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Editorial
Marine Oils for Antiinflammatory Effect — Time to Take Stock
LESLIE G. CLELAND, MD, FRACP;
Adelaide, SA 5000 Australia Address reprint requests to Dr. Cleland. E-mail: lcleland@mail.rah.sa.gov.au SEAL OIL IN PSORIATIC ARTHRITIS The report in this issue of The Journal by Madland and co-workers1 describes the therapeutic use of seal oil in psoriatic arthritis (PsA). The study fails to achieve its primary endpoints of reduced joint pain and patient global assessment of impact on disease after 2 weeks of treatment. This time period was chosen based on improvement in joint symptoms over this period in an earlier study of seal oil in inflammatory bowel disease2,3. The studies differ in that seal oil was given orally in the present study and by intra-duodenal intubation in the earlier study. With duodenal delivery, somewhat higher levels of serum long-chain omega-3 fatty acids (omega-3 fatty acids) were achieved. PUTATIVE MERITS OF SEAL OIL VS FISH OIL The authors explain that seal oil differs from fish oil in that its omega-3 fatty acids are found in the sn1 and sn3 positions in triglycerides and not in the sn2 position, their usual location in triglycerides in fish oils and in membrane phospholipids. They argue that this configuration may favor the absorption of long-chain omega-3 fatty acids from seal oil. However, absorption of long-chain omega-3 fatty acids from fish oil is normally efficient and, in the absence of direct evidence, the notion that omega-3 fatty acids are more bioavailable in seal oil than fish oil is not compelling, particularly in the absence of bowel inflammation sufficient to compromise fat absorption. In addition, the benefit of putative "rapid absorption" of omega-3 fatty acids from seal oil appears to have little relevance for a treatment strategy that is longterm in nature, as discussed below. Indeed, the serum levels of omega-3 fatty acids achieved in the present study were 6.6% w/w of total fatty acids after 2 weeks' treatment with seal oil that provided 6.1 g omega-3 fatty acids per day. These levels are less than half those achieved in plasma in a one-month study of healthy subjects ingesting 5.5 g omega-3 fatty acids per day as Maxepa fish oil. Broadly similar findings were obtained with 2 other brands of fish oil4. LATENCY OF SYMPTOMATIC BENEFIT There have been no previous studies of marine oil in PsA and, to date, most studies have focused on use of fish oil in rheumatoid arthritis (RA)5. The symptomatic benefit seen with fish oil in RA is thought to be related to inhibition of synthesis of nociceptive prostaglandin E2 (PGE2) through competitive inhibition of metabolism of arachidonic acid (AA) by cyclooxygenase (COX) by the long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). This symptomatic effect of fish oil lacks the immediacy of the analgesic response to nonsteroidal antiinflammatory drugs (NSAID) and there is generally a latency of 6 to 12 weeks between commencing antiinflammatory doses of fish oil and symptomatic improvement5. There is no reason to believe this should be different with seal oil and the present study serves as a reminder that treatment of inflammatory diseases with marine oils rich in long-chain omega-3 fatty acids is a longterm, not a short-term, management strategy. ADVANTAGES OF FISH OILS OVER NSAID While not suitable for on-demand use, fish oils have a number of advantages over NSAID. First, they have not been associated with serious upper gastrointestinal complications. Second, they have been shown to reduce risk for cardiovascular events, including cardiac death, through multiple actions (see below)6. This benefit contrasts with the increased cardiovascular risk seen with NSAID, as identified first with COX-2 selective agents and more recently linked to NSAID more generally7,8. Third, fish oils have been shown to reduce synthesis of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin 1 (IL-1) by mononuclear cells9, in contrast to NSAID, which can increase synthesis of these cytokines10. Thus, the 50% reduction in discretionary NSAID use seen with fish oil treatment in RA is clearly an advantage11. This NSAID-sparing effect is especially important as some authorities are now recommending that NSAID be used in doses as small and for periods as short as are required12. Thus longterm fish oil treatment may reduce NSAID use and reduce gastrointestinal and cardiovascular events in potential longterm NSAID users. These advantages may conceivably apply to seal oil, for which very few data are available. Further, the effects of fish oil in the maintenance of remission in Crohn's disease13 and suppression of disease progression in IgA nephropathy14 suggest a disease modifying potential not seen with NSAID. CONTRAST BETWEEN NSAID AND OMEGA-3 FATTY ACIDS FOR EFFECTS ON COX-DERIVED EICOSANOIDS The safety profile of the omega-3 fatty acids in the fish oil, like the risk profile of NSAID, can be largely explained by their unique effects on eicosanoid synthesis. EPA, for example, is a natural homolog of AA, with a structural difference of only one additional double bond (the omega-3 bond) and not surprisingly, it is an alternative substrate and inhibitor of AA metabolism by COX. EPA and DHA inhibit the activity of both COX-1 and COX-2 with a Ki of approximately 2 µM, which is similar to that for ibuprofen15. When long-chain fatty acids are released from cell membranes, the COX isozymes are the immediate enzymes in the pathway of fatty acid metabolism to eicosanoids. Within the context of Western dietary habits, AA is the major COX substrate and prostaglandin H2 (PGH2) its immediate product. PGH2 is converted by respective terminal synthases to PGE2, thromboxane A2 (TXA2), and prostacyclin (PGI2). The balance of TXA2, a vasoconstrictor and promoter of platelet aggregation, and PGI2, a vasodilator and inhibitor of platelet aggregation, is critical for vascular/platelet homeostasis and atherogenesis16,17. Whereas PGH2 is the COX metabolite of AA, PGH3 is the COX metabolite of EPA. Studies of prostanoid metabolism in the presence of dietary EPA or exogenous EPA added in vitro suggest PGH3 is a poor substrate and an inhibitor of PGE synthases18 and TXA synthase19 and a potential substrate without inhibitory effect on PGI synthase20. Indeed, the increased PGI2 synthesis seen with antiinflammatory doses of fish raises the possibility of "shunting" of PGH2 from blocked PGE synthase and TX synthase to uninhibited PGI synthase20. Thus, the overall effect of EPA is suppression of PGE2 synthesis and shifting of the TXA2/PGI2 balance in favor of PGI2. This contrasts with the effects of selective COX-2 inhibitors, which shift the TXA2/PGI2 balance in favor of TXA2 21,22. A likely mechanism for this NSAID effect lies in the different enzyme kinetic characteristics of PGI synthase compared with TXA synthase23. TX synthase has a higher initial reaction velocity, but is saturated at a lower concentration of PGH2 substrate compared with PGI synthase23. Thus, when total COX activity is partially inhibited, as occurs with selective COX-2 inhibition or with all NSAID at certain doses, PGH2 concentration is reduced to an extent that reduces PGI2 synthesis with little or no effect on TXA2 synthesis. CARDIOVASCULAR BENEFITS The cardiovascular benefits of dietary enrichment with omega-3 fatty acids are substantial and include a moderate hypotensive effect24 (possibly prostacyclin-mediated and opposite to the hypertensive effects of NSAID), anti-arrhythmic actions25,26, reduced arterial stiffness27, reduced C-reactive protein28, inhibition of TNF and IL-1 synthesis9 (implicated in atheroma), improved blood lipid profile29 (reduced triglycerides, increase in HDL cholesterol), and most importantly, reduced overall mortality28. The latter effect compared favorably with statins in metaanalysis of the large, longterm randomized trials of antilipemic therapies30. ADVERSE EFFECTS OF MARINE OILS Based on toxicological, population, case control, and clinical studies, it seems unlikely unwanted effects will arise from an excess of constituent omega-3 fatty acids. Recently, attention has been drawn to the adverse effects of mercuric compounds that accumulate in long-lived fish31. Fortunately, mercury does not accumulate in fat and can be removed during processing of marine oils, and levels can be readily monitored. Another class of contaminants to consider are dioxins and dioxin-like polychlorobiphenyls (PCB). These industrial pollutants, which also contaminate the terrestrial food chain, accumulate in body fat and milk. Current levels of intake in Australasia are assessed as very low, but intakes may be higher in other locations32. Antiinflammatory doses (200 mg/kg/day) of fish oil did not increase intakes beyond acceptable levels. However, content within fish oil products can vary33. These contaminants can be reduced by processing and in general, levels in products have fallen over the last decade. Since variability between products has been shown to exist, more stringent measures of analysis of the most relevant congenors are being introduced. As seals are sea mammals atop the marine food chain, seal oil may warrant special attention in this regard. INDUSTRY MARKETING AND ENGAGEMENT OF PRESCRIBERS In conclusion, the benefit/risk profile for longterm use of omega-3-rich marine oils in inflammatory or cardiovascular disease far outweighs that for NSAID. However, there is a considerable mismatch in their use, with widespread routine prescription of NSAID and neglect of fish oils by prescribers. This mismatch says a great deal about the influence of pharmaceutical company marketing. The latter is enabled by the extraordinary profit margins of the industry and is delivered by clinical opinion leaders, who use their product "advisory" relationships with companies to support travel and professional networking habits34. Ironically, rather than more evidence of benefit, which is already ample, a future need will be for larger-scale, sustainable production of omega-3 fatty acids free of environmental pollutants. This might be achieved through plant and microorganism production and may provide the type of product and market conditions that can stimulate the commercial marketing required for broader prescriber engagement. 1. Madland TM, Björkkjaer T, Brunborg LA, Fröyland L, Berstad A, Brun JG. Subjective improvement in patients with psoriatic arthritis after short-term oral treatment with seal oil: a pilot study with double blind comparison with soy oil. J Rheumatol 2006;33:307-10. 2. Arslan G, Brunborg LA, Froyland L, et al. Effects of duodenal seal oil administration in patients with inflammatory bowel disease. Lipids 2002;37:935-40. [MEDLINE] 3. Bjorkkjaer T, Brunborg LA, Arslan G, et al. Reduced joint pain after short-term duodenal administration of seal oil in patients with inflammatory bowel disease: comparison with soy oil. Scand J Gastroenterol 2004;39:1088-94. [MEDLINE] 4. Howland M. Incorporation of eicosapentaenoic acid from three forms of fish oil into human blood cells [honours thesis]. Flinders University of South Australia; 1991. 5. Cleland LG, James MJ, Proudman SM. The role of fish oils in the treatment of rheumatoid arthritis. Drugs 2003;63:845-53. [MEDLINE] 6. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-57. [MEDLINE] 7. Solomon DH. Selective cyclooxygenase 2 inhibitors and cardiovascular events. Arthritis Rheum 2005;52:1968-78. [MEDLINE] 8. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005;330:1366. [MEDLINE] 9. James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000;71 Suppl:343S-8S. 10. Demasi M, Cleland LG, Cook-Johnson RJ, Caughey GE, James MJ. Effects of hypoxia on monocyte inflammatory mediator production: dissociation between changes in cyclooxygenase-2 expression and eicosanoid synthesis. J Biol Chem 2003; 278:38607-16. [MEDLINE] 11. Belch JJF, Ansell D, Madhok R, O'Dowd A, Sturrock RD. Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis: a double blind controlled study. Ann Rheum Dis 1988;47:96-104. [MEDLINE] 12. National Prescribing Service. Elevated cardiovascular risk with NSAIDs? Available at: http://www.npsradar.org.au/site.php?page=1&content=/npsradar/ content/nsaids.html. Accessed December 6, 2005. 13. Belluzzi A, Brignola C, Campieri M, et al. Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease. N Engl J Med 1996;334:1557-60. [MEDLINE] 14. Donadio JV Jr, Bergstralh EJ, Offord KP, Spencer DC, Holley KE. A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group. N Engl J Med 1994;331:1194-9. [MEDLINE] 15. Lands WEM. Biosynthesis of prostaglandins. Annu Rev Nutr 1991;11:41-60. [MEDLINE] 16. Moncada S. Prostacyclin and arterial wall biology. Arteriosclerosis 1982;2:193-207. [MEDLINE] 17. Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002; 296:539-41. [MEDLINE] 18. Hawkes JS, James MJ, Cleland LG. Separation and quantification of PGE3 following derivatization with panacyl bromide by high pressure liquid chromatography with fluorometric detection. Prostaglandins 1991;42:355-68. [MEDLINE] 19. von Schacky C, Fischer S, Weber PC. Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans. J Clin Invest 1985;76:1626-31. [MEDLINE] 20. De Caterina R, Giannessi D, Mazzone A, et al. Vascular prostacyclin is increased in patients ingesting omega-3 polyunsaturated fatty acids before coronary artery bypass graft surgery. Circulation 1990;82:428-38. [MEDLINE] 21. Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 1999;289:735-41. [MEDLINE] 22. McAdam BF, Catella-Lawson F, Mardini IA, et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999;96:272-7. [MEDLINE] 23. Caughey GE, Cleland LG, Penglis PS, Gamble JR, James MJ. Roles of cyclooxygenase (COX) -1 and -2 in prostanoid production by human endothelial cells: selective upregulation of prostacyclin synthesis by COX-2. J Immunol 2001;167:2831-8. [MEDLINE] 24. Geleijnse JM, Giltay EJ, Grobbee DE, Donders AR, Kok FJ. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens 2002;20:1493-9. [MEDLINE] 25. Leaf A. The electrophysiological basis for the antiarrhythmic actions of polyunsaturated fatty acids. Eur Heart J Suppl 2001;3 Suppl D:D98-105. 26. GISSI Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447-55. [MEDLINE] 27. Nestel P, Shige H, Pomeroy S, et al. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. Am J Clin Nutr 2002;76:326-30. [MEDLINE] 28. Ciubotaru I, Lee YS, Wander RC. Dietary fish oil decreases C-reactive protein, interleukin-6, and triacylglycerol to HDL-cholesterol ratio in postmenopausal women on HRT. J Nutr Biochem 2003;14:513-21. [MEDLINE] 29. Harris W. n-3 Fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997;65 Suppl:1645S-54S. 30. Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC. Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch Intern Med 2005;165:725-30. [MEDLINE] 31. Willett WC. Fish balancing health risks and benefits. Am J Prev Med 2005;29:320-1. [MEDLINE] 32. Foods Standards Australia and New Zealand. Dioxins in food. Dietary exposure and risk characterisation. Technical Report Series 27. Available at: http://www.foodstandards.gov.au/mediareleases publications/publications/dioxinsinfooddietaryexposureassessme tandriskcharacterisation/index.cfm. Accessed December 6, 2005. 33. UK Food Safety Authority. 26/02 June 2002. Dioxin and dioxin-like PCBs in fish oil supplements. Available at: http://www.food.gov.uk/multimedia/pdfs/26diox.pdf. Accessed December 6, 2005. 34. Angell M. The truth about drug companies. Melbourne: Scribe Publications; 2005. |
