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Fish oil

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Fish oils, including omega-3 fatty acids or ω-3 fatty acids, are dietary "oils high in unsaturated fats extracted from the bodies of fish or fish parts, especially the livers. Those from the liver are usually high in vitamin A. The oils are used as dietary supplements, in soaps and detergents, as protective coatings, and as a base for other food products such as vegetable shortenings."[1]

Classification of polyunsaturated fatty acids

Polyunsaturated fatty acids (PUFAs):
selected attributes[2]
  ω-3 fatty acids ω-6 fatty acids
Essential fatty acid precursor α-linolenic acid (ALA) linoleic acid (LA)
Proportion of PUFAs in North American diet 9% 89%
Dietary source Leafy green vegetables, canola and soybean oil flaxseed, walnuts Cooking oils including safflower, sunflower, soy, and corn
Metabolic products Eicosapentaenoic acid (EPA)
Docosahexaenoic acid (DHA)
(Fish oils contain EPA and DEA)
Arachidonic acid
Physiology • suppression of inflammatory cytokines • platelet aggregation
• vasoconstriction
• synthesis of inflammatory cytokines


Dietary consumption

About nine ounces per week of oily fish is equivalent to taking about 500 mg eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids per day.[3] Thus, for cardiac protection, at least 6 servings per week of 3 ounces of fish are needed.

Biochemistry

(PD) Image: National Library of Medicine (NLM)
Polyunsaturated fatty acids (PUFAs) metabolic pathways in humans.[2]

Dietary fatty acids can be divided into saturated fatty acids and unsaturated fatty acids.[2] Unsaturated fatty acids can be further divided into monounsaturated and polyunsaturated fatty acids (PUFAs).

PUFAs are divided into two groups: omega-3 fatty acids and omega-6 fatty acids. Whereas omega-3 fatty acid have health benefits due to several mechanisms; omega-6 fatty acids are precursors to arachidonic acid (AA) which leads to thrombaxanes which promote platelet aggregation and vasoconstriction.

Two PUFAs, α-linolenic acid (ALA) and linoleic acid (LA) are called essential fatty acids because human function requires them, yet humans cannot synthesize then in vivo.[2] ALA is a omega-3 fatty acid while AL is a omega-6 fatty acid. In North America, LA comprises 89% of the total PUFAs consumed, while ALA - which leads to the favorable omega-3 fatty acid pathway - comprises only 9%.[2] LA is in many commonly used oils, including safflower, sunflower, soy, and corn oil. ALA is in leafy green vegetables and in canola and soybean oil. Fish oil consumption is 2-4 times higher (1 ounce versus 2-4 ounces) in the Japanese diet than the North American diet.[4]

Dietary fish oils are converted to eicosapentaenoic acid (EPA) which is further converted to docosahexaenoic acid (DHA). Both EPA and HHA are omega-3 fatty acids. About nine ounces per week of oily fish is equivalent to taking about 500 mg eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids per day.[3]

Effect on human health

Biochemical effects

The main effect of fish oils is to reduce triglycerides.[5]

Omega-3 fatty acids may improve endothelial function[6][5] and reduce coagulation[5] but not reduce inflammation as measured by the c-reactive protein.[6][5]

Although proposed to improve membrane stabilization and thus reduce dysrhythmias, this benefit seems unlikely based on the increase in dysrhythmias in a more recent trial.[7]

Clinical effects

The most recent systematic review concluded that fish oil does not provide benefit.[8] Prior reviews were more positive.[9][10]

Coronary heart disease and mortality

The benefit of fish oil on coronary heart disease and mortality is controversial with conflicting conclusions reached by a negative meta-analysis (search dates April, 2011[11] and February, 2002)[12][13] of randomized controlled trials by the international Cochrane Collaboration, a partially positive systematic review (search date July, 2005)[2] by the Agency for Healthcare Research and Quality (AHRQ), and a positive systematic review (search date March, 2007)[9]. The AHRQ review noted differences among types of fish oils, "Evidence suggests that increased consumption of n–3 FAs from fish or fish-oil supplements, but not of α-linolenic acid, reduces the rates of all-cause mortality, cardiac and sudden death, and possibly stroke." They note that less than 5% of α-linolenic acid is converted to EPA or DHA.

Three subsequent randomized controlled trials not included in all of the above systematic reviews have also had conflicting results finding both benefit (reduction on coronary events in Japanese hypercholesterolemic patients[14] and improvement in patients with heart failure[15]).

  • JELIS[14] used "eicosapentaenoic acid...given at a dose of 600 mg, three times a day after meals (to a total of 1800 mg per day)." 20% of patients had prior coronary heart disease. This trial was only included in the 2007 systematic review by León.
  • Gissi-HF[15] used "one capsule per day of 1 g n-3 PUFA (850–882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in the average ratio of 1:1·2)." This trial was not only included in any of the three systematic reviews above. The benefit of fish oil in this study was better than the benefit of rosuvastatin in GISSI-HF.[16]

Dysrhythmias

Raitt[7] studied antiarrhythmic effects in patients with a history of sustained ventricular tachycardia or ventricular fibrillation (73% of patients had prior coronary heart disease) and found an increase in dysrhythmias. This result contradicts the benefit found in the GISSI-Prevenzione randomized controlled trial of patients with recent myocardial infarction who were treated for 3.5 years.[17] and the insignificant improvements in the SOFA[18] and FAATI[19] trials.

The contradictory results have been hypothesized to be from omega3-PUFAs being both pro-arrhythmic or antiarrhythmic, and suppress re-entrant dysrhythmias (patients with acute ischemia or prior sustained ventricular dysrhythmia)and promote triggered dysrhythmias (patients with prior myocardial infarction).[20]

Evidence table

Major randomized controlled trials of fish oils for
death and other outcomes
  Patients Intervention / duration Outcome Relative risk ratio
DART[21]
1989
2033 men with recent myocardial infarction
• None taking statins
≥ at least two portions (200-400 g) of fatty fish weekly
2 years
Any death 0.71‡
GISSI-Prevenzione[17]
1999
11,324 patients with myocardial infarction within 3 months
• 46% taking statins by study end
850–882 mg of EPA & DHA daily
3.5 years
Any death 0.9‡
Raitt[7]
2005
200 patients with an implantable cardioverter defibrillator and prior sustained ventricular dysrhythmia
• 73% had coronary heart disease
• 46% taking statins
1.8 grams of EPA & DHA daily
3 years
• Any death
• Recurrent ventricular dysrhythmia†
0.40
1.10
FAATI[19]
2005
402 patients with an implantable cardioverter defibrillator and prior sustained ventricular dysrhythmia
• 78% had coronary heart disease
• 35% of patients stopped treatment
2.6 gm g of EPA & DHA daily
1 year
• Any death
• Recurrent ventricular dysrhythmia†
Excessive dropout of patients, perhaps due to high dose.
SOFA[18]
2006
546 patients with an implantable cardioverter defibrillator and prior sustained ventricular dysrhythmia
• 76% had coronary heart disease
• 46% on anticholesteremic agent
961 mg of EPA & DHA, and 162 mg other omega-3 PUFAs daily
1 year
• Any death
• Death or recurrent ventricular dysrhythmia†
0.43
0.86
JELIS[14]
2007
18,645 Japanese patients with hypercholesterolemia
• 20% had coronary heart disease
• 100% taking statins (average doses: pravastatin 10.0 mg/day; simvastatin 5.6 mg/day; average LDL 182 mg/dl)
1800 mg of EPA daily
4.6 years
• Any death
• Major coronary event†
1.09
0.81‡
GISSI-HF[15]
2008
6975 patients with heart failure
• 50% had coronary heart disease
• 23% taking statins
850–882 mg of EPA & DHA daily
3.9 years
Any death 0.91‡
Alpha Omega[22]
2010
4837 patients with prior myocardial infarction within 10 years
• 100% had coronary heart disease
• 85% taking statins
400 mg of EPA & 2 g/d of DHA daily
3.4 years
Composite No benefit
† indicates the a prior primary outcome of the study.
‡ p< 0.05

Adverse effects

High doses over 2 grams per day

Gastrointestinal effects are common.[19]

Doses of 1 to 2 grams per day

In the JELIS study, discontinuation rates were increased - 12% in the EPA group and 7% in the control group.[14]

Doses less than 1 gram per day

In the GISSI-HF study, discontinuation rates were not increased - 29% in the EPA/DHA group and 30% in the control group.[14]

References

  1. Anonymous (2020), Fish oil (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, Jordan HS, Lau J (2006). "n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review". Am. J. Clin. Nutr. 84 (1): 5-17. PMID 16825676[e] http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.38290
  3. 3.0 3.1 Harris WS, Pottala JV, Sands SA, Jones PG (December 2007). "Comparison of the effects of fish and fish-oil capsules on the n 3 fatty acid content of blood cells and plasma phospholipids". Am. J. Clin. Nutr. 86 (6): 1621–5. PMID 18065578[e]
  4. Iso H, Sato S, Folsom AR, et al (June 1989). "Serum fatty acids and fish intake in rural Japanese, urban Japanese, Japanese American and Caucasian American men". Int J Epidemiol 18 (2): 374–81. PMID 2767851[e]
  5. 5.0 5.1 5.2 5.3 Balk E, Chung M, Lichtenstein A, Chew P, Kupelnick B, Lawrence A, DeVine D, Lau J. Effects of Omega-3 Fatty Acids on Cardiovascular Risk Factors and Intermediate Markers of Cardiovascular Disease. Evidence Report/Technology Assessment No. 93 (Prepared by Tufts-New England Medical Center Evidence-based Practice Center under Contract No. 290-02-0022). AHRQ Publication No. 04-E010-2. Rockville, MD: Agency for Healthcare Research and Quality. March 2004
  6. 6.0 6.1 Schiano V, Laurenzano E, Brevetti G, et al (April 2008). "Omega-3 polyunsaturated fatty acid in peripheral arterial disease: effect on lipid pattern, disease severity, inflammation profile, and endothelial function". Clin Nutr 27 (2): 241–7. DOI:10.1016/j.clnu.2007.11.007. PMID 18237823. Research Blogging.
  7. 7.0 7.1 7.2 Raitt MH, Connor WE, Morris C, et al (2005). "Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial". JAMA 293 (23): 2884–91. DOI:10.1001/jama.293.23.2884. PMID 15956633. Research Blogging.
  8. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS (2012). "Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.". JAMA 308 (10): 1024-33. DOI:10.1001/2012.jama.11374. PMID 22968891. Research Blogging. Review in: Ann Intern Med. 2012 Dec 18;157(12):JC6-5
  9. 9.0 9.1 León H, Shibata MC, Sivakumaran S, Dorgan M, Chatterley T, Tsuyuki RT (2008). "Effect of fish oil on arrhythmias and mortality: systematic review". BMJ 337: a2931. PMID 19106137. PMC 2612582[e]
  10. Mozaffarian D, Rimm EB (October 2006). "Fish intake, contaminants, and human health: evaluating the risks and the benefits". JAMA 296 (15): 1885–99. DOI:10.1001/jama.296.15.1885. PMID 17047219. Research Blogging.
  11. Kwak SM, Myung SK, Lee YJ, Seo HG, for the Korean Meta-analysis Study Group (2012). "Efficacy of Omega-3 Fatty Acid Supplements (Eicosapentaenoic Acid and Docosahexaenoic Acid) in the Secondary Prevention of Cardiovascular Disease: A Meta-analysis of Randomized, Double-blind, Placebo-Controlled Trials.". Arch Intern Med. DOI:10.1001/archinternmed.2012.262. PMID 22493407. Research Blogging.
  12. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma RA, Ebrahim SB, Davey Smith G (2006). "Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review". BMJ 332 (7544): 752-60. DOI:10.1136/bmj.38755.366331.2F. PMID 16565093. Research Blogging.
  13. Hooper L, Thompson RL, Harrison RA, et al (2004). "Omega 3 fatty acids for prevention and treatment of cardiovascular disease". Cochrane Database Syst Rev (4): CD003177. DOI:10.1002/14651858.CD003177.pub2. PMID 15495044. Research Blogging.
  14. 14.0 14.1 14.2 14.3 14.4 Yokoyama M, Origasa H, Matsuzaki M, et al (2007). "Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis". Lancet 369 (9567): 1090–8. DOI:10.1016/S0140-6736(07)60527-3. PMID 17398308. Research Blogging.
  15. 15.0 15.1 15.2 Gissi-Hf Investigators (August 2008). "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. DOI:10.1016/S0140-6736(08)61239-8. PMID 18757090. Research Blogging.
  16. Gissi-HF Investigators, Tavazzi L, Maggioni AP, et al (October 2008). "Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial". Lancet 372 (9645): 1231–9. DOI:10.1016/S0140-6736(08)61240-4. PMID 18757089. Research Blogging.
  17. 17.0 17.1 (August 1999) "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 354 (9177): 447–55. PMID 10465168[e]
  18. 18.0 18.1 Brouwer IA, Zock PL, Camm AJ, et al (June 2006). "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 295 (22): 2613–9. DOI:10.1001/jama.295.22.2613. PMID 16772624. Research Blogging.
  19. 19.0 19.1 19.2 Leaf A, Albert CM, Josephson M, et al (November 2005). "Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake". Circulation 112 (18): 2762–8. DOI:10.1161/CIRCULATIONAHA.105.549527. PMID 16267249. Research Blogging.
  20. Den Ruijter HM, Berecki G, Opthof T, Verkerk AO, Zock PL, Coronel R (January 2007). "Pro- and antiarrhythmic properties of a diet rich in fish oil". Cardiovasc. Res. 73 (2): 316–25. DOI:10.1016/j.cardiores.2006.06.014. PMID 16859661. Research Blogging.
  21. Burr ML, Fehily AM, Gilbert JF, et al (September 1989). "Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART)". Lancet 2 (8666): 757–61. PMID 2571009[e]
  22. Kromhout D et al for the Alpha Omega Trial Group. n–3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010 Aug 29; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa1003603)