities of fish oil showed side effects included gastrointestinal complaints, mainly diarrhea.[34] Other areas of concern include heavy metal contamination found in fish, specifically mercury. In the general population, diet is the major source of mercury exposure, primarily through fish consumption.[35] Quality control of products is an essential part of safety. To ensure quality, fish oil extractions must be purified by a process that removes environmental toxins such as dioxins, PCBs, and heavy metals.

References
1. Storlien LH, Higgins JA, Thomas TC, et al. Diet composition and insulin action in animal models. Br J Nutr 2000;83:S85-S90.
2. Singleton CB, Walker BD, Cambell TJ. N-3 polyunsaturated fatty acids and cardiac mortality. Aust N Z J Med 2000;30;246-251.
3. Mantzioris E, Cleland LG, Gibson RA, et al. Biochemical effects of a diet containing foods enriched with n-3 fatty acids. Am J Clin Nutr 2000;72:42-48.
4. Schectman G, Kaul S, Kissebah AH. Heterogeneity of low density lipoprotein responses to fish-oil supplementation in hypertriglyceridemic subjects. Arteriosclerosis, Thrombosis and Vascular Biology 1989;9:345-354.
5. Wilt TJ, Lofgren RP, Nichol KL, et al. Fish oil supplementation does not lower plasma cholesterol in men with hypercholesterolaemia. Results of a randomized, placebo-controlled crossover study. Ann Intern Med 1989;111:900-905.
6. McLennan PL, Abeywardena MY, Charnock JS. Dietary fish oil prevents ventricular fibrillation following coronary artery occlusion and reperfusion. Am Heart J 1988;116:709-717.
7. McLennan PL, Abeywardena MY, Charnock JS. Dietary lipid modulation of ventricular fibrillation threshold in the marmoset monkey. Am Heart J 1992;123:1555-1561.
8. McLennan PL. Relative effects of dietary saturated, monounsaturated and polyunsaturated fatty acids on cardiac arrhythmias in rats. Am J Clin Nutr 1993;57:207-212.
9. Kromann N, Green A. Epidemiological studies in the Upernavik district, Greenland. Incidence of some chronic diseases 1950-1974. Acta Med Scand 1980;208:401-406.
10. Oomen CM, Feskens JE, Rasanen L, et al. Fish consumption and coronary heart disease mortality in Finland, Italy, and The Netherlands. Am J Epidemiol 2000;151:999-1006.
11. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997;65:1645S-1654S.
12. Stark KD, Park EJ, Maines VA, et al. Effect of a fish-oil concentrate on serum lipids in postmenopausal women receiving and not receiving hormone replacement therapy in a placebo-controlled, double-blind trial. Am J Clin Nutr 2000;72:389-394.
13. Thomas TR, Fischer BA, Kist WB, et al. Effects of exercise and n-3 fatty acids on postprandial lipemia. J Appl Physiol 2000;88:2199-2204.
14. Bougnoux P. n-3 polyunsaturated fatty acids and cancer. Curr Opin Clin Nutr Metab Care 1999;2:121-126.
15. de Deckere EA. Possible beneficial effect of fish and fish n-3 polyunsaturated fatty acids in breast and colorectal cancer. Eur J Cancer Prev 1999;8:213-221.
16. Calviello G, Palozza P, Piccioni E, et al. Dietary supplementation with eicosapentaenoic and docosahexaenoic acid inhibits growth of Morris hepatocarcinoma 3924A in rats: effects on proliferation and apoptosis. Int J Cancer 1998;75:699-705.
17. Lai PB, Ross JA, Fearon KC, et al. Cell cycle arrest and induction of apoptosis in pancreatic cancer cells exposed to eicosapentaenoic acid in vitro. Br J Cancer 1996;74:1375-1383.
18. Rose DP, Connolly JM, Rayburn J, Coleman M. Influence of diets containing eicosapentaenoic or docosahexaenoic acid on growth and metastasis of breast cancer cells in nude mice. J Natl Cancer Inst 1995;87:587-592.
19. Kontogiannea M, Gupta A, Ntanios F, et al. omega-3 fatty acids decrease endothelial adhesion of human colorectal carcinoma cells. J Surg Res 2000;92:201-205.
20. Smit EN, Oelen EA, Seerat E, et al. Breast milk docosahexaenoic acid (DHA) correlates with DHA status of malnourished infants. Arch Dis Child 2000;82:493-494.
21. Wainwright P. Nutrition and behaviour: the role of n-3 fatty acids in cognitive function. Br J Nutr 2000;83:337-339.
22. Nettleton JA. Omega-3 fatty acids: comparison of plant and seafood sources in human nutrition. J Am Diet Assoc 1991;91:331-337.
23. Holman RT. The slow discovery of the importance of omega 3 essential fatty acids in human health. J Nutr 1998;128:427S-433S.
24. Simon H, Scatton B, Moal ML. Dopaminergic A10 neurones are involved in cognitive functions. Nature 1980;286:150-151.
25. Edwards R, Peet M, Shay J, Horrobin D. Depletion of docosahexaenoic acid in red blood cell membranes of depressive patients. Biochem Soc Trans 1998; 26: S142.
26. Storlien LH, Kraegen EW, Chisholm DJ, et al. Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science 1987;237:885-888.
27. Storlien LH, Jenkins AB, Chisholm DJ, et al. Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes 1991;40:280-289.
28. Ajiro K, Sawamura M, Ikeda K, et al. Beneficial effects of fish oil on glucose metabolism in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 2000;27:412-415.
29. Haines AP, Sanders TA, Imeson JD, et al. Effects of a fish oil supplement on platelet function, haemostatic variables and albuminuria in insulin-dependent diabetics. Thromb Res 1986;43:643-655.
30. Kumar KV, Manimala S, Gayani R, et al. Oxidant stress and essential fatty acids in patients with risk and established ARDS. Clin Chim Acta 2000;298:111-120.
31. Dewsbury CE, Graham P, Darley CR. Topical eicosapentaenoic acid (EPA) in the treatment of psoriasis. Br J Dermatol 1989;120:581.
32. Gallai V, Sarchielli P, Trequattrini A, et al. Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids. J Neuroimmunol 1995;56:143-153.
33. Deutch B. Menstrual pain in Danish women correlated with low n-3 polyunsaturated fatty acid intake. Eur J Clin Nutr 1995;49:508-516.
34. Burns CP, Halabi S, Clamon GH, et al. Phase I clinical study of fish oil fatty acid capsules for patients with cancer cachexia: cancer and leukemia group B study 9473. Clin Cancer Res 1999;5:3942-3947.
35. Salonen JT, Seppanen K, Nyyssonen K, et al. Intake of mercury from fish, lipid peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in eastern Finnish men. Circulation 1995;91:645-655.