The health benefits of omega-3 fatty acids (FAs) have been firmly established in the scientific and medical community for decades, beginning with early research into the cardiovascular benefits of diets rich in high-oil fish consumed by Greenland Eskimos.1 Both essential omega-3s, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), occur naturally in many marine mammals, fish species, and certain marine organisms such as algae. Despite the consensus existing in the scientific community regarding the benefits of omega-3s, Western populations consume very little fish and are consequently deficient in omega-3s.2 In this sense, the recommendation to add omega-3 supplements to the diet has become routine among health professionals. However, many of the omega-3 supplements available today do not provide the benefits consumers expect. This is partly due to cost-saving measures taken by many manufacturers that produce synthetic fish oil supplements in the form of ethyl esters, whose structural difference from natural triglyceride-form oil functionally limits the absorption of essential omega-3 fatty acids.

Are all fish oils the same?

If you are considering supplementing your diet with omega-3, you can be sure that there are many options available. The truly difficult question to answer is:

Which supplement should I buy? 

Making an informed decision means evaluating whether all supplements available on the market are the same and knowing what you should look for when choosing the most suitable omega-3.

The simplest and least adulterated form of essential omega-3 fatty acids is found in cod liver oil, which has long been the gold standard of fish oil supplements. On the other hand, standard food-grade fish oil is generally obtained from the fatty tissues of cold-water fish.

Some manufacturers also enrich their formulations with plant-based omega-3 derivatives rich in alpha-linolenic acid (ALA), which does not possess the same beneficial health effects as those made with marine derivatives with longer omega-3 EPA and DHA chains.

Recommended Daily Intake Doses are always an important consideration in omega-3 supplementation. The cardiovascular benefits originally observed in Greenland Eskimos were linked to a diet exceptionally rich in omega-3 fatty acids. Since then, we have witnessed a growing list of health conditions that can be alleviated or improved with the administration of fish oil supplements. However, the results of clinical and population studies have not always been conclusive, partly due to a lack of clear understanding of the daily dose required to obtain physiological benefits. 

For an average person, a high dose consisting of many capsules a day represents a difficult challenge to meet. Very few are willing to ingest a large number of capsules, and to complicate matters further, there is growing evidence that corroborates the theory that omega-6 type fatty acids present in our diets and coming from sources such as corn and soy counteract the benefits of omega-3s.

Such evidence indicates that the increase in omega-6 fatty acid consumption contributes to the relative insufficiency of omega-3 fats, because both fatty acids compete for the same pathway in the autacoid/prostanoid metabolism via the cyclooxygenase (COX) and lipoxygenase (LOX) enzyme families. 

The United States has been slow to adopt daily intake recommendations for EPA and DHA. Nevertheless, nutrition experts around the world have reached a consensus on the benefits for adults of consuming a minimum of 500 MG of combined EPA and DHA daily.

Furthermore, the American Heart Association recommends that those individuals suffering from cardiovascular disease risk factors consume 1 gram daily and those with hypertriglyceridemia ingest between 2 and 4 grams per day. 

Concentration and Structure of a Supplement

Purification technology has improved considerably in recent decades, allowing manufacturers to concentrate EPA and DHA, meaning fish oils have reached an extremely high level of purity. This makes many consider them today safer than the fish itself. Fish oil purification and concentration consists of several stages. Molecular distillation includes the purification and concentration of fish oils under vacuum conditions. In this process, fatty acids are hydrolyzed from their natural triglyceride form, thus releasing the free fatty acids. (figure 1)

 These fatty acids are then chemically converted into ethyl esters (EE) by adding ethanol. (figure 2) The ethyl esters are then vacuum "distilled" to purify them, removing toxins, and reducing unwanted fats such as short-chain and saturated fatty acids, increasing the concentration of EPA and DHA in a percentage range of between 40 and 85%. 

What happens next in the manufacturing process is a subject of great controversy, and ultimately determines the absorption advantages of a few omega-3 supplements due to the differences in the chemical structure of these select supplements.

Normally, fatty acids in ethyl ester form should be converted back into the triglyceride form they were in at the start of the process with the addition of glycerol and a catalyst. 

However, from a manufacturing standpoint, this stage of the process adds considerable costs to the operation due to the level of refinement required to reconvert ethyl esters into natural triglycerides. The much simpler and less costly alternative is to leave the concentrated omega-3s in ethyl ester form. It should be no surprise that there is considerable debate surrounding the absorption potential and therefore the efficacy of omega-3s in ethyl ester form versus the absorption and efficacy of their counterpart, those in natural triglyceride form.

The first thing people should know is that ethyl esters do not exist naturally in any area of the human diet

Natural supplements versus synthetic supplements

Some argue that the lack of concern regarding the molecular integrity of EPA and DHA within the U.S. Food and Drug Administration and the pharmaceutical industry itself means that consumers should not question the bioavailability of the different molecular structures of omega-3 supplements (triglycerides versus ethyl esters). The reality is that these structural differences determine the functional differences existing between these two forms regarding the organism's ability to absorb omega-3s. 

The consumer should know that ethyl esters have never existed naturally in the human diet.10 Fatty acids in ethyl ester form are a recent chemical creation in which EPA and DHA are attached to an ethyl molecule via an ester bond. To be able to digest this fat molecule, which is new to nature, the human body must remove the ethyl group and convert the fatty acids back into triglycerides during the absorption process1 which raises an important question:

 Does synthetic EPA/DHA offer the same pharmacodynamic potential as triglycerides? 

Clinical comparison of ethyl esters and triglycerides Evidence emerging from clinical studies has been based on the apparent bioavailability of EPA and DHA when administered in their different forms, but the design of many of these studies has rarely addressed confounding aspects that have resulted in contradictory information.

When comparing plasma EPA levels resulting from their administration in ethyl ester form with EPA levels achieved when administered in natural triglyceride or free fatty acid form, it is found that there is a notable delay and reduced bioavailability of the esterified ethyl ester form.

Other studies report no difference in EPA and DHA absorption between the ethyl ester and triglyceride forms. However, it is important to note that these studies used considerably large amounts of fish oil (28 grams) to study bioavailability, which does not accurately reflect actual absorption capacity, as people typically ingest 500 MG, a figure 56 times lower than that studied. Lower rates of lipase hydrolysis during the digestive process could very well explain the reduced bioavailability of ethyl ester form supplements. During normal fat digestion, pancreatic lipase acts on triglycerides to remove the fatty acids, resulting in two free fatty acids and a monoglyceride (figure 3).

After hydrolysis, the two fatty acids and the monoglyceride become polar molecules, allowing them to be easily absorbed in the water phase. For ethyl esters to be absorbed, the added ethyl molecule must be broken down by lipase. It has been reported that pancreatic lipase hydrolyzes ethyl esters between 10 and 50 times slower than triglycerides.

Finally, similar EPA and DHA incorporation was reported for triglycerides and ethyl esters for a dose of 3.5 grams per day for one week. However, the incorporation of EPA in ethyl ester form into plasma cholesterol esters was significantly lower than that of EPA in triglyceride form.

 Fortunately, a very well-designed double-blind, placebo-controlled study has helped determine the bioavailability of EPA and DHA in ethyl ester form versus those in triglyceride form. In this study, the enrichment of EPA and DHA in plasma triglycerides, cholesterol esters, and phospholipids was investigated. The supplements administered over two weeks were cod liver oil, fish oil, ethyl esters, free fatty acids, and re-esterified triglycerides.

The lower bioavailability of EPA and DHA from ethyl esters helped clarify the conflicting data obtained during previous studies.

The observations fit perfectly with the fact that pancreatic lipase hydrolyzes ethyl esters to a lesser degree than it does triglycerides and at a much slower rate. These findings are consistent with certain studies that examined the bioavailability of omega-3s in ethyl ester form, although not with others.

The discrepancy has been explained by differences in intake when combined with different types of meals. For example, when supplements were administered as part of a lipid-rich diet, researchers found that omega-3 rates were similar between ethyl esters and triglycerides. But when they were ingested without a high-fat meal, Lawson and Hughes reported that only 20% of the omega-3 in ethyl ester form had been absorbed.

These findings seem to suggest that the assimilation of EPA and DHA administered in the form of ethyl esters can be improved when they are ingested as part of meals with a high fat content. This effect seems to be lost when subjects are instructed to take their supplements with meals that are not excessively fatty, which results in clearly much higher bioavailability of the supplements in triglyceride form.

Previous studies that had investigated the bioavailability of EPA and DHA from triglycerides or re-esterified triglycerides versus those from ethyl esters were conducted over the short term, with dosing periods of between 2 and 7 weeks. Furthermore, the final focus points of these studies—the fatty acid composition in plasma PLs, TAGs, chylomicron TAGs, or serum PLs—equally reflect short-term intake rather than intake over a prolonged period. Additionally, the high doses (20-30 grams) used in many of these studies contradict the intake recommendations of various international bodies that typically recommend supplements of between 1 and 5 grams daily.

In contrast, a recent and very well-designed placebo-controlled study compared the bioavailability of more moderate doses of omega-3 fatty acids in triglyceride form and ethyl ester form as part of a six-month randomized controlled trial. In this study, the omega-3 index—the percentage of EPA plus DHA in the red blood cell membrane—reflected the status of omega-3 fatty acids in the individuals after long-term intake.

The results of this study suggest that supplementation with identical doses of EPA and DHA for 6 months led to a faster and higher concentration of the omega-3 index when the supplements were administered in the form of triglycerides than when they were ingested as ethyl esters.

It should not be surprising, then, that the natural substrate of EPA and DHA present in triglycerides appears better suited for greater absorption than synthetic derivatives like ethyl ester.

Ethyl esters have only been present in the human diet for the last two decades. As such, their long-term effects are largely unknown. What is more, since ethyl esters lack the glycerol backbone that is naturally present in triglycerides, the body must find one during digestion in order to reconstitute them into triglycerides before absorption.

This may mean that it has to “steal” a fraction of another chain from an already existing molecule, which consequently will try to replace the “stolen” fraction in the same way, thus leaving an excess of free fatty acids in the body.

This competitive process can increase the activity of free radicals in the body, raising oxidative stress, which is generally associated with undesirable health outcomes.

It should not be surprising, then, that the natural substrate of EPA and DHA present in triglycerides has a greater capacity for absorption and bioavailability than synthetic derivatives like ethyl ester.

Conclusions

After considering the scientific evidence from fat metabolism studies, it becomes increasingly evident which type of fish oil supplement we should select when we want to supplement our diet with fish oil, assuming the reason for consuming said supplement is to obtain the pharmacological benefits of EPA and DHA.

It remains to be determined how acceptable consumers might find certain supplements if they are fully aware of the synthetic nature of these so-called “superfoods” and their potential limitations in absorption and bioavailability.

This knowledge will likely cause conscious consumers to refrain from ingesting synthetic presentations of omega-3s in ethyl ester form, especially knowing that such forms are the result of manufacturers' efforts to reduce their production costs. In summary, the obvious differences between the triglyceride form and the ethyl ester form should be a relevant consideration when selecting the ideal omega-3 fatty acid supplement.

Hector L. Lopez, M.D., CSCS, FAAPMR Board-certified Physical Medicine and Rehabilitation specialist, Dr. Héctor López is an active researcher, lecturer, author, and clinical specialist who integrates nutrition, exercise science, sports, musculoskeletal medicine, and endocrinology into his private practice and various public initiatives. He has lectured and published articles on various topics nationally (in the U.S., Editor's Note) in the areas of nutrition, strokes, orthopedic injuries, chronic pain, athletic performance, optimal aging, and medical exercise prescription. Additionally, Dr. López is an advisor to professional athletes and works as a consultant in the supplement industry in the areas of product research and development.

See the Omega 3 collection here: https://ortomolecularchile.cl/collections/nordic-naturals

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