Friday, March 28, 2014

High Dose Fish Oil Supplementation: Short Term Benefits, Long Term Dangers - Will Your Liver Go Rancid?

Does a (very) high fish oil diet entail the risk of going rancid - in spite of all its short-term health benefits?
Don't worry, I am not addressing the prostate cancer issue, again. In a way, I am still going to resume a discussion, you should be familiar with from my article "Sesame Powered High Omega-6 Diet Boosts Endurance Performance in Rodents - High Omega-3 Diet Sucks" | read more. It's the notion that the extensive incorporation of easily oxidizable (or already rancid) omega-3 fatty acids into metabolically highly active tissues, such as our musculature, will only be beneficial until a certain 'optimal' threshold level is reached. Beyond this point, any further increase of the long-chain PUFA content becomes as problematic as the overabundance of other fatty acids.

This article is about balance!

By now, you should have realized that this post is all about balance, the critical balance of 'stable' saturated and 'unstable' (poly-)unsaturated fatty acids - not in your diet, but in cells & tissue.
This is not an "anti-fish oil article" or anti-omega-3 article! It's an article to remind you not fall for the prominent black-and-white thinking and to falsely equate balance with mediocrity.
Recent evidence of the importance of these numbers comes from a study that was conducted by researchers from the INRA UMR in Montpelier, France (Feillet-Coudray. 2013). It is, as you may have suspected, a rodent study. With a study duration of 12 weeks and the aspiration to investigate the long-term effects of diets containing 50 or 300 g lipid/kg  in the form of either lard or fish oil, this was yet more than a concession to financial constraints.

In the life of a rodent, three months are equivalent to several human years (some sources would say 5 years, but I would not bet on that). A similar study in man would thus take several years - years in the course of which all study participants would have to be locked away in a metabolic ward to ensure that they eat nothing but what the scientists serve them.
Figure 1: Total fatty acid (FA) composition of the LIVER and MUSCLE (mg FA/g tissue; Feillet-Coudray. 2013)
Against that background it is unlikely, but not impossible that we will see similar changes (see Figure 1) in the muscle and liver lipid levels of a human subject within only 3 months, even if he or she would reduce his or her overall fat intake to almost zero while upping the amount of fish oil in the diet into the 50g+ range. For 99% of the existing human studies this means that they are 100% irrelevant in view of the long (and if I write "long", I mean "long" like in years!) term high dose fish oil intakes and the corresponding changes in the fatty acid content and ratios of muscle, liver and other tissue.

No changes in muscle fatty acid make-up. How Come?

Apropos changes! If you look a the data in Figure 1 you will realize that the fatty acid make-up of the musculature in the study by Feillet-Coudray et al. did not change at all. In view of the significant changes in the fatty acid composition of the liver, this appears to be counter-intuitive and if we recall the study design and results of the previously cited study by Ayre et al. (1997) probably a result of the comparatively high omega-6:omega-3 ratio of the purported "fish oil" diet, which contained only 15g of omega-3 fatty acids per kg, and a whopping 21.7g of omega-6s. With an additional 25g of monounsaturated and 27.4g of saturated fats it is thus by no means an "omega-3", let alone "fish oil" diet as the one in the Airy study, which lead to major performance impairments in muscular endurance (and probably strength, which was yet not measured in the Ayre study | learn more).
Figure 2: Fatty acid composition of the test diets (Feillet-Coudray. 2013)
If you take a closer look at Figure 2 you will realize that - compared to the allegedly unhealthy lard diet" - the major difference is not, as people who still believe lard contained almost exclusively saturated fats could believe, the saturated-to-polyunsaturated fatty acid ratio, but simply the absence of significant amounts of omega-3 fatty acids in the mixed control and lard diets (one good reason to supplement a lard only diet with reasonable amounts of fish oil; e.g. 1g per day or 4g twice a week).

Not exactly representative of the contemporary diets, but still meaningful

From a scientific point of view the significant, but still small differences may be a limitation. From a practical point of view, the omega-3 : omega-6 ratios are however more realistic than those of a real 'fish oil only' diet:
  • CONTROL & LARD ~ 7:1 vs.  FISH ~ 3:2 
  • SAD ~ 15:1 vs. HIGH N3 ~ 1:1 - 3:1
What they are not, however, is representative of the difference between the SAD (standard American) and a high omega-3 diet (HIGH N3).
You do not necessarily want to supplement daily, not in spite of, but rather because a recent Cambridge study shows that, compared to weekly administration, daily administration of fish oil supplements leads to an increased  incorporation of eicosapentaenoic acid and docosahexaenoic acid into platelets and mononuclear cells in humans (Browning. 2014). Obviously, this doesn't mean that the same will be the case for the liver, but it clearly supports my previous recommendation to do prefer eating fish twice a week over supplements.
As close as the FISH diet may be to the often hailed "optimal 1:1" ratio, the CONTROL and LARD diets both contain much more omega-3s / less omega-6s than the SAD diet. Against that background it's actually quite astonishing that
Meta-Analysis Says: Fish Oil Does Not Help You Lean Out! Plus: It's Still Worth Having Fatty Fish 1-2x/Week | more
  • all rats developed liver steatosis associated with moderate liver injury when fed the 30 % lipid diets
  • the rats in both the CONTROL and FISH group did so without getting obese (only the rats "on" the 30% LARD diet became obese; 11% higher body weight, 32% more body fat)
  • both FISH (+30%) and LARD (+103%) had elevated insulin levels compared to the rodents on the 30% CONTROL diet; despite higher insulin levels, the effective glucose uptake in the FISH group was normal, while it was already compromised in the LARD group
It's yet not all surprising and unexpected. The FISH diet did produce the expected improvements in total cholesterol and the HDL:LDL ratio. In spite of the -35% (vs. CONTROL; -47% vs. LARD) lower triglyceride levels, "[t]he fish-oil 30 % lipid diet failed to prevent the development of hepatic steatosis" (Feillet-Coudray. 2013) - an effect which may be mediated by concomitant increases in liver lipid oxidation, of which the researchers write that it
Additional Read: "Fish Oil Compromises, Fish Improves Adiponectin Levels in "Overweight, But Healthy" Individuals. Neither Promotes Weight or Fat Loss Within a 4-Week Study Period" | more.
"[...] was increased with the fish-oil diet in comparison with the mixed and the lard diets. Within the 5 % lipid diets, the liver TBARS level was increased by 22 % with the fish-oil diet compared with the mixed diet, whereas within the 30 % lipid diets, the liver TBARS level was increased by 104 % with the fish-oil diet compared with the mixed diet." (Feillet-Coudray. 2013)
It turned out that there was a direct correlation of pathological lipid oxidation and the amount of omega-3 fatty acids in the liver (p < 0·001; r = 0·319). Accordingly, the...
"glutathione peroxidase activity was decreased with the fish-oil 30 % lipid diet in comparison with the lard 30 % lipid diet" (Feillet-Coudray. 2013)
The answer to the the question I raised in the caption of the image in the title of this article, i.e. "Does a (very) high fish oil diet entail the risk of going rancid - in spite of all its short-term benefits?" is "Yes, it does!".
Suggested Read: "Sesame Powered High Omega-6 Diet Boosts Endurance Performance in Rodents - High Omega-3 Diet Sucks: Intra-Muscular Lipid Ratios Determine Exercise Performance" | read more.
Bottom line: In the end, the study at hand is just a reminder that "good" and "bad" are - at least in the realms of 'healthy eating' - no constants. A high omega-3 intake, for example, has only been shown to favorably influence someone health if it corrects am existent deficiency. Once the point of optimal balance (whatever this may be) is reached, the beneficial effects such as the often hailed activation of the PPAR-alpha gene (which were not even significant in the study at hand) do no longer compensate for the increasing 'rancidity' and susceptibility of the liver to oxidative damage.

The addition of high amounts of supplemental fish oil to your diet should thus be regarded as a therapeutic intervention with potential long-term side effects. It's a crutch, like any drug people use to avoid making the nevessary life-style changes that include minimizing the amount of processed foods and reducing, but not annihilating the omega-6 content of their diets, regular physical activity and practicing moderation, instead of super-sizing every meal.
  • Ayre KJ, Hulbert AJ. Dietary fatty acid profile affects endurance in rats. Lipids. 1997 Dec;32(12):1265-70 (learn more
  • Browning, Lucy M., et al. "Compared with Daily, Weekly n–3 PUFA Intake Affects the Incorporation of Eicosapentaenoic Acid and Docosahexaenoic Acid into Platelets and Mononuclear Cells in Humans." The Journal of nutrition (2014): jn-113.
  • Feillet-Coudray C, Aoun M, Fouret G, Bonafos B, Ramos J, Casas F, Cristol JP, Coudray C. Effects of long-term administration of saturated and n-3 fatty acid-rich diets on lipid utilisation and oxidative stress in rat liver and muscle tissues. Br J Nutr. 2013 Nov;110(10):1789-802.