Omega-3 fatty acids

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The name derives from chemical nomenclature. The first carbon adjacent to the carboxyl group is designated alpha (α) while omega (ω) refers to the very last carbon atom regardless of the length of the carbon chain. Omega-3 in the context of fatty acids refers to the presence of a carbon double-bond at the 3rd carbon from the end. See also Greek alphabet.

Omega-3 fatty acids, omega-3 polyunsaturated fatty acids and ω-3 PUFAs are popular names for n-3 polyunsaturated fatty acids as found in oily fish. As well as being essential dietary components as they can not be synthesised in man de novo, they can also be used as therapeutic agents, particularly where the diet is deficient.

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  • Marine food source - GOOD as contains DHA
  • Plant source - Some human metabolism of alpha-linolenic acid required to get DHA
  • Too little omega-3 fatty acid is harmful
  • Too much Omega-3 fatty acid might be harmful
  • There is evidence that after myocardial infarction only those unable to tolerate statins benefit from supplementation[1]

Non-fish sources include walnuts, pumpkin seeds and flax seeds but in this case alpha-linolenic acid(ALA) is present and this requires further metabolism. This source is helpful given dwindling fish stocks although the benefits of supplementing normal diets may have been over-hyped.[2] For example the ALA evidence base although consistent with that of fish oils lacks large enough studies and low dose food supplementation does not protect against myocardial infarction for those on optimal drug treatment after a first myocardial infarction[3]. There are some associations with specific disease processes that are not beneficial.

All cause mortality in overview of RCT to 2007. Trials as in [4] except for ISSI-P using original data and JELIS[5]
Cardiovascular events in overview of RCT to 2007. Trials as in [6] except for JELIS[7]
  • Omacor® is a mixture of eicosapentaenoic acid (EPA) ethyl ester 46% and docosahexaenoic acid (DHA) ethyl ester 38% and has been shown to be beneficial in secondary prevention after myocardial infarction in addition to other standard therapy, particularly in the subgroup with heart failure[8] and treating Type IV hypertriglyceridaemia and type IIb/III in combination with statins. It may not be beneficial in those who have an equivalent or large intake of omega-3 fatty acid from the diet. The JELIS trial in Japan that used EPA alone and had a larger postmenopausal female representation than is usual in most cardiovascular trials did not quite reach statistical significance for secondary prevention of major coronary events.[9]
  • In intermediate age related macular degeneration are likely to be ineffective or harmful compared to monosaturated fatty acids[10].
  • Despite claims there are wide areas of unknown effectiveness There is little, if any evidence of long term benefit of Omega-3 fatty acids in primary prevention and other secondary prevention despite many studies, with conflicting meta-analysis to this conclusion being believed to be due to use of short-term outcome data, confounding issues such as toxicity from other food chain toxins, and other forms of bias. When all primary and secondary prevention RCTs are combined, cardiovascular events are reduced by 8% (not significant at 95% level, although significance can be obtained if the DART-2 trial is removed). Meta-analysis is also powered to detect a change in all cause mortality and this last has consistently not been demonstrated, however the data is manipulated. It seems that short term cardiovascular gain does not translate into major mortality gain or reassuringly mortality loss. [11] Omega-3 fatty acids do little harm at least overall.
  • In reducing ventricular arrhythmia in patients with implanted cardiovertor-defibrillators, very long chain Omega-3 fatty acids are unlikely to be benefical[12] and indeed in heart failure patients the patients levels of these fatty acids are correlated with risk of ventricular arrhythmia[13].
  • In patients on TPN likely to be beneficial as it has been found that the hepatic cholestasis syndrome is reversed by omega-3 fatty acids. Randomised controlled trials are awaited.[14]
  • In chronic heart failure likely to be beneficial as 1g/day with a 2% absolute reduction in death at 4 years (number needed to treat 56) [15]
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Recommendations:

  • NICE (CG67 Lipid modification: NICE guideline June 2008):
    • "People should not routinely be recommended to take omega-3 fatty acid supplements for the primary prevention of CVD"
    • "In secondary prevention due to the conflicting results of the two studies ... for oily fish consumption / omega 3 fatty acid supplementation and the lack of evidence for patients with peripheral arterial disease or following stroke, ... the recommendations made by the Joint British Societies' guidelines on prevention of CVD in clinical practice should be adopted, which recommends at least two servings of omega-3 fatty acid containing fish per week. ...There was insufficient evidence to recommend omega 3 fatty acid supplementation in patients with angina, peripheral arterial disease or stroke."
  • SMC (Note SMC guidelines pre-dated the second major Japanese trial)
    • Treatment of hypertriglyceridaemia "Not recommended for use within the NHS in Scotland" SCM Omacor 2002)
    • "Acceptable for general use within NHS Scotland as an additional treatment for the secondary prevention of myocardial infarction." (SMC Omacor 2002)
  • Neonatal brain development. While animal studies have defined conclusively the key role of DHA (and arachidonic acid) in mammalian CNS and retinal development there is no conclusive pre-term or post term intervention study[16][17]. That long-chain polyunsaturated fatty acids (LC-PUFA) are preferentially transferred from mother to fetus across the placenta is an observation yet to be translated into definitive evidence that 3-omega fatty acid supplementation in pregnancy is beneficial. The reason may be that in rats excess as well as deficiency leads to adverse outcomes[18].

How they might work

This is not clear. However it has been observed that electrophilic oxo-derivatives (EFOX) of the omega-3 fatty acids docosahexaenoic acid and docosapentaenoic acid adduct to cysteine and histidine residues of proteins and activate Nrf2-dependent anti-oxidant gene expression. They can act as peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists and inhibit pro-inflammatory cytokine and nitric oxide production, all within biological concentration ranges. Modulation of COX-2 activity by aspirin increases the rate of EFOX production and their intracellular levels[19]. This might suggest a beneficial combination easy to test in clinical research studies.

References

  1. Eussen SR, Geleijnse JM, Giltay EJ, Rompelberg CJ, Klungel OH, Kromhout D. Effects of n-3 fatty acids on major cardiovascular events in statin users and non-users with a history of myocardial infarction. European heart journal. 2012 Feb 1.(Epub ahead of print) (Link to article – subscription may be required.)
  2. Brunner E. Oily fish and omega 3 fat supplements BMJ, doi:10.1136/bmj.38798.680185.47 (published online 24 March 2006)
  3. Kromhout D, Giltay EJ, Geleijnse JM. n-3 fatty acids and cardiovascular events after myocardial infarction. The New England journal of medicine. 2010 Nov 18; 363(21):2015-26.(Link to article – subscription may be required.)
  4. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JPT, Capps NE, Riemersma RA, Ebrahim SBJ, Smith GDS. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review BMJ, doi:10.1136/bmj.38755.366331.2F (published 24 March 2006)
  5. Yokoyama M, Origasa H, Matsuzaki M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis The Lancet 2007 369(9567):1090-98
  6. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JPT, Capps NE, Riemersma RA, Ebrahim SBJ, Smith GDS. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review BMJ, doi:10.1136/bmj.38755.366331.2F (published 24 March 2006)
  7. Yokoyama M, Origasa H, Matsuzaki M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis The Lancet 2007 369(9567):1090-98
  8. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999;354(9177):447-55. Erratum in: Lancet 2001;357(9256):642.
  9. Yokoyama M, Origasa H, Matsuzaki M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis The Lancet 2007 369(9567):1090-98
  10. Parekh N, Voland RP, Moeller SM, Blodi BA, Ritenbaugh C, Chappell RJ, Wallace RB, Mares JA. Association between dietary fat intake and age-related macular degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS): an ancillary study of the Women's Health Initiative. Archives of ophthalmology. 2009 Nov; 127(11):1483-93.(Link to article – subscription may be required.)
  11. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JPT, Capps NE, Riemersma RA, Ebrahim SBJ, Smith GDS. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review BMJ, doi:10.1136/bmj.38755.366331.2F (published 24 March 2006)
  12. Brouwer IA, Zock PL, Camm AJ, Bocker D, Hauer RN, Wever EF, Dullemeijer C, Ronden JE, Katan MB, Lubinski A, Buschler H, Schouten EG; SOFA Study Group. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial.JAMA. 2006;295(22):2613-9.
  13. Wilhelm M, Tobias R, Asskali F, Kraehner R, Kuly S, Klinghammer L, Boehles H, Daniel WG. Red blood cell omega-3 fatty acids and the risk of ventricular arrhythmias in patients with heart failure. American heart journal. 2008 Jun; 155(6):971-7.(Link to article – subscription may be required.)
  14. Gura KM, Duggan CP, Collier SB, Jennings RW, Folkman J, Bistrian BR, et al. Reversal of parenteral nutrition-associated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management. Pediatrics. 2006;118:e197-201.
  15. Gissi-Hf Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Aug 29.(Epub ahead of print) (Link to article – subscription may be required.)
  16. Simmer K, Schulzke SM, Patole S. Longchain polyunsaturated fatty acid supplementation in preterm infants. Cochrane database of systematic reviews (Online). 2008; (1):CD000375.(Epub) (Link to article – subscription may be required.)
  17. Simmer K, Patole SK, Rao SC. Longchain polyunsaturated fatty acid supplementation in infants born at term. Cochrane database of systematic reviews (Online). 2008; (1):CD000376.(Epub) (Link to article – subscription may be required.)
  18. Church MW, Jen KL, Anumba JI, Jackson DA, Adams BR, Hotra JW. Excess omega-3 fatty acid consumption by mothers during pregnancy and lactation caused shorter life span and abnormal ABRs in old adult offspring. Neurotoxicology and teratology. 2010 Mar-Apr; 32(2):171-81.(Link to article – subscription may be required.)
  19. Groeger AL, Cipollina C, Cole MP, Woodcock SR, Bonacci G, Rudolph TK, Rudolph V, Freeman BA, Schopfer FJ. Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids. Nature chemical biology. 2010 May 2.(Epub ahead of print) (Link to article – subscription required.) Diagram in pdf format freely downloadable
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