Conversion of ALA to EPA and DHA – Vegan Health

By Jack Norris, RD, LD

Whether vegetarians and vegans should supplement with the long-chain omega-3 fatty acids, EPA or DHA, or can rely on their conversion from the short-chain omega-3 fatty acid, ALA, remains unclear. In recent years, my position has been that, for optimal health, it’s not necessary to supplement, but conclusive data is lacking.

I recently decided to dig deeper into the assumptions regarding the conversion of ALA to EPA and DHA. As a result, we’ve updated the Conversion of ALA to EPA and DHA section of Omega-3s Part 2: Research with the content below.

Conversion of ALA to EPA and DHA

Measurements of the percentage of total fatty acids as EPA and DHA in the blood are generally considered a marker of omega-3 status. This assumes that higher percentages of total fatty acids in the blood reflect higher and more optimal amounts in the tissues that utilize omega-3s. It also assumes that when blood percentages change due to changes in dietary intake, levels in tissues respond similarly.

In this section, we examine these assumptions. Evidence of omega-3 conversion enzymes in tissues and down-regulation of omega-3 conversion in response to dietary omega-3s suggest that the body can regulate the conversion of omega-3 fatty acids in tissues independent of the percentage in the blood.

There’s evidence that high intakes of EPA and DHA will increase their percentages in both blood and tissues, but it’s not clear if higher percentages are necessary for optimal health. We assess the evidence in our sections Impacts of Lower EPA and DHA on Vegetarians and Omega-3s and Chronic Disease.

ALA Supplementation Results in Little Increase in Blood DHA

Our ALA Trials spreadsheet lists a handful of clinical trials, including all of the trials with vegetarians of which we’re aware, investigating whether increasing dietary ALA subsequently increases the percentage of long-chain omega-3s in the blood. The changes in total fatty acids as long-chain omega-3s show a wide variation with no clear pattern; some even found a decrease in DHA. On average, EPA+DPA+DHA increased by 43.5% while DHA only increased by 4.6%.

It’s safe to say that supplementing with ALA is unlikely to substantially increase the blood percentage of fatty acids as DHA in most adults.

EPA and DHA Correlate between Plasma and the Heart but not the Brain

Studies of ALA supplementation result in very little increase of DHA in the blood, but how much evidence is there to suggest that this reflects the body’s inability to convert ALA to DHA for tissue utilization?

A basic question is, without any dietary changes, how much do blood levels of omega-3 fatty acids typically correlate with tissue levels? It’s difficult to study the omega-3 content of tissues in living humans. In our spreadsheet, Tissue Correlations, we list the correlations between blood and tissue percentages of omega-3s in both humans and animals. A summary of the results follows.

Harris et al. (2004) measured the correlation between the percentage of EPA+DHA in red blood cells and the percentage of EPA+DHA in the hearts of 20 heart transplantation patients having routine heart biopsies, 13 of whom were considered to be high consumers of EPA and DHA; they found a statistically significant, strong correlation (R = 0.82, P ≤ 0.0001).

Harris et al. (2004) also performed an intervention: Heart transplantation patients (n=25) with low EPA+DHA intakes were provided 1,000 mg of EPA+DHA for 6 months. These patients had weaker correlations between red blood cell and heart EPA+DHA at baseline (R = 0.47, P = 0.031). Post-intervention measurements showed that EPA+DHA percentages increased in plasma, red blood cells, heart, and cheek tissue; the correlation between red blood cell and heart EPA+DHA remained the same (R = 0.47, P = 0.06).

Cunnane et al. (2012) performed autopsies on cognitively normal people and found a correlation between percentages of DHA in plasma phosphatidylethanolamine and the angular gyrus region of the brain DHA (R = 0.77, P ≤ 0.005). However, they failed to find correlations between DHA and other regions or in cognitively impaired people stating, “No significant correlations were observed for DHA (% or mg/g) or any other fatty acids in the other brain regions or in the [Alzheimer’s disease] and [mildly cognitively impaired] groups (data not shown).”

Carver et al. (2001) performed autopsies on 58 people and found a negative correlation between the DHA percentage in red blood cells and the cerebral cortex of people aged >18 years; it’s likely this correlation doesn’t achieve statistical significance after a Bonferroni correction for the large number of correlations tested.

For the limited data we have, and on a mostly cross-sectional basis, there appears to be a robust correlation between the blood and tissue percentages of EPA+DHA in the human heart but not the human brain.

There’s much more data from animals than humans. Our spreadsheet, Tissue Correlations, lists 24 correlations between blood and tissue percentages of EPA+DHA among rats, pigs, and mice. The strength of the correlations varies considerably with some being negative.

There’s one other study on animals worth mentioning. Talahalli et al. (2010) fed two groups of rats a reasonable amount of ALA (2.5% and 5.0% of calories). After 60 days, the percentage of fatty acids as DHA in the brain of the rats fed 2.5% and 5.0% ALA was, respectively, 9.4% and 10.4% compared to 8.3% in the control group (see the table, Talahalli 2010). This suggests that ALA supplementation increased the amount of DHA in their brains.

One significant caveat for comparing the conversion of omega-3s in rats, pigs, and mice to humans is that rats, pigs, and mice normally don’t have a dietary source of EPA or DHA and, therefore, would normally rely entirely on the conversion from ALA for any EPA or DHA.

Tissues Contain Enzymes that Convert Omega-3s

Two critical enzymes, delta-5 desaturase and delta-6 desaturase, convert short-chain omega-3 and omega-6 fatty acids into long-chain versions.

Previously, the liver was considered the primary site of EPA and DHA production for peripheral tissue utilization, but studies by Cho et al. (1999a and 1999b) found substantial amounts of mRNA for the delta-5 and delta-6 desaturase enzymes in many tissues of human cadavers.

Cho et al. (1999a) found that delta-5 desaturase mRNA was greatest in the human liver, but that the heart, brain, and lung also contained substantial amounts. They found low but detectable levels in the placenta, skeletal muscle, kidney, and pancreas. Cho et al. (1999b) found that the amount of delta-6 desaturase mRNA in the human liver was comparable to that found in the human lung and heart, while the adult brain had a level several times greater than the liver.

Cho et al. (1999a) point out that the expression of these enzymes can vary greatly among individuals. The authors hypothesize that this might be due to age or, more likely in their view, regulation of the enzymes in response to the dietary intake of fatty acids.

Using cross-sectional data based on the percentage of plasma phospholipids, Welch et al. (2008, United Kingdom) estimated that non-fish-eaters (both vegetarians and meat-eaters) convert ALA to long-chain omega-3s at about a 22% higher rate than fish-eaters.

Dietary DHA Reduces ALA Conversion

In a series of three studies, researchers used a carbon tracer to track the conversion of a 700 mg dose of ALA to long-chain omega-3s in the blood of three different groups of people. The results are in the table below. Only females (all of whom were of reproductive age) showed a substantial conversion of ALA to DHA in the blood.

In addition to the baseline measurements listed in the table above, Burdge et al. (2003) included an 8-week intervention on three groups of older men: a control group (n=5), a group whose daily ALA was increased from their normal intake of 1.7 g to 10 g (n=4), and a group whose daily EPA+DHA was increased from their normal intake of 264 mg to 1.6 g (n=5). After 8 weeks, they fed each person 700 mg of ALA with a carbon tracer and found that the ALA supplemented group’s conversion of ALA to long-chain omega-3s hadn’t increased whereas the EPA+DHA supplemented group’s conversion had decreased.

Vermunt et al. (2000) fed carbon-labeled ALA to humans and found that the conversion of ALA to EPA, DPA, and DHA was much greater after 9 weeks of a diet high in oleic acid compared to after a diet high in ALA or EPA+DHA.

The two trials mentioned above by Burdge et al. (2003) and Vermunt et al. (2000) suggest that there’s a down-regulation of ALA conversion to long-chain omega-3s in humans who have a regular supply of ALA or EPA and DHA. The simplest explanation for this down-regulation is that their tissues had sufficient long-chain omega-3 levels.

Further evidence for enzymatic regulation due to dietary intake is a study by Metherel et al. (2019) who conducted a randomized controlled trial using carbon-labeled DHA. While plasma levels of EPA increased, it wasn’t due to DHA being converted to EPA, suggesting that the dietary supply of DHA resulted in the down-regulation of the conversion of EPA to DHA.

Burdge and Wootton’s data (2002) showed an uneven distribution of omega-3 fatty acids among the different components of plasma lipids (cholesterol esters, phosphatidylcholine, triglycerides, and non-esterified fatty acids). They surmised that plasma cholesterol esters act as a long-term source of ALA within circulation that may provide tissues containing active desaturation and elongation pathways (brain, heart, and skeletal muscles) a steady source of ALA for conversion to EPA, DPA, and DHA while tissues with low expressions of these enzymes, such as the kidney and pancreas, may be dependent upon the supply of pre-formed EPA, DPA, and DHA.

Lower Omega-6 Intake is Associated with Higher Serum EPA and DHA

The traditional way vegetarians have been encouraged to raise blood EPA and DHA levels is by increasing ALA and decreasing the omega-6 fatty acid, linoleic acid (LA). This is because the enzymes that convert ALA into EPA and DHA also convert the omega-6 fatty acids and there is competition for these enzymes. Some evidence for this theory is from a clinical trial by Liou et al. (2007, Canada) who found increasing LA intake resulted in a lower percentage of EPA in plasma phospholipids

Most vegetable oils are high in omega-6s and vegetarians tend to get plenty in their diets. Sanders and Younger (1981, United Kingdom) found a dietary ratio of omega-6s to omega-3s of 16 for vegans and 6 for meat-eaters. Sanders and Roshanai (1992, United Kingdom) found a dietary ratio of 15.8 for vegan men, 10.2 for meat-eating men, 18.3 for vegan women, and 8.2 for meat-eating women.

There are no clinical trials that increase the ALA intake of vegetarians while also decreasing their LA intake, to see what impact this has on blood levels of EPA and DHA.

Salvador et al. (2019, Spain) studied 55 vegans and 49 lacto-ovo-vegetarians and found that those with a serum omega-6 to omega-3 ratio of ≤ 10 had a higher percentage of serum EPA and DHA than those with a ratio between 10 and 20 or >20 (EPA: 0.60%, 0.27%, and 0.23%; DHA: 2.90%, 1.91%, and 1.19% respectively). Flaxseed intakes of once per day and, especially, 2 or more times per day were associated with a much higher percentage of serum ALA (~0.5% vs. ~0.7% and 1.5%, respectively), but not with higher EPA or DHA percentages.

Based on limited research, lowering LA intake could increase blood levels of long-chain omega-3s, but it’s not known if doing so impacts tissues or provides health benefits.

Low Omega-6 to Omega-3 Ratio Foods

At this time, the research indicates that vegetarians with lower dietary omega-6 to omega-3 ratios tend to have higher blood levels of EPA and DHA. For that reason, it’s prudent, when adding ALA to the diet, to choose foods that don’t also substantially increase omega-6 intake, listed in this table.